Title of Invention	IMPROVED CELLULOSE CAPSULE
Abstract	A composition based on water-soluble cellulose derivative, HPMC. The composition comprises a blend of at least two grades of HPMC wherein the first HPMC and second HPMC are present in a specific ratio that imparts good tensile strength and solubility to the capsules. 15 JUL 2006

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FORM2 THE PATENTS ACT, 1970 (39 of 1970) & The Patents Rules, 2003 COMPLETE SPECIFICATION (See section 10; rule 13) 1. Title of the invention: IMPROVED CELLULOSE CAPSULE 2. Applicant(s) (a) NAME : SCITECH CENTRE (b) NATIONALITY: An Indian Company. (c) ADDRESS; 7, Prabhat Nagar, Jogeshwari West, Mumbai 400 102, Maharshtra, India 3. PREAMBLE TO THE DESCRIPTION The following specification particularly describes the invention and the manner in which it is to be performed: Field of Invention The present invention relates to a composition for preparing capsule shell based on water-soluble cellulose derivatives. More particularly, the present invention relates to a composition for preparing capsule shell comprising hydroxypropylmethylcellulose (HPMC / Hypromellose) blend. Background of the invention Capsules are widely used in the pharmaceutical industry as well as in the health food supplement market. The main usage thereof is as dosage form for solid, semi solid, liquid, pellet or herbal preparations. A primary object of these dosage forms is to have a good disintegration after being administered in order to enable an effective dissolution of the active substances in the appropriate digestive organ. The traditional material for forming the capsule shell is gelatin as a base with a plasticizer such as glycerin and sorbitol, opacifying agent, dye, pigment and other additives blended therein. The shell-forming compositions based on gelatin suffer from the problem of plasticity and other properties of shells being largely dependent on water content. It has been frequently seen that shells having low water content are brittle against shocks as encountered on drug filling. Also, as the water content lowers, shells can contract to loosen the cap-body engagement of capsules. Furthermore gelatin capsules are sensitive to heat and humidity besides being of animal origin, which is disfavored in the green environment movement prevalent currently. Hence capsules based on water- soluble cellulose derivatives were proposed to promote non-animal origin source and having no BSE / TSE (bovine spongiform encephalopathy / transmissible spongiform encephalopathy) risk. As a gelatin 2 substitute, the use of water-soluble film forming cellulose derivatives is widely described in the literatures. Reports of capsules made from cellulose derivatives refer to poor dissolution in vitro / in vivo, especially when compared to gelatin. To overcome this drawback, US Patent 5,756,123 discloses capsule shell using hydroxypropylmethylcellulose (HPMC) as a base having viscosity of 2.4-5.4 cps at 20 deg C. It has improved shapability and disintegration ability comparable to conventional gelatin shells. However, very low viscosity of HPMC resulting from low molecular weight induces higher shell brittleness that leads to poor strength of capsule shell. Further, US patent no 6,517,865 relates to non-animal polymer compositions suitable for shell forming, particularly hard and soft capsules, comprising water soluble cellulose ethers, hydrocolloids and sequestering agents. It discloses capsule shell using HPMC blend having viscosity of 3 -15 cps. It attempts overcome loss of transparency of the shell and brittleness [by using a higher viscosity of HPMC (greater than 6 cps) since higher the viscosity of HPMC better the mechanical strength] of the HPMC shell of prior art. In addition to the drawbacks of the HPMC shells as discussed above, it is known that capsule shell based on HPMC with low viscosity have better solubility and disintegration ability however poor mechanical / tensile strength. Capsule shells base on HPMC with high viscosity have better mechanical and tensile strength at the cost of having poor solubility and disintegration, There have been attempts made in the prior art to make capsule shell based on water-soluble cellulose derivative with both good solubility and mechanical / tensile strength, especially using low viscosity HPMC (upto 6 cps only) but none have proved successful. Therefore, there is a long felt need in the prior art for the capsule shells based on water soluble cellulose derivatives that overcomes the problems of the prior art cellulose shells and that can also replace the conventional gelatin shells. 3 OBJECTS OF THE INVENTION Therefore, it is an object of the present invention to provide a composition for capsule shells based on water-soluble cellulose derivative that overcomes the problems of the prior art. It is further object of the present invention to provide a composition for capsule shells based on HPMC. It is further object of the present invention to provide a composition for capsule shells based on HPMC that imparts increased tensile strength and improved solubility to capsules. Yet another object of the present invention to provide a process for the preparation of a composition for capsule shells based on HPMC. SUMMARY OF THE INVENTION According to an aspect of the present invention, there is provided a composition for capsule shell that comprises a blend of at least two HPMC grades wherein the first HPMC grade has the viscosity of about 3 mPa•s and the second HPMC has a viscosity of about 4.5 mPa•s or about 6 mPa•s and wherein the ratio of the amounts of the first to second HPMC grades varies from about 20:80 to about 40: 60. According to further aspect of the present invention there is provided a process for the preparation of an improved capsule shell, said process comprising: i) Dispersing the blend of at least two HPMC grades in the hot water wherein the first HPMC grade has the viscosity of about 3 mPa•s and the second 4 HPMC has a viscosity of about 4.5 mPa•s or about 6 mPa•s and wherein the ratio of the amounts of the first to second HPMC grades varies from about 20:80 to about 40:60; ii) Separately preparing a gelling agent solution and gelling aid solution in hot water and adding the said solutions at a predetermined temperature, in the said water soluble cellulose derivative solution to give a capsule preparing solution; iii) Ageing of the said capsule preparing solution of step (ii) for about 8 to 20 hours at a temperature of about 38 to 46 deg C and diluting the said solution by water, iv) Inserting a dipping mould into the capsule preparing solution of step (iii) at a predetermined temperature; and v) Drawing out the dipping mould and inducing setting of the capsule preparing solution adhering to said mould. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a graph showing the increased tensile strength of the capsule shell of the present invention using carrageenan as a gelling agent prepared from the compositions of the present invention. FIG. 2 is a graph showing increased solubility of the capsule shell of the present invention using carrageenan as the gelling agent. DETAILED DESCRIPTION It has been unexpectedly found that the tensile strength and solubilization properties of the capsule shell based on water-soluble cellulose derivative, especially HPMC is 5 markedly improved when at least two HPMC grades having pre-determined viscosities are blended in a specific ratio to form the HPMC blend. According to the present invention, the preferred water-soluble cellulose derivative is HPMC. The composition of the capsule shell comprises blend of at least two grades of HPMC having pre-determined viscosities. The blend preferably comprises at least two HPMC grades wherein the first grade has a lower viscosity and the second grade has higher viscosity. The composition of capsule shell comprises the HMPC blend of at least two HPMC wherein the first HPMC has a viscosity of about 3 mPa-s and is blended with the second HPMC having a viscosity of 4.5 mPa•s or about 6 mPa•s. As mentioned above, the tensile strength and solubilization of capsule shell based on HPMC is improved by using at least two grades of HPMC in a specific ratio. The capsule shells having different ratios of two HPMC are prepared and it has been unexpectedly found that tensile strength and. solubility are optimum at a specific ratio. The preferred ratio of the first HPMC to second HPMC is from about 20: 80 to about 40:60. In another embodiment, the preferred ratio of the first HPMC to the second HPMC is from about 25:75 to about 35:65. The composition of present invention may further comprise gelling agents, gelling promoters, coloring agents and so on. 6 The gelling agent is selected from carrageenan, gellan gum, and pectin. According to present invention the gelling agent is present in the range of 0.2 to 3.0 % w/w on dry HPMC. The gelling promoters for assisting in gelation of gelling agent are potassium ion, sodium ion or both. The sodium ion may also be blended in the form of a water-soluble compound such as sodium citrate. The potassium ion may be blended in the form of a water-soluble compound such as potassium chloride, potassium phosphate, potassium acetate and potassium citrate and it is present in the range of 0.2 to 95 % w/w on dry gelling agent. These gelling agents can add one or mixture of appropriate gelling promoters to each gelling agent if necessary. For example, potassium ion, ammonium ion, calcium ion, or mixture of these ions are able to be added in case of carrageenan. The coloring agents and opacifiers are selected from permitted colorant and dyes as listed in Rule 27 of Drugs and Cosmetics Act and Rule (India) and permissible under the regulatory requirements of the country of use. They comply with the Bureau of Indian Standards ( BIS) and / or Code of Federal Regulations (CFR) and / or EEC directives. In an embodiment, the coloring agent may be a color selected from the group comprising annatto, carotene, chlorophyll, cochineal, curcumin, caramel, riboflavin, red iron oxide, yellow iron oxide, titanium di-oxide, black iron oxide and mixtures thereof. In yet another embodiment, the coloring agent may be selected from quinazarine green, alizarin cyanine green, fast green, tartrazine, sunset yellow, quinoline yellow, erythrosine, eosin YS, toney red, ponceau 4R, carmoisine, indigo carmine, brilliant blue, orange G, resorcin brown, naphthol blue black, allura red, and combinations thereof. 7 In another embodiment, the coloring agent may be lake salts (example aluminum ) any of the above listed water soluble coloring agents and combinations thereof. The coloring agent is preferably used in an amount of from 0.01 to about 20% w/w of dry HPMC. The detailed manufacturing process for preparation of improved capsule shell comprises the following steps: i) Blend of at least two HPMC grades is dispersed in hot water wherein the first HPMC grade has the viscosity of about 3 mPa•s and the second HPMC has a viscosity of about 4.5 mPa•s or about 6 mPa•s and wherein the ratio of the amounts of the first to second HPMC grades varies from about 20:80 to about 40:60. ii) The solution of gelling agent and gelling aid is separately prepared in hot water and said solutions are added at the predetermined temperature in the said solution of HPMC blend to give a capsule preparing solution; iii) The capsule preparing solution of step (ii) is aged for about 8 to 20 hours at a temperature of about 38 to 46 deg C and then the said solution is diluted by water. iv) A dipping mould is inserted into the capsule preparing solution of step (iii) at a predetermined temperature and then the dipping mould is drawn out and inducing setting of the capsule preparing solution adhering to the pin. According to present invention the preferable time for ageing is about 8 to about 15 hrs. The preferred temperature for ageing is 40-44 deg C and the preferred viscosity of the solution is 1000 to 1200 cps. In a preferred embodiment, the hot water dispersion of said two grades of HPMC is cooled to 20 deg C for total solublization and then heating to about 40 - 44 deg C before adding the same to said solution containing gelling agent and gelling aid. An advantage of the disclosed process is that ageing of the said capsule preparing solution of step (ii) for about 8 to 20 hours at a temperature of about 38 to 46 deg C raises its viscosity to its natural extent and thereafter diluting the said solution by water brings the viscosity of the said solution in the desired range of 1100 to 1600 cps. This manufacturing procedure is only shown as one typical method. Our invention is related with the composition of HPMC but does not limit the manufacturing methods. The present invention shall now be specifically described by way of illustrative and non-limiting examples. It shall be understood that many variations and modifications thereto will be apparent to those skilled in the art without departing from the broadest scope and ambit of the invention as set forth herein above. Experiments: Evaluation methods: 1) Solubility of shells/films and capsules One shell /film (1 cm X 3 cm) or one empty capsule, both are sank into the medium by using the sinker, is tested by the dissolution apparatus (paddle method). The time when the shell or film or the capsules is completely dissolved is defined as the solubility time. Test conditions; 300 ml, 50 rpm, 37 deg C. Test medium; distilled water and 12.5 mM phosphate buffer (pH6.8) 2) Tensile strength Before the evaluation test, the shells/films are kept at the condition of the fixed humidity at least two days(40%RH to 60%RH). The power intensity is 9 measured when the shell is pulled out by using AUTOGRAPH tensile testing equipment. Three shells/films of the same shell/film number are tested. It is evaluated under the controlled room temperature and humidity. Sample preparation Example 1 HPMC film ( with Carrageenan ) (1) 0.4 gm of potassium chloride is dissolved in 350 ml of distilled water (about 80 deg C). Total 100 gm of HPMC is dispersed into this water (about 80 deg C). The temperature of HPMC dispersion is cooled down at about 20 deg C and HPMC is completely dissolved. And then the HPMC solution is heated at about 40 deg C. 0.3 gm of brilliant blue is added to observe its soluble state by naked eyes. (2) 0.4 gm of carrageenan is dissolved into 49.2 ml of water (about 40 deg C). (3) Carrageenan solution is added into HPMC solution keeping the temperature at 40 deg C. (4) This solution is applied to the casting method. Table 1: The composition ratio of HPMC in films Code F1 F2 F3 F4 F5 F6 F7 F8 HPMC A 0 10 20 25 30 35 40 50 HPMCB 100 90 80 75 70 65 60 50 A/(A+B) 0 0.1 0.2 0.25 0.3 0.35 0.4 0.5 HPMC A; about 3 mPa•s, HPMC B; about 4.5 mPa•s Example 2 HPMC film (with Carrageenan ) The procedure of the making films is the same as Example 1. 10 Table 2: The composition ratio of HPMC in films Example 3 HPMC films (with Gellan gum) (1) 0.4 gm of sodium citrate is dissolved in 350 ml of distilled water (about 80 deg C). Total 100 gm of HPMC is dispersed into this water (about 80 deg C). The temperature of HPMC dispersion is cooled down at about 20 deg C and HPMC is completely dissolved. And then the HPMC solution is heated at about 40 deg C. 18gm of brilliant blue is added to observe its soluble state by naked eyes. (2) 0.4 gm of gellan gum is dissolved into 49.2 ml of water (about 40 deg C). (3) Gellan gum solution is added into HPMC solution keeping the temperature at 40 deg C. (4) This solution is applied to the casting method. Table 3: The composition ratio of HPMC in films Example 4 HPMC films (with Pectin) (1) 0.4 gm of potassium chloride is dissolved into 350 ml of distilled water (about 80 deg C). Total 100 gm of HPMC is disperseq into this water (about 80 deg 11 (2) (3) (4) C). The temperature of HPMC dispersion is cooled down at about 20 deg C and HPMC is completely dissolved. And then the HPMC solution is heated at about 40 deg C. 5 gm of brilliant blue is added to observe its soluble state by naked eyes. 0.4 gm of pectin is dissolved into 49.2 ml of water (about 40 deg C). Pectin solution is added into HPMC solution keeping the temperature at 40 deg C. This solution is applied to the casting method. Table 4: The composition ratio of HPMC in films Code F41 F42 F43 F44 F45 HPMC A 20 25 30 35 40 HPMC B 80 75 70 65 60 A/(A+B) 0.2 0.25 0.3 0.35 0.4 HPMC A; about 3 mPa•s, HPMC B; about 4.5 mPa•s Example 5 HPMC capsule (with Carrageenan ) HPMC capsule is manufactured by dipping method. The gelling solution of this method is the same composition as the film making in Ex.1 above. The size of the capsule is #1. Its weight is about 76 mg. Table 5: The composition ratio of HPMC in capsules Code C2 C3 C4 C5 C6 C7 C8 HPMC A 10 20 25 30 35 40 50 HPMC B 90 80 75 70 65 60 50 A/(A+B) 0.1 0.2 0.25 0.3 0.35 0.4 0.5 HPMC A; about 3 mPa•s, HPMC B; about 4.5 mPa•s 12 Evaluation: (1) HPMC film HPMC film dissolved shortly as the ratio of HPMC A increased into the composition. These phenomena were observed in both water and the buffer (pH6.8) [Ref. table 6,7,8 and 9 ]. HPMC A and HPMC B / HPMC C are different on their viscosity. The viscosity reflects the molecular weight distribution of HPMC. Namely, the molecular weight distribution of HPMC A shifts small way compared with HPMC B / HPMC C. It is clear that HPMC A is easily dissolved compared with HPMC B / HPMC C. However, the tensile strength of the films was once weak but it became strong, as the ratio of HPMC A increased and subsequently became weak again. \t was found that when the ratio of A was from 0.25 to 0.3, the tensile strength became the strongest [Ref. table 6,7,8 and 91. The above phenomena was not found to be influenced / affected by type of gelling agent. Table 6 ; The solubility and the tensile strength of HPMC films (with carrageenan) Code F1 F2 F3 F4 F5 F6 F7 F8 A/(A+B) 0 0.1 0.2 0.25 0.3 0.35 0.4 0.5 Solubility in water (min) 5.4 5.2 5.3 5.2 5.1 4.4 4.2 3.5 Solubility in buffer pH 6.8 (min) 11.2 11.2 9.4 9.3 9.1 8.4 7.5 7.4 Tensile strength (kgf/cm2) 453.5 420.9 428.2 456.5 469.1 431.0 428.5 417.8 13 Table 7: The solubility and the tensile strength of HPMC films (with Carrageenan) Code F21 F22 F23 F24 F25 F26 A/(A+C) 0.15 0.2 0.25 0.3 0.35 0.4 Solubility in water (min) 6.3 6.0 5.4 5.3 5.2 5.1 Solubility in buffer pH 6.8 (min) 11.2 10.5 10.1 9.4 9.3 9.2 Tensile strength ( kgf/cm2) 506.4 502.2 510.1 501.1 501.0 500.7 Table 8 : The solubility and the tensile strength of HPMC films (with gellan gum) Code F31 F32 F33 F34 F35 A/(A+B) 0.2 0.25 0.3 0.35 0.4 Solubility in water (min) 7.3 7.1 6.4 6.3 5.4 Solubility in buffer pH 6.8 ( min) 10.3 10.0 9.4 9.3 9.1 Tensile strength (kgf/cm2) 454.1 489.9 485.9 437.4 432.9 Table 9 : The solubility and the tensile strength of HPMC films (with pectin) Code F41 F42 F43 F44 F45 A/(A+B) 0.2 0.25 0.3 . 0.35 0.4 Solubility in water (min) 5.5 5.4 5.3 5.2 4.4 14 Solubility in 9.5 9.3 9.2 9.1 8.5 buffer pH 6.8 ( min) Tensile strength 443.3 495.5 464.4 448.9 443.2 ( kgf/cm2) (2) HPMC capsule HPMC capsule dissolved shortly as the ratio of HPMC A increased into the composition. These phenomena were observed in both water and the buffer (pH6.8). HPMC A and HPMC B are different on their viscosity. The viscosity reflects the molecular weight distribution of HPMC. Namely, the molecular weight distribution of HPMC A shifts small way compared with HPMC B . It is clear that HPMC A is easily dissolved compared with HPMC B . However, the tensile strength of the capsule was once weak but it became strong, as the ratio of HPMC A increased and subsequently became weak again. It was found that when the ratio of A was from 0.25 to 0.35, the tensile strength became the strongest [ Ref table 10]. Table 10: The solubility and the tensile strength of HPMC capsules (with Carrageenan) Code C2 C3 C4 C5 C6 C7 C8 A/(A+B) 0.1 0.2 0.25 0.3 0.35 0.4 0.5 Solubility in water (min) 24.2 23.5 23.1 22.5 22.1 21.5 21.1 Solubility in buffer pH 6.8 ( min) 37.4 36.5 36.2 35.5 35.1 34.5 33.4 Tensile strength (kgf/cm2) 420.8 428.2 456.5 469.1 431.0 428.5 417.8 15 We Claim: 1. A composition comprising a blend of at least two grades of hydroxypropylmethylcellulose (HPMC / Hypromellose) wherein the first HPMC has a viscosity of about 3 mPa•s and the second HPMC has a viscosity of about 4.5 mPa•s or about 6 mPa•s wherein the ratio of the amounts of the first to second HPMC grades varies from about 20:80 to about 40:60. 2. A composition as claimed in claim 1, wherein the ratio of first to second HPMC grades is from about 25:75 to about 35:65. 3. A composition as claimed in claim 1 or claim 2, comprising one or more of the ingredients selected from gelling agent, gelling promoter and coloring agent. 4. A composition as claimed in claim 3, wherein said gelling agents are selected from carrageenan, gellan gum, and pectin. 5. A composition as claimed in claim 4, wherein said gelling agent is present in an amount of 0.2 to 3.0 % w/w of dry HPMC. 6. A composition as claimed in claim 3, wherein said gelling promoters are selected from potassium chloride, potassium phosphate, potassium citrate, potassium acetate and sodium citrate. 7. A composition as claimed in claim 6, wherein said gelling promoter is present in the range of 0.2 to 95.0 % w/w of dry gelling agent. 16 A composition as claimed in claim 3, wherein said coloring agent is selected from the group comprising annatto, carotene, chlorophyll, cochineal, curcumin, red iron oxide, yellow iron oxide, titanium oxide, black iron oxide, caramel, riboflavin, quinazarine green, alizarin cyanine green, fast green, tartrazine, sunset yellow, quinoline yeilow, erythrosine, eosin YS, toney red, ponceau 4R, carmoisine, indigo carmine, brilliant blue, orange G, resorcin brown, naphthol blue black, allura red, lakes salts of above water soluble colours and various possible combinations thereof. A composition as claimed in claim 8, wherein said coloring agent is present in an amount of 0.1 % to 20 % w/w of dry HPMC. A process for the preparation of capsule shell comprising: dispersing the blend of at least two HPMC grades in the hot water wherein the first HPMC grade has the viscosity of about 3 mPa-s and the second HPMC has a viscosity of about 4.5 mPa-s or about 6 mPa-s and wherein the ratio of the amounts of the first to second HPMC grades varies from about 20:80 to about 40:60; separately preparing a gelling agent solution and gelling promoter solution in water and adding the said solutions at a predetermined temperature, in the said water soluble cellulose derivative solution to give a capsule preparing solution; ageing said capsule preparing solution of step (ii) for about 8 to 20 hours at a temperature of about 38 to 46 deg C and diluting the said solution by water to get the viscosity of the said solution in the range of 1100 to 1600 cps; inserting a dipping mould into the capsule preparing solution of step (iii) at a predetermined temperature, then drawing out the dipping mould and inducing setting of the capsule preparing solution adhering to the pin. 17 11. A process as claimed in claim 10 further comprising cooling the hot water dispersion of said two grades of HPMC before adding said dispersion to the solution containing gelling agent and gelling promoter. 12. The process for the preparation of capsule shell as claimed in claim 10 wherein the time required for ageing is about 8-15 hrs. 13. The process for the preparation of capsule shell as claimed in claim 10 wherein the temperature required for ageing is about 40-44 deg C. 14. The process for the preparation of capsule shell as claimed in claim 10 wherein the viscosity of the solution of step (iii) is 1000-1200 cps. 15. A composition substantially as described herein with reference to examples and illustrated by figures. 16. A process for the preparation of a capsule shell substantially as described herein. Dated this 15th day of July 2008 Saloni Rastogi Of S. Majumdar & Co. Applicant's Agent 18

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