Gelatin-free Softgels: Compatibility Studiesof SEDDS and SMEDDS Capsule FillFormulations.Norman Stroud*, Keith Tanner*, Elizabeth Youngblood*, Didier Kiyali*,Shawn McKee*, Julien Meissonnier**, Mathieu Schmitt**, and Nathalie Sicre**

Catalent Pharma Solutions, *St. Petersburg, USA, and **Beinheim, France

INTRODUCTIONPurpose• To evaluate the suitability of polysaccharide-based shell formulations for the encap-

sulation of ingredients and formulations used in self-emulsifying drug deliverysystems and self-microemulsifying drug delivery systems.

• The majority of SEDDS and SMEDDS are mobile liquids at room temperature and assuch are formulations that are ideally suited for development as capsule dosageforms. A number of soft gelatin capsule products have been developed in recentyears using fill vehicles that correspond to Lipid Formulation Classification System(LFCS) Type II and Type III, A and B, formulations.3

Background• It is estimated that approximately 40-50% of new drug candidates possess poor

aqueous solubility.1 These molecules often suffer from low bioavailability, lack ofdose proportionality, and high intra-/inter-subject variability.2 In recent years form-ulation strategies have been developed to overcome these challenges that makeuse of self-emulsifying drug delivery systems (SEDDS) or self-microemulsifying drugdelivery systems (SMEDDS). The vehicle of a SEDDS or SMEDDS typically comprisesa lipophilic solvent and a surfactant often in combination with a co-solvent and/orabsorption enhancer. These types of formulations spontaneously generate fineemulsions or micro-emulsions on contact with aqueous media. The emulsions,alone or in combination with endogenous solubilizers and products of digestion,present the drug to the sites of absorption in the GI tract in a form that allows forready absorption of the drug. In addition, for some of the emulsifying systems, thevehicle is formulated specifically utilizing digestible lipids to allow for a high degreeof in vivo digestion that gives rise to products of digestion that interact with the drug, and substantially aid its absorption.3-5

Table 1. Lipid Formulation Classi�cation System3

1 SEDDS without water-soluble components2 SEDDS/SMEDDS with water-soluble components3 SMEDDS with water-soluble components and low oil content

Excipients in formulation

Oils: triglycerides or mixed mono-and diglycerides

100 40-80SEDDS 1 SEDDS/SMEDDS 2 SMEDDS 3

20-60

40-80 <20

0-20

30-80

0-50

20-5020-40

20-500-40

—

—

—

—

— —

—

—

Water-insoluble surfactants(HLB<12)

Water-soluble surfactants(HLB>12)

Hydrophilic cosolvents (e.g. PEG,propylene glycol, transcutol)

Content of formulation (%, w/w)Type I Type II Type IIIA Type IIIB Type IV

• Formulation studies conducted using conventional, gelatin-based, soft capsuleshave shown that, although SEDDS and SMEDDS exhibit, for the most part, goodcompatibility with the capsule shells, some limitations exist for some of theSEDDS/SMEDDS ingredients.

• This poster presents the results obtained from compatibility studies conducted usingpolysaccharide-based, gelatin-free capsule shells.

Scope• Investigate the compatibility of SEDDS and SMEDDS, and the individual ingredients,

with 1) conventional, gelatin-based capsule shells and 2) gelatin-free capsule shells,in which iota-carrageenan and hydroxypropylated starch comprise the film-formingpolymers.

SEDDS/SMEDDS ingredients• Capmul MCM Glyceryl mono- & dicaprate (5% TG, 36%

DG, 58% TG, 80% C8, 20% C10)• Capmul MCM C8 Glyceryl monocaprylate• Captex 500 Glyceryl triacetate

MATERIALS

• Cremophor EL Polyoxyethylene 35 castor oil (HLB 12-14)• Cremophor RH40 Polyoxyethylene 40 castor oil (HLB 14-16)• Tween 80 Polyoxyethylene 20 sorbitan monooleate

(HLB 15)• Oleic acid 9-octadeconoic acid• Caprylic acid Octanoic acid• Transcutol Diethylene glycol monoethyl ether• Propylene glycol• Ethanol• Water

Figure 1. Structure of Polyoxyethylene 20 sorbitan monooleate

Ingredients used in the shell formulation studies• Gelatin NF

• Polyol plasticizers(Glycerol, Sorbitol, Sorbitol Sorbitan Solution)

• Hydroxypropylated starch

• Iota-carrageenan

• Di-sodium phosphate

• Purified water

METHODS• Polysaccharide-based capsule shell compositions were developed using hydroxypro-

pylated starch and iota-carrageenan in combination with polyol plasticizers andwater. Softgels were prepared from these compositions in accordance with theformulations and processes described in US patents:

- 6,582,727 - 6,340,473

• Gelatin-based capsule shell formulations were prepared using conventional comp-ositions and processes.

• SEDDS and SMEDDS were formulated based on the information obtained fromternary and quaternary mixtures of ingredients known to be compatible withgelatin-based capsule shells. Phase diagrams were constructed, where appropriate.

• Initially, shell/fill compatibility studies were conducted by hand-filling empty tubesoftgels. The study included a comparison of the performance of sealed capsulesproduced using 1) gelatin shell compositions and 2) polysaccharide-based shellcompositions.

• The compatibility of the capsule shells with the SEDDS and SMEDDS ingredient andfill formulations was investigated using room temperature and elevated temp-erature storage conditions.

• Encapsulation trials were conducted using the polysaccharide-based shells in combi-nation with fill formulations that are representative of current SEDDS/SMEDDScapsule products. The gelatin-free softgels were produced using the rotary-dieencapsulation process, as described in US patent:

- 6,884,060

Figure 2. Softgel Manufacture using the Rotary-die Encapsulation Process

Capsule Shell DevelopmentComposition of Capsule Shell Formulations

EXPERIMENTAL STUDIES

Table 2. Composition of Polysaccharide-based Shell Formulations

Hydroxypropylated starch

iota-carrageenan

Polyol plasticizer

Di-sodium phosphate

Water

Shell polymer 33-37

7-12

36-42

1

10-12

Shell polymer

Plasticizer

Buffer

Water associated withplasticizer & polymers

Ingredient Functional role in shell % w/w of dry shell

• Shell formulations were developed containing blends of the twopolysaccharides in the ratio 2.5—3.5 : 1, hydroxypropylated starch :iota-carrageenan. The ratio of plasticizer to shell polymers was keptconstant, at 0.8 : 1.

Fill Formulation DevelopmentPhase Diagrams

• Ternary and pseudo-ternary phase diagrams were constructedusing two techniques:

1) the traditional, ingredient matrix approach, in which appropriate amounts of each component are weighed into glass tubes, mixed well, and assessed for the form, or phase state, of the resulting mixture, and

2) the water titration method in which the surface/co-surfactant, and oil are mixed and then titrated with the aqueous component, mixed well, and assessed for the phase state of the resulting mixture. Graphical representations of the phases were produced using the ProSim Ternary Diagram software program.

Figure 3. Ternary phase diagram for the system Capmul MCM C8, Tween 80 and Water

Figure 4. Pseudo-ternary phase diagram for the system Capmul MCM/Tween 80 (1:1),Captex 500 and Water

Tween 80

0.1

01 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0 0

0.1

0.2

0.3

0.4

0.5

0.7

0.8

0.9

1

0.6

Compatibility studies: ingredient and formulation screening• The initial studies were conducted by hand-filling empty tube softgels. The tubes

were filled with the ingredient or formulation and sealed by melting and fusingtogether the open ends. The sealed softgels were maintained at room and elevatedtemperature storage conditions and monitored for time- and temperature-dependent changes.

Encapsulation trials• Encapsulation trials were conducted using the polysaccharide-based shells, in

combination with examples of the fill formulation types shown in tables 3 and 4.

Table 4. Examples of the characteristics of drugs formulated in SEDDS or SMEDDS

Molecular weight CLog P Calc S

≈720

≈603

≈629

5.3

7.2

6.1

370 ng ml-1 at pH 6, 25°C

5 μg ml-1 at pH 6, 25°C

40 μg ml-1

Capsule Shell Development• The most suitable gelatin-free shell compositions were found to comprise - iota-carrageenan : hydroxypropylated starch in the ratio, 1.0 : 2.5 - Sorbitol-based plasticizers

Plasticizer : shell polymer in the ratio, 0.8 : 1.0

Compatibility studies• The majority of the ingredients evaluated were found to be compatible with both

shell systems. However, ingredients such as ethanol, propylene glycol, and mono-caprylate esters were tolerated at higher levels by the polysaccharide-based shellsystem than by the gelatin shell system. The findings from the studies are summar-ized in table 5.

Encapsulation studies• Liquid-filled soft capsules containing SEDDS or SMEDDS were

successfully produced using the gelatin-free, polysaccharide-basedshell compositions.

• Ingredients such as octanoic (caprylic) acid exhibited limited compatibility with thegelatin-based shell formulations but were found to be fully compatible with thepolysaccharide-based shells. SEDDS formulations containing appreciable amountsof octanoic acid de-stabilized gelatin-based capsule shells. Unlike their gelatin-basedcounterparts, the polysaccharide-based softgels retained their physical integrityduring storage testing.

RESULTS

Table 5. Summary of the �ndings from the compatibility screening study

Medium chain triglycerides, diglycerides

Long chain triglycerides, diglycerides

Caprylate mono- & di-esters

Long chain fatty acids

Medium chain fatty acids (e.g. C8)

Ethoxylated surfactants

Low molecular weight, polar solvents

Similar in both shell systems

Similar in both shell systems

Similar. Slight improvement in compatibilitywith the polysaccharide-based shells

Similar. Slight improvement in compatibilitywith the polysaccharide-based shells

Similar in both shell systems

Significant improvement in compatibility withthe polysaccharide-based shells

Similar in both shell systems

Ingredient type Compatibility,observations and comments

It has been demonstrated that the novel, polysaccharide-based softgel shells arecompatible with ingredients and formulations used in self-emulsifying drugdelivery systems and self-microemulsifying drug delivery systems. In certaincases, the polysaccharide capsule shell exhibits superior compatibility withSEDDS or SMEDDS, compared to conventional gelatin-based shells.

CONCLUSION

Table 3. Examples of di�erent SEDDS and SMEDDS vehicle compositions

Cremophor EL

Ethanol

Propylene glycol

Capmul MCM

Cremophor EL

Ethanol

Oleic acid

4-10

6-14

65-85

55-65

8-18

6-16

8-20

Formula 1

Ingredient % w/w (range) Ingredient % w/w (range)

Formula 2

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Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings.Advanced Drug Delivery Reviews. 2001, 46: 3-26

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3. Pouton, C.W.Formulation of poorly water-soluble drugs for oral administration: physicochemical and physiological issues and the lipidformulation classification system.European Journal of Pharmaceutical Sciences. 2006, 29: 278-287

4. Pouton, C.W., and Porter, C.J.H.Formulation of lipid-based delivery systems for oral administration: materials, methods and strategies.Advanced Drug Delivery Reviews. 2008, 60: 625-637

5. Porter, C.J.H., Pouton, C.W., Cuine, J.F., and Charman, W.N.Enhancing intestinal drug solubilisation using lipid-based delivery systems.Advanced Drug Delivery Reviews. 2008, 60: 673-691

Water Capmul MCM C8