Title of Invention

A PROCESS FOR THE PREPARATION OF PHARMACEUTICAL HARD CAPSULE FROM TAMARIND SEED POLYSACCHARIDE

Abstract

Administering drug in the form of capsule formulation is a common practice. Capsule is in use for about 170 years. Right from its invention gelatine is the only material being used for the preparation of empty capsule although gelatin has many disadvantages. A process for the preparation of hard capsule from tamarind seed polysaccharide has been developed to overcome the drawbacks. The process comprises the following steps: A) removing the testae from roasted tamarind seeds, pulverising the seed kernel and removing fat by soxhlation B) hydrolytic extraction of tamarind seed polysaccharide by boiling the kernel powder with 0.1 N HCI and recovering the polysaccharide by alcohol precipitation C) preparing aqueous solution having the polysaccharide, agar and glycerol D) casting the capsule by dipmoulding technique using separate mould pins for body and cap E) removing the capsule shells from the pins, trimming the same and joining the body and cap

Full Text

This invention relates to the preparation of pharmaceutical hard capsule from tamarind seed polysaccharide. This invention in general relates to pharmaceutical industry. This invention in particular relates to a novel process for the preparation of pharmaceutical hard capsules from degradable materials. This process is carried out by using partially hydrolysed Tamarind seed Polysaccharide and agar combination. The capsule can withstand extreme humidity condition. The capsule prepared by this process does not act as a substrate for microbial growth as it is of vegetable origin. Background of invention Pharmaceutical hard capsules are used as container for delivery of medicaments through oral route. The hard capsule consists of two parts, the body and the cap. The medicaments are filled in the body, closed with the cap and sealed. When the filled capsule is administered, through oral route, the capsule dissolves in the stomach and releases the medicaments. This type of drug delivery system has many advantages like easy to administer, quick release of drug in the stomach, suitable for the drugs which are sensitive to heat. At present gelatin is the only material used for the preparation of empty hard capsules which are available in the market. One of the problems associated with the prior art capsule based on gelatin is that the capsules are susceptible to microbial growth and unstable in high as well as low humidity. In addition to these problems gelatin is a costly material. Further as gelatin is animal origin, it is not acceptable for some sects on religious ground. The present invention overcomes the aforesaid problem. It is well known in the prior art that hard capsules are prepared from gelatin by dip moulding technique. The process for the preparation of pharmaceutical capsules from gelatin was first disclosed in the French patent No. 5648 granted in parts on 25th March 1834 to Dublanc and Mothes and the preparation of hard capsule, in its present form, was disclosed in the French patent No. 4435 granted on 20th October 1846 to Mr. J.C. Lehuby. And no Indian patent has been granted for the preparation of pharmaceutical hard capsules. Gelatin is a protein derived from collagenous material obtained mainly from cattle bone, cattle skin and pig skin. Gelatin has all the required properties to prepare hard capsules. These include solubility, solution viscosity, and reversible thermal gelation properties. It produces strong, clear, flexible, high-gloss films which dissolve readily under the condition existing in the stomach. Gelatin is soluble in water above 37X. Upon cooling the 30 to 40% w/w solution of gelatin in water from a temperature of around 60 -70°C to a temperature of 37°C the solution solidifies. This behaviour is called thermal gelation and this temperature is called gelation temperature. Due to these properties gelatin is the only material being used for the preparation of pharmaceutical capsules on commercial scale for the past 170 years. In the known art, the hard gelatin capsules consists of body and cap and the body is longer than cap where as the internal diameter of the cap is slightly more than the body so that the cap can fit over the body. Based on the size the capsules for human use are numbered, 000, 00, 0, 1,2, 3, 4, and 5. Number 000 is the largest and No. 5 is the smallest. The capsules are prepared by dip moulding technique. The process for the manufacture of hard gelatin capsules has remained essentially the same as that proposed by Lehuby in 1846. The materials used in the preparation of hard capsule are gelatin, colorant, preservatives and surfactants. A solution of gelatin in the concentration of 30-40% w/w is prepared by dissolving gelatin in demineralised water at 60-70X. To this the colorant, preservative and surfactants are added and the viscosity is adjusted to required level. The resultant solution is maintained at 45-55°C. The pin bars containing the mould pins (The mould pins for both caps and body have the same general form, the body being slightly longer of the two. Their diameters are so arranged that the inner diameter of the cap near its closed end is slightly less than the outer diameter of the body at its open end so that the cap can snap fit in to body) are gently lowered into the gelatin solution and slowly withdrawn. Gelatin solution is picked up on the mould pins, the quantity being governed by the viscosity of the solution. To spread the gelatin evenly"over the surface of the mould pins, the pin bars are rotated about a horizontal axis. A blast of cool air over the pin bars helps the gelatin solution to gel and fix the film on the mould pin in the form of a capsule. Then the pin bars are dried initially at low temperature and then at pre determined high temperature. For this the pin bars are passed through a series of drying kilns where a large volumes of controlled humidity air are blown directly over the pins to dry the film. This air is heated to a few degrees above ambient (22-28°C). For operation convenient the drying conditions are adjusted so that the drying rate is low to begin with, slowly reaches maximum and then slows down again. At the end of drying the moisture content of the capsule is approximately 15-18% w/w. The capsule shells are removed from the pins by a set of metal jaws which are placed around in each pin. The gelatin capsules formed on the mould pins are longer than required and to make it right size the capsules are trimmed. Then the cap is joined with the body. In the manufacture of capsule formulation, the medicaments are filled in the body and then the cap is fitted on it using manual, semi automatic or automatic machine. The machines are made for universal usage. When the filled capsule is taken orally it is expected that the capsule shell dissolves in the stomach and release the medicaments. The current state of art is a well developed technology. The versatility with the gelatin is the formation of tough flexible film or capsule shell although the polymer is water soluble. The gelation temperature is 37°C. till now none of other polymer could qualify this combination of unique properties. Hence gelatin remained for 170 years as a versatile material for making Pharmaceutical Hard capsule. Some polymers have been tried as a substitute for gelatin for making hard capsule. These polymers include cellulose derivatives (US Patent 2810659 and British Patent 1144225), starch derivatives (US patent 4026986), synthetic polymers (Japanese Patent 7001277, French patent 2073258, Belgium Patent 758702 and British Patent 1252333). But all these materials miserably failed due to poor in vivo performance or the difficulties in commercial scale production in the existing machinery. No Indian Patent has been granted for the invention related to hard capsules. However the hard gelatin capsules have some serious disadvantages. First, being a protein, it is a good substrate for microbial growth. Second the hard gelatin capsules become soft and deformed in high relative humidity. They become brittle and break at low humidity. Thirdly, gelatin being animal origin is not acceptable to many on religious ground. In view of the above circumstances and trends, there has emerged a need for a process for preparing pharmaceutical hard capsules from suitable material, which is 1) derived from plant kingdom 2) Capable of forming capsule by dip moulding technique, so that the existing machinery used for making gelatin capsules can be used. 3) freely available in abundance and cheap. Further, such capsules are expected to withstand extreme humidity conditions and will not support the growth of micro-organism. Objective of the invention It is the primary object of the invention to invent pharmaceutical hard capsule prepared from a biodegradable material obtained from plant source. It is another object of the invention to invent a process for the preparation of pharmaceutical hard capsule from biodegradable material. It is another object of the invention to invent pharmaceutical hard capsule which is not susceptible to microbial grov\/th. It is another object of the invention to invent pharmaceutical hard capsule which can withstand high and low relative humidities. It is another object of the invention to invent pharmaceutical hard capsule which is a substitute for gelatin for hard gelatin capsule. Further objects of the invention will be apparent from the ensuing description. Summary It is apparent that a material for preparation of hard capsule should have required film forming property, solubility as well as ability to undergo thermal gelation so that capsule can be prepared conveniently by dip-moulding technique. Gelatin is the only material having these properties. Many materials have good film forming property; if thermal gelation property could be incorporated in to these materials then hard capsules could be prepared by dip moulding technique. In the process of the present invention it was found that the biodegradable tamarind seed polysaccharide produces strong, clear, flexible, high-gloss films which dissolve readily in simulated gastric juice. However tamarind seed polysaccharide does not posses thermal gelation property but it was found that the thermal gelation property could be incorporated to tamarind seed polysaccharide by the addition of agar. Based on this preliminary finding a process for the preparation of hard capsule by dip moulding technique, from tamarind seed polysaccharide, has been developed. Further the Tamarind seed polysaccharide has very high solution viscosity necessitating partial acid hydrolysis to the extent necessary for reducing the solution viscosity to the desired level at the same time with out compromising the film forming property. Brief description of the invention A process for the preparation of hard capsule from biodegradable materials such as tamarind seed polysaccharide comprising A) roasting of tamarind seeds to make the testae brittle, B) removing the testae, C) pulverising the seed kernel, D) removing of fat by soxhiation E) Hydroltic extraction of the polysaccharide by boiling the kernel powder with 0.1M hydrochloric acid for 10 mts. F) cooling the slurry and centrifuging G) Collecting the clear supernatant and precipitating the polysaccharide by adding rectified spirit. H) filtering the precipitate, washing with rectified spirit and drying the same. I) preparing aqueous solution having 10% \N/\/ polysaccharide, 2% SNN agar and glycerol 0.5% w/v at 90°C J) cooling to 40""C and maintaining at 40°C K) gently dipping lubricated mould pin, in the solution and withdrawing. L) blowing cool air over the pin so as to set the solution firmly on the pins M) drying the pin at 60°C. N) removing the capsule shells from the pins and trimming the same so as to obtain pharmaceutical hard capsule Now the invention will be described in detail with reference to process diagram and flow chart shown in the accompanying drawing wherein the sole figure shows the flow chart of the novel process. The present invention is applicable for the preparation of pharmaceutical hard capsules by dipmoulding technique using the combination of a suitable film forming material and a suitable substance having thermal gelation property. More particularly the invention is a process for the preparation of pharmaceutical hard capsule using the combination of partially hydrolysed Tamarind seed polysaccharide as film forming material and agar as substance having thermal gelation property. The process involves the preparation of partially hydrolysed Tamarind seed polysaccharide from the Tamarind seed kernel powder by hydrolytic extraction with 0.1N hydrochloric acid and subsequent precipitation and washing of the polysaccharide with rectified spirit. The resultant product as a 2% w/v solution in water has a viscosity of 8-12 cps at 25°C. To prepare pharmaceutical hard capsules, solution containing 5 to 15% w/v of partially hydrolysed Tamarind Seed Polysaccharide, 1 to 3% w/v of agar (Indian Pharmacopoeial grade) and 0.5% w/v glycerol (Indian Pharmacopoeial grade) is prepared and kept above its gelation temperature of SOX to 40°C in a thermostatically controlled water bath. The plastic mould pins are lubricated, gently dipped in the solution and withdrawn slowly. The mould pins are rotated while cool air at 20°C is blown over the pins so that the solution set on the mould pins firmly and then dried at 40-60°C. After drying, the capsules are removed from the moulds, trimmed and then the caps and body are joined. Example Materials: Tamarind seed 0.1M Hydrochloric acid Rectified spirit Agar Glycerol Soft paraffin Apparatus & Equipment Attrition mill Soxhiet extractor Mould pins (separate for hard capsule body and for hard capsule cap: both are made of synthetic polymer and has smooth surface) Constant temperature water bath Cool air blower Centrifuge Procedure: Tamarind seeds are roasted in an open pan at 150°C until the testae become brittle and the testae are removed from the seed kernel using attrition mill. The seed kernel are powdered in the attrition mill to mesh No.40 and defatted by solvent extraction for three hours with petroleum ether (40°C - 60°C) in a Soxhiet extractor and dried at room temperature. 100g of the defatted Tamarind seed kernel powder is dispersed in 2500ml of boiling 0.1M hydrochloric acid and continue the boiling for ten minutes. The slurry is cooled to room temperature, centrifuged at 4000 rpm for 10 mts and the clear supernatant liquid is collected. From the supernatant, the polysaccharide is precipitated by the addition of twice the volume of rectified spirit (95% v/v ethanol). The precipitate is collected by filtration through muslin cloth, washed with rectified spirit until the washing does not give white precipitate with silver nitrate and dried at GCC. To prepare hard capsules, 10g of Tamarind Seed Polysaccharide and 0.5ml of glycerol are dissolved in 100ml of water by stirring with a mechanical stirrer. After complete dissolution of the polysaccharide the solution is heated to about 90°C and 2g of agar is added to the solution. The stirring is continued until the agar is completely dissolved, the solution is cooled to 40°C and maintained at 40°C. The mould pins are lubricated with soft paraffin and gently dipped into the solution and withdrawn so that the solution is taken up by the mould pin. Cool air at 20°C is blown over the pins while the pins are rotated slowly about the horizontal axis, so that the liquid taken up by the pin distributes uniformly around the mould pins and set firmly as a film on the pins. The pins are dried at room temperature initially and then at 60°C in an oven. The dried capsules are removed from the pins and trimmed using knife to required size. The body and cap are joined. The capsules prepared as above are found to withstand relative humidity over wide range than gelatin capsules and did not support microbial growth. Further the in vitro study revealed that the drug release from the capsule prepared from tamarind seed polysaccharide is well within the limit specified in Indian Pharmacopoeia. The advantages of the invention are as follows: 1. The pharmaceutical hard capsule prepared by this invention is of the vegetable origin and hence acceptable to all sects. 2. The novel pharmaceutical hard capsule will not be susceptible for microbial growth. 3. The capsule can withstand wide humidity range. 4. The invention is commercially viable, particularly in India, since large amount of tamarind seed is available in India at very low cost. 5. In India a large portion of tamarind seed is discarded as waste. Another application for the tamarind seed has been found by virtue of this invention. 6. The invented process results in manufacturing hard capsule which is economical. It is to be understood that the invention is described only to illustrate the salient features of the invention. The invention is in no way restricted by virtue of aforesaid description. Within the scope and ambit of the invention various modifications are envisaged. The scope of the invention is appended in the ensuing description. The process is explained below in the form of flow chart FLOW CHART OF THE PROCESS Roast tamarind seeds to make the testae brittle and the testae are removed. i Pulverise the seed kernel i Remove fat from the seed kernel powder by solvent extraction with petroleum ether in soxhiet extractor i Boil the defatted kernel powder with 0.1 M hydrochloric acid for 10 mts. Cool and centrifuge the slurry at 4000 rpm or 10 mts and separate the clear supernatant i precipitate the polysaccharide by adding rectified spirit to the supernatant. I Filter the precipitate, washed with rectified spirit and dried. i Prepare aqueous solution having 10% w/v tamarind seed polysaccharide, 2% w/v agar and 0.5/ w/v glycerol at 90°C i Cool the solution and maintain at 40°C Lubricate the mould pin, gently dip in the solution and withdraw i Blow cool air over the pin so that the solution taken up by the pin set firmly on the pins as film. i Dry the pins initially at room temperature and then at 60°C in an oven. I Remove the capsule shells from the pins and trimmed to required size ▼ The body and the cap are joined Signature of the applicant Dr.M.RATHINASABAPATHI (Nationality - Indian) Registrar Keglstnr. We claim 1. A process for the preparation of pharmaceutical hard capsule from a biodegradable material namely tamarind seed polysaccharide comprising A) roasting of tamarind seeds to make the testae brittle and removing the testae from seed kernel B) pulverising of tamarind seed kernel and removing of fat C) hydrolytic extraction of tamarind seed polysaccharide by boiling the tamarind seed kernel powder vi/ith 0.1 N hydrochloric acid for 10 mts, keeping the solid liquid ratio 1:25. D) centrifugation and removal of clear supernatant liquid containing the partially hydrolysed polysaccharide E) precipitation of partially hydrolysed polysaccharide by the addition of rectified spirit, filtration to collect the precipitate and washing the precipitate with rectified spirit F) addition of agar as gelation agent G) addition of glycerol as plasticizer H) cooling of solution to 40°C I) preparation of hard capsule by conventional dipmoulding technique. 2. The process as claimed in claim 1 where in the tamarind seed is roasted in an open pan at about 150°C till the testae become brittle and the testae are removed. 3. The process as claimed in claim 1 where in the tamarind seed kernel is pulverised to mesh No. 40 in an attrition mill. 4. The process as claimed in claim 1 where in the fat is removed from the tamarind seed kernel powder by solvent extraction with petroleum ether (40°C - 60°C) for three hours in Soxhiet extractor. 5. The process as claimed in claim 1 where in the defatted kernel powder is boiled with 0.1 N hydrochloric acid for 10 mts keeping the solid liquid ratio 1:25 that is for every lOOg of the kernel powder 2500ml of 0.1 N hydrochloric acid is used. 6. The process as claimed in claim 1 where in the slurry is centrifuged at 4000 rpm for 10 mts and the clear supernatant liquid containing the partially hydrolysed polysaccharide is collected. 7. The process as claimed in claim 1 where in the polysaccharide is precipitated from the supernatant liquid by adding twice the volume of 95% v/v ethanol. 8. The process as claimed in claim 1 where in the precipitate is collected by filtration through muslin cloth, washed with rectified spirit and dried at 60°C. 9. The process as claimed in claim 1 where in a solution having 10% w/v partially hydrolysed tamarind seed polysaccharide, 2% w/v agar and 0.5% w/v glycerol in water is prepared at 90°C. 10.The process as claimed in claim 9 where in the solution is cooled to 40°C and kept at the same temperature till the end of the process.

Documents:

910-mas-1998 abstract-duplicate.pdf

910-mas-1998 abstract.pdf

910-mas-1998 claims-duplicate.pdf

910-mas-1998 claims.pdf

910-mas-1998 correspondence-others.pdf

910-mas-1998 correspondence-po.pdf

910-mas-1998 description (complete)-duplicate.pdf

910-mas-1998 description (complete).pdf

910-mas-1998 form-1.pdf

910-mas-1998 form-19.pdf

910-mas-1998 form-3.pdf