Title of Invention

A NOVEL HARD GELATIN CAPSULE SHELL AND METHOD OF PREPARATION THEREOF

Abstract

A method of preparation of novel hard gelatin capsule shell comprising the following the steps , (a) preparing a hole (opening) of 0.5 mm diameter in "body" part of hard gelatin capsule; (b) sealing/coating the hole by pouring technique or spray coating by using the dispersion containing 5% Hydroxypropyl Methylcellulose (HPMC), 10% glycerol and quantity sufficient of ethyl alcohol on the inner surface of the capsule and keeping the mixture for 10 seconds in contact with shell (cap and body); (c) inverting the capsule parts up and down till the internal surface of capsule shell is uniformly covered and drying the capsule shells after draining off the dispersion; (d) finally joining the separated capsule parts (cap and body).

Full Text

FORM - 2 THE PATENTS ACT, 1970 (39 of 1970) COMPLETE SPECIFICATION [SEE SECTION 10, RULE 13] 1. A NOVEL HARD GELATIN CAPSULE SHELL AND METHOD OF PREPARATION THEREOF. 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 describes the nature of invention and the manner in which it is to be performed. ORIGINAL 820/MUMNP/2003 GRANTED 12/4/2004 The present invention relates to A novel hard gelatin capsule shell and method of preparation thereof. Method by which modified hard gelatin capsule shell is prepared, do not show adverse effect on drug dissolution or on aging. Modifications in conventional hard gelatin capsule are proposed to nullify the slowing down of dissolution of gelatin shell on aging. Such modified capsule releases the contents without any hindrances. In order to facilitate penetration of dissolution medium in hard gelatin capsule and subsequent drug dissolution, a hole is drilled in hard gelatin capsule shell and later the hole is sealed with film former, which is pharmaceutically acceptable, that does not undergo cross-linking. BACKGROUND OF THE INVENTION Solid oral dosage forms are widely used today despite the advancements made in the other drug delivery systems. The two 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, are showing 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 of capsule. The rate of water penetration in such capsule is hampered and therefore the drug release is delayed considerably. Under certain conditions, especially the existences of trace amount of aldehyde in the capsule fill material or hot and humid storage; catalyze the cross-linking reaction of gelatin. The presence of formaldehyde is a common cause of cross-linking. Formaldehyde is present in drug/excipients react with the amino function of 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 commonly 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 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 capsule fails 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). PRIOR ART Chen G. and Hao W. prepared sustained released (zero-order kinetic) capsules by drilling hole/s in gelatin capsules. The study was carried out to delay the drug release form the capsules (Chen G. and Hao W, "Factors affecting zero-order release kinetics of porous gelatin capsules", Drug Development and Industrial Pharmacy, 24(6), 557, 1998). The method is not adopted at the pharmaceutical industry since therejs probability of leakage of the contents from the holes present in the capsules during manufacturing, storage and use. The appearance of the capsules is spoiled due to leakage of contents, which affects the patient acceptability. The capsule fails in the content uniformity test (a pharmacopoeial test) on substantial amount of drug is leaked through the hole/s. The content of the capsules would expose to environmental hazards such as air and moisture. Hence, the approach is unsuitable for moisture or light sensitive drugs. Naik and Jain designed slow release capsules using laser drilling technique. Gastrointestinal tract resistant hard gelatin capsules were prepared by formalin treatment. Small pores were drilled in hardened gelatin capsule. The objective of the study was to delay the drug release (Jain N. K. and Naik S. U., "design of slow-release capsule using laser drilling", J. Pharm. Sci., 73(12), 1806, 1994). To overcome the adverse effect caused due to cross linking reaction between gelatin and active pharmaceutical ingredients/excipients filled in the hard gelatin capsule on drug dissolution or on aging the capsule, a novel hard gelatin capsule shell and method of preparation thereof is adopted. The objective of the present invention is to hasten the drug release from the hard gelatin capsule shell. DETAILED DESCRIPTION OF THE INVENTION The present invention overcomes many of the disadvantages outlined above. An object of the present invention is to provide hard gelatin capsule that shows quicker disintegration and dissolution on aging, i.e. the negative effect of cross-linking of gelatin is nullified. Un-modified capsule is defined as the hard gelatin capsule as procured from the market. Pin-holed capsule is defined as a capsule in which an opening is made. Modified capsule is defined as the capsule in which an opening is made in capsule and subsequently the internal surface of the capsule is coated with non cross- linkable film forming agent/s. The hard gelatin capsule is a two-piece capsule. The shorter part is referred to as "cap" and the longer part is referred to as "body". Method of preparation of modified hard gelatin capsule shell: In order to assist fast disintegration of filled capsule, an opening (hole) of 0.5 mm. diameter is made with the help of metal pin in "body" part or in "cap" part or in "body and cap" of hard gelatin capsule before filling the drug or excipients in capsule shell and separating the cap and body. Further the cap and body are separated. The "body" part is fully filled with a coating dispersion consisting of Hydroxypropyl Methylcellulose (HPMC), glycerol (plasticizer) and ethyl alcohol (vehicle). HPMC is a non-cross linkable film former. Afterwards, the cap is replaced back. The filled capsule is inverted in up and down direction to uniformly cover the internal surface of the entire capsule with the coating dispersion. The dispersion is kept in the capsule for 10 seconds and then the capsules shells are opened. Excess of the dispersion is drained off, leaving behind a wet film of the film former. The separated caps and bodies are dried for 24 hr at ambient temperature (25± 2° C) in a closed room. The cap and the body are joined together and stored in a glass jar till further use. These capsules are referred to as modified capsules in the present invention. An ideal film should be flexible, elastic, soft and yet adequately strong to withstand the breakage due to stress. Example of film formers used for coating the capsule shell include polyethylene glycol, polyvinylpyrrolidone and Hydroxypropyl Methylcellulose or combination thereof. Among them Hydroxypropyl Methylcellulose is the most preferable in terms of non-crosslinking property. For the retention of ideal film properties for a long period, plasticizer/s is/are added. The examples of plasticizers are polyethylene glycol 400, propylene glycol and glycerol. The dispersion of the film former can be applied on the outside or inside of the capsule shell. It is more feasible to deposit uniform film inside the shell. Moreover, the gloss of hard gelatin capsule shell is not adversely affected due to application of film of HPMC inside the gelatin shell. The modified capsules are filled with diluents such as starch, dicalcium phosphate dihydrate, lactose, microcrystalline cellulose, disintegrating agents such as croscarmellose sodium, sodium starch Glycollate, pregelatinized starch and crosslinked polyvinylpyrrolidone, lubricating agent such as magnesium stearate and sodium lauryl sulphate and glidant such as colliodal silica or any combination thereof. All these excipients are also filled in un¬modified capsules to serve as a control as well as in capsules wherein the opening is made but the internal surface of hard gelatin capsule is not coated and sealed by hydroxylpropylmethyl cellulose. The filled hard gelatin capsules are stored for a period of 90 days at 25° C at 40% relative humidity. Method of evaluation of modified hard gelatin capsule shell: The capsules are evaluated for disintegration time in Electrolab Disintegration apparatus (Model ED-2). The disintegration time is noted at 37 ± 1° C, using un-modified shells as a control using the same apparatus. Example 1 Preparation of modified capsule shell: Table 1: Percentage composition of coating solution for modified capsule shell. Ingredient % w/v Hydroxypropyl Methylcellulose (5 cPs) 5 Glycerol 10 Ethyl alcohol...quantity sufficient to 100 Hydroxypropyl Methylcellulose is dispersed in glycerol and part of ethyl alcohol. The mixture is heated to 60° C till a homogeneous dispersion is obtained. The dispersion is allowed to cool to room temperature. The final volume is adjusted by adding remaining portion of ethyl alcohol. An opening is made in the body part of hard gelatin capsule using a metal pin having a diameter equal to 0.5 mm. The cap and the body are separated. The "body" part of the gelatin capsule is fully filled by a coating dispersion made up of hydroxypropyl Methylcellulose, glycerol and ethyl alcohol. Afterwards, the cap is replaced back. The filled capsule shells are inverted up and down till the internal surface of the entire capsule is uniformly covered. The dispersion is kept in the capsule for 10 seconds and then excess of the dispersion is drained off after opening the capsule shells. The separated cap and body are dried for 24 hr at ambient temperature (25± 2° C) in a closed room. The cap and the body are joined together and stored in a glass jar till further use. This capsule shell is referred to as modified capsule shell in the present invention. Examples 2-6 Table 2 Disintegration time of Example 2-6 Example Excipient Disintegration time (min. sec) 2 Dicalcium Phosphate 4.40 3 Lactose 5.11 4 Sodium Starch Glycolate 5.55 5 Crospovidone 5.28 6 Sodium lauryl sulphate 5.00 Modified capsule shell of example 1 is filled with the excipient stated in Table 2. The capsule shells of each example are stored separately in glass petri dishes placed in a desiccators maintained at 25° C and 40% relative humidity for 90 days. Unmodified capsule shell shown increase in the disintegration time (more than 15 min) whereas all the modified capsule shell shows disintegration time of less than 6 min. Example 7 Modified capsule shell containing Diltiazem HCL Diltiazem HCL (30mg) is filled in the modified capsule shells of example 1. The capsules are evaluated for in vitro drug release in 0.1 N HCl using a paddle apparatus. After 45 min, 66% of the drug is released. We claim, 1. A method of preparation of novel hard gelatin capsule shell comprising the following the steps , (a) preparing a hole (opening) of 0.5 mm diameter in "body" part of hard gelatin capsule; (b) sealing/coating the hole by pouring technique or spray coating by using the dispersion containing 5% Hydroxypropyl Methylcellulose (HPMC), 10% glycerol and quantity sufficient of ethyl alcohol on the inner surface of the capsule and keeping the mixture for 10 seconds in contact with shell (cap and body); (c) inverting the capsule parts up and down till the internal surface of capsule shell is uniformly covered and drying the capsule shells after draining off the dispersion; (d) finally joining the separated capsule parts (cap and body). 2. A method of preparation of a novel hard gelatin capsule shell as claimed in claim 1 wherein making a hole (opening) of 0.5 mm diameter using a metal pin in "body" part of hard gelatin capsule shell. 3. A method of preparation of a novel hard gelatin capsule shell as claimed in claim 1 wherein preparing the dispersion by mixing 5% (5 cPs) of Hydroxypropyl Methylcellulose (HPMC), 10% glycerol, and quantity sufficient Ethyl alcohol, heating the mixture to 60° C till a homogeneous dispersion is obtained and cooling it at room temperature. 4. A method of preparation of a novel hard gelatin capsule shell as claimed in claim 1(c) wherein drying the separated cap and body of the gelatin capsule for 24 hours at ambient temperature (25 +/- 2° C) in a closed room. 5. A method as claimed in claim 1 wherein opening is/are made in "body" or in "cap" or in both the part of Capsule. 6. A method as claimed in claim 1 wherein opening in body part of hard gelatin capsule is prepared by manual operation or by other suitable method such as laser drilling technique. 7. A method of preparation of a novel hard gelatin capsule shell as claimed in claim 1 wherein sealing and coating the body part of capsule shell with a non cross-linkable film former or combination of film formers soluble in dissolution medium. 8. A method as claimed in claim 1 wherein sealing and coating the opening (hole) from the internal surface of the capsule or the external surface of the capsule or both. 10.A method as claimed in claim 1 wherein sealing/coating of the opening carried out by using dispersion/solution of the film former in pharmaceutically acceptable solvent or combination of solvents. 11. A method as claimed in claim 1 wherein preparing the filling material for dispersion containing film former is resistant to cross-linking. 12.A method of preparation of novel hard gelatin capsule shell substantially as herein described with description. Dated this 15tn day of August 2003

Documents:

820-mum-2003-cancelled pages(12-04-2004).pdf

820-mum-2003-claims(granted)-(12-04-2004).doc

820-mum-2003-claims(granted)-(12-04-2004).pdf

820-mum-2003-correspondence(31-01-2005).pdf

820-mum-2003-correspondence(ipo)-(22-06-2007).pdf

820-mum-2003-form 1(18-08-2003).pdf

820-mum-2003-form 19(17-10-2003).pdf

820-mum-2003-form 2(granted)-(12-04-2004).doc

820-mum-2003-form 2(granted)-(12-04-2004).pdf

820-mum-2003-form 26(21-07-2003).pdf

820-mum-2003-form 3(15-08-2003).pdf

820-mum-2003-form 5(15-08-2003).pdf