Title of Invention

A NOVEL METHOD OF PREPARATION OF HARD CAPSULE SHELL

Abstract

A novel capsule for active pharmaceutical ingredients and method of preparation thereof. For the preparation of novel combination capsule a novel HPMC shells are prepared by dipping the molding pin in the aqueous solution made up of HPMC, co-film former Polyvinylpyrrolidone (PVP K30) and water. Cap and Body part of novel (HPMC) capsule and Gelatin capsule are separated. Cap of Gelatin is combined with Body of HPMC capsules and vice versa. Finally combination capsule prepared is separated and put for cross-linking. Novel capsule consist of "cap" part made up of gelatin and "body" part made up of non-cross-linkable film former (HPMC) or vice versa. Novel capsule is proposed to nullify the slowing down of disintegration and dissolution of capsule on aging. It is a cost effective capsule, more favorable for moisture sensitive drugs.

Full Text

FORM-2 THE PATENTS ACT, 1970 (39 of 1970) COMPLETE SPECIFICATION [SECTION 10; RULE 13] 1. A NOVEL METHOD OF PREPARATION OF HARD CAPSULE SHELL. 2. (a) L, M. COLLEGE OF PHARMACY, run by Ahmedabad Education Society, a Registered Trust (b) P.O. Box NO. 4011, Navrangpura, Ahmedabad-380 009. Gujarat, India. (c) INDIA. The following specification particularly describes and ascertains the nature of the invention and the manner in which it is to be performed. ORIGINAL 956/MUM/2003 15-03-03 1 The present invention relates to a novel method of preparation of hard capsule shell. A hard capsule shell in which either "cap" part or "body" part is made up of non-cross linkable film former and a method by which it is prepared, do not show adverse effect on drug dissolution on aging. It helps in faster drug disintegration and dissolution of capsule. It gives highly cost effective capsules. Modifications in conventional hard Gelatin/HPMC capsule are proposed to nullify the slowing down of dissolution of capsule shell on aging. Such combination capsule releases the contents without any hindrances. A novel capsule shell is proposed wherein either "cap" or "body" part is made up of non-cross-linkable pharmaceutical excipient i.e. a capsule where one part (cap or body) may undergo cross-linking (gelatin) on storage and the other part (body or cap) may not undergo cross-linking on storage (e.g. Hydroxypropyl methylcellulose). BACKGROUND OF THE INVENTION Solid oral dosage forms are widely used today despite the advancements made in the other drug delivery systems. The two 2 most popular oral dosage forms are tablets and capsules. Capsules are more popular because of associated advantages, such as glossy appearance, ability to hold colour, neutral taste and processing convenience. Gelatin is extensively used in solid dosage forms such as hard capsules, soft capsules, microcapsules and coated tablets. Aged gelatin containing products, especially capsules, show slowing down of disintegration of dosage form and/or dissolution of drug, primarily due to cross-linking between the polypeptide chains of gelatin. The cross-linking process causes formation of a swollen, rubbery, water insoluble membrane (pellicle) during dissolution testing. The rate of water penetration in such capsules is hampered and therefore the drug release is delayed considerably. Under certain conditions, especially the existence of trace amount of aldehyde in the capsule fill material or storage in hot and humid condition, catalyze cross-linking reaction of gelatin. The presence of formaldehyde is a common cause of cross-linking. Formaldehyde is believed to react with the amino function of 3 lysine and the guanidino function of arginine residues present in gelatin. Possible sources of the oxidative group contributing to cross-linking are: excipients containing trace amount of aldehydes; decomposition products of excipients; glucose or other aldose sugars, oxidation of capsule component (e.g., plasticizers, preservatives, fats, polyethylene glycols, or non-ionic surfactants); and impurities or degrading products of the active component. Butylated hydroxy anisole is used as an antioxidant in capsule formulation. It contains impurity of butylated hydroxy toluene (BHT). BHT degrades to 2,6-di-tert-butyl-4-hydroxybenzaldehyde. This aldehyde interacts with gelatin. Corn starch may contain traces of stabilizer hexamethyletetramine, which decomposes under humid conditions to form ammonia and formaldehyde. The later may react with lysine residue present in gelatin to form imine, which subsequently can undergo cross-linking reaction. Rayon coiler, a cushioning material used in container, form furfural on standing. Furfural has been shown to react rapidly with gelatin in form of a cross-linked insoluble product. (Digenis G.A., Gold, T. B., and Shah V. P., "Cross-linking of gelatin capsules and its 4 relevance to their in vitro-in vivo performance, J. Pharm. Sci., 83(7), 915, 1994). It is likely that cross-linking of gelatin has a much greater impact on the results of in vitro dissolution testing than on the in vivo bioavailability of drugs formulated in gelatin capsules. A gelatin capsule working group comprised of FDA and industry representative proposed a two-tier dissolution testing for capsules. Gelatin products are initially tested according to USP or NDA/ANDA dissolution test using dissolution medium without enzymes. If the capsules fail the dissolution test, the product is retested in the same dissolution medium with the addition of enzymes (Pharmaceutical Forum, Volume 24, Number 5, September-October, 1998). If the gelatin capsule passes the dissolution test in the enzyme containing medium, the products performance is considered to be acceptable. Meyer et al., reported that the capsules that are cross-linked to the greatest extent are not bioequivalent to the unstressed control capsules, based on maximum plasma concentration (Meyer, M. C, Pharmaceutical Research, 17(8), 2000, 962-966). 5 Efforts are made to arrest the cross-linking reaction by addition of chemicals or to eliminate the negative effect of cross-linking on drug dissolution by adopting other means. The present invention addresses the later issue. PRIOR ART Nowak Edward Zbygniew (WO 0203968) prepared capsules from foamed modified cellulose material for rapidly releasing the material in mouth. In such capsules the wall becomes weak and such capsules shows poor mechanical strength during handling. The capsule shell of present invention doesn't show such problem during handling and storage. Yamamoto et al., (US patent 5,264,223 and 5,431,917) disclosed a method of manufacturing of a hard capsule for pharmaceutical drugs, comprised of a water soluble cellulose derivatives as a capsule base, a gelling agent like carrageenan, and an auxiliary agent like KC1 for gelation. The present invention discloses a novel capsule, which consists of a cap and body comprising of different materials. 6 DETAILED DESCRIPTION OF THE INVENTION The present invention overcomes many of the disadvantages outlined above. An object of the present invention is to provide novel capsule (combination capsule) for pharmaceutical drug that shows quicker disintegration and dissolution on aging, i.e. the negative effect of cross-linking of gelatin is nullified and highly cost effective hard capsule are manufactured. Un-modified capsule is defined as the hard gelatin capsule as procured from the market. Combination capsule is defined as capsules wherein cap and body part are made up of different material, one is of gelatin and other is of non cross-linkable film formers PVP and HPMC. The hard capsule is a two-piece capsule. The shorter part is referred to as "cap" and the longer part is referred to as "body". Pharmaceutical drugs are filled in the body part of the capsule shell. In method of preparation of capsule shell either "cap" or "body" part is HPMC prepared by using dipping technique. The stainless steel pins are dipped in aqueous solution consisting of HPMC and PVP (co-film former) in water as a solvent. The auxiliary agent such as carageenan and KC1 are not used in the 7 process. Commercially available gelatin capsule shells are used in the present invention. The capsule parts (body and cap) of Gelatin and HPMC are separated, then "Body" of HPMC is combine with "Cap" of Gelatin and vice versa. This combination capsule prepared is separated from "cap" and "body" part and put for cross-linking; in which separated "cap" and "body" parts of Gelatin and HPMC are cross-linked by exposure to 30% aqueous solution of formalin vapour, for a period of 24 hours and dried in an oven at 60° C for 24 hours. The process of cross-linking is carried out to investigate the effect of aging on hard capsule disintegration and dissolution. Unmodified capsules, HPMC capsules and combination capsules are evaluated. Disintegration Test: The capsules are evaluated for disintegration time in Electrolab Disintegration Apparatus (model ED-2). The disintegration times are noted at 37±1° C, using unmodified capsules as a control using the same apparatus. Novel capsule of the present invention is used to fill active pharmaceutical ingredient, excipients, drug-excipients complexes or combination thereof. Representative examples of the active 8 pharmaceutical ingredients are not limited to nimesulide, valdecoxib and rofecoxib. More specific application of the present invention will be apparent to those skilled in the art by reviewing the examples. • A novel process of preparation of a novel capsule shell: Table 1: Preparation of Examples 1 and 2: - Shell Example 1 Example 2 Cap HPMC Gelatin Body Gelatin HPMC Example 1 and 2 are the example of novel capsule shell comprising gelatin as a part and HPMC as counter part. The following steps show the preparation of novel capsule shells of Examples 1 and 2. Step-1 Preparation of HPMC capsule shells: An aqueous solution of HPMC, film former Polyvinylpyrrolidone (PVP K-30) and H2O is prepared. Finally, capsule shells are prepared, using the aqueous solution, by dipping technique. The "cap" part and "body" part of the capsule shell is 9 separated from each other. The film former concentration is 1-5% w/v of each and more preferably 2-3% of each. Step-2 Separation of "Cap" and "Body" part of Gelatin capsule shell: Gelatin capsule shells are available in the market. "Body" and "Cap" part of the Gelatin Capsule shells are separated out from each other. Now, "Body" part of HPMC is combined with "Cap" part of Gelatin and "Cap" part of HPMC is combined with "body" part of HPMC. Finally a novel combination capsule is prepared. Step-3 Cross-linking of "cap" and "body" part of Gelatin and HPMC capsule shell: "Cap" and "body" part of the combination capsule shell is separated. Separated parts of combination capsule shell are cross-linked by exposure to the vapour of formalin solution (30% v/v) for a period of 24 hr, and dried in an oven at 60° C for 24 hr. Above shown Examples 1 and 2 are examples of novel capsule shell (combination capsule shell) prepared, are also referred to as Hc+Gb and Gc+Hb respectively. 10 A novel capsule (combination capsule) prepared comprising "Body" of HPMC and "Cap" of Gelatin is used for the filling of moisture sensitive pharmaceutical drugs. Moisture sensitive drugs are filled in the body part of capsule shell, where body is of HPMC. HPMC body contains A novel capsule prepared comprising "Body" of Gelatin and "Cap" of HPMC imparts various colours to the capsule shell. Due to this, the problem of mix-up of different capsules occurs in manufacturing process and packaging process is overcome. HPMC cap helps in faster disintegration and dissolution of the capsule. It also balance the cross-linking occur in gelatin body and prevent the pellicle formation. 11 The following tests are conducted on filling the pharmaceutical drugs in capsule. Representative examples of the active pharmaceutical ingredients are not limited to nimesulide, valdecoxib and rofecoxib. Test-1 Formulation filled in novel capsule shell: A complex of nimesulide and lysine in a molar ratio of 1:1 is prepared using solvent evaporation method. The dried powder of nimesulide-lysine complex is filled in novel capsule (combination capsule) shell of Examples 1 and 2. The filled capsule are referred to as Examples 3 and 4 respectively. Table 2: Results of Examples 3 and 4:- Note: Disintegration of either cap or body made up of HPMC is observed in the stipulated time. Example 3 Example 4 Disintegration time (min) 3 4 % Drug released in 45 min 74 91 The cross-linked hard gelatin capsules failed to disintegrate in 24 hr while the cross-linked HPMC capsules disintegrated in 5 min. The cross-linked gelatin capsules show poor drug dissolution from complex (18.6%). However, the drug release is pretty fast 12 (>74 % in 45 min) from presently prepared novel capsules of Example 3, Example 4 and cross-linked HPMC capsules. Drug dissolution is highest (99%) from the HPMC capsules, due to complete dissolution of Hydroxypropyl methylcellulose. Slower drug release from the novel capsules as compared to HPMC capsules is attributed to non-dissolution of the cap or body consisting of cross-linked gelatin. Test 2: Formulation containing solid dispersion filled in novel capsule: A Valdecoxib-PVP solid dispersion is prepared using solvent evaporation technique. The weight ratio of the drug to PVP is 1:7. The solid dispersion equivalent to 20 mg of valdecoxib is filled in combination capsule shells of Examples 1 and 2. The filled capsules are referred to as Example 5 and 6 respectively. Table 3: Results of Example 5 and 6 Note: Disintegration of either cap or body made up of HPMC is observed in the stipulated time Example 5 Example 6 Disintegration time (min) 3 3 % Drug released in 45 min 84 76 13 The cross-linked hard gelatin capsules are failed to disintegrate in 24 hr while the cross-linked HPMC capsules disintegrated in 5 min. The cross-linked hard gelatin capsules show poor drug dissolution from solid dispersion (11.1%). However, the drug release was pretty fast (>74 % in 45 min) from the combination capsules of Example 5, Example 6 and cross-linked HPMC capsules. Drug dissolution is highest (98%) from the HPMC capsules, due to complete dissolution of Hydroxypropyl methylcellulose. Slower drug release from the novel hard capsules as compared to the HPMC capsules may be attributed to non-dissolution of cap or body consisting of cross-linked gelatin. 14 We claim, 1. A novel method of preparation of hard capsule shell comprising the steps of: (a) Preparing a cap or body by dipping stainless steel pins in aqueous solution containing non-crosslinkable polymer such as hydroxypropyl methylcellulose (HPMC) at a level of 1-5% with a co-film former such as polyvinylpyrrolidone (PVP K-30) at a level of 1-5% or without a co-film former; (b) A complimentary cap or body portion made up of gelatin; (c) Combining the cap and body portions of 1(a) and 1(b). 2. A novel method of preparation of hard capsule shell as claimed in claim 1(a) wherein more preferable concentration of HPMC & PVP is 2-3% w/v. 3. A novel method of preparation of hard capsule shell as claimed in claim 1(a) wherein the hard capsule shell is capable of billing with active pharmaceutical ingredients. 4. A hard capsule shell prepared by process as claimed in claim 1 wherein the dissolution of active pharmaceutical ingredient is not hindered on storing the capsule at ambient condition or under stressed conditions of temperature and humidity. 5. A novel method of preparation of hard capsule shell as substantially herein described with foregoing description and examples. Dated this on 13th day of September 2003. ) Dr. Rajeshkumar H. Acharya. Advocate & Patent agent For and on behalf of the applicant.

Documents:

956-mum-2003-abstract(15-4-2004).doc

956-mum-2003-abstract(15-4-2004).pdf

956-mum-2003-cancelled pages(15-4-2004).pdf

956-mum-2003-claims(granted)-(15-4-2004).doc

956-mum-2003-claims(granted)-(15-4-2004).pdf

956-mum-2003-correspondence(15-4-2004).pdf

956-mum-2003-correspondence(ipo)-(4-5-2007).pdf

956-mum-2003-form 1(15-4-2004).pdf

956-mum-2003-form 1(15-9-2003).pdf

956-mum-2003-form 19(8-12-2003).pdf

956-mum-2003-form 2(granted)-(15-4-2004).doc

956-mum-2003-form 2(granted)-(15-4-2004).pdf

956-mum-2003-form 26(15-9-2003).pdf

956-mum-2003-form 3(15-9-2003).pdf

956-mum-2003-form 5(15-9-2003).pdf