Case Study 3: NCE bioavailability enhancement using a SMEDDS formulation
Objectives Company B (undisclosed due to confidentiality reasons) engaged Tillotts Services for the development of a lipid based oral formulation with the objective of improving the oral bioavailability of their active “Compound X�. A key objective of this work was to establish the long term product stability and effect process transfer to production.
Background Figure 1. The goal of our formulation development
Low Solubility
High Permeability
High Solubility
Class I Formulation Class II High Low Solubility Solubility High High Permeability Permeability 5% 70%
Low Permeability
Today around 70% of the new chemical entities (NCEs) entering drug discovery and development programs in the pharmaceutical industry have sparingly water solubility and high lipophilicity. These compounds are classified as Class II according to the Biopharmaceutical Classification System (see Figure I). The development of lipid self dispersing formulations is in these cases driven by the desire to increase and/ or make reproducible the oral bioavailability of these molecules. Compound X (not disclosed) is a small molecule (MW<600). The aqueous solubility of the active is low in acidic media (0.1 M HCl) and in media with more physiological pHs (up to ca. pH 7.2). Since the lipophilicity of the active is rather high with a CLogP>3, it is classified as a Class II compound. The goal of the formulation development conducted was to identify at least one lipid formulation able to overcome the pH dependent solubility of the active and improving its oral bioavailability at the desired dose in vivo.
Class III High Solubility Low Permeability 5%
Class IV Low Solubility Low Permeability 20%
Formulation Development Strategy Development of Self Micro-emulsifying Drug Delivery Systems (SMEDDS) Solubility in excipients with different H.L.B. values Microemulsion development (pseudo ternary phase diagrams) Dispersion/Precipitation tests in aqueous media In vitro dissolution of hard gelatine capsules Dissolution Parameters 500 ml media, paddle method, 75 rpm, 37°C, 6 hours Media: Fasted State Simulated Intestinal Fluid (FaSSIF) Formulation tested Conventional capsules (powder filled) Oily formulation-capsules SMEDDS-capsules
In vivo Pharmacokinetic (PK) study in beagle dogs
Results and Discussion
Table 1 summarizes the kinetic solubility of Compound X in a set of galenical excipients having different hidrophilic lipophilic balance (H.L.B.) values. While the solubility of the active in cosolvents was rather low, the compound highly dissolved in oily excipients as well as in most of the non-ionic surfactants investigated. Based on these results three lipid formulations were developed for the compound, one as a pure oily formulation (active dissolved in an oil) and the others as SMEDDS developed using pseudo ternary phase diagrams, respectively. The dissolution of the formulations was investigated in vitro using Fasted State Simulated intestinal Fluid (FaSSIF) as biorelevant media. FaSSIF was selected due to a previous finding indicating that conventional oral forms of the active did show lower oral exposure in fasted vs. fed state in the dog. This result was hypothetically attributed to the low solubility of the compound as well as the solubilising properties of the mixed micelles formed after digestion of lipids in fed state.
Š Copyright 2010 : Tillotts Services, a business unit of Tillotts Pharma AG, a subsidiary of Zeria Pharmaceuticals Co. Ltd.
Table 1. Solubility of Compound X in galenical excipients
Excipient
Chemical denomination
Type
H.L.B
PEG 400
Polyethylene glycol 400
Co-solvent
-
S < 25
Ethanol
EtOH
Co-solvent
-
S < 10
Sesame oil
Sesame oil
Oil
1-2
S > 100
Labrafac lipophyle WL 1349
Medium chain triglycerides-MCT
Oil
1
S > 100
Labrafac PG
Propylene glycol dicaprylocaprate
Oil
2
50 > S > 25
Labrafil M-1944 CS
Oleoyl polyoxylglycerides
Co-surfactant
4
S > 100
Labrafil M-2125 CS
Linoleoyl polyoxylglycerides
Co-surfactant
4
S > 100
Lauroglycol FCC
Propylene glycol monolaurate (Type I)
Co-Surfactant
5
50 > S > 25
Lauroglycol 90
Propylene glycol monolaurate (Type II)
Co-Surfactant
5
50 > S > 25
Plurol oleique CC
Polyglyceryl-3 dioleate
Co-surfactant
6
100 > S > 50
Labrasol
Caprylocaproyl polyoxyglycerides
Surfactant
14
S > 100
Gelucire 44/14
Lauroyl polyoxyglycerides
Surfactant
14
S > 100
Solutol HS 15
Macrogol 15 Hydroxystearate
Surfactant
14
S > 100
Cremophor EL
Polyethylene glycol-35 castor oil
Surfactant
14
S > 100
Tween 80
Polyoxyethylene sorbitan monoleate
Surfactant
15
100 > S > 50
Cremophor RH 40
PEG-40 Hydrogenated Castor Oil
Surfactant
14-16
S > 100
Š Copyright 2010 : Tillotts Services, a business unit of Tillotts Pharma AG, a subsidiary of Zeria Pharmaceuticals Co. Ltd.
Solubility
(mg/mL)
% Dissolved
Figure 2 represents the in vitro dissolution behaviour of the lipid based formulations as well as conventional solid form capsules (control) of Compound X. An erratic release was observed with the conventional capsules probably due to the 100 low intrinsic aqueous solubility of the active. A better dissolution profile was observed with90the simple oily solution. This may have 80 been driven by an in situ emulsification and solubilisation process by the sodium taurocholate 70 and lecithin from the media together with the oily excipient of the formulation. However, it only 60 101 100 led to 20% of compound dissolved and a trend to precipitation was observed over time. The 50 most promising results were obtained with the SMEDDS formulations 1 and 2, respectively. In 40 the case of the SMEDDS-1 almost 100% of the active was kept dissolved along the dissolution 30 test. The PK results obtained after the oral administration to fasted dogs of either conventional 20 capsules or capsules containing the SMEDDS-1 are summarized in Figure 3. More than two 10 folds increased in Cmax and of the overall oral exposure was observed in the dogs dosed with 0 the SMEDDS-1. These results perfectly correlate with the findings 0 in vitro 1 2 3 suggesting 4 5 that 6the Time (hours) improved solubility may have led to the improved oral exposure in vivo.
Figure 2.
SMEDDS 2-caps
Pure Oil-caps
Conventional caps
Figure 3.
25000.000
100 Plasma concentration (ng/mL)
90 80 70 % Dissolved
SMEDDS 1-caps
60
101
100
50 40 30 20 10
SMEDDS-capsules
20000.000
Conventional caps (Powder)
101
15000.000
100
10000.000 5000.000 0
0 0
1
2
3 4 Time (hours)
5
6
SMEDDS 1-caps
SMEDDS 2-caps
Pure Oil-caps
Conventional caps
0
5
10
15 20 Time (hours)
25
Plasma concentration (ng/mL)
SMEDDS-capsules
20000.000
Conventional caps
(Powder) Conclusions 101
100
15000.000
The SMEDDS developed shown a significant increase of dissolution of the active in a bio-relevant media (FaSSIF)
10000.000
Two folds increase of oral exposure was observed in dogs with SMEDDS-1 capsules
5000.000 0 0
5
10
Long term physical and chemical stability of the lipid based 15 20 25 30 formulations under investigation
Time (hours)
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For further information on how Tillotts Services* can help with your formulation development options, clinical drug product supply or commercial liquid-fill manufacture, please contact us at: E: services@tillotts.com or W: www.tillotts.com
*Tillotts Services is a business unit of Tillotts Pharma AG, a subsidiary of Zeria Pharmaceuticals Co. Ltd.
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25000.000
30