B2B Nutramedic&Cosmetics No.3

Help for a calmer and deeper sleep / Bone health

Probiotics in Europe / Bakopa and cognitive functions Urea / Collagen / Skin application of niacin

Editor's word

Dear business partners and colleagues,

We are presenting the third issue of the B2B Nutramedic&Cosmetics digital magazine.

In this issue, we focused specifically on sleep difficulties and sleep quality, as this continues to be the fastest growing category in the field of nutritional supplements.

Another important topic that we paid attention to is the maintenance of bone health by means of supplementation with ingredients that can help preserve their health and thus ease the problems caused by the loss of bone mass.

We bring you more about the plant Bacopa monnieri , which has been at the center of research due to its beneficial effect on cognitive functions.

As far as cosmetic topics are concerned, we bring a text about the effectiveness of urea for skin hydration, about collagen, niacin in transdermal application and the new protein peptide.

Hoping you will find interesting and useful information for your business,

Until the new edition, Daria Šurić, M.pharm.

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What can help for a calmer and deeper sleep?

10

DailyZz™: Something to dream about

13

The importance of bones in preserving the integrity of the body’s function and ingredients that help preserve bone mass

20

Functional ingredients for healthy aging and bone support

22

Osteoporosis and vitamin K2

Bimonthly digital magazine for industry professionals in health, nutrition and cosmetics sector

Ingredients and raw materials / Contract manufacturing Equipment & Packaging / Services / Industry events www.nmc­magazine.com info@nmc­magazine.com

Publisher: Darmell d.o.o.

Cvjetna cesta 11, 10000 Zagreb, Hrvatska

Mob: + 385 91 68 12 444 darmell@protonmail.com www.dar­mell.com

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Darmell: Expert in the nutritional supplements field

24

Fine Foods and continuous innovation: competitive advantage and shared value

Urea - an effective molecule for dry skin symptoms

The role of collagen in the skin health

Niacin skin application

Global Omega­3 Day™

NutraFood Poland: B2B event dedicated to food supplements and functional food

Medicinal plants photo herbarium: yarrow

Pomegranate fruit extract linked to improved skin health

Bioline – a solution for your needs

What can help for a calmer and deeper sleep?

Almost one-third of the general population has symptoms of insomnia (defined as difficulty falling asleep and/or staying asleep). The use of drugs for insomnia is limited by their tolerability and the increased risk of addiction, morbidity and mortality with long-term use. The search for safe and effective compounds without harmful effects is crucial in this context.

For a long time, it was believed that sleep is a state of the organism in which most of its functions cease, and the body is completely at rest. Today we know that this is not entirely true, because even though when we close our eyes and fall asleep some processes in the body slow down, others remain surprisingly active. Sleep begins with the activation of an area of the brain called the hypothalamus, where cascading changes occur that induce changes in the body that result in sleep. Nerve cells in the brain reduce alertness and promote sleepiness, while electrical activity in the brain begins to

slow. These and other changes that occur as sleep continues to affect nearly every cell in your body.1 In modern society, there is increasing concern about the risks associated with insomnia and lack of sleep. Recent epidemiological data support the opinion that many segments of the adult population are chronically sleep deprived. On the other hand, there are experts who claim that our basic required amount of sleep is about 6 hours during one night, and that we can easily forget more sleep, because it is completely unnecessary. However, experimental data on the effects of both acute and cumulative partial sleep

AUTHOR: Daria Šurić, M.pharm.

deprivation (PSD) consistently point out that sleep restriction has significant negative effects on sleepiness, motor and cognitive performance and mood as well as on some metabolic, hormonal and immunological variables.

Given that chronic partial sleep deprivation can have serious, long-term adverse health effects, it should be avoided in the general population. In the short term, the effects of sleep restriction appear to accumulate linearly, while the effects of long-term PSD should be further investigated, as the few available studies are flawed by methodological weaknesses. On the other hand, there is evidence that extending sleep by 2­3 hours beyond the norm brings only marginal benefits to the average individual. Finally, it is underlined that, as large individual differences do exist in the need for sleep, the search for the sleep need may be vain. A somnotypology, taking into account age, gender and the position in both the sleep­alert and the morningness­eveningness continuum, should help in the search for the actual individual sleep need. 2

Insomnia and sleep disorders are considered a major problem worldwide, especially in Western societies. Over a year, the prevalence of general sleep disturbance is estimated at around 85%, and a diagnosis of primary insomnia is estimated to be approximately 10%.9

Insomnia is associated with reduced hippocampal volume, daytime cortical gamma­aminobutyric acid (GABA) levels and activation of the caudate nucleus. In several parts of the brain, such as the hippocampus or the prefrontal cortex, inhibition of the usual decline in activity that occurs during the transition from waking to sleep has been observed. Thus, general overactivity of the arousal, emotion regulation, and cognitive systems probably leads to the pathophysiology of insomnia. For the treatment of this disease, there are effective drugs such as benzodiazepines or benzodiazepine receptor agonists. However, the use of these sleep medications is limited by their tolerance and the increased risk of addiction, morbidity and mortality with long­term use.10 In this context, the search for safe and effective compounds without adverse effects is essential.

The extent to which sleep is causally related to mental health is unclear.

The aim of the 2006 study was to to trace the consequences of insufficient sleep in terms of chronic sleep reduction, rather than acute sleep deprivation on fatigue, mood, cognitive performance self­estimation, and daytime sleepiness in different age-social groups. The age group of the subjects reflected their social situation and the organization of working hours: adolescents followed strict school schedules with starting times often before 8:00 h; university students had more flexible timetables; young employees were engaged in regular morning schedules or irregular daytime hours or day or night shifts. 3

The most frequent complaints of adolescents included tiredness on awakening (46%), nervousness and general weakness. University students reported excessive sleepiness (50%), tension and nervousness. Employees suffered the most from negative moods, such as tension (49%), nervousness and irritability.

The findings of the study show that chronic sleep loss seems to affect women more than men. The correlation of fatigue and mood with the need for sleep and the sleep index was more pronounced in younger subjects. Surprisingly, symptoms of fatigue in school children and students were just as common as in hard-working adults. Since the problem of insufficient amount of sleep is already present among young people, it is necessary to pay more attention to the organization of their working time. 3

One way to test the causal link of sleep quality to mental health is to evaluate the extent to which interventions that improve sleep quality also improve mental health. A meta­analysis of randomized controlled trials was conducted, which reported the effects of an intervention that improved sleep on complex mental health and on seven specific mental health problems. 65 trials with 72 interventions and 8,608 participants were included in the meta­analysis. Sleep improvement led to a moderately significant effect on overall mental health, depression, anxiety, and rumination, followed by a small­to­moderately significant effect on stress, and finally a small-significant effect on positive symptoms in psychosis. A cause-and-effect relationship was also clarified, in the sense that greater improvements in sleep quality led to greater improvements in mental health. These findings suggest that sleep quality is causally related to psychological difficulties. Future research might consider how methods that improve sleep quality could be incorporated into services to improve mental health. We should also study the mechanisms that affect mental health by influencing the quality of sleep.4

Problems with sleep are common. A review of several hundred epidemiological studies concluded that nearly one­third of the general population has symptoms of insomnia (defined as difficulty falling asleep and/or staying asleep), between 4% and 26% experience excessive sleepiness, and between 2% and 4%

drowsiness

irritability

anger

increased risk of stress

decreased alertness

impaired concentration

brain fog

fatigue

tremors

reduced coordination

increased risk of mistakes or accidents

food cravings

puffy eyes

dark undereye circles

TABLE 1 Staying awake for 24 hours may cause symptoms like:

Nutramedic &Cosmetics

of people experience obstructive sleep apnea.5 Additionally, a recent study with more than 2,000 participants reported that the prevalence of “general sleep disturbances” was 32%. It was previously assumed that mental health difficulties lead to sleep problems, however the reverse may also be true, such that poor sleep contributes to the onset, recurrence, and maintenance of mental health difficulties.

Sleep disorders and stress have been in the top 3 consumer health concerns in recent years.12 According to the Centers for Disease Control and Prevention (CDC), 24 hours of sleep deprivation is equivalent to a blood alcohol concentration of 0.10%. Such a 24­hour lack of sleep can cause numerous symptoms (Table 1).

Taking into account everything that has been stated so far, there is a clear need to find other ways to contribute to the quality and duration of sleep, in addition to classical drug therapy, which has longterm unwanted effects. In addition to adjusting the diet and introducing bedtime routines, dietary supplements play a key role. We will discuss several ingredients below, as they have shown a positive effect on sleep in studies and in practice.

There are some demographic groups that tend to have irregular melatonin production in their body. Smokers tend to be less responsive to supplementation, and older people tend to not produce as much during night time. Depression has also been associated with lower melatonin levels.

Very rarely, serious adverse effects resulting from melatonin supplementation (often in very high doses) have been reported. Taking melatonin is not associated with negative feedback (when taking a supplement causes your body to produce less of the hormone). It is also not addictive. Melatonin’s primary mechanism is by helping decrease the time it takes to fall asleep (as a hormone, that's its primary job). Doses between 500 mcg (0.5 mg) and 5 mg of melatonin appear to be effective in regulating the sleep cycle. It is recommended to start with 500 mcg, then increase the dose to 1 mg if necessary. Higher doses belong to the drug category and should be taken under the supervision of a doctor. The benefits of melatonin are not dose-dependent, as taking more will not help to fall asleep faster.

For help to fall asleep, it is recommended to take melatonin approximately 30 minutes before bedtime.

As part of the study to determine the optimal dose of melatonin, research was conducted on children. It showed that their treatment compared to the general Dutch population14 can be sustained over a long period of time without significant deviation in development, regarding sleep quality, puberty development and mental health scores.

Melatonin

Melatonin is a neurohormone secreted by the pineal gland in the brain, and is well known for causing and regulating sleep. Light suppresses melatonin synthesis. The primary use of melatonin as a dietary supplement is to normalize abnormal sleep patterns. Melatonin may also have general neuroprotective effects related to its antioxidant effects.

1953 Melatonin contributes to the alleviation of subjective feelings of jet lag.

1698/1780/4080 Melatonin contributes to the reduction of time taken to fall asleep.

Conditions of use: the claim may be used only for food which contains at least 0,5 mg of melatonin per quantified portion. Information to the consumer: the beneficial effect is obtained with a minimum intake of 0,5 mg to be taken close to bedtime on the first day of travel and on the following few days after arrival at the destination.

Conditions of use: the claim may be used only for food which contains 1 mg of melatonin per quantified portion. Information to the consumer: the beneficial effect is obtained by consuming 1 mg of melatonin close to bedtime.

In a multicenter, randomized, placebo­controlled study of 170 ambulatory patients aged 55 years or older, who suffered from primary insomnia, the effects of 2 mg prolonged­release melatonin (PR­melatonin) for 3 weeks were evaluated compared to placebo treatment. It was the first drug shown to significantly improve sleep quality and morning alertness in these patients, suggesting restorative sleep. Also, the patients did not have withdrawal symptoms after discontinuation.15 We emphasize the fact that melatonin in that study belonged to the category of drugs due to the high dose contained.

Here is another study that was conducted to systematically review the effect of melatonin on sleep quality. Evidence from randomized clinical trials (RCTs) investigating the effects of melatonin on sleep quality as assessed by the Pittsburgh Sleep Quality Index (PSQI) in adults with various diseases is summarized. According to this index, it was determined that treatment with exogenous melatonin has positive effects on the quality of sleep in adults.7

In order to overcome the short-term effect of melatonin on easier falling asleep and to prevent late night awakenings, some manufacturers have developed a unique form of micronized melatonin that enables both immediate and prolonged release, thus comprehensively improving the quality of sleep.

In most European countries where melatonin is allowed as an ingredient in food supplements (including Croatia), the maximum dose is 1 mg per day (Table 2). It is different in Turkey, where the content of melatonin is allowed up to 3 mg for adults, but with a mandatory warning on the declaration:"It should not be used by pregnant or breastfeeding women and persons under 18 years of age", "Do not drive, operate machinery or consume alcohol while using this

TABLE 2 Health claims for melatonin (EFSA)

product", "It should not be used for more than two months". Germany, Ireland, Iceland and Slovenia do not allow melatonin in food supplements, but classify it as a drug, regardless of dosage.

sures, and volunteers with varying demographic and psychographic characteristics are required to replicate and extend these findings.16

In conclusion, the above studies provide evidence that saffron extract could be an interesting natural and safe strategy to improve sleep duration and quality of sleep on population presented mild to moderate chronic primary sleep disorder.

Biopeptides from milk

Developed in France, Lactium is the generic name of bioactive milk-derived peptides. They are amino acid chains concentrated from casein, derived from cow milk, that act on GABA receptors.

Saffron, Crocus sativus L.

The saffron extract used in food supplements is among the most expensive extracts, just as the spice used in food preparation is among the most expensive spices. But there is a valid reason for that.

Saffron belongs to the iris family. Its threads located in the center of the purple flower are stigmas (Figure 1). There are only three orange­yellow stigmas in each flower, which means that it takes many flowers to produce a small amount of extract or spice. Each kilogram of saffron contains between 15 and 20 thousand stigmas. If you were to grow saffron yourself, you would need 75 thousand flowers to get half a kilogram.

But that is not the only reason why saffron is so expensive. Saffron flowers are very delicate, and the only way to properly remove the threads is to tear them off by hand. The flower is so delicate that if the saffron threads are not harvested soon after the flowers bloom, they will wilt and become unusable. It takes about 370 to 470 hours of work to harvest one kilogram of saffron. However, if we consider that sleep and the quality of sleep are of inestimable importance for human health, then the price of saffron extract is a justified investment.

The dried stigmas of the saffron plant (Figure 2) used in traditional medicine, and the compounds it contains ­ safranal, crocin and crocetin ­ have been largely studied for their effects on depression and anxiety in humans.5 Additionally, saffron appears to have beneficial effects on sleep duration and quality, as evidenced by previous reports using different approaches and protocols. Some studies used a whole saffron extract, while others examined the effects of its active compound crocetin.

It is undeniable that saffron extract is effective in the context of depression and anxiety, but its effect on sleep quality has not been investigated by objective approaches until recently. For this purpose, a randomized, double­blind, placebo controlled study was conducted in subjects presenting mild to moderate sleep disorder associated with anxiety. Sixty­six subjects were randomized and supplemented with a placebo (maltodextrin) or a saffron extract (15.5 mg per day) for 6 weeks.8

Saffron extract intake was associated with improvements in sleep quality in adults with self­reported sleep complaints. Further studies using larger samples sizes, treatment periods, objective outcome mea­

However, its discovery was ultimately thanks to babies. The enzymes present in babies’ digestive systems are responsible for the release of this bioactive peptide resulting in a state of bliss. The digestive enzyme system of adults is no longer capable of releasing this bioactive milk peptide. After many years of work, researchers have developed an innovative process to reproduce a baby's digestive system. They used the well-known digestive enzyme trypsin to isolate a milk protein hydrolyzate containing the bioactive peptide alpha­casozepine from casein.

Lactium® improves sleep, reduces stress and cortisol levels while inducing relaxation and improving mental function. (Clare&Swaisgood,2000;Delini­Stula & Holsboer­Trachsler, 2009; de Saint­Hilaire, Messaoudi, Desor, & Kobayashi, 2009) . It is an effective alternative to medication for anxiety and insomnia.

The study evaluated the effects of alpha-s1 casein hydrolyzate (ACH) on the subjective and objective sleep profiles in subjects with poor sleep quality. A double­blind, randomized, cross­over trial was conducted with 48 participants (49.0 ± 1.7 years, 65% female) who exhibited a mild to moderate degree of sleep disturbance. During the first four weeks, they received either ACH or placebo, and the counterpart was administered in precisely the same way after a four-week washout period. Findings suggest that refined ACH is well tolerated and may improve sleep quality, with possible cumulative beneficial effects with long­term administration.17

Lactium® can be used as an ingredient in a wide range of products, in capsules, tablets, powders, chewing gums, drinks, as an stand alone active substance or in combination with other ingredients.

Magnesium

Magnesium is found in many food supplements as an independent ingredient, or in combination with other active ingredients for numerous purposes. It

Nutramedic &Cosmetics

is often found in food supplements that are intended to promote healthy sleep. The reason for this is justified. Namely, magnesium plays a role in supporting deep, restorative sleep by maintaining healthy levels of GABA, the neurotransmitter that promotes sleep. Research shows that supplemental magnesium intake can improve sleep quality, especially in people with poor sleep.

There are many other ingredients that offer promising results in improving sleep quality. One of them is DailyZz by Kemin, a clinically tested combination of ingredients for natural sleep support. Clinical data supported by rigorous testing of 100 healthy participants with occasional sleep problems showed that the ingredient can help improve sleep quality, support healthy sleep and improve an individual's functioning during the following day.

One of the interesting new findings is that sleep fragmentation and short sleep duration are associated with intestinal dysbiosis, a fact that will surely gain importance in the future. It was also found that the addition of probiotics improves the subjective quality of sleep. The quality and duration of sleep can be an important goal for maintaining a healthy gut microbiota composition, but the cyclical nature of this relationship should not be overlooked.18

References:

1 https://thesleepdoctor.com/how-sleep-works/what-is-sleep/

2 Ferrara M, De Gennaro L. How much sleep do we need? Sleep Med Rev. 2001 Apr;5(2):155­179. doi: 10.1053/smrv.2000.0138. PMID: 12531052.

3 Oginska H, Pokorski J. Fatigue and mood correlates of sleep length in three age­social groups: School children, students, and employees. Chronobiol Int. 2006;23(6):1317­28. doi: 10.1080/07420520601089349. PMID: 17190716.

4 Scott AJ, Webb TL, Martyn­St James M, Rowse G, Weich S. Improving sleep quality leads to better mental health: A meta­analysis of randomised controlled trials. Sleep Med Rev. 2021 Dec;60:101556.

doi: 10.1016/j.smrv.2021.101556. Epub 2021 Sep 23. PMID: 34607184; PMCID: PMC8651630.

5 Ohayon M.M. Epidemiological overview of sleep disorders in the general population. Sleep Med Res. 2011;2(1):1–9.

6 Kerkhof G.A. Epidemiology of sleep and sleep disorders in The Netherlands. Sleep Med. 2017;30:229–239.

7 Fatemeh G, Sajjad M, Niloufar R, Neda S, Leila S, Khadijeh M. Effect of melatonin supplementation on sleep quality: a systematic review and meta­analysis of randomized controlled trials. J Neurol. 2022 Jan;269(1):205­216. doi: 10.1007/s00415­020­10381­w. Epub 2021 Jan 8. PMID: 33417003.

8 Pachikian BD, Copine S, Suchareau M, Deldicque L. Effects of Saffron Extract on Sleep Quality: A Randomized Double-Blind Controlled Clinical Trial. Nutrients. 2021 Apr 27;13(5):1473. doi: 10.3390/nu13051473. PMID: 33925432; PMCID: PMC8145009.

9 Sarris J., Panossian A., Schweitzer I., Stough C., Scholey A. Herbal medicine for depression, anxiety and insomnia: A review of psychopharmacology and clinical evidence. Eur. Neuropsychopharmacol. 2011;21:841–860. doi: 10.1016/j.euroneuro.2011.04.002.

10 Riemann D., Nissen C., Palagini L., Otte A., Perlis M.L., Spiegelhalder K. The neurobiology, investigation, and treatment of chronic insomnia. Lancet Neurol. 2015;14:547–558. doi: 10.1016/ S1474­4422(15)00021­6.

11 Hausenblas H.A., Saha D., Dubyak P.J., Anton S.D. Saffron (Crocus sativus L.) and major depressive disorder: A meta­analysis of randomized clinical trials. J. Integr. Med. 2013;11:377–383. doi: 10.3736/jintegrmed2013056.

12 Euromonitor survey, 2021

13 Luthringer R, Muzet M, Zisapel N, Staner L. The effect of prolonged­release melatonin on sleep measures and psychomotor performance in elderly patients with insomnia. Int Clin Psychopharmacol. 2009 Sep;24(5):239­49. doi: 10.1097/ YIC.0b013e32832e9b08. PMID: 19584739.

14 Van Geijlswijk IM, Mol RH, Egberts TC, Smits MG. Evaluation of sleep, puberty and mental health in children with long­term melatonin treatment for chronic idiopathic childhood sleep onset insomnia. Psychopharmacology (Berl). 2011 Jul;216(1):111­20. doi: 10.1007/s00213­011­2202­y. Epub 2011 Feb 22. PMID: 21340475; PMCID: PMC3111733.

15 Lemoine P, Nir T, Laudon M, Zisapel N. Prolonged­release melatonin improves sleep quality and morning alertness in insomnia patients aged 55 years and older and has no withdrawal effects. J Sleep Res. 2007 Dec;16(4):372-80. doi: 10.1111/ j.1365­2869.2007. 00613.x. PMID: 18036082.

16 Lopresti AL, Smith SJ, Metse AP, Drummond PD. Effects of saffron on sleep quality in healthy adults with self­reported poor sleep: a randomized, double­blind, placebo­controlled trial. J Clin Sleep Med. 2020;16(6):937–947.

17 Kim HJ, Kim J, Lee S, Kim B, Kwon E, Lee JE, Chun MY, Lee CY, Boulier A, Oh S, Lee HW. A Double­Blind, Randomized, Placebo­Controlled Crossover Clinical Study of the Effects of Alpha-s1 Casein Hydrolysate on Sleep Disturbance. Nutrients. 2019 Jun 27;11(7):1466. doi: 10.3390/nu11071466. PMID: 31252661; PMCID: PMC6682925.

18 Matenchuk, Brittany & Mandhane, Piush & Kozyrskyj, Anita. (2020). Sleep, Circadian Rhythm, and Gut Microbiota. Sleep Medicine Reviews. 53. 101340. 10.1016/j.smrv.2020.101340.

DailyZz™: Something to dream about

DailyZz

AUTHOR: Samanta Maci, Kemin Human Nutrition and Health

Background

Consumers are increasingly recognizing that poor sleeping patterns can have a greater impact on health beyond simply feeling fatigue or short temper after a single poor night’s sleep. Getting enough quality sleep can help protect cognitive and physical health, quality of life, and get the best out of your day1

Research from 2022 shows that 46% of global consumers state their sleeping habits have worsened either slightly or a lot in the last two years. 33% of

European consumers are dissatisfied with the quality of overall life as a result of sleeping habits and 30% do not feel refreshed after sleeping which impacts daytime function and overall health2

In fact, consumer needs translate to a sleep aids global market size of 4.8 billion USD with Eastern Europe reaching proximately 280 million USD and expected to surpass 300 million USD by 2024. Natural, chemical free and additive free are within the top buying characteristics that consumers look for in their supplements and Eastern Europe is no excep­

™ supplementation in healthy people who have occasional sleep problems supports healthy and quality sleep and improves performance the next day. It is a new, dual action of one botanical ingredient and an important point of differentiation that opens up space for innovation in the formulation of sleep products.

FIGURE 1 Benefits of DailyZz™ supplementation in support of sleep quality and next day performance. Findings for DailyZz™ compared to placebo (p<0.05 for all). ISI­Insomnia Severity Index; BART­Baloon Analog Risk Task; PVT-Psychomotor Vigilance Test16

tion with over 70% of botanicals market share3. This creates the perfect momentum for natural and science-based ingredients to breakthrough in this platform.

Kemin Human Nutrition and Health blended science and nature together to create a powerful botanical blend rich in naturally occurring polyphenols providing much­needed sleep quality and the strength of next day performance – meet DailyZz™

Features

DailyZz™ is a proprietary blend of gentle water extraction of a certified sustainably grown spearmint (Menthaspicata L.) and green tea (Camellia sinensis) developed for use as a dietary ingredient in supplements and food and beverages applications. Rich in polyphenols, DailyZz™ is standardized to rosmarinic acid (RA) and epigallocatechin gallate (EGCG) combined and over 25% of total polyphenolic complex.

DailyZz meets the condition of use for Camellia sinensis related to the EU on­hold botanical claims ”Supports natural sleep / relaxing / promotes concentration” (ID 1222 ­ EFSA on hold botanical claims list)*.

Powered by science

Sleep and wakefulness are tightly controlled processes. Many distinct systems with their neurochemicals contribute to specific aspects of the sleep-

wake cycle. Excitatory neurotransmitters such as acetylcholine (Ach), glutamate, and different monoamines promote wakefulness while gamma aminobutyric acid (GABA) together with neuropeptides, promote sleep4. Interestingly, Ach plays a dual role as a sleep and wake neurochemical5

On top of the well-known antioxidant and neuroprotective properties6,7, Mentha spicata and Camellia sinensis have been associated with sleep, relaxation and brain function possibly through the ability of RA, a major polyphenol amongst more than 50 other polyphenols from the spearmint plants, to modulate Ach and of RA and EGCG from the green tea to interact with GABA receptors8­15

In addition to the scientific rational for the potential beneficial role of the polyphenols present in the proprietary blend, supportive evidence from an innovative dual night and day activity was obtained in a randomized, double blind, placebo­controlled, parallel design, clinical trial conducted by leading sleep expert Dr. Michael Grandner in hundred and five healthy men and women with occasional mild sleep complaints16

The study showed that, when taken daily for 30 days before bedtime at 485mg dose, DailyZz™ supports healthy and quality sleep and improves next day (following day) performance parameters such as concentration, judgement, reaction time and executive function when compared to placebo (Figure 1). Remarkably, these are cognitive areas impacted by a

bad night of sleep. Furthermore, benefits from DailyZz™ started to be observed as early as 7 days17

One ingredient – countless applications

DailyZz is a versatile water­soluble tan­dry powder that can be included in different galenic dry formulations such as hard and softgels capsules, tablets, gummies, and water­based applications such as spray, sticks and drops to dissolve in water. The ingredient has a 3­years shelf life, is stable across a range of temperatures and pH values and in formulation with melatonin, vitamins and other botanical ingredients. The suggested dosage is 485 mg/day, 30 minutes before bedtime.

Final remarks

In Eastern Europe the use of botanical sleep aid ingredients is very well established. DailyZz™ supplementation in healthy men and women with occasional sleep complaints supports healthy and quality sleep and improves next day performance. This is a novel finding for a botanical ingredient and an important point of differentiation that unlocks innovation in sleep formulations.

* Consolidated list of Article 13 Health Claims ID1222; Condition of use: Not less than 10 mg of Camellia sinensis leaf extract 5:1 a day. The determination of the acceptability of a botanical health claim rests fully with the food business operator placing the finished food product on the market.

References:

1 U.S. Department of Health & Human Services Sleep Deprivation and Deficiency. https://www.nhlbi.nih.gov/health-topics/ sleep-deprivation-and-deficiency.

2 FMCG Gurus Sleep and Stress Management in 2022 ­ Global Report; 2022;

3 Euromonitor Sleep Aids Eastern Europe 2020 ­ 2025; 2022;

4 España, R.A.; Scammell, T.E. Sleep Neurobiology from a Clinical Perspective. Sleep 2011, 34, 845–858, doi:10.5665/SLEEP.1112.

5 Carley, D.W.; Farabi, S.S. Physiology of Sleep. Diabetes Spectr. 2016, 29, 5–9, doi:10.2337/diaspect.29.1.5.

6 Fonseca, B.A. Key Polyphenols in Neumentix Phenolic Complex K110­42 Can Act in Multiple Ways to Support Cognitive Performance. Kemin Document KHTL­01­134;

7 Cabrera, C.; Artcho, R.; Giménez, R. Beneficial Effects of Green Tea: A Literature Review. J. Am. Coll. Nutr. 2006, 25, 79–99, doi:10.1186/1749­8546­5­13.

8 Falé, P.L.V.; Madeira, P.J.A.; Florêncio, M.H.; Ascensão, L.; Serralheiro, M.L.M. Function of Plectranthus Barbatus Herbal Tea as Neuronal Acetylcholinesterase Inhibitor. Food Funct. 2011, 2, 130–136, doi:10.1039/c0fo00070a.

9 Awad, R.; Muhammad, A.; Durst, T.; Trudeau, V.L.; Arnason, T. Bioassay­Guided Fractionation of Lemon Balm (Melissa Officinalis L.) Using an In Vitro Measure of GABA Transaminase Activity. Phyther. Res. 2009, 23, 1075–1081, doi:10.1002/ptr.

10 Kwon, Y.O.; Hong, J.T.; Oh, K.W. Rosmarinic Acid Potentiates Pentobarbital­Induced Sleep Behaviors and Non­Rapid Eye Movement (NREM) Sleep through the Activation of GABAa­Ergic Systems. Biomol. Ther. 2017, 25, 105–111, doi:10.4062/biomolther.2016.035.

11 Adachi, N.; Tomonaga, S.; Tachibana, T.; Denbow, D.M.; Furuse, M. (­)­Epigallocatechin Gallate Attenuates Acute Stress Responses through GABAergic System in the Brain. Eur. J. Pharmacol. 2006, 531, 171–175, doi:10.1016/j.ejphar.2005.12.024.

12 Vignes, M.; Maurice, T.; Lanté, F.; Nedjar, M.; Thethi, K.; Guiramand, J.; Récasens, M. Anxiolytic Properties of Green Tea Polyphenol (­)­Epigallocatechin Gallate (EGCG). Brain Res. 2006, 1110, 102–115, doi:10.1016/j.brainres.2006.06.062.

13 Park, K.S.; Oh, J.H.; Yoo, H.S.; Lee, Y.M.; Lee, M.K.; Hong, J.T.; Oh, K.W. (-)-Epigallocatechin-3-O-Gallate (EGCG) Reverses Caffeine-Induced Anxiogenic-like Effects. Neurosci. Lett. 2010, 481, 131–134, doi:10.1016/j.neulet.2010.06.072.

14 Caro, D.C.; Rivera, D.E.; Ocampo, Y.; Franco, L.A.; Salas, R.D. Pharmacological Evaluation of Mentha Spicata L. and Plantago Major L., Medicinal Plants Used to Treat Anxiety and Insomnia in Colombian Caribbean Coast. Evidence­based Complement. Altern. Med. 2018, 2018, doi:10.1155/2018/5921514.

15 Campbell, E.L.; Chebib, M.; Johnston, G.A.R. The Dietary Flavonoids Apigenin and (­)­Epigallocatechin Gallate Enhance the Positive Modulation by Diazepam of the Activation by GABA of Recombinant GABA A Receptors. Biochem. Pharmacol. 2004, 68, 1631–1638, doi:10.1016/j.bcp.2004.07.022.

16 Tubbs, A.S.; Kennedy, K.E.R.; Alfonso­Miller, P.; Wills, C.C.A.; Grandner, M.A. A Randomized, Double­Blind, Placebo­Controlled Trial of a Polyphenol Botanical Blend on Sleep and Daytime Functioning. Int. J. Environ. Res. Public Health 2021, 18, 1–11, doi:10.3390/ijerph18063044.

17 Sadewasser Chris DailyZz Shown to Improve Sleep Quality Is Less than 2 Weeks. Tech. Lit. 2020.

The importance of bones in preserving the integrity of the body's function and ingredients that help preserve bone mass

Nutrition, exercise and appropriate supplementation can help maintain better mobility and an active lifestyle in later years. In addition to calcium, vitamins D and K, there are many other ingredients that can help maintain bone health.

Bones and joints play a key role in the musculoskeletal system, a network that includes muscles, ligaments, tendons, and other connective tissue. It is well known that as a result of normal aging, changes occur in the musculoskeletal system that can lead to reduced mobility and pain, and thus to a reduced quality of life.

Bones not only give shape to the body and protect organs, but also produce red and white blood cells, act as a storehouse of minerals such as calcium and phosphorus, and help regulate acidity, i.e. the acidbase balance of the blood. Joints, simply put, are places where bones come together. Some allow movement, such as the knee joints, and others do not, such

as the joints between the bones of the skull.

Bone health is determined by genetics and environmental factors. Throughout life, both intrinsic factors (eg, genetics and hormonal status) and extrinsic factors (eg, exercise and diet) continually influence bone modeling and remodeling. Remodeling occurs through a complex and carefully orchestrated interaction between bone resorption (bone breakdown) and bone deposition (bone formation). Bone mass, i.e. the amount of minerals in the bone, reflects the result of the interaction between these two processes.

Most bone mass is accrued early in life, reaching its peak at the age of 30. In later life, bone remodel­

AUTHOR: Valerija Pandža, M.pharm.

Nutramedic &Cosmetics

ing continues, but more bone mass is generally lost than gained. However, this does not mean that bone health cannot be improved at any age. In fact, it is estimated that most of an adult's skeleton is replaced every ten years, and lifestyle choices can change the strength and health of these "new" bones.

Bone health refers to their strength and structural quality. Their health is assessed by a doctor through a detailed medical history and physical examination that includes proven tools to identify risk factors. The findings of this assessment determine whether and how bone health will be measured. Bone mineral density (BMD) is the most common way of measuring bone health.

Bone health is influenced by nutrient intake, hormonal regulation, exercise and age, among other factors (Table 1).

Age-related bone loss

Decreased bone density, changes in cartilage and connective tissue, and altered muscle function can

TABLE 1 Factors affecting bone health

The amount of calcium in the diet: a diet low in calcium contributes to diminished bone density, early bone loss and an increased risk of fractures.

Physical activity: people who are physically inactive have a higher risk of osteoporosis than do their more­active counterparts.

Tobacco and alcohol use: research suggests that tobacco use contributes to weak bones. Similarly, regularly having more than one alcoholic drink a day for women or two alcoholic drinks a day for men may increase the risk of osteoporosis.

Sex: women are at greater risk of osteoporosis, because women have less bone tissue than do men.

Body constitution: persons who are extremely thin are at risk (with a body mass index of 19 or less) or have a small body frame because you might have less bone mass to draw from as they age.

Age: bones become thinner and weaker as people age.

Race and family history: persons of white or of Asian descendant have greatest risk of osteoporosis. In addition, having a parent or sibling who has osteoporosis puts you at greater risk — especially if you also have a family history of fractures.

Hormone levels: too much thyroid hormone can cause bone loss. In women, bone loss increases dramatically at menopause due to dropping estrogen levels. Prolonged absence of menstruation (amenorrhea) before menopause also increases the risk of osteoporosis. In men, low testosterone levels can cause a loss of bone mass.

Eating disorders and other conditions: severely restricting food intake and being underweight weakens bone in both men and women. In addition, weight-loss surgery and conditions such as celiac disease can affect your body's ability to absorb calcium.

Certain medications: long­term use of corticosteroid medications, such as prednisone, cortisone, prednisolone and dexamethasone, is damaging to bone. Other drugs that might increase the risk of osteoporosis include aromatase inhibitors to treat breast cancer, selective serotonin reuptake inhibitors, methotrexate, some anti­seizure medications, such as phenytoin and phenobarbital, and proton pump inhibitors.

Taken from: https://www.mayoclinic.org/healthy­lifestyle/adult­health/in­depth/bone­health/ art­20045060

occur as part of the normal aging process. Changes in muscle function are also seen as part of normal aging. Fortunately, a healthy diet, exercise and proper supplementation can help maintain better mobility and an active lifestyle well into later years.

Age­related bone loss is often considered a predominantly female problem. However, it is important to emphasize that although osteoporosis rates are low in men, the prevalence of osteopenia (low bone density) in the femoral neck or lumbar spine in men also increases with age.

A study by Center et al. of 852 women and 635 men (60 years and older) without fractures, reported an age­related decrease in volumetric bone mineral density (vBMD) at the hip (Center et al. 2004).

As a result of the aging process, the bone deteriorates in composition, structure and function, which predisposes to osteoporosis. Osteoporosis is defined as a decrease in bone mass and bone micro­architecture, with an increased risk of fragility fractures. Because of the close relationship between the aging process of bone and the pathogenesis of osteoporosis, research on the mechanisms of age­related bone loss has increased significantly in recent years, including a combination of basic, clinical, observational, and translational studies.

Age­related bone loss is a complex and heterogeneous disease. A combination of genetic, hormonal, biochemical, and environmental factors underlie its pathophysiology. The result is a decline in bone quantity and quality that increases fracture risk in a progressive manner. The two most common forms of primary osteoporosis in the elderly are postmenopausal osteoporosis (type 1) and senile osteoporosis (type 2). The strong ability of estrogen to suppress the activity of osteoclasts in the resorption phase and to increase their apoptosis is lost with the reduction of estrogen in menopause. Older postmenopausal women probably have both etiologies.

Despite greater understanding of the mechanisms of these contributing factors through clinical and animal studies, more research is needed to determine the relative contributions of each of these factors in order to improve preventative and therapeutic options.1

Food supplements for preserving bone health

As we age, the health of our bones and joints becomes more and more important. In addition, after an injury, healing should be supported, and it is also necessary to act preventively against osteoporosis and arthritis, and to look for ways to stay healthy. Vitamins, minerals and other ingredients can play an important role in maintaining bone and joint health.

A recent study conducted by strategic consulting and market research firm, Blue Weave Consulting, revealed that the global bone and joint nutritional supplements market was worth USD 10.31 billion in 2021. The market is projected to grow at a CAGR of 9.2%, earning around USD 18.83 billion by the end of 2028. The key growth driver of the global bone and joint health supplements market is the increasing trend of dietary supplements among the elderly population. It is estimated that the bone and joint health nutritional supplements market will experience sig­

nificant revenue growth during the forecast period due to the aging of the baby boom population and the increase in harmful lifestyle habits. Moreover, the growing interest of consumers in an active life, the rise in disposable income and the spread of awareness about health are further significant drivers of the sector. However, high R&D investments and the high cost of clinical trials hinder market growth. 2

Ingredients in food supplements with proven effects on maintaining bone health

Many articles have been written and research done on the topic of the need for supplementation with calcium, vitamin D, vitamin K and other micronutrients to maintain bone health. However, there are many more ingredients that can help preserve bone health, and they deserve additional attention, which we will devote to them in the following text.

In addition to supplementation with useful ingredients, changes in some lifestyle habits that can be undertaken are also important. A balanced diet is certainly the basis of good health, including the maintenance of healthy bones. The best diet plan depends on the possible health problems that the person has. For example, a gluten­free diet can improve bone mass in people with celiac disease. 3

Exercise and movement in nature are essential in the context of maintaining bone health. Regular bone density screenings according to recommended guidelines and doctor's instructions are also important.

Vitamin C

Supplementation with vitamin C can help prevent osteoporosis by reducing oxidative stress and consequent bone resorption. Vitamin C is also an essential factor for the formation of collagen (an important component of the bone matrix). In addition, it potentiates the activity of vitamin E in cells, by supporting the regeneration of α­tocopherol from its oxidized form. Studies have proven the association of higher levels of vitamin C with higher bone density.

A double­blind study of 90 participants showed that supplementation with 1,000 mg of vitamin C and 400 IU of vitamin E was associated with higher bone mineral density after 12 months.4

Phytoestrogens

Phytoestrogens such as soy isoflavones, or resveratrol, have a structural similarity to estrogen and can bind to estrogen receptors and thus achieve a multitude of benefits that estrogen is otherwise responsible for. They have attracted interest as potential therapies for the bone health of postmenopausal women who lack estrogen.

Resveratrol

Resveratrol, a natural polyphenol found in red grapes and berries, can act as a phytoestrogen. A 2­year randomized, double­blind, placebo­controlled crossover trial called RESHAW (resveratrol for healthy aging in women) evaluated the effect of resveratrol (75 mg twice daily) on cognition, cerebrovascular

function, bone health, cardiometabolic markers, and general well­being in women in postmenopause.

After 12 months of resveratrol supplementation, compared to placebo, positive effects on bone density in the lumbar spine (+0.016 ± 0.003 g/cm2) and femoral neck (+0.005 ± 0.002 g/cm2) were recorded, which, also compared to placebo, were accompanied by a 7.24% decrease in the level of collagen C­terminal telopeptide type 1, a marker of bone resorption.

An increase in mineral density in the femoral neck resulted in an improvement in T­score (+0.070 ± 0.018) and a decrease in the 10­year probability of a higher risk of hip fracture. The extent of improvement was greater in women with poor bone health biomarker status. Importantly, the improvement in femoral neck T-score as a result of taking resveratrol correlated with the improvement in perfusion. A subanalysis found that the bone-protective benefit of resvera

trol was greater in participants who took both vita

min D and calcium. In conclusion, regular supplementation with 75 mg of resveratrol twice a day has the potential to slow bone loss in the lumbar spine and femoral neck, common fracture sites in postmenopausal women without significant osteoporosis.5

It is important to note that the dose of 75 mg, whose effectiveness for bone health benefits was determined by this study, is as much as 80 times higher than the average daily intake of resveratrol through food and drink.

Genistein

Another phytoestrogen, the soy isoflavone genistein, has also been proven to benefit bone health in postmenopausal women.

A clinical trial of 389 women with postmenopausal osteopenia evaluated the effects of genistein at a

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dose of 56 mg per day (plus 400 IJ of vitamin D). A significant increase in BMD, compared to placebo, was found in the femoral neck (+0.023 g/cm2) and lumbar spine (+0.055 g/cm2) after 12 months of supplementation. BMD continued to increase in the second year of supplementation.

Participants took 2 tablets with a total of 54 mg genistein or placebo daily for 24 months. The tablets also contained vitamin D3 and calcium, also necessary for healthy bones, and the placebo contained no other active ingredients.

After 24 months, bone density was measured and several blood tests were performed to see if bone breakdown or formation had occurred. Since estrogens can make the lining of the uterus thicker and can lead to cancer, ultrasound tests were also used to measure the thickness of the lining of the uterus to see if genistein causes this side effect as well.

After 24 months, women who took genistein had a greater increase in bone mineral density than women taking a placebo. In addition, bone markers were more favorable in women taking genistein than in women taking placebo. Gastrointestinal side effects were more common in women taking genistein than in women taking placebo. The thickness of the uterine lining did not change in either group, suggesting that genistein may be safe to use in terms of uterine health.

The phytoestrogen genistein, when taken with vitamin D3 and calcium, was proven to have beneficial effects on bone health compared to vitamin D3 and calcium alone.6

Olive leaf extract - bone support from the Mediterranean

In addition to the Mediterranean diet, which has various positive effects on bone health, olive extract also has proven effects. Bonolive® is an olive leaf extract standardized to a high content of oleuropein, a powerful phytonutrient unique to the olive tree. In various studies, it has shown beneficial properties, especially in reducing the risks associated with menopause.

Bonolive® is a patent­protected innovation that can be seamlessly integrated into nutritional supplements, medical nutrition and functional beverages, with the aim of supporting the health of women during menopause. The health benefits of this extract have been evaluated in several clinical studies that have shown its positive effect on the health of bones, joints, the cardiovascular system as well as its strong antioxidant properties. Clinically proven to improve bone health. A randomized, double­blind, placebo­controlled study demonstrated that it has significant effects on bone-building cells (osteoblasts) and bone mineral density in postmenopausal women.7

Preclinical research has shown that compounds from olive (Oleaeuropaea) can protect against bone loss by increasing the activity of osteoblasts at the expense of adipocyte formation. The aim of this exploratory study was to get the first insight into the effect of taking olive extract on bone remodeling in postmenopausal women with osteopenia (reduced bone mass).

The gut-bone axis: pathways and factors starting from gut dysbiosis that determine bone metabolism alterations favoring osteoclasts. Abbreviations — SCFAs: short-chain fatty acids; PAMPs: pathogen­associated molecular patterns; D Cell: somatostatin­producing cells; T Cell: type of leukocyte that is an essential part of the immune system; OB: osteoblast; OC: osteoclast; RNK-L: receptor activator of nuclear factor-κB ligand; OPG: osteoprotegerin; VDR: vitamin D receptor; IGF-1: insulin-like growth factor one.

and Bone Health: The Gut­BoneAxis.Cells.2022Feb21;11(4):743.doi:10.3390/cells11040743.PMID:35203401;PMCID:PMC8870226.

FIGURE 1 The gut­bone axis

Taken from: deSireA,deSireR,CurciC,CastiglioneF,WahliW.RoleofDietarySupplementsandProbioticsinModulatingMicrobiota

A double­blind, placebo­controlled study was conducted in which participants with osteopenia were randomly assigned to treatment or placebo groups. The study included 64 of them, with a T­score of mean bone mineral density (BMD) in the lumbar spine (L2­L4) between ­1.5 and ­2.5. During 12 months, they took 250 mg of olive extract and 1,000 mg of calcium (treatment) or 1,000 mg of calcium alone (placebo) daily. Primary endpoints consisted of assessment of bone remodeling markers. Secondary endpoints included BMD measurements and blood lipid profiles. After 12 months, levels of the pro-osteoblastic marker osteocalcin were found to be significantly increased in the treatment group compared to placebo. At the same time, BMD decreased in the placebo group, while it remained stable in the treatment group. In addition, improved lipid profiles were observed in the therapeutic group, with a significant reduction in total and LDL­cholesterol.7

This research study supports preclinical observations and warrants further research, as it shows that this specific olive polyphenol extract affects serum osteocalcin levels and can stabilize lumbar spine BMD. Moreover, improved blood lipid profiles suggest additional health benefits.

The link between gut health and bone health

The relationship between gut health and bone health - known as the gut-bone axis - is an emerging area of scientific research8 (Figure 1).

Today, altered intestinal homeostasis is being in­

vestigated as a potential additional risk factor for reduced bone health, and therefore as a new potential therapeutic target. Intestinal microflora affects osteoclast activity, regulating serum IGF­1 levels, and at the same time affects intestinal calcium absorption. It is therefore not surprising that gut dysbiosis affects bone health. In this context, it has been hypothesized that dietary supplements, prebiotics and probiotics contribute to the intestinal microecological balance, which is important for bone health.

There are a number of possible ways in which this can be connected. First, intestinal dysbiosis makes it difficult to absorb calcium in the intestines. In addition, several metabolites produced in the gut exert control over the cells responsible for bone repair. Finally, dysbiosis­induced intestinal permeability causes the release of inflammatory cytokines into the bloodstream, which can negatively affect BMD and other factors related to bone health.

Prebiotics and probiotics have been investigated for their ability to improve bone health through effects on the gut microbiome. Although more research is needed, some evidence suggests that probiotics may protect against BMD loss and may improve markers of bone turnover in postmenopausal women.

Modulation of gut microbiota by other means such as diet, synbiotics, postbiotics, antibiotics, and fecal microbiota transplantation is another way to influence the gut­bone axis and improve bone health.

The Mediterranean diet can have a beneficial ef

Lifestyle intervention and supplementation that might reduce bone loss; these modulators might exert their therapeutic effects through different known biological pathways, such as OPG, RANK, and TRAF.

Abbreviations — OPG: osteoprotegerin; RANK-L: receptor activator of nuclear factor-κB ligand; RANK: receptor activator of nuclear factor κB; TRAF: tumor necrosis factor receptor­associated factor.

Taken from: deSireA,deSireR,CurciC,CastiglioneF,WahliW.RoleofDietarySupplementsandProbioticsinModulatingMicrobiota and Bone Health: The Gut­BoneAxis.Cells.2022Feb21;11(4):743.doi:10.3390/cells11040743.PMID:35203401;PMCID:PMC8870226.

FIGURE 2 Gut microbiota modulators

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fect on reducing the risk of bone fractures due to the high content of fiber, fermented milk products and polyphenols that favorably change the composition of the intestinal microbiome (Figure 2).

Prebiotics share the ability to be converted to shortchain fatty acids (SCFAs)—including acetate, propionate, and butyrate—by the microbiota, increasing their levels in the gut and serum, thereby lowering gut pH. In an acidic environment, most minerals such as magnesium and calcium become more soluble, so their absorption is increased. Butyrate also acts as a growth factor for enterocytes and colonocytes.

In addition, SCFAs produced from prebiotics regulate the number and function of regulatory T cells in the colon, thereby controlling inflammation and modulating the synthesis of IGF­1 involved in bone remodeling. Therefore, fructooligosaccharide supplementation may have beneficial effects on bone metabolism, although further research is needed to confirm these findings.

Probiotics and their use have a special place in research related to the maintenance of bone health. A new term ‘osteomicrobiology’ was introduced recently for the rapidly emerging research field of the role of the microbiota in bone health and disease. This research field is aimed to bridge the gaps between bone physiology, gastroenterology, immunology, and microbiology. There has been a rapid translation from experimental animal studies to ongoing clinical trials of the effect of certain probiotic treatments on bone health in postmenopausal women and the results from these studies will be informative to determine if the GM might be a novel therapeutic target for osteoporosis.9

The combination of three Lactobacilli under the commercial name Probi®osteo ­ is a probiotic concept for bone health. It is based on the combination of Lactiplantibacillus plantarum HEAL9 (HEAL9™), Lactiplantibacillus plantarum HEAL19 and Lacticaseibacillus paracasei 8700: 2. This combination is clinically documented in supporting bone health, helps maintain their density and mineral content, maintain a balance in the natural bone remodel, and can lead to stronger bones. It is ideal for capsules and packs in the stick, and for functional foods such as drinks and powder products.12

Its efficiency was proven in a study conducted in

Sweden, aiming to determine if supplementation with a combination of three bacterial strains protect from the rapid loss of bone mass of the spine in healthy women in early postmenopause. This randomized, double­blind, placebo­controlled, multicenter trial, conducted on 249 women randomly arranged in a 1: 1 ratio in a placebo or control group. The control group took probiotic treatment of the said probiotic product consisting of three Lactobacillus strains (Lactobacillus paracasei DSM 13434, Lactobacillus plantarum DSM 15312 and Lactobacillus plantarum DSM 15313; 1x1010).

The primary outcome was the percentage of a change in lumbar spine bone mineral density (LS­BMD) after 12 months, compared to the initial value. The primary analysis was done in all participants both at baseline and at 12 months. In conclusion, the treatment of Lactobacillus reduced LS­BMD loss compared to placebo. Losing LS-BMD was significant in the placebo group, while the loss of bone mass was not observed in a group treated with Lactobacillus11

References:

1 Demontiero O, Vidal C, Duque G. Aging and bone loss: new insights for the clinician. Ther Adv Musculoskelet Dis. 2012 Apr;4(2):61­76. doi: 10.1177/1759720X11430858. PMID: 22870496; PMCID: PMC3383520.

2 Bone And Joint Health Supplements Market Size, Share & Trends Analysis Report By Product, By Formulation, By Consumer Group, By Sales Channel, By Region, And Segment Forecasts, 2022 ­ 2030

3 Mosca C, Thorsteinsdottir F, Abrahamsen B, Rumessen JJ, Händel MN. Newly Diagnosed Celiac Disease and Bone Health in Young Adults: A Systematic Literature Review. Calcif Tissue Int. 2022 Jun;110(6):641­648. doi: 10.1007/s00223­021­00938­w. Epub 2022 Jan 3. PMID: 34978602; PMCID: PMC8721639.

4 Ruiz­Ramos M, Vargas LA, Fortoul Van der Goes TI, Cervantes­Sandoval A, Mendoza­Nunez VM. Supplementation of ascorbic acid and alpha­tocopherol is useful to preventing bone loss linked to oxidative stress in elderly. J Nutr Health Aging. 2010 Jun;14(6):467­72. doi: 10.1007/s12603­010­0099­5. PMID: 20617290.

5 Wong RH, Thaung Zaw JJ, Xian CJ, Howe PR. Regular Supplementation With Resveratrol Improves Bone Mineral Density in Postmenopausal Women: A Randomized, Placebo­Controlled Trial. J Bone Miner Res. 2020 Nov;35(11):2121­2131. doi: 10.1002/ jbmr.4115. Epub 2020 Jul 14. PMID: 32564438; PMCID: PMC7689937.

6 Marini H, Minutoli L, Polito F, Bitto A, Altavilla D, Atteritano M, Gaudio A, Mazzaferro S, Frisina A, Frisina N, Lubrano C, Bonaiuto M, D'Anna R, Cannata ML, Corrado F, Adamo EB, Wilson S, Squadrito F. Effects of the phytoestrogen genistein on bone metabolism in osteopenic postmenopausal women: a randomized trial. Ann Intern Med. 2007 Jun 19;146(12):839­47. doi: 10.7326/0003­4819­146­12­200706190­00005. PMID: 17577003. 7 https://www.bonolive.com

8 Filip R, Possemiers S, Heyerick A, Pinheiro I, Raszewski G, Davicco MJ, Coxam V. Twelve­month consumption of a polyphenol extract from olive (Olea europaea) in a double blind, randomized trial increases serum total osteocalcin levels and improves serum lipid profiles in postmenopausal women with osteopenia. J Nutr Health Aging. 2015 Jan;19(1):77­86. doi: 10.1007/s12603­0140480­x. PMID: 25560820.

9 Ohlsson C, Sjögren K. Osteomicrobiology: A New Cross­Disciplinary Research Field. Calcif Tissue Int. 2018 Apr;102(4):426­432. doi: 10.1007/s00223­017­0336­6. Epub 2017 Oct 27. PMID: 29079994; PMCID: PMC5851705.

10 de Sire A, de Sire R, Curci C, Castiglione F, Wahli W. Role of Dietary Supplements and Probiotics in Modulating Microbiota and Bone Health: The Gut­Bone Axis. Cells. 2022 Feb 21;11(4):743. doi: 10.3390/cells11040743. PMID: 35203401; PMCID: PMC8870226.

11 Per-Anders Jansson, Dan Curiac, Irini Lazou Ahrén, Fredrik Hansson, Titti Martinsson Niskanen, Klara Sjögren, Claes Ohlsson, Probiotic treatment using a mix of three Lactobacillus strains for lumbar spine bone loss in postmenopausal women: a randomised, double­blind, placebo­controlled, multicentre trial, The Lancet Rheumatology, Volume 1, Issue 3, 2019, e154 ­ e162

12 https://www.probi.com/solutions/probiotic­portfolio/probi­osteo/

The name C3 Complex was chosen to represent the ingredient’s three main chemical compounds: Curcumin, Demethoxycurcumin and Bisdemethoxycurcumin, collectively known as Curcuminoids Curcumin C3 Complex is a specific mixture of Curcuminoids, making it a unique form of Curcumin quite different from generic Curcumin extracts. It has been used in more clinical studies than any other Curcumin ingredient in the world Carbon based testing done on every batch to ensure natural status. Low in oxalates, and marketed for over 25 years

Functional ingredients for healthy ageing and bone support

Chicory root fibres Orafti® Inulin and Oligofructose are proven prebiotics and as such support the gut microbiome by promoting the growth of beneficial gut bacteria. They promote digestive health and strengthen the immune system, reduce blood glucose response, help in weight management, and promote calcium absorption for bone health.

Bone and joint disorders

Osteoporosis is a disorder best prevented rather than treated. The best it can be done with diet and exercise is to stop the progress. While at least 15 nutrients are needed for strong, healthy bones, two stars in the nutrient universe are calcium and vitamin D. Men and women over the age of 50 should aim for 1200 milligrams (or 1.2 grams) of calcium in their daily diets.1 Calcium rich foods include dairy foods, such as milk, cheese, yogurt, and kefir. It is also found in fortified plant based milk substitutes, canned fish, tofu, dark leafy greens, almonds, and fortified foods, such as breakfast cereals, juices, and energy bars.

Vitamin D plays many roles in the human body, but regarding bone health the main role is helping the body absorb dietary calcium. Without sufficient Vitamin D, calcium absorption is decreased, contributing to loss of bone mass. 2 Fatty fish provides some vitamin D in the diet, but fortified foods provide the bulk of vitamin D in your diet. Many foods that are calcium-rich are fortified with vitamin D, such as dairy milk, as are most plant-based milk beverages, but other dairy foods, such as cheese or yogurt, may not contain vitamin D.

Bone building occurs with growth and development and peak bone density happens in early adulthood. Therefore, enhancing calcium absorption can have a positive impact on bone health.

Prebiotic fibres not only feed the gut microbiome, but also enhance calcium absorption during adolescence (the best time to build bone) and also later in life (e.g. postmenopausal women). 3,4 That is one more good reason to ensure that prebiotic fibres are part of everyone’s daily diet.

Importance of prebiotics in health

Prebiotic fibres not only feed the gut microbiome, but also enhance calcium absorption during adolescence (the best time to build bone) and also later in life (e.g. postmenopausal women). 3,4

Chicory root fibres Orafti® Inulin and Oligofructose are proven prebiotics and as such support the gut microbiome by promoting the growth of beneficial gut

bacteria, they promote digestive health and strengthen the immune system, reduce blood glucose response, help in weight management, and promote calcium absorption for bone health.

The human gastrointestinal tract is host to one of the most complex ecosystems on the planet­gut microbiota. Fibre­rich foods are good for the gut microbiota, but a specific type of fibre-rich carbohydrate, called prebiotics, can positively influence the microbes in the gut.5 Almost all prebiotics are dietary fibres but not all dietary fibres are prebiotics. Bacteria that reside in the gut, specifically Lactobacilli and Bifidobacteria , are the usual targets for prebiotics, helping these good bacteria grow and multiply.6,7 The term prebiotics is relatively new, but it is well established that they can improve digestive health and research shows that they can positively influence immune system, improve calcium absorption, and keep blood sugar in check. Five grams of prebiotics eaten each day, from whole foods or as an ingredient in functional foods is recommended for well­being.8,9,10 Whole foods like fruits, vegetables, and whole grains contain prebiotics but are present in low levels which is why prebiotics are being added to foods like bars, drinks, yogurts, cereals, and even chocolate. You would have to eat 10 bananas to get 5 grams of the recommended prebiotic fibre.

One of the most well studied prebiotics is called inulin. Inulin is found in the root of the chicory plant (CichcoriumintybusL.). Extracting the inulin from chicory root is a soft process and such concentrated inulin can be added to foods to boost prebiotic intake.11 The ISAPP (International Scientific Association for Probiotics and Prebiotics) published a consensus definition for Prebiotics in 2017. This current consensus definition is: “a substrate that is selectively utilized by host microorganisms conferring a health benefit”. Inulin and FOS are 2 of the 3 recognized proven prebiotics by ISAPP. The Chinese Nutrition Society (CNS), China’s largest professional nutrition body, has concluded that inulin and oligofructose are among the first accepted prebiotics. The recognition includes BENEO’s functional fibres derived from chicory root and is a result of the premier prebiotic scienti­

fic consensus statement in China announced in 2021. The statement defines prebiotics and its criteria for ingredient classification.12

Chicory root fibres increase calcium absorption

Calcium is considered a nutrient of public health concern for Americans.13 With a sufficient calcium intake as well as efficient absorption and retention for increased bone mineral density in early adulthood, the risk for osteoporosis and related fractures can be reduced. Since its bioavailability is very low in humans and calcium absorption is limited, intake recommendations for calcium intake are high. Chicory root fibre helps to increase prebiotic fibre intake and at the same time serves as a dietary approach to increase calcium absorption in the large intestine for maintaining healthy bones.14

In summary, chicory root fibres have been shown to increase calcium absorption through several mechanisms tracing back to their intestinal fermentation pattern and production of organic acids. The favourable effects of chicory root fibres on calcium absorption are attributed to their fermentation in the colon, which increases production of short­chain fatty acids and subsequently decreases pH. Dietary calcium is mostly present as insoluble complexes making it unavailable for absorption. The reduction of pH in the colon brings some of this calcium into solution and, thus, makes it available for absorption.15,16

In addition, several postulated mechanisms may also contribute to the effects of chicory root fibre on intestinal calcium absorption. Fermentation products (short­chain fatty acid butyrate) increase the absorptive area for calcium due to mucosa growth. Also, more calcium is absorbed with chicory root fibre intake as the permeability of the intestinal wall is enhanced and as more calcium from the colon lumen is exchanged for hydrogen from the cells.16­18

A one year intervention study, conducted at the USDA Children’s Nutrition Research Center at the Baylor College of Medicine in Houston, TX, supplied 8 g of Orafti® Synergy1 per day to 100 adolescents to examine long-term effects of chicory root fibre on calcium absorption and bone health. After one year, the Orafti® Synergy1 group had significantly higher calcium absorption and greater bone mineral density (BMD) compared to the control group, i.e. it was demonstrated that the additional calcium absorbed indeed reached the bones. This study is one of a kind in demonstrating long-term benefits of Orafti® Synergy1 (oligofructose­enriched inulin) for bone health.19

The same results were also found in a group of postmenopausal women where 6 weeks of Orafti® Synergy1 (oligofructose­enriched inulin) supplementation improved mineral absorption and impacted markers of bone turnover. 20

References:

1 U.S. Department of Agriculture and U.S. Department of Health and Human Services Dietary Guidelines for Americans, 2020­2025: 9thEdition. December 2020. https://www.dietaryguidelines.gov/

2 National Institutes of Health. Office of Dietary Supplements. Vitamin D. https://ods.od.nih.gov/factsheets/vitamind­healthprofessional/

3 Abrams SA, Griffin IJ, Hawthorne KM et al. (2005) A combination of prebiotic short­ and long­chain inulin­type fructans enhances calcium absorption and bone mineralization in young adoles­

cents. Am J Clin Nutr 82(2): 471–476. https://academic.oup.com/ ajcn/article­pdf/82/2/471/23960080/znu00805000471.pdf

4 Holloway L, Moynihan S, Abrams SA et al. (2007) Effects of oligofructose­enriched inulin on intestinal absorption of calcium and magnesium and bone turnover markers in postmenopausal women. Br J Nutr 97(2): 365–372. http://www.ncbi.nlm.nih.gov/ pubmed/17298707

5 Holscher HD (2020) Diet Affects the Gastrointestinal Microbiota and Health. J Acad.Nutr Diet. 120(4): 495–499. https://pubmed.ncbi. nlm.nih.gov/32199522/

6 Lordan C, Thapa D, Ross RP et al. (2020) Potential for enriching next­generation health­promoting gut bacteria through prebiotics and other dietary components. Gut Microbes 11(1): 1–20. https:// www.tandfonline.com/doi/full/10.1080/19490976.2019.1613124

7 International Scientific Association for Probiotics and Prebiotics. https://isappscience.org/

8 Holscher HD (2017) Dietary fiber and prebiotics and the gastrointestinal microbiota. Gut Microbes 8(2): 172–184. https://www.tandfon line.com/doi/full/10.1080/19490976.2017.1290756

9 International Scientific Association for Probiotics and Prebiotics. https://isappscience.org/

10 Slavin J (2013) Fiber and prebiotics: mechanisms and health benefits. Nutrients 5(4): 1417–1435. https://www.ncbi.nlm.nih.gov/pmc/ articles/PMC3705355/pdf. Accessed 20 Nov 2017

11 https://dietaryfiber.org/

12 Health and Fitness Journal PH. Inulin and Oligofructose Among the First Accepted Prebiotics by the Chinese Nutrition Society.

13 U.S. Department of Agriculture and U.S. Department of Health and Human Services Dietary Guidelines for Americans, 2020­2025: 9th Edition. December 2020. https://www.dietaryguidelines.gov/

14 WHO (2003) Prevention and management of osteoporosis: Report of a WHO Scientific Group. WHO Technical Report Series 921. https://apps.who.int/iris/handle/10665/42841

15 Scholz-Ahrens KE, Acil Y, Schrezenmeir J (2002) Effect of oligofructose or dietary calcium on repeated calcium and phosphorus bal ances, bone mineralization and trabecular structure in ovariectomized rats. Br J Nutr 88(4): 365–377. https:// www.ncbi.nlm.nih.gov/pubmed/12323086

16 Raschka L, Daniel H (2005) Mechanisms underlying the effects of inulin­type fructans on calcium absorption in the large intestine of rats. Bone 37(5): 728–735. https://www.ncbi.nlm.nih.gov/ pubmed/16126464

17 Cashman KD (2006) A prebiotic substance persistently enhances intestinal calcium absorption and increases bone mineralization in young adolescents. Nutr Rev 64(4): 189–196. https://www.ncbi. nlm.nih.gov/pubmed/16673754

18 Roberfroid MB, Cumps J, Devogelaer JP (2002) Dietary chicory inulin increases whole­body bone mineral density in growing male rats. J Nutr 132(12): 3599–3602. https://www.ncbi.nlm.nih.gov/ pubmed/12468594

19 Abrams SA, Griffin IJ, Hawthorne KM et al. (2005) A combination of prebiotic short­ and long­chain inulin­type fructans enhances 20 Holloway L, Moynihan S, Abrams SA et al. (2007) Effects of oligofructose­enriched inulin on intestinal absorption of calcium and magne sium and bone turnover markers in postmenopausal women. Br J Nutr 97(2): 365–372. http://www.ncbi.nlm.nih.gov/ pubmed/17298707

The company Beneo produces natural prebiotics from chicory and other plant functional ingredients (proteins, starch and flour from rice and beans, isomalt, isomaltulose) for the food and pharmaceutical industry. These ingredients help to improve the nutritional and technical properties of a wide range of products, while retain and/or improve flavor and texture. State-ofthe­art production facilities around the world ensure high­quality products, and thanks to its expertise, Beneo offers customers a foundation for new ideas and new product launches.

Distributor: Alimentum Natura Ltd. Gračanska cesta 91, Zagreb, Croatia

T. +385 1 38 73 021 GSM. +385 98 224 393

Osteoporosis and vitamin K2

Without vitamin K2, calcium and vitamin D3 cannot be optimally and safely used for bone health, and daily supplementation of vitamin K2 is a proven way to solve this deficiency.

Our bones play many roles in our bodies –providing structure, protecting organs, anchoring muscles and storing calcium. It is important to build strong and healthy bones during childhood and adolescence which is the most intensive bone – building period. You can also take steps during adulthood to improve and protect your bone health.

What are healthy bones?

Healthy bones are bones that are dense and strong. Your bones are a living part of your body and despite their strength, they are flexible. They can heal themselves when broken, and are constantly being renewed by your body. Your bone health is important as your bones support your body, help you move around and protect sensitive organs like your heart and lungs.

What are the symptoms of poor bone health?

Signs of poor bone health include stooped posture and loss of height, and a common symptom is unexplained back pain or general pain in bones and joints.

Broken bones caused by a minor fall or small injury are also a sign of poor bone health.

If your bones are extremely weak, you may experience damaged or fractured bones caused by everyday movement and pressure on your bones.

What affects bone health?

A number of factors can affect bone health. For example:

• the amount of calcium in your diet

• physical activity

• tobacco and alcohol use

• sex - you're at greater risk of osteoporosis if you're a woman, because women have less bone tissue than do men.

body constitution - you're at risk if you are extremely thin (with a body mass index of 19 or less) or have a small body frame because you might have less bone mass to draw from as you age.

• age

• race family history

• hormone levels

• eating disorders and other conditions

• certain medications.

What is osteoporosis?

Osteoporosis is defined as a metabolic illness of bones, which characterizes with low bone mass and decrease of the bone mass and thickness.

It is a condition where bones become thin and lose their strength, as they become less dense and their quality is reduced. This can lead to broken bones, which cause pain, disability, and make everyday activities extremely difficult. Around the world, one in three women and one in five men over the age of fifty will suffer a broken bone due to osteoporosis. Everyone is at risk for developing osteoporosis and having fractures as a result. Although the main factors for increasing the risk are age and sex. However, women over the age of 50 or postmenopausal women have the highest risk of developing osteoporosis.

Age and osteoporosis affect men also. You might be surprised to know that men over the age of 50 are more likely to have an osteoporosis-induced bone break than to get prostate cancer. About 80,000 men per year worldwide are expected to break a hip, and that number is constantly increasing.

Some common symptoms of osteoporosis are:

• loss of height

• change in posture (stooping or bending forward)

• shortness of breath (smaller lung capacity due to smaller disks)

bone fractures

pain in the lower back.

AUTHOR: Zagorka Blaževska, M.pharm., MBA, Vitanova

Calcium, magnesium, vitamins K2 and D3

Calcium is the building-block of strong bones. Vitamin D3 is an essential helper to calcium because it transports calcium through the intestine wall and into the bloodstream where it can be put to work. Vitamin K2 activates osteo­calcin proteins which incorporate calcium into the bone matrix. Without K2, calcium and D3 are unable to optimally and safely support bone health.

Daily supplementation of vitamin K2 is a proven way to address deficiency. A study with healthy volunteers demonstrated that prior to K2 supplementation levels of inactive osteocalcin (uOC) were high, whereas following supplementation uOC levels were lower and most osteocalcin was activated. Studies indicate that a daily dosage of 90 μg to 120 μg of vitamin K2 is required to achieve adequate osteocalcin activation.

Vitamin K2 regulates bone remodeling

An important review article published in 2017 (V.D. Myneni and E. Messy) summarizes how vitamin K2 regulates bone remodeling, a continuous process that helps maintain bone structure, bone mass, and calcium homeostasis. The skeleton is a living organ comprised of two types of tissues that consist of blood vessels and living cells that need amino acids, fatty acids, carbohydrates, minerals and vitamins to function properly. The cortical bone is the hard, outer layer which provides body support and protection of the organs. The porous and metabolically active inner layer, the trabecular bone, is where minerals are stored. Osteoblasts, osteocytes, and osteoclasts cells are responsible for bone remodeling. Main Evaluation: old and micro­damaged bone are continuously replaced through the bone remodeling cycle, which consists of five distinct and overlapping phases.

Results: vitamin K2 regulates the bone remodeling cycle at several levels:

1. Osteoclasts - vitamin K2 inhibits osteoclast differentiation.

2. Osteoblasts ­ vitamin K2 stimulates osteoblast development and protects them from cell death leading to increased osteoblast , lining cells and osteocytes.

3. Osteocalcin ­ vitamin K2 activates or carboxylates osteocalcin that allows binding the calcium and hydroxyapatite crystals.

Darmell Expert in the nutritional supplements field

KAPPA BIOSCIENCE is a pioneer in the development of biologically active vitamin K2 MK­7 under the name K2VITAL. The innovation of the synthesis of MK­7, combined with other KAPPA innovations, like the patented process of microencapsulation K2VITAL DELTA which ensures the stability of K2 in mineral formulations, are the confirmation of the innovation and quality of the K2VITAL brand.

Official representative: Vita Nova www.vitanova.com.mk/ www.linkedin.com/company/2966991/

Aholistic approach to health has always been our first choice when it comes to ways to support it. Nutritional supplements are an extremely important factor that can contribute to maintaining optimal health and are a good ally in the fight against various health disorders.

That is why professional path of Darmell is focused on developing new nutritional supplements and informing interested industry workers about ingredients, evidence of effectiveness, news, regulation and other relevant information in the field.

By combining many years of business experience, continuous acquisition of knowledge and cultivating business acquaintances, we are able to provide a variety of services.

Services we offer:

• Consulting in the elaboration of ideas and concepts for the development of new products - from the selection of ingredients to the launch of the finished product, with the help of finding the appropriate manufacturer of medicinal forms.

Consulting related to the registration of dietary supplements.

• Writing content for various purposes, in the field of dietary supplements and functional foods, related to individual ingredients and finished products.

• Help in finding a suitable distributor for finished products.

We also actively deal with:

Representing renowned companies producing branded ingredients/raw materials for nutritional supplements.

• Publishing professional publications in the field of nutritional supplements, functional food and cosmetics.

Darmell d.o.o.

20+ years of experience in developing new concepts for food supplements

Mob: + 385 91 68 12 444 darmell@protonmail.com www.linkedin.com/company/darmell/ www.dar­mell.com

Fine Foods and continuous innovation: competitive advantage and shared value

Trusting partner, which, in cooperation with customers, analyzes the needs and identifies the best solutions to their extent, solution that will provide them with a competitive advantage.

Fine Foods & Pharmaceuticals N.T.M. S.p.A. ­ an Italian independent Contract Development & Manufacturing Organisation (CDMO) that develops and manufactures contract products for the pharmaceutical, nutraceutical, cosmetics, biocides and medical devices industries, has been pursuing goals of excellence since its foundation.

With €193 million revenue in 2021 and more than 260 customers, Fine Foods ­ listed on Euronext STAR Milan of Borsa Italiana (Ticker: FF) - is a growing company geared to meet future challenges.

Fine Foods sees innovation as the driving force behind its growth, and a distinctive feature among CDMO market players. It has established a crossfunctional team that meets periodically to address integrated product development. A relentless search for customer satisfaction drives the company's focus on continuous innovation, research and development, quality and sustainability.

Continuous Improvement projects involve every department and are an essential part of Fine Foods' competitive strategy and a shared value. This imple­

mentation involves assigning each initiative to a contact person, project sponsor, project leader and steering committee that meets regularly to monitor progress. Project focus meetings are organised for the benefit of all employees.

This is flexible and proactive organisation that transversally involves every company division with defined and shared roles and responsibilities. It supports a dynamic approach to innovation, and creates a fertile environment to develop the problem solving and Lean Thinking skills of those involved. This fosters the acquisition of new specific and soft skills.

The in­house R&D division studies and formulates new nutraceutical and cosmetic products. The catalogue with more than 100 ready-to-market nutraceutical formulas in 17 health categories enables customers to grasp market trends quickly. In addition, the division assesses the feasibility of transferring the production processes of already existing pharmaceutical, nutraceutical and cosmetic products (technology transfer) to its plants.

With trained and experienced staff, selected raw

materials and up­to­date technology, the R&D division develops result­oriented innovation. Fine Foods is a trusted partner, working alongside customers by analysing needs, based on market trends, identifying the best tailor­made solution which provides a competitive advantage.

The R&D team works closely with customers in finalising the most ambitious projects with ready­tomarket products or by devising out-of-the box solutions presented at meetings where the latest innovations are introduced to customers.

The process for nutraceuticals and cosmetics consists of five key steps:

• research into formulation ideas: a synergistic partnership with the best raw material suppliers and constant market data analysis allow to gather insights and ideas on trends and offer the best formulations supported by scientific evidence;

• feasibility check: using small­scale plants representative of the leading production technologies present in the various plants, Fine Foods can carry out technological feasibility studies and finely-tuned sensory testing.

• product development: working with Quality Control, new products are fine-tuned, enhancing the key aspects of market interest and making the products usable for the consumer, with a focus on sustainability;

• stability studies: the small­scale plants allow the production of samples that are more representa­

tive of industrial production than small laboratory samples. This allows stability studies to be carried out that represent future products to be placed on the market;

• pilot-scale batch production: before proceeding with industrial production, pilot­scale batches are carefully monitored by the industrialisation technicians. This makes it possible to spot any issues not highlighted in small­scale R&D tests.

Fine Foods allocates approximately 120 people (16 percent) of its workforce to scientific, technical, research and development, quality and control activities.

Through synergies and affiliations with Italian (Federsalus, Union Food) and European (FSE) trade associations, Fine Foods supports customers in the regulatory framework, updating them on new developments.

Via Berlino, 39 24040

T. +39 035 482 13 82 www.finefoods.it info@finefoods.it

Fine Foods & Pharmaceuticals N.T.M. S.p.A

Zingonia/Verdellino Bergamo, Italy

Probiotics in Europe: consumer survey in 8 EU countries

The European branch of the International Association for Probiotics (IPA Europe) conducted a survey on a sample of 8,000 consumers. The aim of the research was to obtain information on how familiar consumers are with currently available probiotic products, how much use these products are in individual markets, and what are consumers' wishes in relation to additional information about this type of product.

To monitor the evolution of European consumers' opinions, trends and behaviours regarding probiotic foods and supplements, the International Probiotics Association - Europe1 commissioned the market research company 3Gem to carry out a survey with a representative sample. The online survey was carried out in 8 European countries (Italy, Denmark, the Netherlands, Spain, Poland, Belgium, Germany and Sweden) on a total of 8000 consumers2 to assess people's understanding of the probiotic offer currently on the market, and their use of probiotic foods and supplements in daily life.

The evolution of European consumers’ opinions, trends and behaviours regarding probiotic foods and supplements shows a strong interest in overall health and well­being. It also highlights the fact that consumers would like to be more informed on the labelling and in communications about probiotic food and

food supplements, and about probiotic microorganisms in food and food supplements.

The overall results indicate that probiotics are popular, even people who do not use or buy probiotics know the term.

It appears that for the majority of consumers the answer to “Do you know what probiotics and probiotic foods are?” is “yes” (63%). Women and men seem to consume probiotics almost equally. On average the peak consumption is in the 25-44 age group. There is quite a substantial set of people who know the word ‘probiotic’, even though they say that they do not consume them. This is probably due to the large amount of information available on probiotics in online search engines on the web, mainly from commercial sources and news outlets. However, these sites often fail

to paint a complete picture, so consumers may miss relevant information.

Consumers do not feel well informed about a product containing probiotics.

The survey results show that consumers across Europe are familiar with the word ‘probiotic’, but that they would like to know more.

In fact, the most relevant information is that in 7 out of 8 countries, consumers feel they are not informed about probiotics contained in products they find in shops. Poland is the only market with a bigger group of people feeling they are well informed (55% vs 45%), but even here, 45% of consumers would like to know more.

ucate consumers about the beneficial role that probiotics can play in diet and well­being.

Other terms such as ‘live bacteria’ or ‘live cultures’ are more known than the term ‘probiotic’. This is probably due to the fact that the term ‘probiotic’ was not allowed in Europe since 20073

The traditional use of the term is also a factor that may influence the knowledge of probiotic-related terms in some countries. This is the case for Italy for example, where a very large part of Italian consumers are familiar with ‘live cultures’ (89%) associated with probiotic products.

When food and supplements with probiotics microorganisms are available in shops, 79% of all tested consumers indicate that they would like to see the term ‘probiotic’ on the packaging: e.g. the ingredients list or somewhere else on the packaging of food and food supplements, with Italy and Spain being the countries where the interviewed people feel the strongest about the indication on the labels (90%).

There is an opportunity to inform and further ed­

The result was that consumers are more informed about probiotics in countries that have allowed the use of the term for a longer period of time. Consumers mainly refer to probiotics mentioning their beneficial effect on bacterial flora, the stomach and digestion. Consumers who know what probiotic foods and food supplements are, and who also consume them, mention that their main driver is their overall health and well­being. Very often the guidance for using probiotics comes from healthcare professionals, which also explains why so many people are familiar with this category. However, they find no cor

respondence when looking at product labels on the market.

Spain

Results for Spain show that almost half of the population panel consumes probiotics food and/or food supplements (44%), but even people that do not consume them know the word. In fact, two third of the population (67%) know what probiotics food and food supplements are. Concerning the use of other terms, 72% of people are familiar with ‘live bacteria’, whereas ‘live cultures’ is known by 59%. The markets that would like to see more information on the packaging are Spain and Italy (90%). In Spain, like in Italy, there are national guidelines indicating that the use of the term on labels and in communication is allowed, under certain conditions, for domestic and imported foods and food supplements containing probiotics

Probiotics are part of lactic bacteria or live bacteria, but not all live bacteria are probiotics.

Finally, the survey participants were asked what they think probiotics are useful for, and specifically “for what reasons do they consume probiotics”, if they had previously indicated that they consume them.

▷ Do you know what probiotics food and food supplements are? (n = 1.000 by country)

I know about probiotics

Nutramedic &Cosmetics

Poland

Almost two third of the population panel in Poland consume probiotics food and/or food supplements (59%). Out of the 8 countries, the Polish people are the most aware of what probiotics are. In fact, most of the interviewees (78%) indicated that they know about probiotics food and food supplements. As previously mentioned, Poland is also the only market with a majority of consumers feeling informed that a product contains probiotics (55% vs 45%). Even here, there is still a high proportion of consumers (45%) that would like to have more information. Concerning the use of other probioticrelated terms, almost 9 out of 10 people are familiar with ‘live bacteria’ (87%), whereas ‘live cultures ‘ is known by only 58%. When asked if they would like to see the word probiotic on the packaging, 79% of the Polish panel answered ‘yes’.

Italy

Italy, together with the Spanish and Polish consumers, show a high percentage of probiotic consumption (41%). This percentage increased to 62% when the panel was asked if they knew what probiotics food and/ or food supplements are. A very large portion of the Italian population is also familiar with ‘live cultures’ (89%). This is also due to the traditional use of this term associated with the probiotic category of products and ingredients. The ‘term live bacteria’ is less used, only 55% of the consumer panel knows it As mentioned in the focus on Spain, Italy is also in favour (90%) of having more information on probiotics on the packaging and in communication. Since 2013 Italy enforced national guidance on the use of the term probiotic.

Denmark

Denmark stands out as only one-third of the Danish population knows what probiotics food and food supplements are, and 19% of the panel of consumers use probiotics food and/or food supplements. Denmark also has the lowest percentage of the population that feels informed about probiotics in products (31%). People in Denmark are mo-

re familiar with the terms ‘live bacteria’ (68%) and ‘live cultures’ (59%). This is also due to the national definition used in this country. Concerning the appearance of the term probiotics on the packaging, 56% declared they would like to know more. This is a significant percentage if we consider the fact that until 2021 the term probiotic was banned, and Denmark was following the interpretation of the European Commission indicating that ‘probiotic’ could be used as a health claim only. Since 2021, Denmark recognises the use of the term referring to a category of ingredients in food supplements, and the authorities are in favour of a better European approach, a legal certainty and a harmonised way forward at the EU level.

Sweden

Half of the population of Sweden knows what probiotics food and food supplements are, but 76% of the Swedish panel are in favour of the information about the presence of probiotics on the packaging. Approximately one-quarter of the Swedish population consumes probiotics food and/or food supplements (27%).

Concerning the familiarity with terms, 3 out of 4 people are familiar with both ‘live bacteria’ (77%) and ‘live cultures’ (76%). Sweden joined Denmark in June 2022 and the group of countries asking for a better approach for probiotics food and food supplements in the EU.

Germany

Probiotics are popular in Germany, despite the fact that this country was following the interpretation of the European Commission of the use of the term probiotic as a health claim only. In Germany, more than 60% of the German panel indicates that they know what probiotics food and food supplements are, and 38% answered that they consume probiotics food and/or food supplements. Consumers are also familiar with the terms ‘live bacteria (66%) and ‘live cultures’ (74%). When asked if they would like to have the indication of probiotics on the packaging, 82% of the population panel responded favourably.

▷ Do you consume probiotics food and/or food supplements?

(n = 4.491 subset of total population, only those who know what probiotics are, but don't consume probiotics)

I know but do not consume them

The Netherlands

Half of the population panel declares that they know what probiotics food and food supplements are. About 27% of the Dutch population consumes probiotics food and/or food supplements. In the Netherlands, other terms are also well known: 76% are familiar with ‘live bacteria’, whereas ‘live cultures’ is only known by 59%. When asked if they would like to have the term ‘probiotic’ listed on the packaging, 76% of the panel consumers responded favourably. The Netherlands has a pragmatic approach, the term ‘probiotic’ is used as the name of the category on the label of probiotic food and food supplements.

Belgium

Half of the population panel declares that they know what probiotics food and food supplements are, and 29% of the Belgian panel stated that they consume probiotics food and/or food supplements. The low results are probably due to the strict approach of the authorities regarding the use of the term, which is currently allowed only for probiotic yoghurt. Belgian people are familiar with ‘live bacteria’ (76%), whereas ‘live cultures’ is less common (52%).

A high percentage of consumers (83%) declared that they would be in favour of the appearance of the term ‘probiotic’ on the packaging.

Conclusion

The panel (8.000 consumers in 8 European countries) would like to be more informed about probiotics food. Also, consumers declare that they are better informed in countries where the term ‘probiotics’ is (partially) allowed by National guidance/standard: this is the case, for example, in Italy, Spain, and Poland. Very often, the guidance for using probiotics comes from health professionals, which also explains why so many people are aware of this category but find no match when looking at product labels. The regulatory situation is influencing the European market. It is evident that the need for a coherent EU regulatory approach for probiotics goes hand in hand with the opportunity to further educate consumers on the correct use of these micro­organisms. The high level of uncertainty for most probiotic health claims found online hinders the rational use of probiotics, leaving the field open to unsubstantiated allegations and misuse.

1 IPA Europe is the European chapter of IPA, the International Probiotics Association; it was established in Brussels in 2015. The members of IPA Europe are Companies directly engaged in Europe in the manufacture of probiotic cultures or probiotic foods, supplements, and nutritional or therapeutic products. The IPA Europe mission is to gain acceptance of the term “probiotic” throughout Europe as a defined category and to create a favourable environment for probiotics in Europe.

2 3Gem conducted this online survey in 8 European countries on a total of 8000 consumers. Per country: n= 1000 respondents/18+ years old/nat.rep. by age, gender, and region. In Italy, Denmark, the Netherlands and Spain the term ‘probiotic’ is (partially) allowed by National guidance/standards; Poland, Germany, Belgium and Sweden do not have national standards and follow the interpretation of the European Commission indicating the term probiotic as an example of health claim only.

3 European Commission’s guidance of 2007 on the implementation of regulation 1924/2006 https://www.fsai.ie/uploadedFiles/ EU_guidance_ClaimsRegulation.pdf

IPA expands its scope of work

The International Probiotics Association (IPA) announces a major expansion of its scope to include the “biotics” categories of prebiotics, postbiotics, and synbiotics within the human, infant, and companion animal segments of food and dietary supplements.

The IPA Board of Directors voted to expand the association’s scope to complement its historical focus on probiotics. The expansion is part of the organization’s strategy to help the ’biotics’ industry grow in response to market demands and strengthen its ownership within the ‘biotics’ categories.

The move will not impede IPA’s focused efforts regarding the probiotics category but, rather, it will only strengthen the organization’s efforts. “We are better together” said Amy Smith, the newly appointed IPA President.

IPA will work on building the required frameworks and organizational structure to ensure a successful future for the probiotics, prebiotics, postbiotics and synbiotics industry.

“It is a natural progression for the evolution of IPA, and we are delighted to announce this expansion in strategic focus”, said George Paraskevakos, Executive Director, IPA. “We will continue our solid path of driving and advancing the probiotic category as we replicate our past achievements in these additional ‘biotic’ categories”.

The International Probiotics Association is a global non-profit organization that brings together, through its membership, participants in the probiotic sector including academia, scientists, healthcare professionals, consumers, industry and legislators. The mission of the International Probiotics Association is to promote the safe and effective use of probiotics worldwide. Having pre­Codex Alimentarius non­governmental organization status and ISO observer status, IPA is also recognized as the unique "global voice of probiotics" worldwide.

www.internationalprobiotics.org

Bacopa (Bacopa monnieri) and its effect on cognitive functions

Bacopa has been at the center of research because of its effect on cognitive functions such as memory, focus and concentration. Numerous researches in the last thirty years have enabled a better understanding of the effects of this plant and the popularization of its application in the cognitive health segment.

AUTHOR:

Ana Gjergja Sekulić, M.pharm., univ.mag. phytotherapy and dietotherapy

Bacopa monnieri (Scrophulariaceae) is a small creeping plant that grows naturally in India and tropical areas. (Figure 1) It likes moist and wet soil, shallow water and swamps, and is easy to grow if it has a sufficient amount of water available.

It is traditionally used in Ayurvedic medicine for the treatment of various disorders of the nervous system such as epilepsy and anxiety, and as a learning support for the development of memory and concentration. It is also used for digestive problems, skin diseases, and as an antipyretic and analgesic.1,2 Bacopa has been at the center of research precisely because of its effect on cognitive functions such as memory, focus and concentration. Numerous researches in the last thirty years have enabled a better understanding of the effects of this plant and the popularization of its application in the cognitive health segment.

The pharmacological action of bacopa is attributed to alkaloids, saponins and sterols. The main saponins are identified as bacoside A and bacoside B, alkaloids brahmin and herpestin, and sterols stigmasterol and beta­sitosterol.

Numerous other ingredients

have also been identified, including betulinic acid and numerous bacosaponins. 3­7

As already mentioned, the focus of research is the effect of bacopa on brain functions. Some of the more interesting ones are highlighted below. (Table 1)

Anxiolytic and antidepressant effect

Research conducted on rats showed that bacopa extract containing 25% bacoside A showed anxiolytic activity comparable to lorazepam. An additional positive effect is manifested in the fact that the bacopa extract did not cause amnesia like lorazepam, but, on the contrary, showed an effect on improving memory.8

The antidepressant potential of bacopa extract tested in an animal study showed that a dose range of 20-40 mg/kg once a day for 5 days has an effect comparable to the standard antidepressant drug imipramine.

The same study suggested that the antidepressant and anxiolytic effects are mediated by the action on the mechanism of serotonin and gammaaminobutyric acid.9

Although animal studies have shown promising results, clinical studies of the anxiolytic and antidepressant effects of bacopa on humans are currently still scarce. A review by Brimson et al. from 2021, described four randomized, placebo­controlled, double­blind studies that used bacopa as monotherapy and two studies that used a multi­herb intervention, and analyzed levels of depression or anxiety. It is important to note that not all patients were diagnosed with clinical depression. The authors emphasize that it is very difficult to draw any general conclusion, given that the studies used different assessment and analysis methods, and some showed statistically significant results, while some did not. What is interesting to point out is the study that showed that the use of bacopa for a period of 12 weeks can reduce geriatric depression in Alzheimer's patients to the level of healthy people.10 The potential for use in the field of anxiety and depression certainly exists, but further research will certainly give more precise data on the profile of patients who could benefit from bacopa therapy.

Memory improvement

Various animal studies have shown that bacopa improves motor learning and the acquisition and retention of newly learned behavior.11 It also has a beneficial effect on improved memory acquisition and retention in pre­existing benzodiazepine and phenytoin therapy, where it reverses drug­induced amnesia and cognitive impairment.12,13

A clinical trial on people older than 55 years was conducted with a 12-week application of bacopa at a dose of 300 mg/day. It has been recorded that bacopa significantly improves the acquisition and retention of memory in the elderly.14 The test was also conducted on younger people, and the results showed that the application of 300 mg of bacopa extract containing 55% of combined bacosides for a period of 12 weeks significantly improves verbal learning, memory, consolidation and speed of early information processing. These effects were not recorded at the beginning, nor after five weeks of application of the preparation.15

A randomized, double­blind, placebo­controlled study including sixty older adults examined the effects of bacopa on attention, cognitive processing, working memory, and cholinergic and monoaminergic functions. The group treated with bacopa showed improved working memory, attention and cognitive processing. The study was conducted for 12 weeks, and the first changes were noticed after 4 weeks of application.16

Another study, randomized, double­blind and placebo­controlled, included 60 medical students. Bacopa extract (Bacognize), administered 2 x 150 mg twice a day, for 6 weeks, has been shown to significantly improve cognitive abilities and performance in various neuropsychological tests (logical memory test, digit span, memory task, etc.). That study showed that bacopa helps with better focus and concentration.17

One study was also conducted on children aged 6 to 14 years. The study was randomized, double­blind, placebo-controlled, and examined the effectiveness of bacopa on cognitive performance. Bacopa is do­

TABLE 1 Summary of various clinical studies

sed 1 x 160 mg for body weight 20-35 kg, and 2 x 160 mg for body weight over 35 kg. The study was conducted for 16 weeks and showed a significant beneficial effect on symptoms of hyperactivity or attention deficit hyperactivity disorder (ADHD) and on cognitive improvement.18 (Table 2)

Effect in Parkinson's disease

The effect of bacopa extract was tested on different animal models. An alcoholic extract in which the main active ingredients were bacosides was investigated on the nematode model Caenorhabditis elegans. Application of the extract has been shown to reduce the aggregation of α-synuclein, a key protein that leads to the degeneration of nerve cells. This prevents dopaminergic neurodegeneration and enables the restoration of nematode lipids.19

A study on mice showed that bacopa extract offers a dopaminergic neuroprotective effect by modulating oxidative stress and apoptotic mechanisms.20 Another study was conducted by treating mice suffering from Parkinson's disease with bacopa extract or mucuna extract. The one­month treatment significantly reduced the elevated levels of oxidati-

TABLE 2 Summary of clinical studies of Bacopa extract on cognitive functions Participants/study

Healthy children, 6­8 years old from rural India. Double­blind randomized placebo controlled study.

Healthy adults (average age 73.5 years). A double­blind randomized placebo­controlled clinical trial conducted at the University of Catania, Italy. Trial with the introduction of a placebo for 6 weeks.

Children in need of individual educational support, 10.5 years at the Center for Research on Mental Retardation (CREMERE), Mumbai, India. The research was conducted on an outpatient basis, a procedure in hospital conditions, with close monitoring.

Seventeen healthy volunteers (13 women and 4 men) with an average age of 25.23±5.97. A double­blind placebo­controlled crossover study conducted in Melbourne, Australia.

One teaspoonful of Bacopa syrup 3 times daily for 3 months. Each teaspoonful was equivalent to 350 mg of crude Brahmi.

Bacopa extract, 300 mg daily, for 12 weeks.

ve stress. In behavioral tests, a comparative analysis of bacopa extract and mucuna extract showed a significant increase in spontaneous locomotor activity and the grip strength test. It was found that the use of bacopa extract significantly improved the activity of tyrosine hydroxylase, caspase­3 and the expression of a neurogenic gene in the brain area ­ substantia nigra. 21 All these results are certainly in favor of bacopa as a potentially beneficial plant for treating and alleviating the symptoms of Parkinson's disease.

Effect in Alzheimer's disease

The effect of bacopa extract in patients with Alzheimer's disease was tested using different models. An in silico study examined the effects of two bacopa saponins, bacosaponin G and bacosaponin N2, in comparison to donepezil, a drug commonly used in the treatment of Alzheimer's disease. The study showed that bacosaponins have a more favorable binding affinity for therapeutic targets in Alzheimer's disease, specifically for caspase-3 and tau protein kinase I receptors. 22 The results of that research point to the excellent potential of bacopa.

Strengthened exploratory drive (as measured by maze learning), improved perceptual images of patterns, and increased perceptual organization and reasoning ability (as measured by reaction time).

Improved delayed memory AVLT scores word recall compared to placebo, significantly improvement in Stroop test results (P<0.05) and decreased CESD­10 depression score during time as well as anxiety scores.

Bacopa extract, 225 mg daily, for 16 weeks.

Significant change in the baseline value of working memory and short­term verbal memory from 5.21 ± 0.32 to 6.38 ± 0.25 (P ≤ .05) and 5.33 ± 0.44 to 6.54 ± 0.35 (P ≤ .05). Significant improvement (P ≤ .05) was also seen in logical memory, memory related to personal life and also in visual as well as auditory memory.

Thirty elderly subjects with an average age of 66±3 years. Double­blind crossover placebo­controlled group study, conducted in Bologna, Italy.

Bacopa extract, 320 mg or 640 mg daily, 1 hour and 2 hour after application.

Positive cognitive effects confirmed in the first and second hours after application. The effects were confirmed by the results of the Stroop test and the letter search test. Some nootropic and adaptogenic effects have been observed. The positive effects of the modification and the reduction of cortisol levels (a physiological response to stress) were associated by the participants with the consumption of bacopa.

Combined nutraceuticals containing Bacopa dry extract (320 mg), L-theanine (100 mg), Crocus sativus (30 mg), copper (2 mg), folate (400 µg), B complex (450 µg-9 mg) and vitamin D (25 µg).

After 2 months of therapy, the results of the mental state mini­test and stress perception questionnaire significantly improved compared to the initial results examinations.

in

Taken from: AbdulManapAS,VijayabalanS,MadhavanP,ChiaYY,AryaA,WongEH,RizwanF,BindalU,KoshyS.Bacopamonnieri,aNeuroprotectiveLead

AlzheimerDisease:A ReviewonItsProperties,MechanismsofAction,andPreclinicalandClinicalStudies.DrugTargetInsights.2019Jul31;13:1177392819866412.doi:10.1177/1177392819866412.PMID: 31391778; PMCID: PMC6669844.

A study was also conducted that compared the effects of herbal therapy (a combination of Bacopamonnieri, Hippophae rhamnoides and Dioscorea bulbifera) in patients suffering from Alzheimer's disease compared to donepezil therapy. Two groups of subjects were included in the study, which lasted 12 months: a group of patients (aged 60 to 75) and a group of healthy subjects. The study, comparing herbal therapy and placebo, observed a significant improvement in the results of neuropsychological tests such as the mini mental state test, digital symbol substitution, results of delayed word recall, attention span, frequently asked questions and depression scores in healthy patients.

In patients with Alzheimer's disease, improvement was comparable to that achieved with donepezil in the Mini Mental State Test, Dementia Screening Scale, Immediate Word Recall, Delayed Word Recall, Attention Span, Frequently Asked Questions, and Depression Score. 23

Another study on patients with Alzheimer's disease examined the effect of bacopa in a daily dose of 600 mg for 6 months. The study revealed a statistically significant increase in performance in various aspects of mental state tests, and concluded that B. monnieri is beneficial in patients with Alzheimer's disease. 24

Regulation and labeling

In Croatia, the plant species Bacopa monnieri is on the list of permitted plant species that can be used in formulating food supplements. When labeling the product, it is necessary to state that people who take medication should consult a doctor before taking a product containing bacopa, and that the use is not recommended for thyroid diseases, asthma, emphysema, disorders of the digestive and urinary systems, heart disorders, pregnant women, nursing mothers and to children.

In other countries of the European Union, such as Italy, France, Belgium and the Czech Republic, bacopa is also on the list of permitted plant species, but no special notes are required when labeling.

Conclusion

All available studies are certainly in favor of the use of bacopa in individuals with difficulties and illnesses, but also in healthy patients who are in states of mental effort. Of particular interest is the wide range of possible patient ages, from the pediatric to the geriatric population. Although bacopa is still a lesser-known plant species in our area, considering the specific effects it shows in the field of cognitive health and functioning, we can conclude that it will surely become recognized in professional circles and among patients.

References:

1 Bammidi SR, Volluri SS, Chippada SC, Avanigadda S and Vangalapati M. A review on pharmacological studies of Bacopa monniera. J Chem Bio PhySci 2011;1(2), Sec B: 250­259.

2 Mukherjee DG, Dey CD. Clinical trial on Brahmi. I. J Exper Med Sci 1966;10:5­11

3 Kapoor LD. CRC Handbook of Ayurvedic Medicinal Plants. Boca Raton, FL: CRC Press Inc;1990;61.

4 Chakravarty AK, Garai S, Masuda K, et al. Bacopa sides III-V: three new triterpenoid glyco sides from Bacopa monniera. Chem Pharm Bull (Tokyo) 2003;51:215-217.

5 Hou CC, Lin SJ, Cheng JT, Hsu FL. Bacopa side III, bacopa saponin G, and bacopa sides A, B, and C from Bacopa monniera. J Nat Prod 2002;65:1759­1763.

6 Mahato SB, Garai S, Chakravarty AK. Bacopa saponins E and F: two jujubogenin bisdesmosides from Bacopa monniera. Phytochemistry 2000;53:711­714.

7 Chakravarty AK, Sarkar T, Masuda K, et al. Bacopa side I and II: two pseudo jujubogenin glycosides from Bacopa monniera. Phytochemistry 2001;58:553­556

8 Bhattacharya SK, Ghosal S. Anxiolytic activity of a standardized extract of Bacopa monniera: An experimental study. Phytomedicine 1998;5(2):77­82

9 Shader RI, Greenblatt DJ. Pharmacotherapy of acute anxiety. In: Bloom FE, Kupfer DJ, editors. Psycopharmacology: Fourth Generation of Progress. New York: Raven Press; 1995. p. 1341-8.

10 Brimson JM, Brimson S, Prasanth MI, Thitilertdecha P, Malar DS,Tencomnao T. The effectiveness of Bacopa monnieri (Linn.) Wettst. as a nootropic, neuroprotective, or antidepressant supplement: analysis of the available clinical data. ScientificReports | (2021) 11:596. https://doi.org/10.1038/s41598­020­80045­2

11 Singh HK and Dharwan BN. Neuropsychopharmacological effects of the Ayurvedic nootropic Bacopa monniera Linn (Brahmi). Indian Journal of Pharmacology 1997; 29:S359­S365.

12 Saraf MK, Prabhakar S, Pandhi P and Anand A. Bacopa monniera ameliorates amnesic effects of diazepam qualifying behavioral molecula partitioning. Neuroscience 2008; 155(2): 476­484.

13 Vohora D, Pal SN and Pillai KK. Protection from phenytoin­induced cognitive deficit by Bacopa monniera, a reputed Indian nootropic plant. J Ethnopharmacol 2000;71:383­390

14 Morgan A, and Stevens J. Does Bacopa monnieri improve memory performance in older persons? Results of a randomized, placebo controlled, double­blind trial. The Journal of Alternative and Complementary Medicine 2010; 16(7):753–759

15 Stough C, Lloyd J, Clarke J, et al. The chronic effects of an extract of Bacopa monniera (Brahmi) on cognitive function in healthy human subjects. Psychopharmacology 2001;156:481­484

16 Peth­Nui T, Wattanathorn J, Muchimapura S, Tong­Un T, Piyavhatkul N, Rangseekajee P, et al. Effects of 12-week Bacopa monnieri consumption on attention, cognitive processing, working memory, and functions of both cholinergic and monoaminergic systems in healthy elderly volunteers. EvidBasedComplemAltern Med. (2012) 2012:606424. doi: 10.1155/2012/606424

17 Kumar N, Abichandani L, Thawani V, Gharpure K, Naidu M, Venkat Ramana G. Efficacy of standardized extract of Bacopa monnieri (Bacognize R ) on cognitive functions of medical students: a six-week, randomized placebo-controlled trial. EvidBasedComplemAltern Med. (2016)2016:4103423. doi: 10.1155/2016/4103423

18 Kean JD, Kaufman J, Lomas J, Goh A, White D, Simpson D, et al. A randomized controlled trial investigating the effect of a special extract of Bacopa monnieri (CDRI 08) on hyperactivity and in attention in male children and adolescents: BACHI study protocol (ANZCTRN12612000827831). Nutrients. (2015) 7:9931–45. doi: 10.3390/nu7125507

19 Jadiya P, Khan A, Sammi SR, Kaur S, Mir SS, Nazir A. Anti-Parkinsonian effects of Bacopa monnieri: insights from transgenic and pharmacological Caenorhabditis elegans models of Parkinson’s disease. BiochemBiophysResCommun. (2011) 413:605–10. doi: 10.1016/j.bbrc.2011.09.010

20 Singh B, Pandey S, Yadav SK, Verma R, Singh SP, Mahdi AA. Role of ethanolic extract of Bacopa monnieri against 1­methyl­4­phenyl­1, 2, 3, 6­tetrahydropyridine (MPTP) induced mice model via inhibition of apoptotic path ways of dopaminergic neurons. BrainResBull. (2017) 135:120­8. doi: 10.1016/j.brainresbull.2017.10.007

21 Singh B, Pandey S, Verma R, Ansari JA, Mahdi AA. Comparative evaluation of extract of Bacopa monnieri and Mucuna pruriens as neuroprotectant in MPTP model of Parkinson’s disease. Indian J ExpBiol. 2016 Nov;54(11):758­66. PMID: 30179419.

22 Roy S, Chakravarty S, Talukdar P, Talapatra SN. Identification of bioactive compounds present in Bacopa monnieri Linn. against caspase­3 and Tau Protein Kinase I to prevent alzheimer’s disease: an insilico study. Pharma Innov. J. (2019)8:855–61.

23 Sadhu, A. et al. Management of cognitive determinants in senile dementia of Alzheimer’s type: Therapeutic potential of a novel polyherbal drug product. Clin. Drug Investig. 34, 857–869. https:// doi.org/10.1007/s40261­014­0235­9 (2014).

24 Goswami, S. etal. Effect of Bacopa monnieri on cognitive functions in Alzheimer’s disease patients. Int. J. Collab. Res. Internal Med. Public Health 3, 285–293 (2011).

Inspirational success story: Adena Natura

We are introducing the Croatian company Adena Natura d.o.o. which produces and sells herbal food supplements to help with stress, restlessness, anxiety, insomnia, chronic fatigue, problems with concentration and memory...

We present an interview with Ana Gjergja Sekulić, M.pharm. and Adrijana Tomičić, B.Sc., founders of the company.

NMC: How did it all start?

We are both big lovers of nature and plants, so we have always loved helping our bodies with herbal preparations. We came up with and tried various combinations for personal needs, but also for the needs of our loved ones. In one period of our lives, we were both exposed to an extremely high level of stress, and it was with the help of plants that we mitigated its consequences. Given that the designed formulations gave excellent results, we decided to raise everything to a professional level and turn our experience and knowledge into a business in order to help as many people as possible to improve their health. We received financial support from the city of Zagreb for self­employment and started full of energy... However, just at the moment of launching the products on the market, we were caught by the corona crisis. Like for others, it wasn't easy for us, but we didn't gi-

ve up. We continue to strive, work and believe in our products.

NMC: What was the initial idea and what inspired you?

We know from our own experience how today's busy lifestyle can negatively affect health. People are often not aware of where stress can take them, nor that they can prevent it. And when they find themselves in that negative vortex, they don't know how to get out of it. Stress is an inevitable part of our lives, but the problem arises when it is frequent and intense and when we do not get enough rest and recovery from it.

Restlessness, anxiety, insomnia, chronic fatigue, problems with concentration and memory, workload and difficulty keeping up with obligations - these are common problems of modern society.

Aware of this, we designed four products that naturally bring the body back into balance and ease the discomfort we feel when we are exposed to shortterm or long­term stress. We designed them so that

they can be used individually, but also combined with each other for the best effect.

The product Calma offers instant calm, without the effect of falling asleep during the day; Sleepy allows you to fall asleep faster and easier; Cogny can provide support in a state of great mental effort when better concentration and memory are needed, it can alleviate the decline of cognitive functions as a result of illness or old age, and it can help with exposure to high long­term stress and with feelings of chronic mental and physical fatigue. The Adapto product can help restore the necessary strength and energy.

We are very happy and fulfilled by the fact that we can help people feel good and raise their quality of life, because this way coexistence will be better and of higher quality for everyone.

NMC: What did it take for the idea to come true?

Product development itself lasted a little over two years. Formulations, dosages, raw materials, manufacturing, testing, packaging, design, regulations... that's a lot of things that had to be thought about and harmonized. The process of starting production and introducing the product to the market was challenging, but everything is solvable. As exciting as it is, it is also stressful, but when you come up with preparations for stress, it is certainly easier to deal with it.

NMC: Are you satisfied with your achievements?

We encountered a lot of obstacles during the process and it took us longer to put the product on the market, however, plan and life are not always the same. We entered the entrepreneurial waters with enthusiasm and a desire to pass on our knowledge and help people feel good. The most important thing for us is that today our users are satisfied with the products and we are happy with every positive feedback we receive. We do what we love, and we do it for the benefit of people. We are building trust in the Adena Natura brand following carefully planned step, which is shown by the recommendations that people give to each other, and this gives us the motivation to continue and to develop new products for which there is a demand.

NMC: What are you most proud of?

We are proud of everything we have achieved from the very beginning until today, of perseverance despite all the challenges we are facing. And most of all, of our products, in which all our knowledge and experience are woven, behind which we stand proudly, because we know that they can help everyone, in whatever stressful life situation they find themselves. These are products that will allow them to get out of the negative vicious circle they entered, help them feel good and with which they can realize the full potential of their mental and physical health.

Adena Natura Ltd.

Huga Ehrlicha 3, Zagreb, Croatia

T. +385 91 8813 016

www.adenanatura.hr

info@adenanatura.hr

Nutramedic &Cosmetics

B2B events calendar

An overview of the B2B live events during 2023

7-11 March 2023, Anaheim, USA

https://www.expowest.com/

16-18 March 2023, Bologna, Italy

https://www.cosmoprof.com/en/

28-30 March 2023, Barcelona, Spain

https://www.in­cosmetics.com/global

31 March – 2 April 2023, Düsseldorf, Germany

https://www.beauty­duesseldorf.com

16-17 April 2023, London, Great Britain

https://www.naturalproducts.co.uk/

18-19 April 2023, New Jersey, USA

https://east.supplysideshow.com

18-20 April 2023, Warsaw, Poland

https://nutrafood.pl

6-7 May 2023, Hannover, Germany

https://www.cosmetica.eu/cosmetica­hannover/

9-11 May 2023, Geneva, Switzerland

https://www.vitafoods.eu.com/

7-10 September 2023, Bologna, Italy

https://www.sana.it

22-24 October 2023, Paris, France

https://natexpo.com

24-26 October 2023, Barcelona, Spain

https://www.cphi.com/europe/

28-30 November 2023, Frankfurt, Germany

https://www.figlobal.com

NADES solvents –a green revolution

Nowadays, plant extracts have drawn attention for their positive effects on human health. Plant extracts are rich in various biologically active compounds such as antioxidants, essential oils, aromas, vitamins, colors and pigments, organic acids, pectins and others, which possess antioxidant, antibacterial, antiviral, anti-inflammatory, antitumor and/ or antimutagenic and other positive activities1. Therefore, plant extracts have found wide use in the pharmaceutical industry, in the food and beverage industry, and in the cosmetic industry.

Consequently, the extraction and identification of biologically active compounds from different plants have become a very important area of scientific research. The market value of plant extracts in 2022 is estimated at 34.4 billion USD, and the market is still growing. The current technology on the market of plant extracts is not in accordance with innovations and ecological trends, and it is necessary to find a solvent that would dissolve both hydrophilic and lipo­

philic phytochemicals from plants, because biologically active compounds from plants are a chemically diverse group of compounds. Some of them are soluble in water as a solvent, while most dissolve in petroleum­based solvents. Petroleum­based solvents used in extract preparation are toxic, flammable, volatile and explosive, resulting in air pollution. These solvents cause 60% of all industrial emissions and 30% of emissions of volatile organic compounds. Although is the fact that in the 21st century according to the directive 2009/32/EC (Food) it is still allowed to consume 2.9 mg/kg of hexane or 6 mg/kg of dichloromethane per day, the goal of the green deal is to replace such solvents with ecological acceptable alternatives.

Natural deep eutectic solvents (NADES), which can extract both polar and non­polar biologically active compounds, showed great potential for application in extraction of biologicaly active compounds. NADES are mixtures obtained by the complexation between a hydrogen acceptor such as non­toxic qua­

Environmentally acceptable, natural low-temperature eutectic solvents (NAtural Deep Eutectic Solvents) have a low melting point, low volatility, non-flammability, low vapor pressure, chemical and thermal stability, their price is low and they are easy to prepare on an industrial scale. Therefore, they are good candidates for carrying out plant extraction in industry.

AUTHOR: Ph.D. Manuela Panić, Nades Design

ternary ammonium salt (e.g. cholinium chloride) and a naturally­derived uncharged hydrogen­bond donor (e.g. amines, sugars, alcohols and carboxylic acids) in a certain molar ratio, bonded with hydrogen bonds between NADES components2,3 (Figure 1).

Structurally, NADES consists of at least two inexpensive, non­toxic and easily available components which are able to self­associate at a certain molar ratio to form a new eutectic phase characterized by a melting point below 100°C. Beside their green character, one of the prominent characteristics of these solvents is the possibility of designing their structure, and thus changing their physical and chemical properties, which consequently affects the possibility and effectiveness of their application in the selective isolation of biologically active molecules. Since the number of possible chemical structures of these solvents is tremendeous, as many as 106 different solvents, there is the possibility of designing them for specific purposes4 .

NADES fully represent the green chemistry principles owning to their specific properties: (i) the cost of NADES is comparable or even lower than conventional solvent; (ii) sustainable production with 100% atom economy production, (iii) chemical and thermal stability, (iv) non-volatility and non-flammability, (v) low toxicity and biodegradability. Since NADES building components can be considered safe for human consumption NADES extracts could be used as ready­to­use in food and pharmaceutical industry without demanding and expensive downstream purification steps5,6.

Another positive aspect of the use of these solvents in extraction processes is related to the efficiency of NADES extraction compared to conventional solvents. The true benefit of each plant is delivering at least 100 times higher concentrations of biologically active molecules compared with conventional solvents used now in the industry. Comparing the activity of NADES­based extracts with the extracts on the market, NADES extracts possess superior activity. Furthermore, NADES solvents also affect the stability of biologically active compounds. Therefore, by applying the extracts prepared in this way, the added value of the final product is achieved, which can have an improved composition and better, longer stability. NADES extracts are characterized by antioxidant properties, increase product longevity and bioavailability7,8. Such extracts have shown good compatibility with skin cells, and their biological effectiveness such as hydration, anti-aging and UV protection has been proven9

A team of scientists from the Faculty of Food and Biotechnology decided to enter the market with NADES solvents and products based on them. Female scientists are trying to bridge the gap between academia and industry and bring sustainable green products to market. Their story with NADES solvents began in 2013 in the academic community, and since then they have been working and creating innovations in the field of green chemistry. They believe that now is the right time and that the industry is ready to implement green solvents in their products.

As entrepreneurs, they started a journey in SPOCK start up incubator. They received the first grant from the ACT group to start their business and develop the products. They are also the winners of Green Hackaton competition in 2022, which was organised in cooperation with the British Embassy and Algebra LAB at the Greencajt festival. They received support from EIT Food through the EWA program implemented by Lean Start Up Croatia, where they won first prize. Recently, they won 3rd place at the LAQOTHON competition for the best green idea.

References:

1 F. Chemat, M. A. Vian and G. Cravotto, Int. J. Mol. Sci., 2012, 13, 8615–8627.

2 M. Ruesgas­Ramon, M. C. Figueroa­Espinoza and E. Durand, J. Agric. Food Chem., 2017, 65, 3591–3601.

3 M. A. R. Martins, S. P. Pinho and J. A. P. Coutinho, J. Solution Chem., 2019, 48, 962–982.

4 A. Paiva, A. A. Matias and A. R. C. Duarte, Curr. Opin. Green Sustain. Chem., 2018, 11, 81–85.

5 K. Radošević, N. Ćurko, V. Gaurina Srček, M. Cvjetko Bubalo, M. Tomašević, K. Kovačević Ganić and I. Radojčić Redovniković, LWTFood Sci. Technol., 2016, 73, 45–51.

6 E. Wang, Y. Yin, C. Xu and J. Liu, J. Chromatogr. A, 2014, 1327, 39–48.

7 J. M. Silva, E. Silva, R. L. Reis and A. R. C. Duarte, Sustain. Chem. Pharm., 2019, 14, 100192.

8 Y. Dai, E. Rozema, R. Verpoorte and Y. H. Choi, J. Chromatogr. A, 2016, 1434, 50–56.

9 P. Manuela, S. Drakula, G. Cravotto, R. Verpoorte and M. Hruškar, Innov. Food Sci. Emerg. Technol., 2020, 66, 102514.

For more information about the products and the NADES team, visit their website www.nades­design.hr or social media : www.linkedin.com/in/nades-design-a2aab0221/ www.twitter.com/NADES_Design?s=20&t=t6cJ8_Gp9_xW0GQ­Q3WHsA)

FIGURE 1

Natural deep eutectic solvents

FIGURE 2 Plant material used for extract preparation

Experience the world's nutraceutical event: Vitafoods Europe 2023

The much-loved nutraceutical event returns both in person and online this May with an expanded offering including new, premium content.

Registrations are now open for Vitafoods Europe 2023, the leading global platform for nutraceutical, functional food and beverage, and dietary supplement professionals. The organizers of the event, whose main sponsor is KSM­66 Ashwagandha, expect over 15,000 attendees to the Palexpo Convention Centre in Geneva (9­11 May) and online (1­12 May). Visitors can experience exclusive expert-led content on consumer trends, market opportunities and scientific innovations, as well as connect with like-minded peers and suppliers to inspire new collaborations and finished products.

In addition to returning favourites, this year’s event will offer brand new show features – such as the new Sustainability Resource Centre and the Startup Innovation Challenge, plus the Future of Nutrition Summit and the Vitafoods Europe Conference.

Presenting Vitafoods Europe 2023 Andy Mather, Brand Director of Vitafoods Europe at Informa Markets, said “Vitafoods Europe 2023 aims to create a unique experience that visitors will not just find valuable, but that they will also really enjoy. This year, we are introducing a host of new content, designed to inspire, engage and provide the spark to propel the industry forward.

The new Sustainability Resource Centre will feature innovations and insights from passionate experts dedicated to driving sustainable change in the nutrition industry. Meanwhile, the Startup Innovation Challenge provides an opportunity for upcoming nutraceutical stars to make their mark on the industry and develop their innovative projects through a specialised support programme. We welcome everyone in the Vitafoods community back for 2023 both in Geneva and online – including those joining us for the first time – to experience the creativity and collaborations on offer.”

Show highlights

• NEW: Future of Nutrition Summit (8 May, Marriott Hotel, Geneva) – join a diverse range of C­suite industry leaders and futurist thinkers for an exclusive, paid­for one­day summit discussing the trends and technologies that will shape the nutrition industry in 5+ years’ time.

• NEW: Vitafoods Europe Conference (9­10 May) –this premium, two­day conference returns in a new format, focused on current challenges and opportunities in sports and active nutrition; cognitive and emotional health; metabolic and immune health;

life stages and healthy ageing. Now located in a purpose­built theatre on the Vitafoods Europe show floor, visitors can easily combine attending the conference alongside their regular show floor and expo experience.

• The Vitafoods Insights Theatre – returning for 2023, the Vitafoods Insights Theatre offers freeto­attend expert sessions diving into current global consumer trends, updates on regulatory and supply chain issues, as well as insights into delivery formats and packaging.

• NEW: Startup Innovation Challenge – discover cutting­edge innovations from the most exciting health and nutraceutical startups as they pitch their ideas live. Together with the popular Startup Pavilion, this challenge provides a unique opportunity for companies to find innovative ingredients, technologies, services, and finished products to help their businesses grow.

• NEW: Sustainability Resource Centre – dedicated to driving sustainable change in the nutrition industry, this resource centre offers expert presentations and insights into the full spectrum of sustainability issues, including supply chain traceability, regulatory compliance, certifications, carbon offsetting, alignment with the UN Sustainable Development Goals, and gender and LGBTQ+ inclusivity.

Experience innovations and ideas

“Standing still simply isn’t an option in this industry; people return to Vitafoods Europe year­after­year to drive their businesses forward and be inspired.” says Mather. “This year, we are offering another lively agenda, packed full of exciting opportunities to connect and gather knowledge. This includes both new and reimagined premium, paid­for events that will dive deeper into current trends and future industry predictions; the Vitafoods Europe Conference and the Future of Nutrition Summit. The latter joins the Vitafoods Europe 2023 family after being a huge success at previous Food Ingredients Europe events. We truly believe that Vitafoods Europe 2023 has something for everyone, and that this year's attendees will experience the very best in industry innovations and insights to keep their businesses at the leading-edge of nutrition.”

To register and to learn more about the new premium content offerings, visit:

www.vitafoods.eu.com/

Elasderma®

Elasderma® is a protein peptide that helps maintain skin elasticity, healthy arteries and the heart, and strengthens bone structure by improving joint health. Also, Elasderma® has proven to be a powerful antioxidant with a unique anti-aging effects. When taken continuously, it promotes cell growth. The restoring effect of Elasderma® makes the skin younger, smoother and fresher.

Elasderma® is a US Patented Elastin ingredient. This amazing molecule is the most stable protein of the extracellular matrix (ECM) which is composed of collagen, glycoproteins, glycosaminoglycans and proteoglycans. Elastin has been widely used as a skin booster by helping the skin maintain its elasticity and young age, though, this is not the only benefit of this powerful protein.1­3

Along with collagen, elastin is a vital component of the blood vessels and plays a significant role in the remodeling and elasticity of conduit arteries like the carotid and femoral. In terms of cardiovascular health, elastin protein is believed to provide a protective effect against cardiac rupture, to decrease the area of infarction and help lower the risk of cardiovascular disease by suppressing the formation of harmful blood clots. 2­3

Elastin peptides have also shown protective effect as antioxidative having the advantage of being ef­

fective at low concentrations and safe. The ability of elastin peptides as radical scavenger may be due to their ability to chelate metal ions and their good affinity for oils, as well as the presence of hydrophobic amino acids.4

Among other benefits, soluble elastin shows antioxidative properties, and the presence or hydrophobic aminoacids (Val and Pro) could potentially contribute to the high antioxidant activity.4­5

In recent studies, it has been shown that consuming elastin or tropoelastin may positively impact the bone regenerative capacity by enhancing and accelerating osteogeonesis (the process by which new bone is made by the cells). 29

Elasderma® is considered a skin conditioner, which is purported to help skin maintain its elasticity and young age. This protein has also been used as a skin booster. When taken regularly, it stimulates elastin biosynthesis. Elastin’s renewing effect makes skin

look younger, smoother and refreshed.

Elasderma® is obtained from Atlantic Cod Fish through a process involving several steps to refine elastin: from washing and defatting previously inspected and cleaned Atlantic Cod Skin to enzymatic hydrolysis using different proteases to remove nonelastin proteins, followed by various purification steps to deliver a fully water soluble, additive and high purity product.

Elastin is a critical skin protein which combines with microfibrils to form elastic fibers that provide stretch and recoil to the skin. Normal levels of elastic fiber production, organization, and integration with other cutaneous extracellular matrix proteins (ECM) are integral to maintaining healthy skin structure, function, and youthful appearance.1 Also, elastin is present in several connective tissues and confers a unique physiological elasticity.7­12

Elastogenesis, the process of elastin formation, mainly occurs during the fetal and early neonatal development of organs such as blood vessels, lungs, and skin, principally in elastogenic cell types, such as fibroblasts,11­12 and containing high amounts of elastin to assure their correct function.13 Elastin and elastic fibers are unique in that there is very low and slow turnover. In fact, in skin, the overall half-life of elastin is similar to the human lifespan.14

The benefits of elastin hydrolysate have been clinically proven. Among them are a better condition and greater elasticity of the skin.15­17 Elastin hydrolysate activates human skin fibroblasts and has beneficial effects on skin conditions.18 In a Japanese clinical study, ingestion of elastin hydrolysate enhanced the proliferation of fibroblasts and elastin synthesis, improving skin elasticity and blood flow and decreasing the number of wrinkles.19

Studies suggest that elastin increases the expression of long­chain base 1, dihydroceramide desaturase 1, elastin, hyaluronan synthase 2, and ceramide synthase 4 mRNA or protein as well as hyaluronic acid and sphingomyelin levels in UVB­irradiated HaCaT cells. Moreover, elastin regulated factors related to collagen production, wrinkles, and melanin production in UVB­irradiated HS27 cells and IBMX­stimulated B16F10 cells. 28

Elastin shows protective effects against UVA irradiation induced skin damage. 20­21 Other clinical studies on Elastin showed an improvement in blood flow providing a significant improvement in vascular health after 4 and 8 weeks. 22­23 Also, elastin showed a significant improvement in knee joint pain after 12 weeks. 24 After a injury, elastin mechanical properties are adapted to allow for proper work at higher pressures. 25

The formation of Desmosine and Isodesmosine cross-links via allysine-allysine or allysine-lysine reactions also contribute to the biomechanical properties of elastic fibers, as these cross-links can resist elastolysis. 26­27

Elasderma® is the only known elastin with a scientifically validated method to test, verify and quantify the presence of Desmosine (DES) and Isodesmosine (IDES), two amino acid isoforms uniquely found in elastin.

To measure the quantity of these biomarkers in products containing elastin, Nutraceuticals Group, in collaboration with Dr. Illya Gertsman, Ph.D (University of California­San Diego) and Vertex Analytical

Labs an FDA registered and ISO 17025:2017 Accredited Laboratory, developed and validated a simple, accurate and precise HPLC­UV method to analyze elastin hydrolysates. The test method allows to detect each amino acid individually.

Lipids and small peptides are removed from elastin with ice cold ethanol. After that elastin is centrifuged and elastin hydrolysates was prepared by acid hydrolysis in 6 M HCl for 24 h at 110 °C under vacuum. The hydrolyzed elastin was neutralized with NH4OH, evaporated and dried at 60 °C under stream nitrogen. The sample was resuspended in 10% MeOH and tested by ion­paring RP­HPLC.

HPLC analyses were carried out on a Shimadzu Prominence Series system (LC­20AT Pumps, SIL­20A Autosampler, CTO­20AC Column Oven, SPD­20A UVVis Detector). Data and chromatograms were processed with Shimadzu Lab Solutions HPLC Software. Samples (50 μL) were injected into a C18 HPLC Column (Nucleosil C18, 5μm, 150 mm x 4.6 mm, Sigma­Aldrich, cat# Z226173; St. Louis, MO) at 30 °C.

The separation mode of each amino acid was the ionpaired chromatographic technique because both DES and IDES amino acids contain pyridinium nucleus in their chemical structure. Ion pairs consisted of amino groups (positively [+] charged) and/or pyridinium nitrogen (positively [+] charged for DES and

FIGURE 1 Stock standards solution chromatogram. Peak assignments and approximate retention times for IDES (13.27 min), and DES (13.50 min).

FIGURE 2 Hydrolyzed ELASDERMA® sample chromatogram. Peak assignments and approximate retention times for IDES (13.18 min), and DES (13.53 min).

Nutramedic &Cosmetics

IDES), and the alkylsulfonate group (negatively [-] charged) as the other member of the ion pair. The carboxyl residues were suppressed by 0.1 M MSA (pH 2.0) containing 1.2 mM HSA like mobile phase A, and mobile phase B was used acetonitrile/0.2% FA with a flow rate to 1mL/min and 25°C column temperature. The optical density was monitored at 275 nm for the determination of DES and IDES amino acids.

Standard solution, a mix of IDES/DES (Sigma­Aldrich), was used to identify retention time and peak chromatographic parameters. A commercial sample (Elasderma®, Nutraceuticals Group USA; Lot. NIGELAS2008V478067 and NIGELAS­2012V964125) were analyzed. The retention time of IDES/DES standard solution (Sigma-Aldrich) were identified at 13.2 and 13.5 respectively (Figure 1).

The presence of IDES/DES on elastin hydrolysate can be observed in Figure 2, with a similar retention time (RT ± 2.0%) compared with stock standards solutions.

Finally, Desmosine and Isodesmosine peaks were identified and integrated using Shimadzu LabSolutions and the amount of each amino acid in Elasderma® is calculated as μg/g using calibration curves prepared from DES/ISO reference materials (standards).

Reerences:

1 Aumailley, M., & Gayraud, B. (1998). Structure and biological activity of the extracellular matrix. Journal of molecular medicine (Berlin, Germany), 76(3­4), 253– 265. https://doi. org/10.1007/s001090050215

2 Basu, P., Sen, U., Tyagi, N., & Tyagi, S. C. (2010). Blood flow interplays with elastin: collagen and MMP: TIMP ratios to maintain healthy vascular structure and function. Vascular health and risk management, 6, 215–228. https://doi.org/10.2147/vhrm.s9472

3 Protti, A., Lavin, B., Dong, X., Lorrio, S., Robinson, S., Onthank, D., ... & Botnar, R. M. (2015). Assessment of myocardial remodeling using an elastin/tropoelastin specific agent with high field magnetic resonance imaging (MRI). Journal of the American Heart Association, 4(8), e001851.

4 Hattori, M., Yamaji-Tsukamoto, K., Kumagai, H., Feng, Y., & Takahashi, K. (1998). Antioxidative Activity of Soluble Elastin Peptides. J. Agric. Food Chem., 46, 6, 2167– 2170.

5 Nadalian, M., Kamaruzaman, N., Yusop, M. S. M., Babji, A. S, and Yusop, S.M. (2019) Isolation, Purification and Characterization of Antioxidative Bioactive Elastin Peptides from Poultry Skin. Food Sci Anim Resour. 2019, 39(6), 966-979. doi: 10.5851/kosfa.2019.e90

6 Shiratsuchi, E., Nakaba, M., Shigemura, Y., Yamada, M., & Sato, K. (2013). Fish­elastin Hydrolysate: Development and Impact on the Skin and Blood Vessels. In: Kim, S. E. (Ed.). Marine Proteins and Peptides: Biological Activities and Applications. Wiley. https://doi. org/10.1002/9781118375082.ch23 7 Skjøt-Arkil, H., Clausen, R.E., Nguyen, Q.H. et al. (2012).

7 Skjøt-Arkil, H., Clausen, R.E., Nguyen, Q.H. et al. (2012). Measurement of MMP­9 and ­12 degraded elastin (ELM) provides unique information on lung tissue degradation. BMC Pulm. Med., 20, 12–34.

8 Calleja-Agius, J., Brincat, M. & Borg, M. (2013). Skin connective tissue and aging. Best. Pract. Res. Clin. Obstet. Gynaecol., 27, 727–740.

9 Momot, K.I., Powell, S.K., Mithieux, S.M. & Weiss, A.S. (2013). Biomechanics of synthetic elastin: insights from magnetic resonance microimaging. Adv. Mat. Res., 699, 257–463.

10 Halper, J. & Kjaer, M. (2014). Basic components of connective tissues and extracellular matrix: elastin, fibrillin, fibulins, fibrinogen, fibronectin, laminin, tenascins and thrombospondins. Adv. Exp. Med. Biol., 802, 31–47.

11 Kristensen, J.H., & Karsdal, M.A. (2016). Elastin. Biochemistry of Collagens, Laminins and Elastin. London: Academic Press.

12 Chiquet, M., Renedo, A.S., Huber, F., & Flück, M. (2003). How do fibroblasts translate mechanical signals into changes in extracellular matrix production? Matrix Biol., 22,73­80.

13 Le Page, A., Khalil, A., Vermette, P., Frost, E. H., Larbi, A., Witkowski, J. M., & Fulop, T. (2019). The role of elastin derived peptides in human physiology and diseases. Matrix Biol., 84, 81­96. https://doi. org/10.1016/j.matbio.2019.07.004

14 Shapiro, S.D., Endicott, S.K., Province, M.A., Pierce, J.A., & Campbell, E.J. (1991). Marked longevity of human lung parenchymal elastic fibers deduced from prevalence of D-aspartate and nuclear weapons­related radiocarbon. J Clin Invest., 87(5),1828­1834. https://doi.org/10.1172/JCI115204

15 Shiratsuchi, E., Nakaba, M., Shigemura, Y., Yamada, M., & Sato, K. (2013). Fish­elastin Hydrolysate: Development and Impact on the Skin and Blood Vessels. In: Kim, S. E. (Ed.). Marine Proteins and Peptides: Biological Activities and Applications. Wiley. https://doi. org/10.1002/9781118375082.ch23

16 Pezzoli, D., Di Paolo, J., Kumra, H., Fois, G., Candiani, G., Reinhardt, D.P., & Mantovani, D. (2018). Fibronectin promotes elastin deposition, elasticity and mechanical strength in cellularised collagen-based scaffolds. Biomaterials, 180,130-142. https://doi. org/10.1016/j.biomaterials.2018.07.013

17 Wang, R., Yu, X., & Zhang, Y. (2021). Mechanical and structural contributions of elastin and collagen fibers to interlamellar bonding in the arterial wall. Biomech Model Mechanobiol. 20(1),93­106. https://doi.org/10.1007/s10237­020­01370­z

18 Robert, L., Jacob, M.P., Frances, C., Godeau, G., & Hornebeck, W. (1984). Interaction between elastin and elastases and its role in the aging of the arterial wall, skin and other connective tissues. A review. Mech Ageing Dev., 28(2­3), 155­66. https://doi.org/10.1016/ 0047­ 6374(84)90015­0

19 Shiratsuchi, E., Nakaba, M., & Yamada, M. (2016). Elastin hydrolysate derived from fish enhances proliferation of human skin fibroblasts and elastin synthesis in human skin fibroblasts and improves the skin conditions. Journal Science, Food and Agriculture, 96, 1672–1677. https://doi.org/10.1002/jsfa.7270

20 Amakye, W. K., Yang, L., Yao, M., Yuan, E., Ren, R., & Ren, J. (2021). Skipjack (Katsuwonus pelamis) elastin hydrolysate­derived peptides attenuate UVA irradiation-induced cell damage in human HaCaT keratinocytes. Food Frontiers, 2(2), 184-191. https://doi.org/10.1002/fft2.74

21 Liu, Y., Su, G., Zhou, F., Zhang, J., Zheng, L., & Zhao, M. (2018). Protective Effect of Bovine Elastin Peptides against Photoaging in Mice and Identification of Novel Antiphotoaging Peptides. J Agric Food Chem., 66(41),10760­10768. https://doi.org/10.1021/acs. jafc.8b04676

22 Takemori, K., Yamamoto, E., Ito, H., & Kometani, T. (2015). Prophylactic effects of elastin peptide derived from the bulbus arteriosus of fish on vascular dysfunction in spontaneously hypertensive rats. Life Sciences, 120, 48­53. https://doi. org/10.1016/j.lfs.2014.10.011

23 Takemori, K., Akahoshi, Y., & Kometani, T. (2018). Hypertensive vascular changes were suppressed by elastin peptide obtained from fish bulbus arteriosus. Pathophysiology, 25(3), 183-184. https://doi.org/10.1016/j.pathophys.2018.07.055

24 Schauss, A. G., Stenehjem, J., Park, J., Endres, J. R., & Clewell, A. (2012). Effect of the Novel Low Molecular Weight Hydrolyzed Chicken Sternal Cartilage Extract, BioCell Collagen, on Improving Osteoarthritis­Related Symptoms: A Randomized, Double­Blind, Placebo­Controlled Trial. Journal of Agricultural and Food Chemistry, 60, 4096­4101. https://doi.org/10.1021/jf205295u

25 Faury, G. (2001). Function­structure relationship of elastic arteries in evolution: from microfibrils to elastin and elastic fibres. Pathol Biol, 49(4), 310­25. https://doi.org/10.1016/s0369­8114(01)00147­x

26 Akagawa, M., & Suyama, K. (2000). Mechanism of Formation of Elastin Crosslinks. Connective Tissue Research, 41(2), 131-141. https://doi.org/10.3109/03008200009067665

27 Lamberg, S.I., Poppke, D.C., & Williams, B.R. (1980). Isolation of elastic tissue microfibrils derived from cultured cells of calf ligamentum nuchae. Connect Tissue Res., 8(1), 1­8. https://doi. org/10.3109/03008208009152115

28 Park, S. J., Kim, D., Lee, M., Jung, J., Eun, S., & Kim, O. K. (2022). Effects of Bonito Elastin HC on Skin Dryness, Wrinkles, and Pigmentation In Vitro and In Vivo. Journal of Medicinal Food, 25(1), 48­60.

29 de Moraes, R., de Guzzi Plepis, A. M., da Conceição, A. M. V, Duarte, M. A. H., Alcalde, M. P., Buchaim, R.L., Pomini, K.T., Machado, E. G., de Azevedo, E., Sousa Munhoz, M., Cunha, F. B., Calegari, A. R. A., Iatecola, A., Silva, S. K., da Cunha, M. R. (2019). Suitability of the use of an elastin matrix combined with bone morphogenetic protein for the repair of cranial defects. Am J Transl Res, 11(8):5261­5271

Nutraceuticals Group USA(a)

Vertex Analytical Labs(b)

(a) 50 Sindle Avenue, Little Falls, NY 07424

(b) 7098 Miratech Dr Ste 120, San Diego, CA 92121 customersupport@vertexanalytical.com

www.elasderma.com

UREA - an effective molecule for dry skin symptoms

Urea is molecule naturally present in epidermis, as a component of natural moisturizing factor (NMF) and is fundamental for the optimal skin water capacity and proper skin barrier function. Applied topically, urea helps improve symptoms of dry skin by providing hydration and by reducing dead skin cells. Urea is also used in dermatology for treatment of skin disorders.

AUTHOR: Lana Brkić, M.Eng.

Function of skin

The main role of the skin is to protect the body form the environmental harmful factor, such as dirt, air pollutants, irritants, harmful microorganism. Microbiota supports skins defense role. Also, it regulates the body temperature.

The stratum corneum is the outermost layer of the skin, the outer sublayer of epidermis. Although it is 0,015 mm thick, it plays an important role as a barrier, protecting the inner layers of skin. Most body parts contains about 20 layers of cells, while the eye area has fewer layers and parts of hands and heels have thicker layers.

The stratum corneum is often described as a brick wall or “brick and mortal wall”. “The brick” is formed of dead cells, called corneocytes, which are mainly filled with fibrous proteins – keratin and filaggrin. “The

brick” gives mechanical strength. Corneocytes are surrounded by lipids and fats – ceramides, fatty acids, cholesterol) and they are organized into lamellar membranes. “The mortal” fills the area around corneocytes and stops water from moving across the stratum corneum . Brick and mortal wall is strong and impermeable, it keeps water in the skin and microorganisms out. If the wall is damaged by environmental conditions, chemicals, change of temperature or by intrinsic factors, the skin barrier function is weakened. It leads to disturbance of filaggrin expression or reduction of lipids. The result is increased water loss. The proper skin function is disturbed. The skin barrier is now favoring the penetration of irritants and allergens, triggering inflammation and skin becomes prone to infections.

The hydroscopic substances, with properties of absorption and retaining water molecules are natural­

Nutramedic &Cosmetics

ly present in stratum corneum, within corneocytes. They are known as natural moisturizing factor (NMF). Among these ingredients are: urea, free amino acids, lactic acid and pyrrolidone carboxylic acid. The NMF components act as humectant by keeping the moist and maintaining hydrated skin barrier. The skin stays smooth and maintains a healthy appearance.

Water capacity of the stratum corneum is influenced by two factors. First is the presence of hydroscopic substances within corneocytes, natural moisturizing factors (NMF) and second factor is undisturbed lipid intracellular structure.

Dry skin

Dry skin is also known as xserosis. The causes of dry skin are different, from environmental causes to health conditions. Environmental factors depend on the way of living and everyday habits. Certain diseases tend to cause dry skin.

It is considered that stratum corneum contains about 10­20% water and that if the water content is reduced to below 10%, visible symptoms of dry skin occur.

First symptoms of dry skin that appear are roughness and tightness. Without treating the symptoms and with further water loss, the skin will become itchy, start to crack and scaling will occur. Severe symptoms may include flaky skin with rough peeling surface, deep painful cracks, skin that burns. In cases of more serious dry skin symptoms medical treatment is needed.

Different types of eczema and dermatitis are skin conditions that cause itchy and inflamed dry skin.

The NMF production can decrease in the skin and is influenced by:

• ageing and hormonal changes, genetic predisposition,

• environmental factors: climate, dry air, UV radia­

tion, smoking, exposure to chemicals, skin conditions: irritant contact dermatitis, atopic dermatitis, xserosis, ichthyosis.

Lack of natural moisturizing factors (NMF) leads to a reduction of hygroscopic capacity of skin, resulting in increased transepidermal water loss (TEWL). Water loss disrupts the proper functioning of the skin resulting in xserosis. Reduction of water in the epidermis influence the proper function of the skin barrier, allowing the penetration of irritants or becoming the predisposing factor to skin infections.

Application of topical preparations containing urea, a hygroscopic molecule, will support the water­binding capacity of NMF and enable hydration of the stratum corneum and contribute to its barrier function.

Urea

Urea is today the most common ingredient, which is added to preparations for topical application to help eliminate the problems of dry skin. Urea is a wellknown ingredient in dermatology for the skin disorders such as atopic eczema, ichthyosis, psoriasis and contact dermatitis. Urea is recognized to have positive effects in skin function. It is a fundamental molecule for adequate hydration, which the skin needs to function properly.

Urea is the major constituent of NMF, the hygroscopic substance, and is present up to 7%. As a highly reactive molecule, urea is capable of drawing water from the dermis into the epidermis and attracting water from the external environment. Higher humidity favors better water absorption. In addition, urea retains water within skin cells.

The following effects of xserosis skin are attributed to the action of urea: hydration, exfoliation, regeneration, irritation calming. Also, further effects on the skin are antimicrobial action and increase of drug

The precursor protein, profilaggrin, is present in the keratinocyte in the granular layer. As the cells transition into corneocytes, proteases cleave the precursor into filaggrin where it aggregates keratin filaments into macrofibrils. In the upper layers of the stratum corneum, the filaggrin is proteolyzed to form the NMF, where they absorb and bind water from the atmosphere. Adapted with permission from O’Regan, et al.

Taken from: UnderstandingtheRoleofNaturalMoisturizingFactorinSkinHydration,JosephFowler,PracticalDermatology,July2012

FIGURE 1 The process of natural moisturizing factor (NMF) production.

penetration. Urea has antifungal and antimicrobial efficacy. It can improve skin penetration of other substances or drugs.

Urea – moisturization effect

Urea is providing moisturization by drawing water from deeper layers and from the air and by locking the water in the stratum corneum . In addition, urea has an emollient function, meaning it soften and smoothes the skin. By reduction of water loss, it keeps the outer layers of the skin moisturized. Urea improves the water binding capacity, keeps the stratum corneum well hydrated.

Urea – exfoliation effect

Urea is a keratolytic agent. It breaks down the hydrogen bond in protein keratin, the outer layer of skin. It softens the horny layer and enables the easier removal of rough skin. Thus, it eliminates skin flakes and scales. This improves the appearance of treated skin and relieve symptoms. Dead skin cells are removed from the surface. Breakage through the surface layer allows better hydration of the new skin cells.

Skincare products with urea

As urea is a highly water­soluble molecule, it can be easily incorporated into skin care products for topical applications. Many dermatological preparations contain urea for treatment of different skin disorders.

The skincare market offers a variety of different products that include urea in combination with other active ingredients and with various urea concentrations.

Most of the topically applied products are intended to moisturize the skin and help exfoliation, but also to improve conditions of scaly and dry skin.

Urea concentration ranges vary between 5­40%, intended for the treatment of different skin conditions:

• 5 - 10% urea concentration – skin moisturization, as a humectant or an emollient

• 10 – 30% urea concentration – reduce itching, improve scaly skin conditions

40% urea concentration – proteolytic effect.

The moisturization can be achieved with products containing up to 10% of urea, it enables the binding of water to the protein chain in the stratum corneum. As a moisturizer, urea acts as a humectant – with a function to attract and hold moisture, and as an emollient – with a function to soften and smooth the skin. Products with lower urea concentration can also be used for prophylactic use in preventing more difficult skin disorders. Such moisturizers are suitable for the long-term care of large skin areas.

Topical products with urea concentration of 10% and higher are considered to have keratolytic effect. They can reduce itching and improve conditions of scaly skin and are appropriate for the treatment of xerotic skin conditions such as eczema, dermatitis, or psoriasis. Such products reduce the feeling of tightness and provide skin comfort.

Products containing 40% of urea have proteolytic effect, helping to break down molecules of proteins. They are suitable for skin areas with thicken dead cells patches, found on hands, feet, and elbows. Their mechanism is exfoliation, and they purify the skin. These

products can be used for the treatment of dystrophic nails, nails that are thickened or deformed.

Most of the marketed products are face creams and body lotions for the care of dry and rough skin, providing intensive skin moisturization. They provide a quick relief effect and reduce tightness. Body washes effectively clean the skin and do not leave a feeling of dryness.

Urea is the most common ingredient included in feet care creams due its intensive moisturizing property and exfoliating effect. Feet care cream is also recom

mended for treatment of corns and calluses. It can also help treating the nail condition like fungal infections. Hair shampoos are mainly intended for dry and itchy scalp, providing relieve of itching and irritation. They relieve dryness by moisturization and exfoliation of scalp. Scalp is becoming hydrated and contribute to healthier hair and stimulates hair grow. As urea has the antifungal effect, urea-containing shampoo is beneficial against dandruff. With so many beneficial effects, shampoo with urea is considered as a complete scalp treatment.

In dermatology urea is used for topical application of skin disorders, like atopic dermatitis, ichthyosis, seborrheic dermatitis, and psoriasis. The increase of water content in the stratum corneum and improvement of the skin barrier function are considered as fundamental for the treatment of skin disorders. Therefore, urea with its mechanism of action is often used in dermatological preparations.

From the safety point of view, urea is considered safe and well tolerated. Studies have shown not significant side effects. Known side effects are sting

ing, redness or irritation. But, these side effects are rare and temporary.

Urea is a well-known humectant and emollient used in skincare products to help moisturize and exfoliate the skin. Urea is effective in reducing water loss and thus improves skin barrier function. Dermatological urea-containing products treat conditions of skin disorders. Application of urea products will improve dry skin condition: itchy skin, scaly skin, flaky skin, rough texture, cracks in the skin. Skin discomfort like stings, redness, irritation, tightness will be relieved. Urea will support healthier skin appearance.

References:

Berardesca E, Cameli N. Non-invasive assessment of urea efficacy: A review. Int J Clin Pract. 2020 Dec;74 Suppl 187:e13603. doi: 10.1111/ ijcp.13603. PMID: 32639641.

Dirschka T. Mode of action of urea. Int J Clin Pract. 2020 Dec;74 Suppl 187:e13569. doi: 10.1111/ijcp.13569. PMID: 33249710.

Celleno L. Topical urea in skincare: A review. Dermatol Ther. 2018 Nov;31(6):e12690. doi: 10.1111/dth.12690. Epub 2018 Oct 30. PMID: 30378232.

Verdier-Sévrain S, Bonté F. Skin hydration: a review on its molecular mechanisms. J Cosmet Dermatol. 2007 Jun;6(2):75­82. doi: 10.1111/j. 1473­2165.2007.00300.x. PMID: 17524122.

Voegeli, David. (2012). Urea creams in skin conditions: composition and outcomes. Dermatology in Practice. 18. 13­15.

Piquero­Casals, J., Morgado­Carrasco, D., Granger, C., Trullàs, C., Jesús­Silva, A., & Krutmann, J. (2021). Urea in Dermatology: A Review of its Emollient, Moisturizing, Keratolytic, Skin Barrier Enhancing and Antimicrobial Properties. In Dermatology and Therapy (Vol. 11, Issue 6, pp. 1905–1915). Adis. https://doi.org/10.1007/s13555­021­00611­y

Pan, M., Heinecke, G., Bernardo, S., Tsui, C., & Levitt, J. (2013). Urea: a comprehensive review of the clinical literature. Dermatology Online Journal, 19(11). https://doi.org/10.5070/D31911020392

Fowler, J. (2012.). Understanding the Role of Natural Moisturizing Factor in Skin Hydration. Practical dermatology, July 2012., 36-40.

The role of collagen in the skin health and beauty

In recent years, the food supplement market has become increasingly rich in collagen-containing products. The reason for this lies in numerous confirmations of its effectiveness in preserving and improving the youthful appearance and overall condition of the skin, as well as in preserving the health of the musculoskeletal system.

AUTHOR:

Vesna Marijanović

Jukić, M.pharm., univ.spec.oec., Pharmatop

Collagen is a strong and flexible fibrous protein that is produced daily in the body, and is the main component of connective tissue, muscles and skin. It makes up 25-35% of the protein content in the human body, which makes it one of the most abundant proteins. The word collagen itself comes from the Greek word "kolla" which translates as "glue" (collagen type I and type III join in the dermis like connective pads).

In addition to being necessary for the health and appearance of the skin, this protein is also necessary for reducing the typical signs of aging, which begin to appear as early as the twenties. It is a true ally in preserving flawless skin, tissues and healthy joints, so it must be taken into the body regularly.

Collagen also has numerous benefits for the health of joints, tendons and bones ­ it improves joint mobility, reduces bone pain and helps regenerate the cartilage that protects the joints. As its amount in the body decreases with age, the risk of osteoarthritis and other painful conditions in the joints increases. It also helps to preserve the strength of bones, as it is an integral part of them, which has been confirmed by studies.

However, as we age, collagen production in the body decreases more and more. Already after the age of 21, the production process slows down significantly, by about 1.5% every year. This means that the number and activity of cells that produce collagen (fibroblasts) decrease with aging. As the number of new fibers noticeably decreases from year to year, signs of aging gradually begin to appear.

The amount of collagen in the body begins to decrease even more significantly after the age of 40. This process is influenced by internal factors such as genetic inheritance and hormonal changes, but it can also be accelerated by external influences such as alcohol consumption, smoking, photoaging, diet, stress and air pollution. Free radicals and glycation (the biological process by which sugar molecules attach to collagen) can provoke existing collagen fibers to harden and join together. Ultraviolet rays stimulate enzymes that break down collagen (matrixins).

Food supplements containing collagen

Due to all the previously mentioned knowledge about the importance of collagen in preserving youth, vitality and improving the overall condition of the skin and in preserving the health of the musculoskeletal system, the over-the-counter products market has in recent years increasingly turned to the production of food supplements based on collagen for oral use, in the form of capsules and /or in liquid form.

Considering the popularity that liquid form products currently enjoy, various types are available on the market, the most common being collagen of animal origin ­ bovine collagen, and marine collagen from fish. Marine collagen has long been used in the production of cosmetics and contains predominantly type I collagen. On the other hand, bovine collagen contains type I and III collagen, which, in addition to the health of the skin, are also important for the health of the intestines, bones, joints and connective tissue.

Type I and type III collagens are secreted by fibroblasts, cells in the dermis, the deeper layer of the skin, which are also responsible for the formation of elastin. Together with elastin and other proteins called glycoproteins, collagen forms the extracellular matrix. It is the network that makes up the skin and, like muscle, provides it with physical properties such as tone, resilience and firmness. Although it seems that bovine collagen is better, because in addition to

helping maintain the health of the skin, it is also important for the health of the whole body, marine collagen contains smaller peptide molecules, so it is easier to digest than animal collagen, and because of this, it is absorbed faster in the body.

No matter which origin of collagen you choose, you can't go wrong because each one provides health benefits.

The role of collagen in the skin health and beauty

We can thank collagen for the youthful, fresh and radiant appearance of the skin and hair. When we are young, our body continuously produces collagen. Its most important role is to maintain the structure and resistance of the skin. In the middle layer of the skin - the dermis - it contributes to the creation of a fibrous network that strengthens the layers of the skin, enabling the growth of new cells.

Smooth, firm and youthful skin requires an optimal level of well-organized collagen fibers that will ensure that the skin maintains its elasticity, firmness and ability to bind moisture. Research has shown that exogenous collagen can stimulate the synthesis of new collagen fibers by stimulating fibroblasts.

Collagen loss occurs throughout the whole body. The first signs of collagen loss are the appearance of fine lines and wrinkles, dry and sagging face and neck skin, thinner and more brittle hair and weaker nails. This should not be surprising, given that 75% of the skin's composition is made up of collagen and that with aging the production of collagen decreases. It happens because the number and activity of the cells that produce collagen decrease, so the skin becomes thin and dehydrated.

In addition, the thickness of the skin is constantly decreasing ­ on average by 7% every 10 years. After menopause, the situation worsens drastically – in the first five years of menopause, as much as a third of collagen is lost from the skin. This is exactly why supplementation is necessary to maintain the elasticity and health of the skin. After menopause, skin thickness decreases by 1.13% per year, and skin elasticity by 0.55% per year. A decrease in skin collagen is also associated with a decrease in bone mineral density.

Use of collagen in cosmetic preparations

There is no outfit luxurious enough, nor a piece of jewelry extravagant enough to distract attention from the face. Well-nourished, healthy and glowing skin is still the best "decoration" that can be worn. We often hear from dermatologists, cosmetic surgeons and other beauty professionals that it is crucial to create a good "base" for a smooth, youthful and flawless complexion and skin appearance. Experts believe that to create such a "base" it is necessary to use treatments for deep hydration of the skin, have a balanced diet and compensate for the necessary collagen3. Dermatologists advise that after the age of 35, products containing collagen, i.e. products that stimulate its production, should be included in the beauty routine.

When it comes to the application of collagen in cosmetic preparations, we can find it in various creams, serums and ampoules for application on the face.

Collagen is a very powerful ally in the fight against skin aging. It is also called "natural botox", because it

increases the elasticity of the skin and slows down its aging. In addition, it actively works to alleviate existing wrinkles and slows down the formation of new ones. Collagen creams usually contain a high concentration of natural, active collagen of marine origin.

Today, there is more and more evidence that collagen can be "returned" to the skin, or that its disappearance and destruction can at least be slowed down, with a healthy diet (especially by consuming less sugar) and avoiding excessive exposure to the sun light. Skin care that protects collagen has a double effect: it protects the existing collagen in the skin and at the same time stimulates the production of additional collagen. Skin care creams fill the skin with peptides and can target certain signs of skin aging that are the result of collagen loss: wrinkles, skin laxity, loss of firmness and tone.

Although it is a powerful anti­aging ingredient, its local application can be difficult to transfer to the skin. Therefore, in addition to local therapy, it is ideal to use mesotherapy and microneedling to enable safe application in the right skin layer, where it will have maximum effectiveness. In order to be able to penetrate the skin, the collagen molecule must be extremely small, which is very difficult to achieve in preparations that are applied locally. However, the popularity of these products lies in the fact that the collagen and other proteins leave a film on the skin that fills in irregularities on the surface. When the product dries, the protein film tightens, causing a subtle tightening of wrinkles.

With regular use of face creams containing collagen, the skin looks younger and fresher, and the depth and length of wrinkles are reduced. Thanks to their natural composition, such face creams are suitable for all skin types. They are especially recommended for the care of dry and photodamaged skin. If the cream with collagen additionally contains almond oil, it will also additionally hydrate, care for and nourish the skin, making it soft and silky. The combination of collagen and almond oil is an excellent formulation for skin care, as both ingredients improve its elasticity.

In addition to the previously described benefits of collagen in reducing wrinkles and skin dryness, it can also help with other skin problems. When the amount of collagen in the skin is sufficient, it is more resistant to the influence of external factors. It also provides the skin with better regeneration and faster recovery after injuries.

In case the skin is damaged by acne, collagen is used for wound healing. It plays a key role in scarring, as the immune system uses it to close the wound and create "new" skin in that area.

Genetics is something that cannot be fought and it is largely responsible for whether someone is prone to cellulite. But collagen can help fight against its appearance on the skin. Namely, one of the consequences of a decrease in collagen levels is thinning of the skin, and it is precisely this thinning that causes cellulite and stretch marks to become more visible. By maintaining a high level of collagen (which gives the skin firmness and elasticity), the appearance or appearance of cellulite is less likely. Studies have shown that regular intake of dietary supplements with collagen improved the appearance of the skin of women with moderate cellulite.

Skin application of niacin and its action in skin detoxification

Menthylnicotinate is a lipophilic derivative of niacin, capable of significantly activating the microcirculation of the skin, without causing irritation or a sudden rush of heat known as “niacin flush”. It is also characterized by the delivery of high doses of niacin to the epidermis, very fast absorption and enabling prolonged release in the skin.

AUTHOR:

Tea Višek, Director, Cos Chem, Fraktal Beauty

As we age, our skin's natural barrier often times becomes damaged due to intrinsic and extrinsic factors and does not provide the needed protection to our skin. This is specialy true if we look at the skin of perimenopausal and menopausal women. Due to lower levels of estrogen in the body, intrinsic factors include loss of collagen production, thinner skin, dryness and dehydration, skin sensitivity and in some cases even atopic skin and acne. Additionaly, there are different extrinsic factors that influence the skin today – exposure to UV light, indoor and outdoor air pollution. If we consider all these factors together, the amount of possible damage to the skin, especially for that specific age group of women, is notable and cannot be underestimated.

Having in mind these influences, we have embarked on the project to create the skin care product that will address some of these factors and try to regenerate skin at the cellular level, so that the skin would get new life from within. This concept was very important to us and after an extensive research into possible active ingredients and formulation frameworks that could give that result, we have chosen menthyl nicotinate as the main active ingredient to deliver this task.

Menthylnicotinate as an active ingredient in cosmetics

Findings of different studies on mechanisms of the skin responsible for defense against intrinsic and extrinsic damage were underlined by few studies (Ref. 1­3). Mentioned studies have evidenced the importance of niacin (nicotinic acid or vitamin B3), a precursor of the coenzyme NAD+ (nicotinamide adenine dinucleotide). NAD+ plays a very important role in skin's ability to respond to stressors and start repairing DNA damage that UV light and air pollutants cause in the skin. Consequently, the deficiency of NAD+ can cause the inability of skin cells to regenerate from extrinsic factors and lead to oxidative stress, premature skin ageing, lipid peroxidation, skin irritation and with time to more serious skin cellular damage.

Menthyl nicotinate is a lipophilic derivative of niacin, capable of significantly activating the skin microcirculation, without causing an irritation or sudden flushes known as „niacin flush“.

Other interesting characteristics of menthylnicotinate are that it is able to deliver high doses of niacin in epidermis and that it absorbs rapidly into the skin, with prolonged release of niacin.

In-vitro absorption study of menthyl nicotinate

3000 μg of menthyl nicotinate was applied to a sample of RHE (in vitro reconstructed human epidermis). In 30 minutes 53,8% menthylnicotinate was absorbed into the stratum corneum. After 24 h from application nearly the whole dose (87,8%) of menthylnicotinate is absorbed.

HPLC analysis was conducted subsequently to establish the release of niacin into the sample of RHE. Results showed that 254 μg of released niacin penetrated through the skin barrier (from the initial 1413 μg contained in the 3000 μg applied dose of menthyl nicotinate). The result is: menthyl nicotinate provides niacin absorption rate of approx. 18% of the applied dose in 24 hours.

Compared to the absorption rate of the commonly used niacinamide, which is only 2.2% in 24 hours; or to the absorption rate of pure niacin itself, which is less than 0.2% in 24 hours, menthyl nicotinate has shown significantly better results.*

Nutramedic &Cosmetics

TO SKIN BY MENTHYL

The GST activity was observed in skin explants when exposed to urban pollutants in repeated conditions.

Test 2. Glutathione S Transferase (GST) assay (Ex-vivo)

Source: *Cfr.: ABSORPTION OF SOME ORGANIC COMPOUNDS THROUGH THE SKIN IN MAN ­ Robert J. Feldmann, Howard J. Maibach. The Journal of Investigative Dermatology – © 1970 The Williams & Wilkins Co.

Finished

cosmetic formulation with 5%

menthylnicotinate – efficacy tests

Finished formulation chosen for delivery of menthyl nicotinate was a light fast absorbing oil, to enhance the active ingredient delivery into the skin, while also leaving skin nurtured.

INCI of the finished cosmetics formulation that was tested for efficacy is:

Caprylic/Capric Triglyceride, Propylheptyl Caprylate, Undecane, Menthyl Nicotinate, Tridecane, Parfum,Tocopherol,PentaerythritylTetra­di­t­butylHydroxyhydrocinnamate, Benzyl Salicylate, Citronellol, Eugenol,Geraniol,Hydroxycitronellal,Linalool

The dosage of menthyl nicotinate used in tested formulation is 5,0% (purity grade > 99.0 %).

Efficacy test methods used and test results

The ability of the skin cells to recover after an acute exposure to the UVA / UVB light was tested, with following results:

Test 2. represents the values obtained for skin explants that were treated with the test item and were exposed to the different environmental stressors (urban pollutants) ­ (Repeated). The bar chart represents mean ± SEM. * represents p value <0.05, ** represents p <0.01, and *** represent p<0.001

Skin cell damage prevention efficacy of tested formulation, after repeated exposure to cigarette smoke, was tested with following results:

Test 3. Human malondialdehyde Assay (MDA) (Ex-vivo)

Test 1. represents the values obtained for skin explants that were treated with the test item and were either left unexposed or exposed to UV­A/UV­B (Acute). The bar chart represents mean ± SEM. *represents p value <0.05, ** represents p <0.01, and *** represent p<0.001

Test 3. The graphs above showed the concentration of MDA (ng/mL) observed in skin explants that were exposed to cigarette smoke in repeated conditions. The bar chart represents mean ± SEM. * represents p value <0.05, ** represents p <0.01, and *** represent p<0.001

Nutramedic &Cosmetics

Global Omega-3 Day™

Conclusion

Light oil formulation with 5,0% of menthyl nicotinate has proven to have a significant efficacy in:

1. Recovery of skin cells after UVA / UVB damage by 104 %;

2. Recovery of skin cells after repeated exposure to urban pollutants by 61%

3. Prevention of skin cell damage after exposure to cigarette smoke by 39%.

Above mentioned efficacy results prove that this light oil formulation provides unique set of performances that will enable, in particular to perimenopausal and menopausal skin, to recover and regenerate from extrinsic factors of aging at a deep cellular level, thanks to successfully enhanced skin microcirculation and targeted prolonged niacin delivery.

References:

1 Benavente CA, Jacobson MK, Jacobson EL (2009) NAD in Skin: Therapeutic Approaches for Niacin. Current Pharmaceutcal Design 15(1):29­38

2 Jacobson EL, Hyuntae K, Moonsun K, Georg T. Wondrak GT, Jacobson MK (2005) Developing Topical Prodrugs for Skin Cancer Preventon Reprint from: Alberts David S, Hess Lisa M (Eds) Fundamentals of Cancer Preventon pp 139­160 © Springer­Verlag Berlin Heidelberg (2005)

3 Jacobson EL, Kim H, Kim M, Williams JD, Coyle DL et al (2007) A topical lipophilic niacin derivatve increases NAD, epidermal differentaton and barrier functon in photodamaged skin. Experimental Dermatology 16(6):490­499

Every March 3rd, GOED rallies its members, communications partners and the public to shine a spotlight on EPA and DHA omega­3s, under­consumed nutrients that help support a healthy heart, brain, eyes and pregnancy.

The original International Omega­3 Awareness Day was established in 2010 by Dr. Carol Locke, founder of GOED member OmegaBrite, as a non-profit international initiative to raise awareness of the science and benefits of omega-3 fatty acids. GOED is proud to continue the Global Omega­3 Day™ tradition with an expanded goal, which is to raise awareness of the importance of omega­3s around the world through outreach to stakeholders including those in the omega-3 industry, consumers, key influencers and health professionals. With more than 180 GOED members representing companies throughout the EPA and DHA omega­3 supply chain, we now have many avenues to get the word out about the importance of EPA and DHA omega­3s.

Key Messages

80% of people worldwide are not getting enough EPA and DHA omega­3s (and in the US it's higher than 95%).

• When it comes to omega­3s, EPA and DHA are most important, not just for your heart or during pregnancy, but throughout your entire life.

• The best food source of EPA+DHA omega-3s are fatty/oily fish. You can also get these nutrients from an omega­3 supplement.

Aim for at least 500mg EPA+DHA per day. Get this from eating fatty/oily fish, eating foods fortified with EPA/DHA, and by taking an omega-3 supplement.

• Pregnant and lactating women should get at least 700 mg per day of EPA+DHA, with at least 300 mg of that as DHA.

There is no concern about the safety of EPA and DHA omega­3s. Both the US Food and Drug Administration (FDA) and the European Food Safety Authority (EFSA) recognize that long-term intake of 5g/day of EPA+DHA is safe.

“We’ve been working on growing Global Omega-3 Day with new activities each year, and for 2023 we feel we’ve truly gone global,” said Ellen Schutt, managing director of GOED. “It’s so important to reach consumers about the need to increase EPA and DHA omega­3 levels, and we’re hoping that the broader omega­3 industry will help us spread this important message.”

For this year's Global Omega-3 Day, GOED prepared a toolkit for communication with consumers, organized retail activities in several grocery chains in the US, and media campaigns in Poland and Turkey aimed at consumers. Also current were special discounts on access to the GOED Clinical Studies Database and on the prices of the Ingredient Market Report and the Finished Product Report.

tea.visek@coschem.hr

www.goedomega3.com

Approximately 80% of people worldwide are not getting enough EPA and DHA omega-3s, and GOED would like to see that statistic improve.

NutraFood Poland: the only B2B event in Poland dedicated to food supplements and functional food

Thousands of visitors, more than a hundred manufacturers and distributors of nutritional supplements, pharmaceutical products and suppliers of raw materials and services, await you in Warsaw from April 18-20, 2023.

NutraFood Poland

NutraFood Poland is the only fair of nutritional supplements and functional food supplements in Poland. Visitors, who last year numbered more than 7,000 from a total of 25 countries, are presented with a large selection of novelties among nutritional supplements, pharmaceutical products, functional food, nutraceuticals, equipment and services for industry as well as active ingredients and raw materials needed in the production process.

NutraFood Poland is the main place for meeting, socializing and negotiating deals in the food supplements industry in this part of Europe, and a platform that offers numerous presentations and content dedicated to trends, business and current legislation.

Exhibitors and visitors at NutraFood Poland come from various industry sectors: ingredients and raw materials, functional food and beverages, nutritional supplements, nutraceuticals, equipment and services, and contract manufacturing.

Participation in the fair will be especially interesting for companies that want to bring their products from the field of nutritional supplements or functional foods and beverages to the Polish market.

WorldFood Poland

The NutraFood Poland fair is part of WorldFood Poland ­ the largest B2B food industry fair in Poland. The WorldFood Poland fair has an international character and over the years has become the main event for all participants in the food industry. Today, it is a platform for business development in the food market, which offers the possibility of meeting and talking with existing and potential new partners, participating in panels and conferences, and a platform for mo­

nitoring new trends and discovering new products.

WorldFood Poland gives exhibitors the opportunity to arrange meetings in advance with key customers and other participants present at the fair, and gives customers the opportunity to ­ by arranging meetings in advance - they use their time effectively and get to know the offer of the selected exhibitors.

A survey conducted among last year's visitors showed that 38% of them were interested in food supplements and functional foods, and 56% in healthy products and products of organic origin. More than 82% of the respondents from the exhibiting companies rated the established business contacts as "significant" for future business, and 88% of the participants would recommend participation in the fair to other companies.

Attractive Polish market

• Poland is the largest economy in the middle and east Europe and the 6th strongest market in the European Union.

• The population of Poland exceeds 38 million, making it one of the largest Eastern European markets.

• Since joining the European Union in 2004, Poland has adopted many legislative reforms. The ease of doing business has improved significantly, according to this criterion ranked 55th in the world. In the last two decade, Poland almost doubled its GDP.

• Poland's positive attitude towards foreign direct investment makes the country an attractive business environment.

Poland has a favorable location and provides easy access to Southeastern Europe and the Baltic countries.

More detailed information: www.nutrafood.pl

Nutramedic &Cosmetics

medicinal plants photo herbarium

Yarrow

Yarrow (Achillea millefolium L., Asteraceae) is one of the oldest medicinal plants known, and the main areas of its application are dyspeptic complaints and spasms in the stomach and digestive tract. Due to its anti-inflammatory, antimicrobial and antifungal effects, it was also used in folk medicine for wound healing.

Yarrow (Achillea millefolium L.) is a perennial herb distributed in Europe, Asia and North America. It was introduced to Australia and New Zealand a long time ago, so today it is considered domesticated and invasive.

Yarrow is a perennial herbaceous plant from the Asteraceae family. The stem is upright, mostly simple, covered with woolly hairs, and grows up to 80 cm in height. The rhizome is horizontal, crawling. The leaves are alternate, oblong­lanceolate, double or triple pinnately divided into numerous fine small segments. The flower heads are 3-5 mm in diameter, gathered in dense, paste-like inflorescences at the top of the stem. They are composed of tubular flowers in the middle and tongue-shaped white or pink flowers on the rim. The fruit is a pod about 2 mm long. 3

It grows wild all over Europe, usually in groups, on dry pastures, fields, meadows and as a weed in gardens. It is propagated by seeds or by dividing the roots in spring or autumn. 3

Use for medicinal purposes

For medicinal purposes, the green parts of the plant Milefolli herba , harvested from VI­X months, or the flowers of the yarrow Milefolli flos are used. The dried flowers contain at least 0.02% of Milefolli aetheroleum essential oil. The stem has no medicinal properties, so it is unnecessary ballast.

The drug is obtained by drying the collected parts in a thin layer at a temperature of 35­40°C.

Ingredients

• essential oil in which: pinene, cineole, azulene, thujone, borneol, caryophyllene prevail

• formic acid

• valeric acid

• bitter substances: achillein

• aconic acid

• sesquiterpene lactones

• tannins

• flavonoids.

Use for medicinal purpose

Yarrow is used in folk medicine to treat skin inflammation, pain, wounds, bleeding and gastrointestinal disturbances.

The bitter substance (achilein) acts as a tonic. It is

used for stomach problems, lack of appetite and dyspepsia.

The results of a study conducted on mice show the anti­ulcer potential of the aerial parts, which is not accompanied by signs of toxicity even with very long chronic exposure.6

Milefolli aetheroleum essential oil is dark blue in color due to its azulene content. It should not be used orally, because it is neurotoxic due to the thujone content, but it is used in cosmetics. Azulene is a highly valued ingredient in suntan creams and oils. It also works well for inflammation of the mucous membrane and skin.

References:

1 Flora Croatica database, hirc.botanic.hr

2 Josip Gelenčir, Jasenka Gelenčir: Atlas ljekovitog bilja, izdavač: Prosvjeta Zagreb 1991.

3 Source: Stolisnik https://www.plantea.com.hr/stolisnik

4 SCHAFNER, Willi: Ljekovito bilje: kompendij, Izdavač:Leo-commerce, 1999.

5 Prof.dr.sc.Zdenka Kalođera, Sveučilište U Zagrebu, Farmaceutsko-biokemijski fakultet, Farmakognozija II, Zagreb, 2006/2007.

6 Cavalcanti AM, Baggio CH, Freitas CS, Rieck L, de Sousa RS, Da Silva­Santos JE, Mesia­Vela S, Marques MC. Safety and antiulcer efficacy studies of Achillea millefolium L. after chronic treatment in Wistar rats. J Ethnopharmacol. 2006 Sep 19;107(2):277­84. doi: 10.1016/j.jep.2006.03.011. Epub 2006 Mar 22. PMID: 16647233.

TAXONOMY

kingdom: Plantae

order: Asterales

family: Asteraceae

genus: Achillea

species: Achillea millefolium

common name common yarrow, old man's pepper, devil's nettle, sanguinary, milfoil, soldier's woundwort, thousand seal

flowering time VI, VII, VIII, IX month

Pomegranate fruit extract linked to improved skin health

Natural ingredient Pomanox® can positively modulate skin health and beauty related parameters

According to a recent in­vitro study conducted by EURECAT and published in the International Journal of Food Sciences1, Euromed's pomegranate fruit extract Pomanox® may reduce unaesthetic signs of skin ageing such as hyperpigmentation, skin dryness and loss of elasticity, by reducing melanogenesis and oxidative stress while modulating collagen and hyaluronic acid metabolism. The results from this proof of concept, in­vitro assay with human foreskin fibroblast cells, therefore suggest that Pomanox® is a promising ingredient for nutricosmetic and beauty­from­within applications.

Skin photoageing is primarily caused by ultraviolet radiation and can lead to the degradation of skin extracellular matrix components, resulting in hyperpigmentation and loss of skin elasticity. In this area, polyphenols have become of great interest because of their antioxidant, anti-inflammatory and healthy ageing properties.

Pomanox®P30 is standardised to more than 50% total polyphenols and not less than 30% punicalagins α+β, making it an ideal candidate for skin ageing studies. Multiple assays evaluated the effects of various concentrations of Pomanox® on human fibroblast Hs68 cells under normal and UV­induced photoageing conditions. The inhibitory effects of Pomanox® on tyrosinase activity were also investigated.

Analysis showed that under normal conditions, Pomanox® significantly increased the collagen and hyaluronic acid metabolism. In cells exposed to UV, both preventive and regenerative treatments with Pomanox® positively influenced hyaluronic acid metabolism and decreased ROS (Reactive Oxygen Species) levels. A significant decrease in levels of MMP1, the main inhibitor of collagen synthesis, was also verified. Finally, Pomanox® showed a significant inhibitory effect on tyrosinase activity, thus potentially reducing hyperpigmentation by decreasing melanin synthesis.

In summary, the results highlight strong properties of Pomanox® in the modulation of several skin health­associated parameters. A clinical study is now being prepared to further investigate and explore these insights.

Pomanox® is a standardised pomegranate fruit extract obtained from pomegranates cultivated in Mediterranean regions of Spain through sustainable farming. It is available in organic form and extracted with an eco­friendly, water­only proprietary techno­

logy. Beyond skin health, Pomanox® is also known to provide proven benefits for cardiovascular and metabolic health, sports nutrition, mood and cognitive health.

Reference:

1 Roger Mariné­Casadó et al. (2022); Pomegranate natural extract Pomanox® positively modulates skin health-related parameters in normal and UV-induced photoaging conditions in Hs68 human fibroblast cells Foods; https://doi.org/10.1080/09637486.2022.2152189

Founded in 1971 by the German pharmaceutical company Madaus, Euromed S.A. is a vertically integrated leading producer of standardised botanical extracts and natural active substances for the pharmaceutical, nutraceutical, food and cosmetic industries to support health and well­being with plant­based solutions. All extracts comply with worldwide GMP norms, international pharmacopoeias and regulations. EUROMED has a long history of expertise in research and development, laboratory analyses and extraction technologies, and is committed to the highest quality standards in terms of analytics, chemistry and evidence­based therapeutics.

www.euromedgroup.com

Bioline a solution for your needs

A company committed to customers' needs and timely service

Bioline is an independent company specializing in providing a variety of pharmaceutical services. Through its representative office, it provides the opportunity to cooperate with a number of selected internationally renowned pharmaceutical companies and manufacturers of medicines, medicinal products, food supplements, cosmetics and food.

We have been a reliable partner for your projects for 23 years. We realize finished products professionally and on time. Our professionalism has been recognized by many clients in the region.

Our advantages:

✓ Speed of product placement – we have a ready range of products ready for placement;

✓ Innovation laboratory ­ "out of the box" ideas;

✓ Superior taste masking, excellent texture, color, quality and stability (stability studies by arrangement);

✓ Development of new product formulations in accordance with market needs, with "added value" that separates you from the competition;

✓ Careful approach that adapts to your needs, professional and timely service, quick reactions to all your inquiries and short deadlines for implementation.

We provide various potential projects and various pharmaceutical forms - tablets, capsules, sticks, sticks for dissolving in the mouth (direct), soft gelatin capsules, sachets with powder for dissolving in water.

We cover numerous markets throughout the region: Slovenia, Croatia, Bosnia and Herzegovina, Serbia, Kosovo, North Macedonia and Montenegro, which we connect with service providers in Portugal, Italy, Poland and Spain, selected with care and emphasis on quality, innovation, flexibility and speed of delivery of desired products.

We give added value to all projects in the form of proposals for new product concepts, thanks to our many years of experience on the international market. So far, we have participated in the successful implementation of more than 50 projects, and the services we offer our partners provide the opportunity to always find the most suitable solution.

Medicines:

• Capsules

• Effervescent granules, granules

• Tablets, film-coated tablets

• Powder

Food supplements:

• Products based on granules: effervescent tablets, water­soluble granules, granules directly dissolving in the mouth without water

Tablets, chewable tablets, fast­dissolving tablets, sublingual tablets, effervescent tablets, coated tablets

• Hard gelatine\vegetarian capsules

• Powders

Sprays Drops

• Twist off soft gelatin capsules

• Soft Gelatin Capsules

• Packaging: sachets, blisters, glass bottles for tablets, tubes, secondary packaging in boxes.

Medicinal products for oral use:

Soft Gelatin Capsules

• Spray

• Syrups

• Drops

Cosmetics, biocides, medicinal products:

• Liquids, gels, creams, ointments, pastes, wipes

• Shower gel, baths, srubs, liquid soaps, intimate care soaps

Creams, milks and oils for the body

• Creams, serums, lotions, tonics, micellar face water

• Toothpastes and tooth gels

• Mouthwash

Wipes

Sun protection products

• Perfumes, scented waters, aftershave lotions, deodorant sticks, deodorant sprays

• Natural and BIO products for disinfection