WO1996040083A2

WO1996040083A2 - Methods and compositions for preparing soft gelatin capsules having shells resistant to permeation by fill materials

Info

Publication number: WO1996040083A2
Application number: PCT/US1996/009145
Authority: WO
Inventors: Mani R. Sundararajan; Elizabeth Youngblood; Gilbert T. Rodrigues; David J. Walker; Peter Beke; Norman S. Stroud
Original assignee: R.P. Scherer Corporation
Priority date: 1995-06-07
Filing date: 1996-06-06
Publication date: 1996-12-19
Also published as: SK164897A3; HUP9900858A2; CZ381897A3; AU6154696A; MX9709198A; WO1996040083A3; CA2222120A1; BR9608608A; PL323790A1; KR19990022443A; EP0837675A2; NZ310708A; IL122422A0; CN1186429A; JPH11506785A

Abstract

Disclosed are gelatin capsules having a means for isolating the fill material from the gelatin material forming the shell of the capsule.

Description

METHODS AND COMPOSITIONS FOR PREPARING

SOFT GELATIN CAPSULES HAVING SHELLS

RESISTANT TO PERMEATION BY FILL MATERIALS

BACKGROUND OF THE INVENTION Field of the Invention

This invention relates to the field of gelatin capsules containing a fill material comprising a liquid phase. More specifically, this invention relates to gelatin capsules compris¬ ing a gelatin shell rendered impervious to migration of the fill material into the gelatin shell. Description of the Related Art

Soft gelatin capsules or softgels are predominantly used to contain liquids wherein the active ingredients are present in the dissolved or suspended state. The liquids employed as a portion of the fill materials commonly include vegetable oils, animals oils, mineral oils, liquid hydrocarbons, etheral oils, polyethyl¬ ene glycol . Fats and waxes are also commonly used or added to the fill to modify its consistency. In addition, the soft gelatin capsule fill material may contain at most about 8% water by weight.

However, certain liquid materials migrate into and/or interact with the gelatin forming the shell of the capsule. This migration or interaction has a harmful effect on the stability and structure of the gelatin capsule. For example, water, a solvent for the proteinaceous material forming gelatin, dissolves gelatin. Thus, fill materials for gelatin capsules may only be prepared to include a liquid phase comprising at most about 8% water by weight. Similar problems are encountered using other liquids in fill materials for gelatin capsules. Polyethylene glycol, ethanol, propylene glycol and similar low molecular weight, polar solvents also adversely interact with the gelatin shell. These problems are described in U.S. Patent Nos. 4,888,239 and 4,780,316. It is noted that the problems associated with these liquids are not solely tied to migration of the liquid into the shell. Certain liquids, e.g., polyethylene glycol, are hygroscopic and tend to absorb plasticizers from the shell material causing the shell to become brittle.

Consequently, a need exists for preparing gelatin capsules that will be substantially resistant to migration of liquid fill materials into the gelatin capsule thereby rendering the gelatin capsule to have a predetermined stability. Further, a need exists to prevent migration of components of the shell into the fill material. SUMMARY OF THE INVENTION

The invention encompasses gelatin capsules having a barrier that effectively isolates the gelatin shell and its components from the fill material. Thus, the invention provides gelatin capsules comprising a multilayer shell having an outer layer and at least one inner layer acting as a barrier. Within the multilayer shell is disposed the fill material which comprises a hydrophilic or a hydrophobic component. The outer layer of the gelatin capsule typically comprises gelatin while the barrier (in certain cases the layer in contact with the fill) is formed from a material resistant to migration of hydrophilic or hydrophobic components from the fill material into the outer layer. A variety of combinations of the outer gelatin layer adhered to other layers including the barrier are encompassed within the scope of the invention.

The invention thus provides gelatin capsules capable of containing a fill material comprising in excess of 8% by weight water. The resulting gelatin capsules comprising water have excellent long-term stability and are capable of encapsulating a variety of liquid fill materials. The invention further encom¬ passes gelatin capsules capable of containing a fill material having a tendency to absorb water or other shell materials without any of the shell components from being absorbed by the fill.

The resulting gelatin capsules can be prepared to include a variety of solutions, lotions, emulsions, creams, gels or suspen¬ sions.

The invention further provides gelatin capsules capable of encapsulating within the fill material a variety of components that may adversely affect the physical or chemical stability of the gelatin capsule shell. Thus, the fill material may include pharmaceuticals such as synthetic drugs and proteins, various antibodies and enzymes, and vitamins and minerals, fine chemicals, industrial chemicals, solvents, insecticides, etc.

The invention further provides a method for manufacturing gelatin capsules where the gelatin capsules are capable of containing a liquid fill material that is also capable of interacting adversely with the gelatin shell . The method comprises forming a gelatin ribbon, the gelatin ribbon having an outer layer comprising gelatin and an inner layer resistant to migration of hydrophilic and hydrophobic materials; preparing a fill material to comprise a system comprising a liquid that may adversely interact with gelatin; and encapsulating the fill

-3- material within the gelatin ribbon using a rotary die encapsula¬ tion apparatus. The invention also provides composite films comprising a gelatin layer and a barrier layer where the barrier layer is resistant or impervious to migration of hydrophilic and hydrophobic materials across the barrier.

The composite films, i.e., the multilayer gelatin ribbons, prepared according to the invention to have a gelatin layer and at least one barrier layer can also be used as sheets to wrap a package or a variety of articles.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGURE 1 is a cross-sectional diagram of a die having a single slot coat-hanger cavity configuration showing port 2 and die lip 1; FIGURE 2 is a cross-sectional diagram of a coextrusion feedblock die showing ports 4, 4a and 4b, and exit port 3;

FIGURE 3 is a cross-sectional diagram of a multi-slot multiexit die showing ports 5, 5a and 5b, and die lip 6; and

FIGURES 4 and 5 are cross-sectional diagrams of multi- manifold single exit dies showing ports 7, 7a and 7b, and die lip 8.

^■5- DETAILED DESCRIPTION OF THE INVENTION

The gelatin capsules of the invention comprise a shell and a fill material disposed within the shell. The shell comprises at least one outer layer and at least one inner layer functioning as a barrier layer. The outer layer typically comprises gelatin while the barrier layer is formed from a material that is resistant to permeation by the materials forming the fill material. Thus, the shell includes a barrier layer as an inner layer that prevents migration of the liquid material from the fill into the outer gelatin layer. The barrier layer may be adjacent to the fill material and in contact with the fill material or may be isolated from the fill material by an interposed layer of gelatin or other material. Further, the barrier layer may comprise a plurality of layers of material impervious or resistant to permeation by the fill material.

The fill material comprises any of a variety of liquid components in addition to various solid materials. The liquid may be a hydrophilic liquid or may be a hydrophobic, i.e., lipophilic, liquid. Representative hydrophilic components include water, Cη-C₃ alcohols, polyethylene glycols, glycerol, propylene glycol, C^C_j acids, saturated polyglycolyzed C₈-C₁₀ glycerides, glycofural, diethylene glycol monoethyl ether, high fructose corn syrup, maltose syrup, maltitol syrup, glucose syrup, sugar syrup, honey, and sorbitol . Representative hydrophobic or lipophilic components include hydrocarbons such as, for example, mineral oils, petrolatum, polyethylene waxes, and microcrystalline waxes, synthetic esters such as, for example, isopropyl myristate; natural esters such as, for example, vegetable oils, animal fats and lanolin; natural long-chain alcohols; synthetic chain alcohols; natural long-chain fatty acids; synthetic long-chain fatty acids; ethers such as, for example polyoxypropylenes; silicones such as, for example, substituted or unsubstituted silicones; mixed plant waxes such as candelilla; mixed animal waxes such as bees wax; or mixtures of any of these components.

As noted above, the shell comprises an outer layer and at least one barrier layer that may be the inner layer in contact with the capsule fill material. These layers are discrete layers that preferably are blended at their interface to improve adherence between layers. The invention encompasses a variety of combinations of an outer gelatin layer and inner layers where at least one inner layer is a barrier layer. The other inner layers may be formed from gelatin or other suitable material, such as, for example, agar, pectin, alginate, starch, carrageenan, cellulose or similar polysaccharides or other film forming polymers, such as, for example, shellac or whey protein. The capsule shell is a multi-layer composite of an outer layer and at least one inner layer. The composite may be a bi-layer, a tri- layer, or a quad-layer shell. Optionally the shell may be multi¬ layer composite having more than four layers. The particular properties of the desired final product may be altered by using such combinations. Examples of these alternative combinations are the following: Outer layer Inner layers gelatin barrier gelatin barrier barrier gelatin barrier gelatin gelatin gelatin barrier gelatin barrier gelatin barrier gelatin barrier agar barrier gelatin agar gelatin barrier

The multilayer ribbons for use in the invention are from about 0.01 to 0.07, preferably from about 0.02 to 0.05, and more preferably from about 0.03 to 0.035, inches in thickness.

The layer in contact with the fill material may be a layer of gelatin, optionally modified as described below, to protect and isolate the barrier layer during manufacturing of the ribbon and the final gelatin capsule. This gelatin layer may be a protective or lubricating layer isolating the tacky barrier from the encapsu¬ lation apparatus.

The outer layer comprises gelatin and a plasticizer for the gelatin. The gelatin mass used to prepare the capsule shell is made according to conventional methods using traditional compo¬ nents. The gelatin may optionally include an embrittlement inhibiting composition comprising materials such as a mixture of sorbitol and one or more sorbitans. See U.S. Patent No. 4,780,316. Further, the gelatin may optionally include a tackifier or a viscosity modifier. Examples of tackifiers and viscosity modifiers are ethylene acrylic acid copolymer and amylose, respectively.

A preferred gelatin outer layer comprises gelatin, glycerin as a plasticizer, and water. In preferred embodiments of a dry

-8- finished capsule according to the invention, the gelatin present in the outer layer is about 40-70% by weight of the outer layer; glycerin is from about 20-40% by weight of the outer layer; and water is about 5-15% by weight of the outer layer. Where the layer in contact with the fill material is a layer of gelatin, that gelatin layer may optionally be modified by the addition of hydrophobic components. Representative suitable hydrophobic components include colloidal silicas, modified silicas, silicones, modified silicones, magnesium stearate, oxidized polyethylene homopolymer, polyethylene homopolymer, paraffin wax, or mixtures of these materials.

The barrier layer of the shell comprises any of a variety of homopolymers or copolymers. Such polymers can be derived from the polymerization of a monomer from the group consisting of acryl- amide, acrylic acid, acrylonitrile, caprolactones, ethylene, furan, maleic anhydride, methacrylate, methacrylic acid, methacry¬ late, methylpropylene, styrene, vinyl acetate, vinyl alcohol, vinyl chloride, vinyl ethylether, vinyl propylether, vinyl pyrrolidone, salts of any of the above-mentioned acids or mixtures of these materials. The inner layer may also comprise a paraffin wax. The barrier layer further may comprise hydrocarbons such as polyethylene waxes or microcrystalline waxes, synthetic esters such as isopropyl myristate, natural esters such as vegetable oils, animal fats, or lanolin, natural long-chain alcohols, synthetic long-chain alcohols, natural long-chain fatty acids, synthetic long-chain fatty acids, ethers such as for example polyoxypropylenes, silicones, mixed plant waxes, mixed animal waxes such as bees wax or mixtures thereof. By microcrystalline wax is meant a solid mixture of hydrocarbons having from 18 to 36

-9- carbon atoms. Such solid hydrocarbons have molecular weights from about 490 to 800 and viscosities from about 45 to 120 Saybolt Universal Seconds (SUS) at 210°F (99°C) .

Preferred inner layers of the shell comprise paraffin waxes, polyethylene homopolymers or polyethylene copolymers. A parti¬ cularly preferred inner layer comprises ethylene acrylic acid copolymer available from Allied Signal, Inc., Morristown, N.J. and microcrystalline wax available from Witco Corporation, Greenwich, CT. In the particularly preferred inner layers of the inventive capsules, ethylene acrylic acid copolymer is about 50-90% by weight of the inner layer and a microcrystalline wax is about 10- 50% by weight of the inner layer. Other preferred inner layers have the following compositions:

Composition of Barrier Layer

Component %W/W Supplier(s) of com- ponents

Ethylene Acrylic Acid 70 Allied Signal, Inc, Copolymer, A-C5180

Microcrystalline Wax 30 Witco Corp.; or Petrolite Corp.

The shell is formed in a manner such that each layer adheres securely to every other layer. For example, in a bi-layer capsule shell, the gelatin layer, i.e., the outer layer, adheres to the inner layer, i.e., the barrier layer.

The shell according to the invention is prepared from a multi-layer, e.g., a bi-layer or tri-layer, ribbon that comprises materials that allow for processing into a soft gelatin capsule on a rotary die encapsulation machine without delamination or separa¬ tion of the various layers of the multilayer ribbon. Satisfactory

^■10- adhesion is defined as adhesion between the layers sufficient to prevent separation or delamination during all stages of the encapsulation process.

The barrier layer material is selected such that it is impervious to hydrophilic materials such as for example water, polyethylene glycols, glycerol, propylene glycol, various C_η-C₃ alcohols, etc. The barrier layer must also be impervious to a variety of hydrophobic or lipophilic vehicles such as fractionated coconut oil, light mineral oil, petrolatum, etc. The materials forming the shell must act as a uniform single ribbon of shell material, i.e., the materials must possess properties similar to that of a typical gelatin ribbon. Each inner layer, including the barrier layer, when adhered to the outer layer must have suffi¬ cient elasticity, strength and heat sealing abilities to allow processing of the multilayer material into a capsule on a rotary die encapsulating machine.

The adhesion of each layer to another layer, e.g., the barrier layer to the gelatin layer, may be enhanced by incorporat¬ ing tackifiers into the gelatin mass, or the inner layer or barrier layer formulations, or each layer material; alternatively, it may be enhanced by physically modifying the layers during the manufacturing process. Examples of tackifiers and viscosity modifiers include ethylene acrylic acid copolymer and amylose, respectively. To obtain suitable material for preparing a multi-layer shell of gelatin and at least one barrier material, either the gelatin mass or barrier material may be modified by the addition of viscosity modifiers in either the gelatin mass or the barrier fill formulation. Alternatively, the rheological characteristics of

-11- these materials may be modified by physically changing the manufacturing process. A variety of methods exist for preparing a multilayer ribbon suitable for use in preparing gelatin capsules. The apparatus to prepare the inventive gelatin capsules are rotary die encapsulation machines modified such that the inner and outer layers of the capsule shell simultaneously are formed by coextrusion on a casting drum using a coextrusion feedblock and a single manifold, single exit sheet die.

Preferred embodiments include machines modified such that the inner and outer layers are coextruded on a casting drum using a multi manifold, multi exit sheet die. Another alternative includes preparing the inner and outer layers sequentially by extruding onto casting drum using a single-manifold, single exit coat-hanger slot die. Typically, the gelatin ribbon is formed by simultaneously coextruding the inner and outer layers on a casting drum.

The extrusion dies suitable for preparing the multilayer films of the invention are typically capable of (1) forcing the melted gelatin and barrier materials into thin films, (2) maintaining the melted materials at a constant temperature; and (3) metering the melted materials at a constant pressure and rate to the die land to prepare a film of a uniform gauge. Examples of extrusion dies suitable for use in the invention include those listed in the following table:

Type of Extrusion Die Manufacturer(s)

Single-Manifold Single-Exit Extrusion Dies, Inc., Chippewa Falls, I

(Coat-Hanger Manifold Con- f. uration₎ Killion Extruders, Inc, . Cedar Grove, NJ

Liberty Tool Corp., Rochester, NY

•12- Multi-Manifold Single-Exit Extrusion Dies, Inc., Chippewa Falls, I

Multi-Manifold Multi-Exit Liberty Tool Corp., Rochester, NY

Coextrusion Feedblock & Die Randcastle Extrusion Systems, Inc., Cedar Grove,

NJ

The Cloeren Company, Orange, TX

In a coextrusion feedblock system, a coextrusion feedblock such as that shown in Figure 2 is mounted on a coat-hanger type die such as the one shown in Figure 1, such that the exit port 3 is adjacent the feed port 2. The coextrusion feedblock and die are mounted adjacent a casting drum to provide the drum with a film of material . In the dies shown in Figures 1, 3, 4 and 5, the ports provide the die lip with single-layer, bi-layer or multilayer material, depending on the configuration. The die is mounted on a rotary die encapsulation apparatus such that the die lips are adjacent a casting drum and provides the casting drum with a thin film of material .

Other methods that may be exploited for preparing a multilayer ribbon include:

(1) spray coating uniform layers of a coating material onto a substrate layer; (2) laminating a preformed layer onto a substrate layer; and (3) applying a coating layer onto a substrate using a system of transfer rollers. The following examples are included to illustrate the practice of this invention. EXAMPLE 1

^■13- Bi-layer soft gelatin capsules are manufactured on a rotary die encapsulation apparatus using the materials shown below in Table I. The bi-layer (gelatin-barrier) ribbons are formed by a coextrusion technique. This bi-layer ribbon is formed by a multi- manifold multi-exit die.

TABLE I

Bi-Layer Soft Capsule Shell Composition

Soft Capsule Lay- Dry Shell Composition e_

Ingredient % w/w Outer Layer Gelatin, NF (150 43

Bloom)

Glycerin, USP 20

Purified Water, 8

USP

Inner Layer Ethylene Acrylic 20

Acid Copolymer (A-C5180)

Microcrystalline 9

Wax

Formulation 1: A PEG 400 solution containing 20% w/w of water was encapsulated in the bi-layer capsule with the shell composition described in Table I. Soft gelatin capsules with good seals were obtained.

Formulation 2 : A PEG solution containing 40% w/w of water was encapsulated in the bi-layer capsule with the shell composition described in Table I. Soft gelatin capsules with good seals were obtained.

^■14- Formulation 3 : A bi-layer capsule with the shell composition described in Table I containing a 100% purified water as fill was prepared. Soft gelatin capsules with good seals were obtained. Formulation 4 : A bi-layer capsule with the shell composition

described in Table I containing as a fill a water- in-oil ointment comprising about 25% water by weight was prepared. Soft gelatin capsules with good seals were obtained using a rotary die encap- sulation apparatus.

Formulation 5; A hydro-alcoholic solution containing 35% w/w of

water, 5% w/w of propylene glycol and 60% w/w of alcohol was encapsulated in a bi-layer capsule having the shell composition described in Table 1. Soft gelatin capsules with good seals were ob¬ tained. Formulation 6 ; An oil-in-water emulsion cream containing 68% w/w of water, 6% w/w cetaryl alcohol, 6% w/w cetylester wax, 2.5% w/w sorbitan monostearate, 2.5% w/w polysorbate 60, 13% w/w octyl dodecanol, and 2% w/w benzyl alcohol was encapsulated in a bi-layer capsule having the shell composition described in Table 1. Soft gelatin capsules with goods seals were obtained. Formulation 7 ; A water-in-oil emulsion containing 56.3% w/w of water, 10% w/w POE glycerol sorbitan, isostearate, 3% w/w beeswax, 3% w/w lanolin, 11% w/w cap- rylic/capric triglyceride, 11% w/w squalane, 3% w/w

-15- sunflower oil, 2% w/w glycerin, and 0.7% w/w magne¬ sium sulfate was encapsulated in a bi-layer capsule having the shell composition described in Table 1. Soft gelatin capsules with good seals were ob¬ tained. Formulation 8 : A clear emollient gel containing 58% w/w ethanol,

1% w/w hydroxypropyl cellulose, and 41% w/w ethoxy- diglycol was encapsulated in a bi-layer capsule having the shell composition described in Table 1. Soft gelatin capsules with good seals were ob¬ tained.

EXAMPLE 2 Bilayer and gelatin-barrier composite ribbons are prepared to comprise a barrier layer containing a 70:30 blend of ethylene acrylic acid copolymer and microcrystalline wax where the gelatin and barrier layers have thicknesses of 0.019 and 0.033 inches, respectively. For purposes of comparison, a gelatin layer 0.032 inches thick is prepared utilizing conventional gelatin ribbon casting methods. Water vapor permeation rates for each ribbon are shown in Tables II and III below:

TABLE II

Water Vapor Permeation Through Bilayer Ribbon at 23% Relative Humidity and 25°C

Time (Hours) Water Loss (%w/w/cm²)

41 0.291

48 0.311 120 0.394 216 0.423 360 0.476 456 0.493 1488 0.502 TABLE I I I

Water Vapor Permeation Through Gelatin Ribbon at 23% Relative Humidity and 25°C

Time (Hours) Water Loss (% w/w/cm²) 48 14

96 33

168 87

336 100

Many other embodiments not specifically disclosed or dis- cussed above may nevertheless fall within the spirit and scope of the present invention and claims.

•17-

Claims

WHAT IS CLAIMED IS:

1. A gelatin capsule comprising:

(a) a shell having an outer layer and a barrier layer; and

(b) a fill material disposed within the shell, the fill comprising a hydrophilic component, a hydrophobic component, or mixtures thereof; the outer layer comprising gelatin and the barrier layer being resistant to migration of hydrophilic or hydrophobic components from the fill material into the outer layer.

2. A gelatin capsule according to claim 1, wherein the barrier layer is adhered to the outer layer.

3. A gelatin capsule according to claim 1, wherein the aqueous component is water, or C₁-C₃ alcohols, polyethylene glycol, glycerol , or propylene glycol.

4. A gelatin capsule according to claim 1, wherein the non¬ aqueous component is an oil.

5. A gelatin capsule according to claim 1, wherein the barrier layer comprises a paraffin wax, a polyethylene homopolymer, a polyethylene copolymer, a polymer derived from the polymerization of a monomer selected from the group consisting of acrylamide, acrylic acid, acryloni- trile, caprolactones, ethylene, furan, maleic anhydride, methacry- late, methacrylic acid, methacrylate, methylpropylene, styrene, vinyl acetate, vinyl alcohol, vinyl chloride, vinyl ethylether, vinyl propylether, vinyl pyrrolidone, salts or mixtures thereof, a hydrocarbon, a polyethylene wax, a microcrystalline waxes, a synthetic esters, a natural esters, a natural long-chain alcohols, a synthetic long-chain alcohols, a natural long-chain fatty acids, a synthetic long-chain fatty acids, an ether, or mixtures thereof.

6. A gelatin capsule according to claim 1, wherein the outer layer comprises gelatin modified with a tackifier.

7. A gelatin capsule according to claim 1, wherein the barrier layer comprises a tackifier.

8. A gelatin capsule according to claim 6, wherein the outer layer further comprises a viscosity modifier.

9. A gelatin capsule according to claim 7, wherein the barrier layer further comprises a viscosity modifier.

10. A gelatin capsule according to claim 1, wherein the barrier layer comprises ethylene acrylic acid copolymer and microcrystalline wax.

-19-

11. A gelatin capsule according to claim 1, wherein the fill material comprises a solvent system comprising up to about 100% water.

12. A method for manufacturing a gelatin capsule capable of carrying a fill material comprising up to about 100% water, the method comprising:

(a) forming a gelatin ribbon, the gelatin ribbon having an outer layer comprising gelatin and a barrier layer resistant to migration of hydrophilic or hydrophobic materials;

(b) preparing a fill material to comprise a solvent system comprising up to about 100% water by weight of the solvent system; and (c) encapsulating the fill material within the gelatin ribbon using a rotary die encapsulation apparatus.

13. A method according to claim 12, wherein forming a gelatin ribbon comprises simultaneously coextruding the barrier layer and outer layer on a casting drum.

14. A method according to claim 13, wherein the barrier layer and outer layers are coextruded onto the casting drum using a multi-manifold multi-exit sheet die.

15. A method according to claim 12, wherein the outer layer comprises gelatin and a tackifier.

16. A method according to claim 12, wherein the barrier layer comprises

-20- a paraffin wax, a polyethylene homopolymer, a polyethylene copolymer, a polymer derived from the polymerization of a monomer selected from the group consisting of acrylamide, acrylic acid, acryloni- trile, caprolactones, ethylene, furan, maleic anhydride, methacry¬ late, methacrylic acid, methacrylate, methylpropylene, styrene, vinyl acetate, vinyl alcohol, vinyl chloride, vinyl ethylether, vinyl propylether, vinyl pyrrolidone, salts or mixtures thereof, a hydrocarbon, a polyethylene wax, a microcrystalline waxes, a synthetic esters, a natural esters, a natural long-chain alcohols, a synthetic long-chain alcohols, a natural long-chain fatty acids, a synthetic long-chain fatty acids, an ether, or mixtures thereof.

17. A gelatin capsule comprising:

(a) a shell; and

(b) a fill material encapsulated within the shell, the fill material comprising from about 8 to 100% water by weight of the fill material.

18. A gelatin capsule according to claim 17, wherein the shell comprises a barrier layer and an outer layer.

-21-

19. A gelatin capsule comprising:

(a) a shell; and

(b) a fill material encapsulated by the shell, the fill material comprising a solvent system comprising from about 8 to 100% water by weight of the solvent system.

20. A method for preventing migration of materials from a fill material disposed within a gelatin capsule into the gelatin layer of the gelatin capsule comprising manufacturing a capsule shell comprising a gelatin layer isolated from the fill material by a barrier layer.

21. A composite film comprising a gelatin layer and a barrier layer resistant to permeation of hydrophobic and hydro¬ philic materials.

22. A composite film according to claim 21, where in the barrier layer is resistant to permeation of water.

23. A gelatin capsule comprising:

(a) a multilayer shell having an outer layer and a plurality of inner layers where at least one inner layer is a barrier layer; and

(b) a fill material disposed within the shell, the fill comprising a hydrophilic component, a hydropho¬ bic component, or mixtures thereof; the outer layer comprising gelatin and the barrier layer being resistant to migration of hydrophilic or hydrophobic components from the fill material into the outer layer.

-22-

24. A gelatin capsule comprising:

(a) a bilayer shell having an outer layer and a barrier layer; and

25. A gelatin capsule comprising:

(a) a trilayer shell having an outer layer and two inner layers, where at least one inner layer is a barrier layer; and