Galenic forms of dietary supplements - from capsules to gummies

The major concern in the development of dietary supplements is the requirement to obtain a stable finished product that releases the contents appropriately into the digestive system and at specific points of absorption and utilization.

Today, in contrast to the beginnings of the development of the food supplements market, the dosage or galenic forms in which food supplements are available on the market are diverse. There is a large number of dosage forms, over time this number becomes larger, and the production technology is more and more sophisticated and complex. The direction in which this development is moving is guided by the needs of consumers.

With consumers, there is often a so­called pill fatigue especially in the elderly population, chronic patients, or patients who have difficulty swallowing. These groups of consumers need to take several types of medicine every day. Medicines are usually found in capsules or tablets that must be swallowed with

water or another liquid. In addition to medication, i.e., regular therapy, they often take nutritional supplements that support the therapy. In such cases, a person should swallow 7 or more types of tablets or capsules daily. It is no wonder that such a daily intake of a large number of medicines and/or food supplements can cause "pill fatigue".

Because of this, the food supplement market has moved in the direction of finding new solutions and developing new technologies. The main motive and direction of this development are to make the consumption of dietary supplements as pleasant as possible and thereby increase the cooperation of consumers. In addition to this motive, the simplicity of application is also important, the so­called on­the­go

The major concern in the development of dietary supplements is the requirement to obtain a stable finished product that releases the contents appropriately into the digestive system and at specific points of absorption and utilization.

AUTHOR: Daria Šurić, M.pharm.

variants, consumption without the need to drink the liquid. In addition, one of the demands of consumers is that supplementation should be a pleasant and positive experience.

There are exact data available to the food supplement industry, which deal with the analysis of the representation of individual pharmaceutical forms in the food supplement market. The research conducted by Saldanha et al.1 on the American market showed that due to the different forms of food supplements, can affect not only the bioavailability of the ingredients they contain but also the methods needed for their analysis. Consumers may also prefer certain product forms, for example, powders and softgel capsules or gummies over tablets. The research results showed that 48% of all products on the market were in the form of capsules, followed by tablets (22%), powders (14%), and liquids (11%). All other forms accounted for 5% of the product, including 0.8% of gummies.

The PlantLIBRA2 consumer survey included a total sample of 2,359 adult herbal products consumers from Finland, Germany, Italy, Romania, Spain, and the United Kingdom. The popularity of herbal products in Europe is increasing, and consumers are using them

to supplement their diet or to maintain their health. The products are taken in many different forms (e.g., teas, juices, herbal medicines, and herbal dietary supplements). The aim of the survey was to provide an overview of the characteristics and usage patterns of herbal dietary supplements among consumers in six European countries. The survey showed that the most commonly used dosage forms are capsules (38.3%) and tablets/lozenges (36.8%). No significant difference was observed by gender or age (Table 1). In the six countries, solid forms were generally the most popular, although capsules were less frequently used in Romania (17.7%). Liquid forms were less common in Great Britain (8.2%) and Germany (9.9%), but more common in Finland (26.2%) and Italy (26.4%) (Table 2). There is a lack of data on the use of such products at the European level.

Capsules

The word capsule is derived from the Latin word "capsula" which means a small box or container. The gelatin capsule was invented at the beginning of the 19th century as a result of the need to mask the unpleasant taste of many medicinal substances. 3

Hard capsules

Hard capsules consist of two parts that "enter" each other and thus close the capsule. They can contain filling in the form of powder, granules, liquids, minitablets, pellets, microcapsules, or even smaller hard capsules in liquid filling. In the case of granules, pellets, and spherical microcapsules, the mass of active substances in the filling mass is reduced compared to the powder itself, because the lower density of the filling and the production of these forms require additional auxiliary substances.

Hard capsules as a galenic form are particularly suitable for vitamins and minerals as well as herbal powders and powdered extracts. They consist of two halves. The lower half, which is slightly smaller in diameter and is called the "body" - is filled, while the larger diameter "cap" is placed on the filled lower half as a cap or lid. The fine grooves ensure that the body and lid are tightly closed, which means that the capsule cannot break into two halves and that the powder cannot escape through the joint.

Capsule shells exist in different, internationally standardized sizes. When it comes to nutritional supplements, sizes from 1, 0, to 00 are most often used (Table 3). Depending on the density of the powder, hard capsules can generally contain between 288 to 1,080 mg of filling.

Hard capsules can be made of different basic materials. The most important of these are gelatin and HPMC (hydroxypropyl methylcellulose) as a vegetarian alternative (cellulose derived from plant material). HPMC capsules are also suitable for encapsulating hygroscopic active ingredients due to their low moisture content. Gelatin for the production of gelatin hard capsules is obtained by a production process from pig or beef collagen. There are also fish collagen capsules. Gelatin capsules are easily broken down in the body.

Products with prolonged release of active substances are often found in capsule form. For example, pellets or granules coated with polymeric substances that dissolve at different pH values can extend the time of the continuous release of the active substance.

An interesting option are HPMC capsules that are resistant to the acidic pH of the stomach and that allow the capsule shell to dissolve in the intestines.

Thus, a delayed release of the active substance is achieved. Probiotics and enzymes are sensitive to acids, so their effectiveness may decrease as they pass through the stomach and low pH on the way to the intestinal tract. Delayed­release capsules are an ideal delivery method that can help maintain the maximum effectiveness of probiotics and food enzymes. Even organic products can be developed in hard capsules because according to Annex VIII of Regulation (EC), no. 889/2008 allowed the use of HPMC capsules as long as the capsule shells do not contain other excipients.

Consumers like hard capsules, because they are easy to swallow and mask the taste and smell of active substances. They can be transparent, and of different colors, and there is also the possibility of printing text, logos, and product names.

Soft capsules

Soft capsules can be used for solid, liquid, and semi­liquid ingredients. They can be round (pearls), ovoid, or cylindrical with rounded ends. They contain additives (e.g. sorbitol, propylene glycol, glycerin) that give them flexibility. They are usually filled with oil or suspensions. They may also contain dry substances, including compressed tablets (geltabs).

The primary types of gelatin used in soft gelatin capsules are usually from beef or pork sources. Depending on the filling, formulation, and target market group, producers have flexibility in the type of raw materials, with some opting for a combination of pork and beef options. Bovine bone gelatin, for example, contributes to the strength of the capsule. Pig options, on the other hand, offer the characteristics of flexibility.

Gelatin dissolves in the human body at normal body temperature, which makes it an ideal ingredient for soft gelatin capsules. The valuable active substances inside the capsule are protected from oxygen, light, moisture, and dust, and such a capsule allows consumers to easily swallow it. Soft capsules can be from a vegetarian source, starch, or, for example, based on carrageenan. It is a group of long­chain carbohydrates (polysaccharides) found in the cells of various types of red algae.

Soft capsules are particularly suitable for encapsulating oils, emulsions, or other similar materials to a paste­like consistency. Unlike the two halves of a hard capsule, these capsules are not prefabricated. Instead, they are made directly during the filling process from two ribbons of capsule material running over each other via a so­called "rotary die" process, which uses rotating rollers. The material to be placed inside the capsule is then enclosed in two capsule shells of the same shape, which are firmly stitched together.

There are different shapes of soft capsules - round, oval, oblong, or so-called. twist-off capsules. They have a small extension that can be unscrewed by hand. This means that the material inside the capsule can be emptied and consumed through the opening thus created, without the need to consume the capsule itself. A wide range of sizes is also available, with fill amounts of around 1.200 mg typically representing the upper limit of what a person can reasonably be expected to ingest.

Gelatin capsules contain a certain percentage of

moisture. This can lead to unwanted interactions with highly hygroscopic ingredients, such as magnesium oxide or tannins. Hygroscopic powder binds moisture from the gelatin capsule shell. Because of this, the capsule shell loses its flexibility, so this should be taken into account when developing formulations for soft gelatin capsules.

Chewable soft gelatin capsules

Soft gelatin chewable capsules are one of the newer forms of dietary supplements. They are suitable for ingredients that are normally found in large capsules that are difficult to swallow, e.g., for omega-3 fatty acids. The development of technology strives for thinner shells in order to accelerate their dissolution in the mouth, for a more positive consumer experience. When chewing, there is a pleasant taste of the sweet, creamy liquid contained in the capsule.

What is the difference between soft and hard capsules?

Hard capsules consist of two cylindrical parts ­ each closed at one end, which fit perfectly into a hermetically sealed unit. The hard capsule parts are manufactured before filling with the active ingredient. In the next manufacturing step, contract manufacturers or brand owners fill the active ingredient or drug into empty gelatin capsules.

Soft capsules are one­piece and hermetically sealed and contain a liquid or semi-solid filling. Unlike hard capsules, soft capsules are filled at the same time as the capsule is manufactured. They have a larger range of dimensions, and they differ from manufacturer to manufacturer, depending on the filling and production technology. The exact dimension of the capsule is known only after the production of the filled capsules is completed, unlike hard gelatin capsules, where the dimension is pre­standardized since the empty capsules are produced before filling.

The biggest advantage of capsule production technology is that they can be filled without applying any pressure, or with relatively little pressure. Exposure of nutrients to heat stress is another aspect that can be minimized or avoided entirely. Moreover, the envelope not only protects the contents from environmental influences but also protects the taste receptors from a potentially unpleasant taste. For example, many people prefer fish oil capsules whose capsule shell prevents direct contact of the oil with the mucous membrane of the oral cavity, or hard capsules that envelop the active substances and thus give them a shape that can be easily swallowed. Hard capsules can be opened if necessary and the contents consumed without a capsule, e.g., probiotics for small children. A similar option is offered by the so-called twist-off soft gelatin capsules. An example of such a product is vitamin K1 capsules for infants.

Tablets

Tablets are ingredients in powder form, which are mixed with auxiliary substances (additives) so that they retain a certain shape. They can be coated or uncoated. One of the advantages of tablets is that the ingredients are compressed, so in some cases, they can contain a larger amount of active substances than capsules.

Sometimes creating a formulation for a technically optimal tablet requires a complex development process. However, tablets allow for some variations that capsules do not. Effervescent tablets or tablets with a dividing line that allows breaking into smaller pieces are just one example. Coatings are another aspect that can be easily implemented on tablets, for visual or technical reasons, or to ensure the gastro­resistance of the tablet. After being swallowed, the tablet breaks down very quickly into smaller and smaller units until it finally dissolves completely. According to the European Pharmacopoeia, a maximum decomposition time of 15 minutes is to be expected. With filmcoated tablets, this is extended to 30 minutes.

High pressure is required to press the tablets. For this reason, not all raw materials are suitable for tablets. For example, high pressure can have a negative effect on the structure of the oil matrix of most oil powders, leading to the release of free oils immediately, or after some time. This is a phenomenon that can be seen on the surface of the tablet in the form of a greasy stain.

The gentlest process is the so­called "direct compression". When the raw materials are suitable for this, they are directly mixed with the excipients of the tablet and pressed. This means that it is not necessary to carry out granulation in advance, which is time­consuming, expensive, and potentially aggressive toward the content.

The entire tablet­making process requires compression in a confined space, where the upper and lower punches are pressed from opposite directions within the die under a certain pressure, sometimes up to six tons, to produce the finished tablet. When choosing the ingredients for the formulation, it is important to consider the heat generated by such pressure. This heat is often harmful to the sensitive components in the tablets, so they sometimes need to be added in excess to ensure shelf­life stability. Compounds that are sensitive to heat, moisture, or UV light must also be protected within the tablet, which is why many tablets go through an additional film-coating process, involving a protein or polymer, usually with a final thickness between 20 and 100 micrometers (very thin). The reason why tablets are often coated is to protect the ingredients from deterioration, to reduce tablet edges from erosion du­

ring packaging and transport, and to mask the unpleasant taste or smell of the ingredients.

Multilayer tablets

The advantage offered by the technology of multilayer tablets is the division into different layers of otherwise incompatible active ingredients, which should be released at different times and in different places of the gastrointestinal tract. An example is probiotics in combination with vitamins and minerals ­ probiotics are in a separate layer from vitamins and minerals, protected from the harmful effects that certain minerals and vitamins can have. This ensures the stability of the product.

Products containing melatonin are another example. Namely, one layer enables the rapid release of melatonin, while the other enables a prolonged release, which ultimately ensures a continuous release during the night, important for the effect of such a dietary supplement.

Effervescent tablets

The production of effervescent tablets is a particularly sensitive technology. Formulations generally include an agent capable of releasing CO2 (e.g., sodium carbonate and sodium bicarbonate) and an agent that promotes the release of CO2 (e.g., citric acid). The formation of carbon dioxide is the result of a chemical reaction that takes place between a carbonate or bicarbonate salt (e.g., sodium bicarbonate) and a weak organic acid (e.g., citric or tartaric acid) in the presence of water. That is why strict humidity control is mandatory in all production areas. Any packaging material used for effervescent tablets should protect them from external influences and keep as little air as possible in the package since moisture present in trapped air can lead to physical and/or chemical degradation of the tablet (Altomare et al., 1997). They are most often packaged in plastic tubes that contain desiccant in plastic caps.

The development process of the formulation may take longer in the phase of defining the organoleptic characteristics. It is necessary to make a suitable sample that meets the organoleptic requirements.

Effervescent tablets may contain higher dosage amounts compared to conventional tablets. There is no need to swallow, thus improving compliance, especially for elderly and pediatric users. Also, they enable improved dosing, and due to the generation of CO2, all ingredients are automatically mixed.

Orally Dissolving Tablets (ODT)

These are products designed to quickly disintegrate, or dissolve in the mouth on contact with saliva, eliminating the need to chew the tablet, swallow the tablet intact, or take the tablet with liquid. Initially, it was expected that this route of administration would be useful in the production of drugs for pediatric and geriatric patients, for people with conditions related to impaired swallowing, and for the treatment of patients who are difficult to cooperate with (e.g., in psychiatric disorders). Today, ODT appears more and more often in the category of food supplements, and products for better sleep in this form are especially interesting because they do not require additional liquid consumption before bedtime.

Sticks and sachets

In the field of dietary supplements, sticks, and sachets are a newer and very "trendy" alternative to capsules and tablets. They cause great interest among consumers. Depending on the concentration, the sticks may contain approx. 1­10 grams of powder or granules. In this way, it is also possible to develop products that meet health claims and contain higher amounts of active substances. One stick can replace many capsules, and reducing intake to one serving per day makes the product less complicated and more popular among consumers. Stik powder can be taken according to the consumer's taste ­ directly dissolved in the mouth (direct), dissolved in water, juice, or milk, mixed in yogurt, or in various other food.

Granules and powders have different advantages. While granules can be well mixed together and do not create fine dust, the advantage of powders is that they do not undergo expensive and time­consuming preliminary treatments. Granulation burdens the contents due to the heat of drying. Moreover, it is necessary to add a carrier material ­ usually sugars and to some extent solvents. However, granulate is much more suitable than powder for sticks that dissolve directly in the mouth (it is possible to achieve a better taste and less dusting when applied in the mouth).

As with other shapes, it is important that the finished mixture is uniform and flowable. Moreover, when it comes to them, the components should not have too strong an individual taste. If the basic mixture of ingredients is relatively neutral, it is easily combined with aromas and with sweet and fruity­sour ingredients. This enables a wide range of product variety, which benefits the consumer.

A portion of powder or granules in stick form is the ideal dosage form for those who have problems swallowing capsules or tablets. Individual sticks or sachets are also easier to carry in your bag than a blister pack or a whole box of the product.

Sachets containing powder with probiotics are the most popular way of using probiotics because by dissolving them in water before consumption, the probiotics are reactivated before they are introduced into the body.

Recently, sticks with liquid or gel filling are gaining popularity. They are particularly interesting for use by athletes or, for example, for single doses of syrup.

Sachets with powder that dissolves in a liquid have been on the market for a long time and are the most common way of applying rehydration solutions.

Gummies

Gummy candy is currently the star of the industry ­ it's the most sought­after and most popular new form of dietary supplement according to the Nutrition Business Journal's (NBJ) 2022 Report. Last year, when NBJ surveyed 1,005 consumers who preferred the pharmaceutical form—27.4% of respondents chose gummy candy, 25 .1% chose tablets, 19.7% opted for capsules, and 13.1% chose soft gelatin capsules as their choice.

These "crossbreeds" between the pharmaceutical form and sweets, the so­called "candyceuticals", cover various purposes, from sleeping to sports.

Key factors driving the gum products market include their availability in different flavors for cus­tomers looking for tasty health benefits, ease of use, variety of unique flavors, and tasty formulations offered by manufacturers to appeal to children and adult consumers.

Gummy candies can be produced with gelatin, and vegetarian variants with pectin.

Sprays

Proponents of oral sprays point out that they enable faster absorption of nutrients. The study, published in the European Journal of Clinical Nutrition, was part of a three­year research project that concluded that the oral spray method of vitamin D was as effective as taking capsules, and supported the same rate of improvement in vitamin D levels in subjects. Taking vitamin D in an oral spray is just as effective as taking a pill, according to research from the University of Sheffield.4

Nutrients are absorbed sublingually in larger quantities than with other forms that first pass through the digestive tract and are metabolized by the liver and kidneys. For this reason, nutrients should have better bioavailablity. This effect is especially pronounced when one of the organs is damaged, for example with leaky intestines. Several studies have provided results in support of this claim.5,6 However, since there are still many unknowns about the application and stability of the various ingredients in the spray, much more research is needed on this topic. For now, it looks like a promising form whose additional advantages are ease of application and a small number of additives.

Other forms

In addition to the mentioned forms, there are many more classic galenic forms such as syrups, and modern ones such as lollipops. Dietary supplements are increasingly becoming attractive and at the same time a practical way to improve the quality of life by taking in nutrients. All the mentioned dosage forms enable the taking of nutritional supplements to be adapted to today's flexible and fast lifestyle. Despite this, classic forms such as capsules and tablets still have their important place on the market.

References:

1 Saldanha, Leila G et al. “Characteristics and Challenges of Dietary Supplement Databases Derived from Label Information.” The Journal of nutrition vol. 148,suppl_2 (2018): 1422S-1427S.

2 Garcia­Alvarez A, Egan B, de Klein S, Dima L, Maggi FM, Isoniemi M, Ribas­Barba L, Raats MM, Meissner EM, Badea M, Bruno F, Salmenhaara M, Milà­Villarroel R, Knaze V, Hodgkins C, Marculescu A, Uusitalo L, Restani P, Serra­Majem L. Usage of plant food supplements across six European countries: findings from the PlantLIBRA consumer survey. PLoS One. 2014 Mar 18;9(3):e92265.

3 Kathpalia, Harsha and Gaurav Mahesh Doshi. “Recent trends in Hard Gelatin capsule delivery System.” (2014).

4 Claire E. Williams, Elizabeth A. Williams, Bernard M. Corfe. Rate of change of circulating 25­hydroxyvitamin D following sublingual and capsular vitamin D preparations. European Journal of Clinical Nutrition, 2019.

5 Jacobson BH, Smith DB, Warren AJ, Glass RG, Kline C, Fedick JL, Stemm J. Assessment of the effectiveness of a sublingual, ergogenic spray on muscle strength and power. J Strength Cond Res. 2009 Nov;23(8):2326­30.

6 Satia, M., Mukim, A., Tibrewala, K. et al. A randomized two way cross over study for comparison of absorption of vitamin D3 buccal spray and soft gelatin capsule formulation in healthy subjects and in patients with intestinal malabsorption. Nutr J 14, 114 (2015).