Food additives Europe numbers: E441
Functional Category
Coating agent; film-forming agent; gelling agent; suspending agent; tablet binder; viscosity-increasing agent.
Applications in Pharmaceutical Formulation
Gelatin is widely used in a variety of pharmaceutical formulations, including its use as a biodegradable matrix material in an implantable delivery system,(1) although it is most frequently used to form either hard or soft gelatin capsules.(2–4) Gelatin capsules are unit-dosage forms designed mainly for oral administration. Soft capsules on the market also include those for rectal and vaginal administration. Hard capsules can be filled with solid (powders, granules, pellets, tablets, and mixtures thereof), semisolid and liquid fillings, whereas soft capsules are mainly filled with semisolid or liquid fillings. In hard capsules, the active drug is always incorporated into the filling, while in soft capsules the drug substance can also be incorporated into the thick soft capsule shell. Gelatin is soluble in warm water (>308C), and a gelatin capsule will initially swell and finally dissolve in gastric fluid to release its contents rapidly.(5) Hard capsules are manufactured in two pieces by dipping lubricated stainless steel mold pins into a 45–558C gelatin solution of defined viscosity, which depends on the size of the capsules and whether cap or body are to be formed. The gelatin is taken up by the pins as a result of gelation, and the resulting film thickness is governed by the viscosity of the solution. The capsule shells are passed through a stream of cool air to aid setting of the gelatin, and afterwards they are slowly dried with large volumes of humidity controlled air heated to a few degrees above ambient temperature and blown directly over the pins. The capsule halves are removed from their pins, trimmed and fitted together. Gelatin that is used to produce hard capsules may contain various coloring agents and antimicrobial preservatives. Surfactants may be present in small quantities in the shells being a residue of the pin lubricant. However, the use of preservatives is no longer encouraged in line with current GMP principles. Capsule shells may be treated with formaldehyde to make them insoluble in gastric fluid. Standard capsules vary in volume from 0.13 to 1.37 mL. For veterinary use, capsules with a volume between 3 and 28 mL are available, and capsules with a capacity of 0.025 mL are available for toxicity studies in rats. In contrast to two-piece hard capsules, soft gelatin capsules are manufactured, filled and sealed in one process. The gelatin used to form the soft shells has a lower gel strength than that used for hard capsules, and the viscosity of the solutions is also lower, which results in more flexible shells. Additives to soft shell formulations are plasticizers such as polyalcohols (glycerin, propylene glycol, polyethylene glycol). Sorbitol can be added as moisturizing agent, whereby the larger amount of water will act as plasticizer. Coloring and opacifying agents are also added. The filling can interact with the gelatin and the plasticizer chemically. There may be migration of filling components into the shell and plasticizer from the shell into the filler. These interactions have to be taken into account during the formulation of the gelatin shell and the filling. The main method to produce soft gelatin capsules is the rotary die method (RP Scherer), and an alternative method for small volumes of round capsules is the Globex system (Industrial Techno-logic Solutions Ltd).(4) Soflet Gelcaps (Banner Pharmacaps) are tablets that have been coated with a gelatin film. Gelatin is also used for the microencapsulation of drugs, where the active drug is sealed inside a microsized capsule or beadlet, which may then be handled as a powder. The first microencapsulated drugs (beadlets) were fish oils and oily vitamins in gelatin beadlets prepared by coacervation. Low-molecular-weight gelatin has been investigated for its ability to enhance the dissolution of orally ingested drugs.(6) Ibuprofen–gelatin micropellets have been prepared for the controlled release of the drug.(7) Other uses of gelatin include the preparation of pastes, pastilles, pessaries, and suppositories. In addition, it is used as a tablet binder and coating agent, and as a viscosity-increasing agent for solutions and semisolids. Therapeutically, gelatin has been used in the preparation of wound dressings(8) and has been used as a plasma substitute, although anaphylactoid reactions have been reported in the latter application.(9) Absorbable gelatin is available as sterile film, ophthalmic film, sterile sponge, sterile compressed sponge, and sterile powder from sponge. Gelatin sponge has hemostatic properties. Gelatin is also widely used in food products and photographic emulsions.
Description
Gelatin occurs as a light-amber to faintly yellow-colored, vitreous, brittle solid. It is practically odorless and tasteless, and is available as translucent sheets, flakes, and granules, or as a coarse powder
Stability and Storage Conditions
Dry gelatin is stable in air. Aqueous gelatin solutions are also stable for long periods if stored under cool conditions but they are subject to bacterial degradation.(4) At temperatures above about 508C, aqueous gelatin solutions may undergo slow depolymerization and a reduction in gel strength may occur on resetting. Depolymerization becomes more rapid at temperatures above 658C, and gel strength may be reduced by half when a solution is heated at 808C for 1 hour. The rate and extent of depolymerization depends on the molecular weight of the gelatin, with a lower-molecular-weight material decomposing more rapidly.(11) Gelatin may be sterilized by dry heat. The bulk material should be stored in an airtight container in a cool, well-ventilated and dry place.
Incompatibilities
Gelatin is an amphoteric material and will react with both acids and bases. It is also a protein and thus exhibits chemical properties characteristic of such materials; for example, gelatin may be hydrolyzed by most proteolytic systems to yield its amino acid components. Gelatin will also react with aldehydes and aldehydic sugars, anionic and cationic polymers, electrolytes, metal ions, plasticizers, preservatives, strong oxidizers, and surfactants. It is precipitated by alcohols, chloroform, ether, mercury salts, and tannic acid. Gels can be liquefied by bacteria unless preserved. Some of these interactions are exploited to favorably alter the physical properties of gelatin: for example, gelatin is mixed with a plasticizer, such as glycerin, to produce soft gelatin capsules and suppositories; gelatin is treated with formaldehyde to produce gastroresistance; see Section 7
Safety
Gelatin is widely used in a variety of pharmaceutical formulations, including oral and parenteral products. In general, when used in oral formulations gelatin may be regarded as a nontoxic and nonirritant material. However, there have been rare reports of gelatin capsules adhering to the esophageal lining, which may cause local irritation.(12) Hypersensitivity reactions, including serious anaphylactoid reactions, have been reported following the use of gelatin in parenteral products.(9,13) There have been concerns over the potential spread of BSE/TSE infections through bovine derived products. However, the risk of such contamination of medicines is extremely low. LD50 (rat, oral): 5 g/kg(14) TDLo (mouse, IP): 700 mg/kg(15)