Hard (two-piece) capsules were developed as an edible container of medicine(s), mainly for oral use. These two-piece capsules have been used for over a century for pharmaceutical purposes. J. C. Lehuby, a Frenchman, is credited with the invention of the two-piece capsule. He was granted a French patent in 1846 for a method of making 'medical coverings'. However, J. Murdoch of London, in 1848, was the first to create two-piece capsule, which was made from the sole use of animal-based gelatin. The design of this original hard shell capsule has remained unchanged over the decades except for changes in shape to create self-locking tamper-resistant capsules and in sealing process to allow pastes and liquids to be filled into capsules. In addition to having the advantages of elegance, ease of use, capsules (especially hard shells) enjoy wide-spread popularity, because of their relative ease of manufacturing and their ability to efficiently mask the taste and odour of the medicines. As a result of the advances made in drug delivery technology during the last 20 to 30 years, the importance of capsules as delivery device has increased enormously.

Substitute for gelatin
Until recently capsules refer to 'gelatin' capsules i.e. the capsule shells are made from gelatin. The default material for the two-piece hard capsules is gelatin. The raw material gelatin is derived from animal source, primarily collagen. The collagen, a fibrillary protein, forms the connective and supportive tissues of mammalian (bovine and swine) body. Gelatin has been the raw material of choice due to its ability to undergo a reversible phase change from a solution to gel at a temperature only few degrees above ambient, which enables a homogenous film of gelatin to be prepared easily. Today, however, several materials have been investigated as a substitute for the classic gelatin in the two-piece hard shell capsules.

Hydroxypropyl methylcellulose (HPMC), also knows as hypromellose, has become a successful alternative material for hard shell gelatin capsules and is actually on the market. HPMC capsules are made of plant-derived (cellulose derivatives) material and do not contain components of animal origin. Another non-animal capsule material pullulan, a water-soluble polysaccharide produced through a fermentation process, has achieved regulatory acceptance.

Emergence of gelatin substitute
The success achieved by the hard gelatin capsules, popularly known as HGC, is well known and is reflected by the fact that hard gelatin capsule shells have been used in the pharmaceutical field for more than 100 years and continue to grow in acceptance as the preferred oral dosage form. Hard gelatin capsules do have some drawbacks. The principal drawback of hard gelatin capsules is that capsule shells have 13 to 16 per cent water content and therefore may not be suitable for use with readily hydrolysable drugs. Some drugs react with amine groups of gelatin, causing formation of cross-link between gelatin molecules and reducing the solubility of the capsule shell. Furthermore, gelatin products are avoided by many as a result of religious, cultural or vegetarian restrictions. In addition, recent safety report suggests a theoretical risk of transmitting spongiform encephalopathy via gelatin capsules.

To overcome these problems, pharmaceutical scientists have been working for decades to develop capsules made of starch, cellulose derivatives and polyvinyl alcohol copolymer. In 1998, Shionogi Qualicap successfully manufactured HPMC capsules, Quali-V, with properties suitable for pharmaceutical products and dietary supplements. Quali-V is the first HPMC capsule developed for pharmaceutical market, can be filled with many kinds of liquid or semisolid dosage forms. Today, HPMC capsules are produced by many manufacturers; viz. Vcaps by Capsugel division of Pfizer, Cellulose capsules by Natural Capsules Ltd., and Naturecaps by Associated Capsules.

HPMC capsules
HPMC capsules can be manufactured by the same dipping and forming method that is employed for the manufacture of classic hard gelatin capsules. Various grades of HPMC are suitable for forming the two-piece shells and are accepted by the pharmacopoeias of the US, Europe and Japan. As HPMC alone gels at temperatures above 60 degree Celsius, small amounts of carrageenan as a gelling agent and potassium chloride as a co-gelling agent are added to the HPMC solution to enable gelling at lower temperatures (45 to 55 degree Celsius). HPMC capsules available are different from each manufacturer because each uses own patented gelling system using different techniques and additives to solve specific issues related to gel formation. Thus HPMC capsules, unlike gelatin capsules, from different manufacturers are not interchangeable.

HPMC capsules are odourless, flexible and exhibit similar dissolution character to the hard gelatin capsules. The main difference in their physicochemical properties from gelatin capsules, as mentioned earlier, is that their moisture content is less, 2 to 5 per cent as opposed to 13 to 16 per cent for gelatin, and water does not act as a plasticizer for the HPMC shells and thus maintain mechanical integrity under low-moisture conditions. Dissolution profiles of HPMC and gelatin capsules are comparable over a wide range of pH values. Studies describing the bioavailability of drugs, as reported till date, show that oral bioavailability in HPMC capsules is identical to that delivered in gelatin capsules.

HPMC capsules have been widely used in the nutritional market. To date, HPMC capsules have been successfully utilized for pharmaceutical products on the Japanese market. There are a few pharmaceutical products on the world market. Many giant companies are actively including HPMC capsules in their developmental studies.

Conclusion
HPMC capsules offer numerous and unique benefits as dosage form for pharmaceuticals. Among the long list of advantages, perhaps one of the most significant is that non-animal sources capsule allows consumers for addressing a variety of cultural and dietary requirements. These capsules avoid concerns about the spread of animal originated disease. The property of mechanical integrity even at low shell moisture content enable its use in dry powder inhalers (DPIs) and in formulations containing water-unstable drugs. Increasing commercial availability, offer of overcoming problems inherent with gelatin capsules coupled with their rapid progress in manufacturing; make HPMC capsules an ideal alternative to classic gelatin capsules.

(The author is Reader in Pharmacy,Annamalai University, Annamalainagar 608 002, TN)
Email: cdl_scbasak@sancharnet.in