A Review on the Polymers for Vegetarian Soft Gel Capsule Films

 

Soumya Verma, Vamshi Krishna Tippavajhala*

Department of Pharmaceutics, Manipal College of Pharmaceutical Sciences, Manipal University, Manipal, Karnataka, India.

 

ABSTRACT:

Soft capsules are a single piece, unit dosage forms containing hermetically sealed soft gelatin shell encapsulating a fill material which is mainly a solution, suspension or semisolid. Soft gel capsules are effective in the delivery of low dose drugs and easily degradable drugs due to the presence of a protective gelatin shell. However the use of gelatin as the shell material has certain demerits like it leads to the spread of bovine spongiform encephalopathy (BSE, Mad Cow disease) and is not preferred by people belonging to certain religious groups or those who have dietary restrictions. In this context, this review article details the various polymers obtained from vegetarian sources that can act as alternatives for the gelatin and succeed in dealing with the disadvantages of gelatin.

 

 

 

INTRODUCTION:

Soft Gelatin Capsules (SGC):

Soft capsules are a single piece, unit dose hermetically sealed soft gelatin shell containing a solution, a suspension, or a semisolid, referred to as fill material. Soft capsules are finding their applications widely in the pharmaceutical, chemical, nutraceuticals and cosmetic industry. They are being used increasingly as delivery systems for hydrophobic drugs, low dose drugs, easy-oxidized drugs¹.

 

Composition of SGC:

A SGC contains gelatin, plasticizer, and water. It may additionally contain preservatives, colouring and opacifying agents, flavouring agent and sweeteners. Gelatin is a protein obtained from hydrolytic oxidation of native protein collagen. Collagen for the production of gelatin is present in porcine skin, hide and bones.

 

It has physicochemical properties (solubility, solution viscosity, thermally reversible gelation properties) which make it suitable for the pharmaceutical capsule industry. Produced gelatin films are strong, clear, flexible, and easily soluble in gastric juices. Gel strength depends upon the gelatin concentration, pH, temperature, and maturing time². The Bloom strength is an important industrial criterion for evaluating a batch of commercial gelatin. It defines the gelatin gel strength as the force required for a 12.7 mm diameter flat-bottomed cylindrical plunger to depress the surface of a 6.67% w/w gelatin gel (matured at 10° C for 16-18 hours) to a depth of 4 mm. An ideal soft capsule gelatin should have gel strength of 150-200 bloom³.

 

The weight ratio of plasticizer to gelatin determines the shell strength and varies from 0.3 to 1. Plasticizers are added to the capsules to retain their elasticity during the drying process, also do not turn brittle on storage. The hardness and mechanical stability of the capsule is determined by the type of plasticizer, concentration of the plasticizer, residual moisture and the thickness of the shell (250-500 μm). Glycerol is mostly used as the plasticizer, due to its high plasticizer efficacy, sufficient compatibility and no interference with the formation of a three-dimensional gelatin network. Immediately after encapsulation, the capsule shell contains high water content (≥30 % w/w). During a two-step drying process water goes from the shell into the environment and capsule fill until an equilibrium moisture content of 10-15 % w/w after the first step of drying and final capsules have a moisture content of 4-10 % at the completion of drying process^{2, 4}.

 

Advantages of soft gelatin capsules:

·        Increase in the absorption rate of the fill formulation – Rate determining step for absorption of a poorly soluble drug from a tablet is the disintegration into granules before drug dissolution into gastrointestinal fluid. However in a soft gel capsule this is not a concern as it ruptures within minutes to release the formulation. This also leads to increased bioavailability of drugs ^{2, 4}.

·        Patient compliance and consumer preference -  improving swallowbility, masking

·        odor and unpleasant taste ^{2, 4}.

·        Dose uniformity of low-dose drugs – Dose uniformity in low-dose drug is generally not achieved by mixing them with larger quantities of excipients for tablet preparation or for filling into hard-shells.  However in SGC encapsulation process the drug is solubilized or suspended in a liquid fill. A positive displacement pump is employed for the filling process hence a much higher degree of reproducibility is obtained compared to tablets and hard gelatin capsules filled with powder or granules. Eg- accurately delivering ultra-low dose drug like cardiac glycosides^{2, 4}.

·        Product stability - preparations of liquid-filled SGC protects the drug against oxidative or hydrolytic degradation thereby enhancing the stability^{2, 4}.

 

Challenges and limitations of soft gelatin capsules:

·        The animal sources of gelatin – Consumers are now concerned about what they ingest. Gelatin is not consumed by people who observe religious/dietary laws that forbid the use of animal products e.g. Vegetarians, Jews, Hindus, Muslims².

·        Cross linking is observed in gelatin to a great extent which inhibits the in vitro release of medicament. Cross-linking is chemical covalent bonding between different polypeptide chains, which may result in partially insoluble gelatin protein. This phenomenon can affect in vitro drug release by forming swollen, rubber like water-insoluble structure known as pellicles that act as a barrier to drug release. However, in vivo disintegration of cross-linked capsules is rapid, so a two-tier in vitro dissolution test is done for gelatin capsules using enzymes (e.g. pepsin)².

·        The spread of transmitting animal diseases, namely bovine spongiform encephalopathy (mad cow disease) raised many concerns among both manufacturers and consumers².

·        Gelatin is temperature and moisture sensitive which limits the use of soft gelatin capsules in very hot and humid regions².

 

These demerits have led the pharmaceutical industries to develop alternate shell forming material to replace the traditional capsule shell material, i.e. gelatin.

 

Alternate Polymers for Soft Capsules:

The materials mostly used for films/ edible coatings belong to the following categories –

·        Hydrocolloids

·        Polysaccharides – Gums (carageenan, gellan gum), Starch

·        Proteins – Collagen

·        Lipids

·        Fatty acids

·        Waxes

 

Polysaccharides exhibit great diversity of structural features in terms of the monosaccharide composition, linkage types and patterns, chain shapes, and degree of polymerization, thus influencing their physical properties⁵.

 

Starch:

Starch is the polysaccharide energy storage material of the plant kingdom. It consists of amylose which is linear α – (1→4) glucan and amylopectin which is a highly branched, high molecular weight glucan. Amylopectin has α – (1→4) glycosidic linkages containing α – (1→6) branch points^{6, 7, 8} as depicted in Figure 1.

 

Figure 1: Structure of starch, b) is amylose, c) is amylopectin

 

Amylose and amylopectin molecules are packed aggregates which are systematically present in the starch granules. The size, structure and particular utility of starch granules in each plant species depends on the length of the α-glucan chains, amylose-amylopectin ratio and branching degree of amylopectin^{6, 7}.

 

Gelatinization and Retrogradation of Starch:

Gelatinization:

Crystalline regions of starch are amylopectin polymers of which the outer branches are hydrogen bonded to each other to form crystallites that break during gelatinization. The amorphous regions of granules are mainly composed of amylose and amylopectin branch points. Starch granules are insoluble in cold water. When starch is heated in water, granules absorb water and swell. The absorption of water by amorphous regions within the granules destabilizes their crystalline structure, resulting in the loss of birefringence, which is gelatinization. Upon continuous heating, granules tend to swell to greater extents, and the crystallites melt, resulting in increased molecular motion that eventually leads to complete separation of amylose and amylopectin. The temperature at which granules lose their birefringence is referred to as the gelatinization temperature; this temperature depends in part on the botanical source of starch⁷.

 

Retrogradation:

It is the molecular interaction after gelatinization and cooling of the paste. During retrogradation, amylose molecules associate with other molecules to form a double helix, while amylopectin molecules re-crystallize by association of its small chains. Amylose being the linear glucan, contributes more towards retrogradation. Retrogradation is undesirable in film formation⁸.

 

The naturally found starch is chemically processed to be used for various purposes like edible coatings/films, protective layer over food items, encapsulation. This is known as modified starch. The various modifications of starch are substituted starch, cross linked starch, degraded starch which is illustrated in Figure 2.

 

Polymerparticles are present separately in wet state of film, they come in close contact, deform, coalesce and fuse together to form a film. Drying causes evaporation of water/ solvent so the polymer particles increase in proximity to each other which leads to coalescence with adjacent particles and these mutually diffuse into one another forming a film. Therefore film formation occurs when starch granules rupture and amylose, amylopectin get dispersed in the aqueous medium hence film forming modified starches are designed not to have granule integrity^7,8.

 

Figure 2: Modifications of starch

 

Kramer et al., 2009 illustrated the importance and benefit of hydroxypropylation of native starch in lowering of starch gelatinization temperatures and better hydration of starch granule. Hydroxypropylation is a substitution reaction where starch is etherified with propylene oxide as indicated in Figure 3. The advantages being that introduced functional groups facilitate opening up the granule, increasing its hydrophilicity. This results in lower starch gelatinization temperature⁹.

 

Another advantage is that the resulting starch gel is soft and has better clarity. In native starches, the amylose portion of starch can re-associate with time due to retrogradation⁷. As retrogradation proceeds, the gel gradually becomes more opaque as water is expelled out. Steric hindrance caused by substituted groups on the polymer chains prevents re-associations, so that retrogradation does not readily occur. This advantage also makes the gel more resistant to breakdown during successive freeze-thaw cycles, which generally cause unmodified native starch gels to lose water and thus, their functionality¹⁰.

 

Figure 3: Hydroxypropylation of starch

 

Amylose being linear molecules align with stronger hydrogen bonds hence, the film strength and gel strength of high amylose starches is more. High amylose starches are highly crystalline, requiring high temperatures to achieve full gelatinization⁹. High amylose starches can also undergo retrogradation with time henceVorwerg et al., in 2004 concluded that different types of hydroxypropylated starches were suitable for the preparation of the films. To produce films with high mechanical strength, elasticity and clarity, HP-starch with high amylose content should be preferred¹¹.

 

A number of gelling agents are added to the hydroxypropylated, high amylose strach film composite to improve the gelling and thermoreversible sol gel properties of the film forming composite. Thermoreversible sol gel behaviour is essential to ensure sealing of soft gel capsule. These gelling agents are polysaccharide gums like gellan gum, carageenan, locust bean gum, xanthan gum¹².

 

Carageenan:

Carrageenan is obtained by extraction with water or alkaline water of certain species of the class rhodophyceae (red seaweeds). Carrageenans are composed of alternating (1→3)-linked β-D-galactose and (1→4)-linked α-D-galactose, where galactose residues are partially sulfated at the positions of 2 and/or 6 and/or 3, 6-anhydride as depicted by chemical structures of carageenan in Figure 4. Important species are Eucheumacottonii, which yields kappa carrageenan, and Eucheumaspinosum which yields iota-carrageenan^{6, 12}.

 

Figure 4: Chemical structures of forms of carageenan Gelling Properties of Carageenan

 

Morris.R et al., 1984 had demonstrated by light scattering and membrane osmometry that gelation in carageenan follows a temperature dependent coil to double helix transformation. The thermoreversible sol gel property is necessary in sealing of the soft capsules. The experiments showed a doubling molecular weight on cooling, which illustrates the rigidity of carageenan gels on cooling¹³.

 

Gelling in both κ (kappa) and ι (iota) carageenan requires cations. Figure 5 depicts the aggregation of cations to the anionic residues( -OSO₃^- , also known as kinks) to form helix structures. The strongest gels by evaluating yield stress are formed with potassium and rubidium ions, which seemingly have an equal effect, while caesium and ammonium ions lead to weaker gels¹³.

 

Gelation takes place in the aqueous solutions of κ- and ι-carrageenans with the presence of salt, but not in the aqueous solution of λ-carrageenan (lambda)¹⁴. κ-carageenan formed strong, rigid gels whereas iota carageenan formed soft, elastic gels and lambda carageenan did not gel at all⁶. This different gelling behavior is due to different number of sulfate groups per repeating units in each carageenan types and the conformational restriction by anhydrous residues (kinks in the structure of carrageenan) κ, ι carrageenan possesses one and two sulfate groups per repeating unit, respectively, while λ-carrageenan contains three sulfate groups¹⁴.

 

Figure 5: Gelation mechanism of carrageenan

 

Gellan gum:

Gellan gum is a polysaccharide produced by fermentation of a pure culture of Sphingomonas elodea. The composition and structure of gellan gum produced by commercial fermentation is exactly similar to the naturally occurring polysaccharide formed by Sphingomonas elodea on plants of Lily pad varieties¹⁵. The molecular structure of gellan gum, as depicted in Figures 6 and 7 is a straight chain consisting of repeating glucose, rhamnose, and glucuronic acid units. In its native or high acyl form, two acyl substituents acetate and glycerate are present. In low acyl gellan gum, the acyl groups are removed completely. The acyl groups have a marked influence on gel characteristics¹⁵.

 

Figure 6: Chemical structure of High acyl Gellan gum

 

Figure 7: Chemical structure of Low acyl Gellan gum Gelling Properties of Gellan Gum

 

Miyoshi et al., 1999, carried a study on gelling properties of gellan gum and the need to add ions to facilitate proper gelation of gellan gum. Gellan gum like carageenan follows the thermoreversible sol gel phenomenon. The coil-double helix thermoreversible phenomenon is observed in gellan gum. The order of effectiveness of the monovalent cations in promoting gelation followed the series Cs⁺> K⁺> Na⁺> Li⁺. Cations agrregate the anionic carboxyl residues to agregate the coils of gellan gum into double helix¹⁵.

 

Pullulan:

It is an edible, tasteless, odourless polymer, produced extracellularly by Aureobasidium pullulans by fermentation process with sugars. Pullulan is a linear polysaccharide which has building blocks of maltotriose units.Three units of glucose of maltotriose are linked with α- (1→4) glycosidic bonds while subsequent maltotriose units are linked with α-(1→6) glycosidic bonds, which is illustrated in Figure 8. The molecular weight is between 10 - 400 kDa¹⁶.

 

Figure 8: Chemical structure of pullulan

 

Gelling Properties of Pullulan:

Pullulan easily dissolves in hot/cold water to give a stable, viscous solution however it doesnot gel. It is insoluble in organic solvents. With some ions for example borate  complex formation with hydroxy group is observed but still it does not gel. Pullulan is highly adhesive when dissolved in water. It readily forms films which are edible,rapidly soluble in water, transparent, have low oxygen permeability. These reasons have led to the use of pullulan in orally dissolving films, capsule shells and as a coating agent¹⁶.

 

Krull et al., 2015, formulated fast dissolving pullulan films containing BCS class II drug nanoparticles, they also added xanthan gum as a thickening agent. They concluded that films with lower concentration of xanthan gum gave better drug release results, also pullulan is suitable as a fast dissolving film former for the release of poorly soluble drugs¹⁷.

 

Guglani et al., 2011, studied the effect of PEG,glycerin and polyethylene glycol on the film forming and disintegration of pullulan films. They concluded that propylene glycol is the best plasticizer for pullulan, followed by glycerin¹⁸.

 

Hydroxypropylmethyl cellulose (Hypromellose):

HPMC is a modified natural carbohydrate that contains a repeating structure of anhydroglucose units. The structure of HPMC is shown in Figure 9. During the manufacture of cellulose ethers, cellulose fibers are heated with a caustic solution and then treated with propylene oxide, leading to hydroxypropyl substitution on the anhydroglucose units of methyl ether of cellulose. The fibrous reaction product is purified and ground to a fine, uniform powder⁶.

 

where R is H, CH₃ or CH₃CH(OH)CH₂

Figure 9: Chemical structure of HPMC

 

Hypromellose possess varying ratios of Hydroxypropyl and Methyl substitution which affects the solubility as well as thermal gelation temperature of aqueous solution. The extent of substitution known as the degree of substitution (D.S) is designated by weight percentage of substituent group attached to the ring. A lower D.S. results in lower solubility. The letters E, K, J and F are different grades of HPMC, they differ in their properties. The suffix S denotes surface treated, G denotes granular grade while CR  denotes controlled release grade⁶.

 

CONCLUSION:

This review article has provided the details of various polymers from vegetarian sources that can act as a possible replacement for gelatin in the preparation of soft gel capsule films. These polymers can overcome the demerits associated with the gelatin like the spread of bovine spongiform encephalopathy (BSE, Mad Cow disease) and not being preferred by the people belonging to certain religious groups or those who have dietary restrictions.

 

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Accepted on 15.07.2017        © RJPT All right reserved