Indian Patents. 254997:"A PROCESS FOR THE PREPARATION OF A RAPIDLY DISINTEGRATING BIOADHESIVE PHARMACEUTICAL COMPOSITION"

Title of Invention	"A PROCESS FOR THE PREPARATION OF A RAPIDLY DISINTEGRATING BIOADHESIVE PHARMACEUTICAL COMPOSITION"
Abstract	The present invention relates to a process for the preparation of novel pharmaceutical formulation of tablets, which contain at least one high molecular weight polymeric agent which rapidly disintegrate in contact with water to form a smooth, homogenous, viscous and bioadhesive dispersion.

Full Text	FIELD OF INVENTION The present invention relates to a process for the preparation of novel pharmaceutical formulation of tablets, which contain at least one high molecular weight polymeric agent which rapidly disintegrate in contact with water to form a smooth, homogenous, viscous and bioadhesive dispersion. TECHNICAL PROBLEM The main concern of the present invention is to incorporate two exactly bpposite properties viz. rapid disintegration and bioadhesion together in a tablet. Bioadhesive properties can be incorporated in tablets by using bioadhesive polymers, which are usually high molecular weight matrix forming polymers'that swell in contact with water. Because of the swelling behavior, high molecular weight polymers tend to absorb water and form a gel on the surface of tablet. This gel layer prevents penetration of fluid into the core of tablet thereby preventing further disintegration of tablets. In addition, viscosity of the surrounding disintegrating fluid increases as a result of dissolution of the high molecular weight polymer. Formation of gel layer and increase in viscosity of surrounding fluid slow down further penetration of fluids into tablets, hence prevent the disintegration of tablets. PRIOR ART Rapidly disintegrating tablets are either dispersible or effervescent in nature. Most of the dispersible tablets are prepared by conventional methods of dry and wet granulation and contain one or more intragranular and/or extragranular disintegrating agents. Methods for preparation of water dispersible tablets containing one or more disintegrating agents are well known in prior art (US patents 5047247, 5629016, 4774083, 5948422, and 5955107). Effervescent tablets contain a carbonate source and a pharmaceutically acceptable acid. The effervescent compositions when come in contact with water, an effervescent reaction takes place between the carbonate and acid resulting in evolution of carbon dioxide, which aids in rapid disintegration of tablet. Effervescent tablets are prepared by standard techniques of dry or wet granulation (with non aqueous granulating fluids). These methods for preparation of effervescent tablets are well known in prior art (US patents 5211957, 5178878, and 6274172). US patent 4886669 discloses a galenical formulation of a water dispersible tablet consisting of (a) microparticles which contain at least one pharmaceutically active substance, (b) a disintegrant, and (c) swellable material which is able to generate high viscosity on coming in contact with water. The tablets disclosed in this invention disintegrate rapidly in contact with water and form a homogenous suspension of high viscosity that can be easily swallowed. These tablets consist of (a) coated or uncoated microparticles containing drug, prepared by extrusion and spheronization, (b) granules of guar gum, the swelling agent, (c) dry granules containing inactive excipients such as Avicel (microcrystalline cellulose), Polyplasdone (cross-linked poly vinyl pyrrolidine), (d) lubricant such as magnesium stearate, and (e) taste enhancing agents such as saccharine sodium. The present invention is different from that of US patent 4886669 in several ways. US patent 5055306 discloses a granular sustained release formulation of a pharmacologically active substance presented in the form of a water dispersible or effervescent tablet, which disintegrate rapidly into granules on coming in contact with water. The granules are prepared by coating the core particles, in order to provide sustained release of the drug. The present invention is different from that of US patent 5055306. The present invention does not involve any complicated procedures like coating. Another method of preparing rapidly disintegrating tablets is disclosed in US patent 5298261. The tablets described in this patent consist of a collapsed matrix network (consisting of a gum, a carbohydrate and the drug) that has been vacuum dried above the collapse temperature of the matrix. The method of preparation of vacuum dried tablets involve steps of (a) preparing a mixture of gum, carbohydrate and water, (b) forming the mixture into a tablet shape, (c) freezing below equilibrium freezing temperature of the mixture. The present invention is different from US patent 5298261 since it does not involve any complicated procedures like vacuum drying. The rapidly disintegrating bioadhesive tablets in the present invention are prepared by simple techniques such as dry and/or wet granulation. US patent 4832956 describes a process for preparation of disintegrating tablets. The process comprises of melting a filler material, dispersing an effective amount of at least one disintegrating agent in the solid melt, cooling the melt, comminuting the cooled melt into granules of pre-determined particle size, admixing an active agent with granules, and pressing said matrix into tablet form. The present invention is different from US patent 4832956 since it does not involve any complicated procedures like melting and the rapidly disintegrating tablets of the present invention are prepared by simple techniques such as dry and/or wet granulation. In addition, the tablets of present invention are bioadhesive in nature. In another invention, US patent 6248358 discloses bioadhesive progressive hydration tablets for buccal and/or vaginal administration and the method for preparing the same. The bioadhesive tablets consist of a water soluble polymer (e.g. Carbopol 974P), insoluble Polycarbophil (Noveon®), hydroxypropylmethyl cellulose as binder, lactose, corn starch, and magnesium stearate and are prepared by conventional methods of wet granulation. These tablets remain in vaginal cavity and deliver active agents for as much as 72 hours or more. The tablets hydrate progressively whereby the inner core of tablets remains intact. This kind of tablets that do not disintegrate and remain as a solid structure in vaginal cavity may cause inconvenience to the users. To avoid inconvenience to users vaginal tablets must disintegrate in vaginal cavity as soon as possible after administration. On the other hand, present invention discloses a process to prepare tablets that disintegrate rapidly and are bioadhesive at the same time, hence will prolong the retention of formulation at the site without causing any inconvenience to the users. US patent 4153678 describes using 2 parts of granules for preparation of effervescent tablets of levamisole for oral administration in animals. The two parts of granules were used to separate the effervescent producing salts, sodium bicarbonate and adipic acid. The present invention is different from US patent 4153678. The present invention describes a method of preparing rapidly disintegrating and bioadhesive tablets containing high molecular weight matrix forming agents. In the present invention, the one part of granules (Part A) contain a high molecular weight matrix forming agent and another part of granules (Part B) do not contain any high molecular weight matrix forming agent. In the present invention, 2 parts granulation approach is used to form pores for penetration of fluid that aids in disintegration of tablets and prevents rapid swelling of the matrix forming agent. Objects of the invention The main object of the present invention is to provide a process for the the preparation of novel pharmaceutical formulation of tablets, which contain at least one high molecular weight polymeric agent which rapidly disintegrate in contact with water to form a smooth, homogenous, viscous and bioadhesive dispersion. Another object of the present invention wherein the above tablets, when in contact with water disintegrate into granules in less than 5 minutes, in a small volume of fluid at 37°C. Still another object of the invention is to provide tablets, which disintegrate rapidly to form a smooth, homogenous, viscous, and bioadhesive dispersion. Summary of the Invention Accordingly, the present provides a process for the preparation of novel pharmaceutical formulation of tablets, which contain at least one high molecular weight polymeric agent which rapidly disintegrate in contact with water to form a smooth, homogenous, viscous and bioadhesive dispersion. The present invention consists of only two types of granules - one with and other without a high molecular weight polymeric agent, and other excipients such as a disintegrant, glidant and/or lubricant. A drug may be added in either type of granules. The granules of present invention are simple to prepare and does not require any complicated and expensive processes such as extrusion, spheronization, and coating. The granules can be prepared by simple methods of dry granulation or wet granulation, well known in prior art. In addition, tablets of present invention possess two exactly opposite pharmaceutical properties i.e. rapid disintegration and bioadhesion. These tablets disintegrate rapidly in contact with water and form a smooth, homogenous, viscous and bioadhesive dispersion. DETAILED DESCRIPTION OF PRESENT INVENTION The present invention relates to a process for the preparation of rapidly disintegrating bioadhesive formulation containing a high molecular weight polymeric agent, the said process comprising steps of: a) mixing high molecular weight polymeric agent with intragranular diluents, disintegrants / superdisintegrants, binders and optionally intragranular lubricants and glidant; b) converting a mixture of step (a) to part A granules by adopting either dry or wet granulation; c) mixing intragranular diluents, disintegrants / superdisintegrants binder with or without low molecular weight drug and optionally with intragranular glidant and lubricant, d) converting the mixture of step (c) to part B granules by adopting either dry or wet granulation; e) mixing part A and part B granules obtained in steps (b) and (c), adding extra granular disintegrant(s)/superdisintegrant(s), lubricant and optionally an extra granular glidants; and f) compressing the mixture of step (e) to obtain the required formulation in the form of tablets. An embodiment of the present invention, the high molecular weight polymeric agent may be an active ingredient or an excipient. Yet another embodiment of the present invention, the high molecular weight polymeric agent is selected from a group of polymers like cellulose based polymers such as cellulose sulfate, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, sodium carboxymethylcellulose, methylcellulose; natural gums such as xanthan gum, acacia, gum Arabic, guar gum, tragacanth; acrylic acid polymers such as Carbopols, Polycarbophil; starches, chitosan, alginic acid, alginates, pectins, dextrans, polysaccharides, gelatin, polystyrene sulfonate and mixtures thereof. Still another embodiment of the present invention, the high polymeric agent is water swellable and possess a high molecular weight ranging from 2,000 Da to 4 million Dalton, and above, preferably 5000 Da to 3 million Da. Yet another embodiment of the present invention, the part A granules comprise of 10 to 90% w/w of final formulation. One more embodiment of the present invention, the part A granules comprise of 20 to 60% w/w of final formulation. Still another embodiment of the present invention, the concentration of high molecular weight polymeric agent used is in the range of 40 to 99% w/w of part A granules. Yet another embodiment of the present invention the concentration of high molecular weight polymeric agent used is in the range of 80 to 95% w/w of part A granules. Still another embodiment of the present invention, the tablets on coming in contact with water disintegrate into granules in less than 5 minutes, in a small volume of fluid (10 to 50 ml), at 37°C. Yet another embodiment of the present invention, the tablets on coming in contact with water disintegrate into granules in less than 2 minutes, in a small volume of fluid (10 to 50 ml), at 37°C. Still another embodiment of the present invention, the tablets disintegrate rapidly to form a smooth, homogenous, viscous and bioadhesive dispersion. Yet another embodiment of the present invention, the tablets provides in water a homogenous dispersion with a viscosity ranging between 5 to 1000 cPs. Still another embodiment of the present invention, the tablets provides in water provides a homogenous dispersion with a viscosity ranging between 10 to 500 cPs. Yet another embodiment of the present invention, the concentration of the disintegrant is in the range of 1 to 40% w/w of final formulation. Still another embodiment of the present invention, the concentration of the extragranular disintegrant is in the range of 5 to 30% w/w of final formulation. Yet another embodiment of the present invention, the extragranular disintegrant is selected from a group of starches, silica, microcellulose, cross-linked carboxymethyl cellulose, cross-linked polyvinylpyrrolidone, ion exchange resins, clays such as Bentonite, Veeghum, alginates, and a mixture thereof. Still another embodiment of the present invention, the extragranular lubricant is present in concentration of 0.5 to 10% w/w, preferably 1 to 5% w/w. Yet another embodiment of the present invention, the extragranular lubricant is selected from a group of metallic stearates, stearic acid, talc, polyethylene glycols, soluble salts such as sodium chloride, sodium benzoate, sodium lauryl sulfate, spray dried magnesium lauryl sulfate, boric acid and a mixture thereof. Still another embodiment of the present invention, the extragranular glidant is present in concentration of 0.5 to 10% w/w, preferably 1 to 5% w/w. Yet another embodiment of the present invention, the extragranular glidant is selected from a group of silica derivatives, talc, starch and a mixture thereof. Yet another embodiment of the present invention, the extragranular portion of tablets may or may not contain a low molecular weight drug. Still another embodiment of the present invention, the granules A containing high molecular weight polymeric agent can be prepared by wet granulation or dry granulation. Yet another embodiment of the present invention, the granules A containing high molecular weight polymeric agent are prepared by dry granulation and contain a diluent, disintegrant, glidant and/or lubricant in addition to the matrix forming agent. Still another embodiment of the present invention, the granules A may or may not contain low molecular weight drug. Yet another embodiment of the present invention, the granules A containing high molecular weight polymeric agent are prepared by wet granulation and contain a diluent, disintegrant, and a binder in addition to the matrix forming agent. Still another embodiment of the present invention, the granules A may or may not contain low molecular weight drug. Yet another embodiment of the present invention, the granules B without high molecular weight polymeric agent can be prepared by wet granulation or dry granulation. Still another embodiment of the present invention, the granules B without high molecular weight polymeric agent are prepared by dry granulation and contain a diluent, disintegrant, superdisintegrant, glidant and/or lubricant. Yet another embodiment of the present invention, the granules B may or may not contain low molecular weight drug. Still another embodiment of the present invention, the granules B without high molecular weight polymeric agent are prepared by wet granulation and contain a diluent, disintegrant, superdisintegrant, and a binder. Yet another embodiment of the present invention, the granules B may or may not contain low molecular weight drug. Still another embodiment of the present invention, both the types of granules contain a diluent selected from a group of lactose, starches, sugars such as mannitol, sorbitol, xylitol, dextrose, sucrose, cellulose derivatives microcrystalline cellulose, dibasic calcium phosphate, calcium sulfate, and mixtures thereof. Yet another embodiment of the present invention, both the types of granules contain a disintegrant selected from a group of starches, silica, microcellulose, cross-linked carboxymethylcellulose, cross-linked polyvinylpyrrolidone, ion exchange resins, clays such as Bentonite, Veeghum, alginates, and a mixture thereof. Still another embodiment of the present invention, both the types of granules contain a glidant selected from a group of silica derivatives, talc, starch and mixtures thereof. Yet another embodiment of the present invention, both the types of granules contain a binder selected from a group of starch paste, sorbitol, alginates, polyvinyl pyrrolidine, hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose, carboxymethylcellulose, methylcellulose, ethylcellulose, and mixtures thereof. Still another embodiment of the present invention, both the types of granules contain a lubricant selected from a group of metallic stearates, stearic acid, talc, polyethylene glycols, soluble salts such as sodium chloride, sodium benzoate, sodium lauryl sulfate, spray dried magnesium lauryl sulfate, boric acid and a mixture thereof. Yet another embodiment of the present invention, the granules B without high molecular weight polymeric agent may or may not contain effervescent salts. Still another embodiment of the present invention, the granules obtained are effervescent in nature and contain a source of carbonate, a pharmaceutically acceptable acid which react together on coming in contact with water to produce effervescence that aids in the disintegration of tablets. Yet another embodiment of the present invention, the source of carbonate, is selected from the group consisting of sodium, magnesium or calcium carbonate salts, bicarbonate salts, sesequicarbonate salts and mixtures thereof. Still another embodiment of the present invention, the acidic component is at least one acid selected from the group consisting of citric acid, tartaric acid, malic acid, fumaric acid, adipic acid, succinic acid, acid anhydrides of said acids or salts of said acids or mixtures thereof. Yet another embodiment of the present invention, the pharmaceutical tablets are prepared for oral and/or topical application. Still another embodiment of the present invention, the tablets can be optionally coated with a suitable water soluble coating material which immediately dissolves in water, and enables in delaying the process of disintegration by one or two minutes. BRIEF DESCRIPTION OF DRAWINGS AND TABLES Figure Figure 1. Bioadhesive strength and work of adhesion (average of 5 replicates ± standard deviation) of tablets of the present invention as compared to other vaginal formulations currently underdevelopment or in market. Table Table 1: Different characteristics of tablets of present invention. (Table Removed) EXAMPLES The following examples are given by the way of illustration and therefore should not be construed to limit the scope of the present invention. Example 1: Sodium polystyrene sulfonate (PSS) is a synthetic high molecular weight (500,000 to 800,000 Da), polydisperse (polydispersity index 4.5), linear polymer comprised of repeated sulfonated styrene units. PSS is water soluble and contrasts with clinically used form of polystyrene sulfonate (Unites States Pharmacopeia 2000, 24th Edition), which is a sulfonated copolymer of styrene/divinyl benzene and is insoluble in nature. PSS possesses antimicrobial activities against several sexually transmitted pathogens including human immunodeficiency virus (HIV), herpes simplex virus (HSV), bovine papilloma virus, Neisseria gonorrhoea, and Chlamydia trachomatis. In addition, PSS also possess sperm inhibiting and contraceptive properties (US Patent 6239182; Anderson RA, Feathergill K, Diao X, Cooper M, Kirkpatrick R, Spear P, Waller DP, Chany C, Doncel GF, Herold B, Zaneveld LJ. Evaluation of poly(styrene-4-sulfonate) as a preventive agent for conception and sexually transmitted diseases. J Andrology 2000; 21: 862-875; Herold BC, Bourne N, Marcellino D, Kirkpatrick R, Strauss DM, Zaneveld LJ, Waller DP, Anderson RA, Chany CJ, Barham BJ, Stanberry LR, Cooper MD. Poly(sodium 4-styrene sulfonate): an effective candidate topical antimicrobial for the prevention of sexually transmitted diseases. J Infectious Diseases 2000; 181: 770-773; Zaneveld LJD, Waller DP, Anderson RA, Chany C, Rencher WF, Feathergill K, Diao XH, Doncel GF, Herold B, Cooper M. Efficacy and safety of a new vaginal contraceptive formulation containing high molecular weight poly(sodium 4-styrenesulfonate). Biology of Reproduction 2002; 66: 886-894]. Composition of rapidly disintegrating and bioadhesive tablets containing PSS as high molecular weight polymeric agent is as follows: (Table Removed) Two types of granules were made one with (Part A granules) and other without high molecular weight polymeric agent (Part B granules). Part A granules were prepared by dry granulation. Slugs were prepared by compression of the powder mix in a single station tablet machine and the slugs were broken into granules using a dry granulator attached to Kalweka multipurpose machine (Kamavati Engineering Ltd., India) For Part A granules, only the particles that passed through BSS sieve number 22 and retained on BSS sieve number 60 were used in tablets. Part B granules were prepared by wet granulation. The powder mix was granulated with an aqueous dispersion of L-HPC (5% w/w of total weight of part B granules). Wet mass was passed through BSS sieve 16 and granules were dried at 50°C for 8 hours and dried granules passed through BSS sieve 22. Composition of both types of granules is as follows: Part A Granules (Table Removed) Part A and Part B granules were mixed with a superdisintegrant, glidant and a lubricant for 10 minutes. The powder mix was compressed into tablets weighing 1.2 gm using a single station tablet machine (Cadmach, Ahmedabad, India). The composition of the final mixture for compression is as follows: (Table Removed) * Only granules (part A) of particle size that pass through mesh BSS 22 and retained on mesh BSS 60 were used in final tablets. These tablets are non-effervescent, rapidly disintegrating (disintegration time Example 2: Another composition of rapidly disintegrating and bioadhesive tablets, containing PSS as high molecular weight polymeric agent is as follows: (Table Removed) Part A and Part B granules were prepared by dry granulation as mentioned in Example 1. The composition of both types of granules is as follows: Part A Granules (Table Removed) Part B granules (Table Removed) Part A and Part B granules were mixed with a superdisintegrant, glidant and a lubricant for 10 minutes. The powder mix was compressed into tablets weighing 1.2 gm using a single station tablet machine (Cadmach, Ahmedabad, India). The composition of the final mixture for compression is as follows: (Table Removed) * Only granules (part A) of particle size that pass through mesh BSS 22 and retained on mesh BSS 60 were used in final tablets. These tablets are effervescent, rapidly disintegrating (disintegration time Example 3: Sodium cellulose sulfate (CS) is a linear polymer comprising basic monomelic units of D-glucose, linked through 1,4 glycosidic linkage. CS is a sulfated polysaccharide with peak and average molecular weights of approximately 2.3 million and 1.9 million Daltons respectively. It is soluble in hot water, partially soluble in cold water, soluble in solutions of aqueous alkalies and sparingly soluble in methanol. Sodium cellulose sulfate (CS, also known as Ushercell) is a non-cytotoxic polysaccharide with potent anti-HIV, anti-HSV, antichlamydial, anti-gonococcal, anti-papilloma virus properties. CS also possesses sperm function inhibiting and contraceptive properties (US patent 6063773; Anderson RA, Feathergill KA, Diao XH, Cooper MD, Kirkpatrick R, Herold BC, Doncel GF, Chany C, Waller DP, Rencher WF, Zaneveld LJD. 2002. Preclinical evaluation of sodium cellulose sulfate (Ushercell) as a contraceptive antimicrobial agent. J Andrology 23,426-438) Composition of rapidly disintegrating and bioadhesive tablets containing CS as high molecular weight polymeric agent is as follows: (Table Removed) Two types of granules were made one with (Part A granules) and other without the high molecular weight polymeric agent (Part B granules). Part A granules were prepared by dry granulation. Slugs were prepared by compression of the powder mix in a single station tablet machine and the slugs were broken into granules using a dry granulator attached to Kalweka multipurpose machine. Only the granules that passed through BSS sieve number 22 and retained on BSS sieve number 60 were used in tablets. Part B granules were prepared by wet granulation. The powder mix was granulated with an aqueous dispersion of L-HPC (3.3% w/w of total weight of part B granules). The granules were dried at 50°C for a period of 8 hours. The composition of both types of granules is as follows: Part A Granules (Table Removed) Part A and Part B granules were mixed with a superdisintegrant, glidant and a iubricant for lO minutes. The powder mix was compressed into tablets weighing 1.2 gm using a single station tablet machine (Cadmach, Ahmedabad, India). The composition of the final mixture for compression is as follows: (Table Removed) * Only granules (part A) of particle size that pass through mesh BSS 22 and retained on mesh BSS 60 were used in final tablets. These tablets are non-effervescent, rapidly disintegrating (disintegration time Another composition of rapidly disintegrating and bioadhesive tablets, containing CS as polymeric agent is as follows: (Table Removed) Both Part A and Part B granules were prepared by dry granulation as mentioned in Example 2. The composition of both types of granules is as follows: Part A Granules (Table Removed) Part A and Part B granules were mixed with a superdisintegrant, glidant and a lubricant and the mixture was compressed using a single station tablet machine (Cadmach, Ahmedabad, India). The composition of the final mixture for compression is as follows. (Table Removed) * Only granules (part A) of particle size that pass through mesh BSS 22 and retained on mesh BSS 60 were used in final tablets. These tablets are effervescent, rapidly disintegrating (disintegration time Example 5: Clotrimazole is a chlorinated imidazole derivative, used to treat topical fungal, dermatophytic and yeast infections. It is the most widely prescribed antimycotic agent for vaginal candidiasis. Clotrimazole has a low molecular weight (344.84 Da) and is practically insoluble in water (United States Pharmacopoeia 24). Composition of rapidly disintegrating and bioadhesive tablets containing Clotrimazole is as follows: (Table Removed) Two types of granules were made one with (Part A granules) and other without high molecular weight polymeric agent (Part B granules). Clotrimazole was incorporated in Part A granules and Part A granules were prepared by dry granulation. Slugs were prepared by compression of the powder mix in a single station tablet machine and the slugs were broken into granules using a dry granulator attached to Kalweka multipurpose machine (Karnavati Engineering Ltd., India) For Part A granules, only the particles that passed through BSS sieve number 22 and retained on BSS sieve number 60 were used in tablets. Part B granules were prepared by wet granulation. The powder mix was granulated with an aqueous dispersion of L-HPC (5% w/w of total weight of part B granules). Wet mass was passed through BSS sieve 16 and granules were dried at 50°C for 8 hours and dried granules passed through BSS sieve 22. Composition of both types of granules is as follows: Part A Granules (Table Removed) lubricant for 10 minutes. The powder mix was compressed into tablets weighing 1.0 gm using a single station tablet machine (Cadmach, Ahmedabad, India). The composition of the final mixture for compression is as follows: (Table Removed) * Only granules (part A) of particle size that pass through mesh BSS 22 and retained on mesh BSS 60 were used in final tablets. These tablets are non-effervescent, rapidly disintegrating (disintegration time The performance of present pharmaceutical invention was evaluated by conducting following tests: Hardness Hardness of the tablets was tested with Erweka Hardness Tester TBH 20 (Erweka, GmbH, Germany). Disintegration test Disintegration time and behavior of tablets were evaluated using an in vitro method developed in house (Garg S, Vermani K, Kohli G, Tambwekar K, Kandarapu R, Garg A, Waller DP, and Zaneveld LZD. 2002 Survey of vaginal formulations available in Indian market and evaluation of selected products, Int. J. Pharm. Med., 16, 141-152). A defined volume of disintegrating fluid (10 ml) was taken in a cylindrical container fitted with a screen (BSS mesh # 10), maintained at 37°C and stirred at fixed rpm (300) with the help of magnetic stirrer. Test tablets were placed above the screen and disintegration time recorded. A tablet was considered to disintegrate when it completely dissolved or separated into component parts or became soft such that the mass had no solid core offering resistance to pressure with a glass rod. Disintegration was studied using water as disintegrating fluid. Disintegration time and behavior were recorded. Disintegration of tablets was also studied by IP method in 800 ml of water at 37°C. Uniformity of dispersion (Indian Pharmacopoeia, 1996) Two tablets were placed in 100 ml water and stirred gently until completely dispersed. The dispersion was passed through a sieve screen with a nominal mesh aperture of 710 ixM (sieve number 22). The tablet passes the test if the dispersion passes through the mesh. Viscosity determination of the dispersion Viscosity of dispersion of 1 tablet in 10 ml of water was measured using a Brookfield RVDV III+ Programmable Rheometer (Brookfield Engineering, USA) with coaxial cylinders (measuring spindle - SC4-21, small sample adapter). Viscosity of 8 ml of the sample maintained at 37°C was measured by rotating the spindle at 250 rpm for 1 minute (Garg S, Vermani K, Kohli G, Tambwekar K, Kandarapu R, Garg A, Waller DP, and Zaneveld LZD. 2002 Survey of vaginal formulations available in Indian market and evaluation of selected products, Int. J. Pharm. Med., 16, 141-152). Bioadhesion The method to measure bioadhesion is based on the principle of measuring the force required to break the adhesive bond between a model membrane and test formulation. Isolated sheep vaginal mucosa was used as the model membrane (Institute animal ethics committee's permission was obtained for the use of isolated sheep vagina in the experiments). The test formulation is sandwiched between two model membranes fixed on flexible supports in the modified probes of Texture Analyzer for a sufficient period of time. After the adhesive bond has formed, the force required to separate the bond is measured as bioadhesive strength (Garg S, Vermani K, Kohli G, Tambwekar K, Kandarapu R, Garg A, Waller DP, and Zaneveld LZD. 2002 Survey of vaginal formulations available in Indian market and evaluation of selected products, Int. J. Pharm. Med., 16, 141-152). Bioadhesive strength of vaginal formulations was measured using a calibrated Texture Analyzer (Model TA-XT2i, Stable Micro Systems, UK) equipped with a 5 kg load cell and modified probes. Data was acquired at a rate of 50 points per second, using fully integrated data acquisition and analysis software (Texture Expert, Version 1.22, 1999). The probes of equipment were modified so as to hold and provide a flexible support to sheep vaginal mucosa. Sheep (Ovis aries, non descriptive local breed) vaginal tissue was obtained immediately after the sacrifice of animals at a slaughterhouse. Vaginal tissue was cleaned, separated from the supporting muscular and connective tissues taking care to maintain the integrity of mucosa. The isolated tissue was frozen at -20°C till further use. Before experiments, sheep vaginal tissue was thawed in normal saline containing 0.1% w/v Sodium azide as preservative. Vaginal tube was incised longitudinally and tied with a thread to the modified probes with mucosal side exposed. For measuring bioadhesive strength, 0.5 gm of the dispersion (1 tablet dispersed in 3 ml normal saline) was applied in between the sheep vaginal mucosa on an area of 464 mm . Membranes were kept in contact with the test sample for a period of 5 minutes under a constant force of 0.25 N in order to establish proper contact between membrane and sample to allow the formation of adhesive bond. Force required to separate the two membranes (with dispersion in between) was measured by upper support of Texture Analyzer moving at a rate of 0.1 mm/sec. Maximum force required to break the adhesive bond was measured as bioadhesive strength and area under curve measured as work of adhesion. All the formulations were evaluated using isolated sheep vaginal mucosa (n = 5) and mean bioadhesive strength and work of adhesion were determined. Bioadhesive properties of tablets were compared with that of other vaginal formulations including Replens (Columbia Laboratories, Aventura, FL, claimed to have bioadhesive properties), KY Jelly® (Advanced Care Products, Raritan, NJ; a frequently used marketed vaginal lubricant), Acidform gel (an investigational acid buffering bioadhesive vaginal gel formulation being developed at TOPCAD, Rush Presbyterian St Luke's Medical Center, Chicago, USA, presently in clinical trials), CS gel (6% w/w gel, presently in clinical trails, being developed by TOPCAD, Chicago, USA) and PSS gel (10% w/w gel of PSS, presently in clinical trials, being developed by TOPCAD, Chicago, USA). NOVELTY: In the present invention, the formulation in the form of a tablet containing high molecular weight agent having bioadhesive and dispersible properties together has been achieved for the first time. Main advantages of the present invention 1 The present invention provides a method for preparation of rapidly disintegrating and bioadhesive tablets of high molecular weight polymeric agent(s). 2 The present invention provides an easy and economical process for the preparation of rapidly disintegrating and bioadhesive tablets. 3 The tablets of the present invention on coming in contact with water form a smooth, homogenous, viscous and bioadhesive dispersion. References 1. Anderson RA, Feathergill K, Diao X, Cooper M, Kirkpatrick R, Spear P, Waller DP, Chany C, Doncel GF, Herold B, Zaneveld LJ. Evaluation of poly(styrene-4-sulfonate) as a preventive agent for conception and sexually transmitted diseases. J Andrology 2000; 21: 862-875 2. Herold BC, Bourne N, Marcellino D, Kirkpatrick R, Strauss DM, Zaneveld LJ, Waller DP, Anderson RA, Chany CJ, Barham BJ, Stanberry LR, Cooper MD. Poly(sodium 4-styrene sulfonate): an effective candidate topical antimicrobial for the prevention of sexually transmitted diseases. J Infectious Diseases 2000; 181: 770-773 3. Zaneveld LJD, Waller DP, Anderson RA, Chany C, Rencher WF, Feathergill K, Diao XH, Doncel GF, Herold B, Cooper M. Efficacy and safety of a new vaginal contraceptive formualtion containing high molecular weight poly(sodium 4-styrenesulfonate). Biology of Reproduction 2002; 66: 886-894 4. Anderson RA, Feathergill KA, Diao XH, Cooper MD, Kirkpatrick R, Herold BC, Doncel GF, Chany C, Waller DP, Rencher WF, Zaneveld LJD. 2002. Preclinical evaluation of sodium cellulose sulfate (Ushercell) as a contraceptive antimicrobial agent. J Andrology 23, 426-438 5. Garg S, Vermani K, Kohli G, Tambwekar K, Kandarapu R, Garg A, Waller DP, and Zaneveld LZD. 2002 Survey of vaginal formulations available in Indian market and evaluation of selected products, Int. J. Pharm. Med., 16, 141-152 6. Vermani K, Garg S, and Zaneveld LZD, 2002 Assemblies for in vitro measurement of bioadhesive strength and retention characteristics in simulated vaginal environment, Drug Dev. Ind. Pharm., 28 (9), 1133-1146 US Patent Documents (Table Removed) WE CLAIM: 1. A process for the preparation of a rapidly disintegrating, bioadhesive, pharmaceutical composition for topical application, wherein the said composition is non-effervescent and comprises: a. A specific high molecular weight polymeric agent selected from polystyrene sulfonate or cellulose sulphate present in the concentration range of 10% to 40%; and b. Pharmaceutical excipients and the process comprises the steps of: a. mixing the specific high molecular weight polymeric agent selected from polystyrene sulfonate or cellulose sulphate with intragranular diluents, disintegrants / superdisintegrants, binders and optionally intragranular lubricants and glidant followed by dry or wet granulation to form a distinctive set of part A granules; b. mixing another set of intragranular diluents, disintegrants / superdisintegrants binder without the high molecular weight polymeric agent and optionally with intragranular glidant and lubricant followed by dry or wet granulation to form a distinctive set of part B granules; c. mixing part A and part B granules so obtained, adding extra granular disintegrant(s)/superdisintegrant(s), lubricant and an extra granular glidant followed by compression of the mixture to obtain the required formulation in the form of tablets. 2 The process as claimed in claim 1, wherein the high molecular weight polymeric agent has antimicrobial and/or contraceptive property. 3 The process as claimed in claim I, wherein the final formulation comprises of 10 to 90% w/w of Part A granules and Part B granules. 4 The process as claimed in claim 1, wherein the concentration of the extragranular disintegrants is in the range of 1 to 40% w/w of final formulation and comprises an excipient selected from a group of starches, silica, microcellulose, cross-linked carboxymethyl cellulose, cross-linked polyvinyl pyrrolidone, ion exchange resins, clays such as Bentonite, Veeghum, alginates and a mixture thereof. 5 The process as claimed in claim 1, wherein the extragranular lubricant is present in concentration of 0.5 to 10% w/w and is selected from a group of metallic stearates, stearic acid, talc, polyethylene glycols, soluble salts such as sodium chloride, sodium benezoate, sodium lauryl sulfate, spray dried magnesium lauryl sulfate, boric acid and a mixture thereof. 6 The process as claimed in claim 1, wherein part A and Part B granules contain a diluent selected from a group of lactose, starches, sugars such as mannitol, sorbitol, xylitol, dextrose, sucrose, cellulose derivatives such us microcrystalline cellulose, dibasic calcium phosphate, calcium sulfate, and mixtures thereof. 7 The process as claimed in claim 1, wherein part A and Part B granules contain a disintegrant selected from a group of starches, silica, microcellulose, cross-linked carboxymethylcellulose, cross-linked polyvinylpyrrolidone, ion exchange resins, clays such as Bentonite, Veeghum, alginates, and a mixture thereof. 8 The process as claimed in claim 1, wherein part A and Part B granules contain a glidant selected from a group of silica derivatives, talc, starch and mixtures thereof. 9 The process as claimed in claim 1, wherein part A and Part B granules contain a binder selected from a group of starch paste, sorbitol, alginates, polyvinyl pyrrolidine, hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose, carboxymethylcellulose, methylcellulose, ethylcellulose, and mixtures thereof. 10 The process as claimed in claim 1, wherein part A and Part B granules contain a lubricant selected from a group of metallic stearates, stearic acid, talc, polyethylene glycols, soluble salts such as sodium chloride, sodium benzoate, sodium lauryl sulfate, spray dried magnesium lauryl sulfate, boric acid and a mixture thereof. 11 A rapidly disintegrating, bioadhesive, pharmaceutical composition for topical application obtained by the process as claimed in claim 1, wherein the said composition is non- effervescent and comprises: a. A specific high molecular weight polymeric agent which possesses the dual properties of bioadhesion and bioactivity, thus acting both as drug and excipient and is present in the concentration range of 10% to 40%; and b. Pharmaceutical excipients.

Full Text

FIELD OF INVENTION
The present invention relates to a process for the preparation of novel pharmaceutical formulation of tablets, which contain at least one high molecular weight polymeric agent which rapidly disintegrate in contact with water to form a smooth, homogenous, viscous and bioadhesive dispersion.
TECHNICAL PROBLEM
The main concern of the present invention is to incorporate two exactly bpposite properties viz. rapid disintegration and bioadhesion together in a tablet. Bioadhesive properties can be incorporated in tablets by using bioadhesive polymers, which are usually high molecular weight matrix forming polymers'that swell in contact with water. Because of the swelling behavior, high molecular weight polymers tend to absorb water and form a gel on the surface of tablet. This gel layer prevents penetration of fluid into the core of tablet thereby preventing further disintegration of tablets. In addition, viscosity of the surrounding disintegrating fluid increases as a result of dissolution of the high molecular weight polymer. Formation of gel layer and increase in viscosity of surrounding fluid slow down further penetration of fluids into tablets, hence prevent the disintegration of tablets.
PRIOR ART
Rapidly disintegrating tablets are either dispersible or effervescent in nature. Most of the dispersible tablets are prepared by conventional methods of dry and wet granulation and contain one or more intragranular and/or extragranular disintegrating agents. Methods for preparation of water dispersible tablets containing one or more disintegrating agents are well known in prior art (US patents 5047247, 5629016, 4774083, 5948422, and 5955107).
Effervescent tablets contain a carbonate source and a pharmaceutically acceptable acid. The effervescent compositions when come in contact with water, an effervescent reaction takes place between the carbonate and acid resulting in evolution
of carbon dioxide, which aids in rapid disintegration of tablet. Effervescent tablets are prepared by standard techniques of dry or wet granulation (with non aqueous granulating fluids). These methods for preparation of effervescent tablets are well known in prior art (US patents 5211957, 5178878, and 6274172).
US patent 4886669 discloses a galenical formulation of a water dispersible tablet consisting of (a) microparticles which contain at least one pharmaceutically active substance, (b) a disintegrant, and (c) swellable material which is able to generate high viscosity on coming in contact with water. The tablets disclosed in this invention disintegrate rapidly in contact with water and form a homogenous suspension of high viscosity that can be easily swallowed. These tablets consist of (a) coated or uncoated microparticles containing drug, prepared by extrusion and spheronization, (b) granules of guar gum, the swelling agent, (c) dry granules containing inactive excipients such as Avicel (microcrystalline cellulose), Polyplasdone (cross-linked poly vinyl pyrrolidine), (d) lubricant such as magnesium stearate, and (e) taste enhancing agents such as saccharine sodium. The present invention is different from that of US patent 4886669 in several ways.
US patent 5055306 discloses a granular sustained release formulation of a pharmacologically active substance presented in the form of a water dispersible or effervescent tablet, which disintegrate rapidly into granules on coming in contact with water. The granules are prepared by coating the core particles, in order to provide sustained release of the drug. The present invention is different from that of US patent 5055306. The present invention does not involve any complicated procedures like coating.
Another method of preparing rapidly disintegrating tablets is disclosed in US patent 5298261. The tablets described in this patent consist of a collapsed matrix network (consisting of a gum, a carbohydrate and the drug) that has been vacuum dried above the collapse temperature of the matrix. The method of preparation of vacuum dried tablets involve steps of (a) preparing a mixture of gum, carbohydrate and water, (b) forming the mixture into a tablet shape, (c) freezing below equilibrium freezing temperature of the mixture. The present invention is different from US patent 5298261 since it does not involve any complicated procedures like vacuum drying. The rapidly
disintegrating bioadhesive tablets in the present invention are prepared by simple techniques such as dry and/or wet granulation.
US patent 4832956 describes a process for preparation of disintegrating tablets. The process comprises of melting a filler material, dispersing an effective amount of at least one disintegrating agent in the solid melt, cooling the melt, comminuting the cooled melt into granules of pre-determined particle size, admixing an active agent with granules, and pressing said matrix into tablet form. The present invention is different from US patent 4832956 since it does not involve any complicated procedures like melting and the rapidly disintegrating tablets of the present invention are prepared by simple techniques such as dry and/or wet granulation. In addition, the tablets of present invention are bioadhesive in nature.
In another invention, US patent 6248358 discloses bioadhesive progressive hydration tablets for buccal and/or vaginal administration and the method for preparing the same. The bioadhesive tablets consist of a water soluble polymer (e.g. Carbopol 974P), insoluble Polycarbophil (Noveon®), hydroxypropylmethyl cellulose as binder, lactose, corn starch, and magnesium stearate and are prepared by conventional methods of wet granulation. These tablets remain in vaginal cavity and deliver active agents for as much as 72 hours or more. The tablets hydrate progressively whereby the inner core of tablets remains intact. This kind of tablets that do not disintegrate and remain as a solid structure in vaginal cavity may cause inconvenience to the users. To avoid inconvenience to users vaginal tablets must disintegrate in vaginal cavity as soon as possible after administration. On the other hand, present invention discloses a process to prepare tablets that disintegrate rapidly and are bioadhesive at the same time, hence will prolong the retention of formulation at the site without causing any inconvenience to the users.
US patent 4153678 describes using 2 parts of granules for preparation of effervescent tablets of levamisole for oral administration in animals. The two parts of granules were used to separate the effervescent producing salts, sodium bicarbonate and adipic acid. The present invention is different from US patent 4153678. The present invention describes a method of preparing rapidly disintegrating and bioadhesive tablets containing high molecular weight matrix forming agents. In the present
invention, the one part of granules (Part A) contain a high molecular weight matrix forming agent and another part of granules (Part B) do not contain any high molecular weight matrix forming agent. In the present invention, 2 parts granulation approach is used to form pores for penetration of fluid that aids in disintegration of tablets and prevents rapid swelling of the matrix forming agent.
Objects of the invention
The main object of the present invention is to provide a process for the the
preparation of novel pharmaceutical formulation of tablets, which contain at least one high molecular weight polymeric agent which rapidly disintegrate in contact with water to form a smooth, homogenous, viscous and bioadhesive dispersion.
Another object of the present invention wherein the above tablets, when in contact with water disintegrate into granules in less than 5 minutes, in a small volume of fluid at 37°C.
Still another object of the invention is to provide tablets, which disintegrate rapidly to form a smooth, homogenous, viscous, and bioadhesive dispersion.
Summary of the Invention
Accordingly, the present provides a process for the preparation of novel pharmaceutical formulation of tablets, which contain at least one high molecular weight polymeric agent which rapidly disintegrate in contact with water to form a smooth, homogenous, viscous and bioadhesive dispersion.
The present invention consists of only two types of granules - one with and other without a high molecular weight polymeric agent, and other excipients such as a disintegrant, glidant and/or lubricant. A drug may be added in either type of granules. The granules of present invention are simple to prepare and does not require any complicated and expensive processes such as extrusion, spheronization, and coating. The granules can be prepared by simple methods of dry granulation or wet granulation, well known in prior art. In addition, tablets of present invention possess two exactly opposite pharmaceutical properties i.e. rapid disintegration and bioadhesion. These
tablets disintegrate rapidly in contact with water and form a smooth, homogenous, viscous and bioadhesive dispersion.
DETAILED DESCRIPTION OF PRESENT INVENTION
The present invention relates to a process for the preparation of rapidly disintegrating bioadhesive formulation containing a high molecular weight polymeric agent, the said process comprising steps of:
a) mixing high molecular weight polymeric agent with intragranular diluents, disintegrants / superdisintegrants, binders and optionally intragranular lubricants and glidant;
b) converting a mixture of step (a) to part A granules by adopting either dry or wet granulation;
c) mixing intragranular diluents, disintegrants / superdisintegrants binder with or without low molecular weight drug and optionally with intragranular glidant and lubricant,
d) converting the mixture of step (c) to part B granules by adopting either dry or wet granulation;
e) mixing part A and part B granules obtained in steps (b) and (c), adding extra granular disintegrant(s)/superdisintegrant(s), lubricant and optionally an extra granular glidants; and
f) compressing the mixture of step (e) to obtain the required formulation in the form of tablets.
An embodiment of the present invention, the high molecular weight polymeric agent may be an active ingredient or an excipient.
Yet another embodiment of the present invention, the high molecular weight polymeric agent is selected from a group of polymers like cellulose based polymers such as cellulose sulfate, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, sodium carboxymethylcellulose, methylcellulose; natural gums
such as xanthan gum, acacia, gum Arabic, guar gum, tragacanth; acrylic acid polymers such as Carbopols, Polycarbophil; starches, chitosan, alginic acid, alginates, pectins, dextrans, polysaccharides, gelatin, polystyrene sulfonate and mixtures thereof.
Still another embodiment of the present invention, the high polymeric agent is water swellable and possess a high molecular weight ranging from 2,000 Da to 4 million Dalton, and above, preferably 5000 Da to 3 million Da.
Yet another embodiment of the present invention, the part A granules comprise of 10 to 90% w/w of final formulation.
One more embodiment of the present invention, the part A granules comprise of 20 to 60% w/w of final formulation.
Still another embodiment of the present invention, the concentration of high molecular weight polymeric agent used is in the range of 40 to 99% w/w of part A granules.
Yet another embodiment of the present invention the concentration of high molecular weight polymeric agent used is in the range of 80 to 95% w/w of part A granules.
Still another embodiment of the present invention, the tablets on coming in contact with water disintegrate into granules in less than 5 minutes, in a small volume of fluid (10 to 50 ml), at 37°C.
Yet another embodiment of the present invention, the tablets on coming in contact with water disintegrate into granules in less than 2 minutes, in a small volume of fluid (10 to 50 ml), at 37°C.
Still another embodiment of the present invention, the tablets disintegrate rapidly to form a smooth, homogenous, viscous and bioadhesive dispersion.
Yet another embodiment of the present invention, the tablets provides in water a homogenous dispersion with a viscosity ranging between 5 to 1000 cPs.
Still another embodiment of the present invention, the tablets provides in water provides a homogenous dispersion with a viscosity ranging between 10 to 500 cPs.
Yet another embodiment of the present invention, the concentration of the disintegrant is in the range of 1 to 40% w/w of final formulation.
Still another embodiment of the present invention, the concentration of the extragranular disintegrant is in the range of 5 to 30% w/w of final formulation.
Yet another embodiment of the present invention, the extragranular disintegrant is selected from a group of starches, silica, microcellulose, cross-linked carboxymethyl cellulose, cross-linked polyvinylpyrrolidone, ion exchange resins, clays such as Bentonite, Veeghum, alginates, and a mixture thereof.
Still another embodiment of the present invention, the extragranular lubricant is present in concentration of 0.5 to 10% w/w, preferably 1 to 5% w/w.
Yet another embodiment of the present invention, the extragranular lubricant is selected from a group of metallic stearates, stearic acid, talc, polyethylene glycols, soluble salts such as sodium chloride, sodium benzoate, sodium lauryl sulfate, spray dried magnesium lauryl sulfate, boric acid and a mixture thereof.
Still another embodiment of the present invention, the extragranular glidant is present in concentration of 0.5 to 10% w/w, preferably 1 to 5% w/w.
Yet another embodiment of the present invention, the extragranular glidant is selected from a group of silica derivatives, talc, starch and a mixture thereof.
Yet another embodiment of the present invention, the extragranular portion of tablets may or may not contain a low molecular weight drug.
Still another embodiment of the present invention, the granules A containing high molecular weight polymeric agent can be prepared by wet granulation or dry granulation.
Yet another embodiment of the present invention, the granules A containing high molecular weight polymeric agent are prepared by dry granulation and contain a diluent, disintegrant, glidant and/or lubricant in addition to the matrix forming agent.
Still another embodiment of the present invention, the granules A may or may not contain low molecular weight drug.
Yet another embodiment of the present invention, the granules A containing high molecular weight polymeric agent are prepared by wet granulation and contain a diluent, disintegrant, and a binder in addition to the matrix forming agent.
Still another embodiment of the present invention, the granules A may or may not contain low molecular weight drug.
Yet another embodiment of the present invention, the granules B without high molecular weight polymeric agent can be prepared by wet granulation or dry granulation.
Still another embodiment of the present invention, the granules B without high molecular weight polymeric agent are prepared by dry granulation and contain a diluent, disintegrant, superdisintegrant, glidant and/or lubricant.
Yet another embodiment of the present invention, the granules B may or may not contain low molecular weight drug.
Still another embodiment of the present invention, the granules B without high molecular weight polymeric agent are prepared by wet granulation and contain a diluent, disintegrant, superdisintegrant, and a binder.
Yet another embodiment of the present invention, the granules B may or may not contain low molecular weight drug.
Still another embodiment of the present invention, both the types of granules contain a diluent selected from a group of lactose, starches, sugars such as mannitol, sorbitol, xylitol, dextrose, sucrose, cellulose derivatives microcrystalline cellulose, dibasic calcium phosphate, calcium sulfate, and mixtures thereof.
Yet another embodiment of the present invention, both the types of granules contain a disintegrant selected from a group of starches, silica, microcellulose, cross-linked carboxymethylcellulose, cross-linked polyvinylpyrrolidone, ion exchange resins, clays such as Bentonite, Veeghum, alginates, and a mixture thereof.
Still another embodiment of the present invention, both the types of granules contain a glidant selected from a group of silica derivatives, talc, starch and mixtures thereof.
Yet another embodiment of the present invention, both the types of granules contain a
binder selected from a group of starch paste, sorbitol, alginates, polyvinyl pyrrolidine,
hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose,
carboxymethylcellulose, methylcellulose, ethylcellulose, and mixtures thereof.
Still another embodiment of the present invention, both the types of granules contain a lubricant selected from a group of metallic stearates, stearic acid, talc, polyethylene glycols, soluble salts such as sodium chloride, sodium benzoate, sodium lauryl sulfate, spray dried magnesium lauryl sulfate, boric acid and a mixture thereof.
Yet another embodiment of the present invention, the granules B without high molecular weight polymeric agent may or may not contain effervescent salts.
Still another embodiment of the present invention, the granules obtained are effervescent in nature and contain a source of carbonate, a pharmaceutically acceptable acid which react together on coming in contact with water to produce effervescence that aids in the disintegration of tablets.
Yet another embodiment of the present invention, the source of carbonate, is selected from the group consisting of sodium, magnesium or calcium carbonate salts, bicarbonate salts, sesequicarbonate salts and mixtures thereof.
Still another embodiment of the present invention, the acidic component is at least one acid selected from the group consisting of citric acid, tartaric acid, malic acid, fumaric acid, adipic acid, succinic acid, acid anhydrides of said acids or salts of said acids or mixtures thereof.
Yet another embodiment of the present invention, the pharmaceutical tablets are prepared for oral and/or topical application.
Still another embodiment of the present invention, the tablets can be optionally coated with a suitable water soluble coating material which immediately dissolves in water, and enables in delaying the process of disintegration by one or two minutes.
BRIEF DESCRIPTION OF DRAWINGS AND TABLES
Figure
Figure 1. Bioadhesive strength and work of adhesion (average of 5 replicates ± standard deviation) of tablets of the present invention as compared to other vaginal formulations currently underdevelopment or in market.
Table
Table 1: Different characteristics of tablets of present invention.
(Table Removed)
EXAMPLES
The following examples are given by the way of illustration and therefore should not be construed to limit the scope of the present invention.
Example 1:
Sodium polystyrene sulfonate (PSS) is a synthetic high molecular weight (500,000 to 800,000 Da), polydisperse (polydispersity index 4.5), linear polymer comprised of repeated sulfonated styrene units. PSS is water soluble and contrasts with clinically used form of polystyrene sulfonate (Unites States Pharmacopeia 2000, 24th Edition), which is a sulfonated copolymer of styrene/divinyl benzene and is insoluble in nature. PSS possesses antimicrobial activities against several sexually transmitted pathogens including human immunodeficiency virus (HIV), herpes simplex virus (HSV), bovine papilloma virus, Neisseria gonorrhoea, and Chlamydia trachomatis. In addition, PSS also possess sperm inhibiting and contraceptive properties (US Patent 6239182; Anderson RA, Feathergill K, Diao X, Cooper M, Kirkpatrick R, Spear P, Waller DP, Chany C, Doncel GF, Herold B, Zaneveld LJ. Evaluation of poly(styrene-4-sulfonate) as a preventive agent for conception and sexually transmitted diseases. J Andrology 2000; 21: 862-875; Herold BC, Bourne N, Marcellino D, Kirkpatrick R, Strauss DM, Zaneveld LJ, Waller DP, Anderson RA, Chany CJ, Barham BJ, Stanberry LR, Cooper MD. Poly(sodium 4-styrene sulfonate): an effective candidate topical antimicrobial for the prevention of sexually transmitted diseases. J Infectious Diseases 2000; 181: 770-773; Zaneveld LJD, Waller DP, Anderson RA, Chany C, Rencher WF, Feathergill K, Diao XH, Doncel GF, Herold B, Cooper M. Efficacy and safety of a new vaginal contraceptive formulation containing high molecular weight poly(sodium 4-styrenesulfonate). Biology of Reproduction 2002; 66: 886-894].
Composition of rapidly disintegrating and bioadhesive tablets containing PSS as high molecular weight polymeric agent is as follows:

(Table Removed)
Two types of granules were made one with (Part A granules) and other without
high molecular weight polymeric agent (Part B granules). Part A granules were prepared by dry granulation. Slugs were prepared by compression of the powder mix in a single station tablet machine and the slugs were broken into granules using a dry granulator attached to Kalweka multipurpose machine (Kamavati Engineering Ltd., India) For Part A granules, only the particles that passed through BSS sieve number 22 and retained on BSS sieve number 60 were used in tablets. Part B granules were prepared by wet granulation. The powder mix was granulated with an aqueous dispersion of L-HPC (5% w/w of total weight of part B granules). Wet mass was passed through BSS sieve 16 and granules were dried at 50°C for 8 hours and dried granules passed through BSS sieve 22. Composition of both types of granules is as follows:
Part A Granules

(Table Removed)
Part A and Part B granules were mixed with a superdisintegrant, glidant and a lubricant for 10 minutes. The powder mix was compressed into tablets weighing 1.2 gm using a single station tablet machine (Cadmach, Ahmedabad, India). The composition of the final mixture for compression is as follows:

(Table Removed)
* Only granules (part A) of particle size that pass through mesh BSS 22 and
retained on mesh BSS 60 were used in final tablets.
These tablets are non-effervescent, rapidly disintegrating (disintegration time Example 2:
Another composition of rapidly disintegrating and bioadhesive tablets, containing PSS as high molecular weight polymeric agent is as follows:

(Table Removed)
Part A and Part B granules were prepared by dry granulation as mentioned in Example 1. The composition of both types of granules is as follows:
Part A Granules

(Table Removed)
Part B granules

(Table Removed)
Part A and Part B granules were mixed with a superdisintegrant, glidant and a lubricant for 10 minutes. The powder mix was compressed into tablets weighing 1.2 gm using a single station tablet machine (Cadmach, Ahmedabad, India). The composition of the final mixture for compression is as follows:

(Table Removed)
* Only granules (part A) of particle size that pass through mesh BSS 22 and retained on mesh BSS 60 were used in final tablets.
These tablets are effervescent, rapidly disintegrating (disintegration time Example 3:
Sodium cellulose sulfate (CS) is a linear polymer comprising basic monomelic units of D-glucose, linked through 1,4 glycosidic linkage. CS is a sulfated polysaccharide with peak and average molecular weights of approximately 2.3 million and 1.9 million Daltons respectively. It is soluble in hot water, partially soluble in cold water, soluble in solutions of aqueous alkalies and sparingly soluble in methanol. Sodium cellulose sulfate (CS, also known as Ushercell) is a non-cytotoxic polysaccharide with potent anti-HIV, anti-HSV, antichlamydial, anti-gonococcal, anti-papilloma virus properties. CS also possesses sperm function inhibiting and contraceptive properties (US patent 6063773; Anderson RA, Feathergill KA, Diao XH,
Cooper MD, Kirkpatrick R, Herold BC, Doncel GF, Chany C, Waller DP, Rencher WF, Zaneveld LJD. 2002. Preclinical evaluation of sodium cellulose sulfate (Ushercell) as a contraceptive antimicrobial agent. J Andrology 23,426-438)
Composition of rapidly disintegrating and bioadhesive tablets containing CS as high molecular weight polymeric agent is as follows:

(Table Removed)
Two types of granules were made one with (Part A granules) and other without the high molecular weight polymeric agent (Part B granules). Part A granules were prepared by dry granulation. Slugs were prepared by compression of the powder mix in a single station tablet machine and the slugs were broken into granules using a dry granulator attached to Kalweka multipurpose machine. Only the granules that passed through BSS sieve number 22 and retained on BSS sieve number 60 were used in tablets. Part B granules were prepared by wet granulation. The powder mix was granulated with an aqueous dispersion of L-HPC (3.3% w/w of total weight of part B granules). The granules were dried at 50°C for a period of 8 hours. The composition of both types of granules is as follows:
Part A Granules

(Table Removed)
Part A and Part B granules were mixed with a superdisintegrant, glidant and a iubricant for lO minutes. The powder mix was compressed into tablets weighing 1.2 gm using a single station tablet machine (Cadmach, Ahmedabad, India). The composition of the final mixture for compression is as follows:

(Table Removed)
* Only granules (part A) of particle size that pass through mesh BSS 22 and retained on mesh BSS 60 were used in final tablets.
These tablets are non-effervescent, rapidly disintegrating (disintegration time Another composition of rapidly disintegrating and bioadhesive tablets,
containing CS as polymeric agent is as follows:

(Table Removed)
Both Part A and Part B granules were prepared by dry granulation as mentioned in Example 2. The composition of both types of granules is as follows:

Part A Granules

(Table Removed)
Part A and Part B granules were mixed with a superdisintegrant, glidant and a lubricant and the mixture was compressed using a single station tablet machine (Cadmach, Ahmedabad, India). The composition of the final mixture for compression is as follows.

(Table Removed)
* Only granules (part A) of particle size that pass through mesh BSS 22 and retained on mesh BSS 60 were used in final tablets.
These tablets are effervescent, rapidly disintegrating (disintegration time Example 5:
Clotrimazole is a chlorinated imidazole derivative, used to treat topical fungal, dermatophytic and yeast infections. It is the most widely prescribed antimycotic agent for vaginal candidiasis. Clotrimazole has a low molecular weight (344.84 Da) and is practically insoluble in water (United States Pharmacopoeia 24). Composition of rapidly disintegrating and bioadhesive tablets containing Clotrimazole is as follows:
(Table Removed)
Two types of granules were made one with (Part A granules) and other without high molecular weight polymeric agent (Part B granules). Clotrimazole was incorporated in Part A granules and Part A granules were prepared by dry granulation. Slugs were prepared by compression of the powder mix in a single station tablet machine and the slugs were broken into granules using a dry granulator attached to Kalweka multipurpose machine (Karnavati Engineering Ltd., India) For Part A granules, only the particles that passed through BSS sieve number 22 and retained on BSS sieve number 60 were used in tablets. Part B granules were prepared by wet granulation. The powder mix was granulated with an aqueous dispersion of L-HPC (5% w/w of total weight of part B granules). Wet mass was passed through BSS sieve 16 and granules were dried at 50°C for 8 hours and dried granules passed through BSS sieve 22. Composition of both types of granules is as follows:
Part A Granules

(Table Removed)
lubricant for 10 minutes. The powder mix was compressed into tablets weighing 1.0 gm
using a single station tablet machine (Cadmach, Ahmedabad, India). The composition of the final mixture for compression is as follows:

(Table Removed)
* Only granules (part A) of particle size that pass through mesh BSS 22 and retained on mesh BSS 60 were used in final tablets.
These tablets are non-effervescent, rapidly disintegrating (disintegration time The performance of present pharmaceutical invention was evaluated by conducting following tests: Hardness
Hardness of the tablets was tested with Erweka Hardness Tester TBH 20 (Erweka, GmbH, Germany). Disintegration test
Disintegration time and behavior of tablets were evaluated using an in vitro method developed in house (Garg S, Vermani K, Kohli G, Tambwekar K, Kandarapu R, Garg A, Waller DP, and Zaneveld LZD. 2002 Survey of vaginal formulations available in Indian market and evaluation of selected products, Int. J. Pharm. Med., 16, 141-152). A defined volume of disintegrating fluid (10 ml) was taken in a cylindrical container fitted with a screen (BSS mesh # 10), maintained at 37°C and stirred at fixed rpm (300) with the help of magnetic stirrer. Test tablets were placed above the screen and disintegration time recorded. A tablet was considered to disintegrate when it completely dissolved or separated into component parts or became soft such that the mass had no solid core offering resistance to pressure with a glass rod. Disintegration was studied using water as disintegrating fluid. Disintegration time and behavior were recorded. Disintegration of tablets was also studied by IP method in 800 ml of water at 37°C.
Uniformity of dispersion (Indian Pharmacopoeia, 1996)
Two tablets were placed in 100 ml water and stirred gently until completely dispersed. The dispersion was passed through a sieve screen with a nominal mesh aperture of 710 ixM (sieve number 22). The tablet passes the test if the dispersion passes through the mesh. Viscosity determination of the dispersion
Viscosity of dispersion of 1 tablet in 10 ml of water was measured using a Brookfield RVDV III+ Programmable Rheometer (Brookfield Engineering, USA) with coaxial cylinders (measuring spindle - SC4-21, small sample adapter). Viscosity of 8 ml of the sample maintained at 37°C was measured by rotating the spindle at 250 rpm for 1 minute (Garg S, Vermani K, Kohli G, Tambwekar K, Kandarapu R, Garg A, Waller DP, and Zaneveld LZD. 2002 Survey of vaginal formulations available in Indian market and evaluation of selected products, Int. J. Pharm. Med., 16, 141-152). Bioadhesion
The method to measure bioadhesion is based on the principle of measuring the force required to break the adhesive bond between a model membrane and test formulation. Isolated sheep vaginal mucosa was used as the model membrane (Institute animal ethics committee's permission was obtained for the use of isolated sheep vagina in the experiments). The test formulation is sandwiched between two model membranes fixed on flexible supports in the modified probes of Texture Analyzer for a sufficient period of time. After the adhesive bond has formed, the force required to separate the bond is measured as bioadhesive strength (Garg S, Vermani K, Kohli G, Tambwekar K, Kandarapu R, Garg A, Waller DP, and Zaneveld LZD. 2002 Survey of vaginal formulations available in Indian market and evaluation of selected products, Int. J. Pharm. Med., 16, 141-152).
Bioadhesive strength of vaginal formulations was measured using a calibrated Texture Analyzer (Model TA-XT2i, Stable Micro Systems, UK) equipped with a 5 kg load cell and modified probes. Data was acquired at a rate of 50 points per second, using fully integrated data acquisition and analysis software (Texture Expert, Version 1.22, 1999). The probes of equipment were modified so as to hold and provide a flexible support to sheep vaginal mucosa. Sheep (Ovis aries, non descriptive local breed) vaginal tissue was obtained immediately after the sacrifice of animals at a slaughterhouse. Vaginal tissue was cleaned, separated from the supporting muscular
and connective tissues taking care to maintain the integrity of mucosa. The isolated tissue was frozen at -20°C till further use. Before experiments, sheep vaginal tissue was thawed in normal saline containing 0.1% w/v Sodium azide as preservative. Vaginal tube was incised longitudinally and tied with a thread to the modified probes with mucosal side exposed.
For measuring bioadhesive strength, 0.5 gm of the dispersion (1 tablet dispersed in 3 ml normal saline) was applied in between the sheep vaginal mucosa on an area of 464 mm . Membranes were kept in contact with the test sample for a period of 5 minutes under a constant force of 0.25 N in order to establish proper contact between membrane and sample to allow the formation of adhesive bond. Force required to separate the two membranes (with dispersion in between) was measured by upper support of Texture Analyzer moving at a rate of 0.1 mm/sec. Maximum force required to break the adhesive bond was measured as bioadhesive strength and area under curve measured as work of adhesion. All the formulations were evaluated using isolated sheep vaginal mucosa (n = 5) and mean bioadhesive strength and work of adhesion were determined.
Bioadhesive properties of tablets were compared with that of other vaginal formulations including Replens (Columbia Laboratories, Aventura, FL, claimed to have bioadhesive properties), KY Jelly® (Advanced Care Products, Raritan, NJ; a frequently used marketed vaginal lubricant), Acidform gel (an investigational acid buffering bioadhesive vaginal gel formulation being developed at TOPCAD, Rush Presbyterian St Luke's Medical Center, Chicago, USA, presently in clinical trials), CS gel (6% w/w gel, presently in clinical trails, being developed by TOPCAD, Chicago, USA) and PSS gel (10% w/w gel of PSS, presently in clinical trials, being developed by TOPCAD, Chicago, USA).
NOVELTY: In the present invention, the formulation in the form of a tablet containing high molecular weight agent having bioadhesive and dispersible properties together has been achieved for the first time.
Main advantages of the present invention
1 The present invention provides a method for preparation of rapidly disintegrating and bioadhesive tablets of high molecular weight polymeric agent(s).
2 The present invention provides an easy and economical process for the preparation of rapidly disintegrating and bioadhesive tablets.
3 The tablets of the present invention on coming in contact with water form a smooth, homogenous, viscous and bioadhesive dispersion.
References
1. Anderson RA, Feathergill K, Diao X, Cooper M, Kirkpatrick R, Spear P, Waller DP, Chany C, Doncel GF, Herold B, Zaneveld LJ. Evaluation of poly(styrene-4-sulfonate) as a preventive agent for conception and sexually transmitted diseases. J Andrology 2000; 21: 862-875
2. Herold BC, Bourne N, Marcellino D, Kirkpatrick R, Strauss DM, Zaneveld LJ, Waller DP, Anderson RA, Chany CJ, Barham BJ, Stanberry LR, Cooper MD. Poly(sodium 4-styrene sulfonate): an effective candidate topical antimicrobial for the prevention of sexually transmitted diseases. J Infectious Diseases 2000; 181: 770-773
3. Zaneveld LJD, Waller DP, Anderson RA, Chany C, Rencher WF, Feathergill K, Diao XH, Doncel GF, Herold B, Cooper M. Efficacy and safety of a new vaginal contraceptive formualtion containing high molecular weight poly(sodium 4-styrenesulfonate). Biology of Reproduction 2002; 66: 886-894
4. Anderson RA, Feathergill KA, Diao XH, Cooper MD, Kirkpatrick R, Herold BC, Doncel GF, Chany C, Waller DP, Rencher WF, Zaneveld LJD. 2002. Preclinical evaluation of sodium cellulose sulfate (Ushercell) as a contraceptive antimicrobial agent. J Andrology 23, 426-438
5. Garg S, Vermani K, Kohli G, Tambwekar K, Kandarapu R, Garg A, Waller DP, and Zaneveld LZD. 2002 Survey of vaginal formulations available in Indian market and evaluation of selected products, Int. J. Pharm. Med., 16, 141-152
6. Vermani K, Garg S, and Zaneveld LZD, 2002 Assemblies for in vitro measurement of bioadhesive strength and retention characteristics in simulated vaginal environment, Drug Dev. Ind. Pharm., 28 (9), 1133-1146
US Patent Documents
(Table Removed)

WE CLAIM:
1. A process for the preparation of a rapidly disintegrating, bioadhesive, pharmaceutical
composition for topical application, wherein the said composition is non-effervescent and comprises:
a. A specific high molecular weight polymeric agent selected from polystyrene
sulfonate or cellulose sulphate present in the concentration range of 10% to 40%; and
b. Pharmaceutical excipients
and the process comprises the steps of:
a. mixing the specific high molecular weight polymeric agent selected from
polystyrene sulfonate or cellulose sulphate with intragranular diluents,
disintegrants / superdisintegrants, binders and optionally intragranular lubricants
and glidant followed by dry or wet granulation to form a distinctive set of part A
granules;
b. mixing another set of intragranular diluents, disintegrants / superdisintegrants
binder without the high molecular weight polymeric agent and optionally with
intragranular glidant and lubricant followed by dry or wet granulation to form a
distinctive set of part B granules;
c. mixing part A and part B granules so obtained, adding extra granular
disintegrant(s)/superdisintegrant(s), lubricant and an extra granular glidant
followed by compression of the mixture to obtain the required formulation in the
form of tablets.
2 The process as claimed in claim 1, wherein the high molecular weight polymeric agent has antimicrobial and/or contraceptive property.
3 The process as claimed in claim I, wherein the final formulation comprises of 10 to 90% w/w of Part A granules and Part B granules.
4 The process as claimed in claim 1, wherein the concentration of the extragranular disintegrants is in the range of 1 to 40% w/w of final formulation and comprises an excipient selected from a group of starches, silica, microcellulose, cross-linked carboxymethyl cellulose, cross-linked polyvinyl pyrrolidone, ion exchange resins, clays such as Bentonite, Veeghum, alginates and a mixture thereof.
5 The process as claimed in claim 1, wherein the extragranular lubricant is present in concentration of 0.5 to 10% w/w and is selected from a group of metallic stearates, stearic
acid, talc, polyethylene glycols, soluble salts such as sodium chloride, sodium benezoate, sodium lauryl sulfate, spray dried magnesium lauryl sulfate, boric acid and a mixture thereof.
6 The process as claimed in claim 1, wherein part A and Part B granules contain a diluent
selected from a group of lactose, starches, sugars such as mannitol, sorbitol, xylitol,
dextrose, sucrose, cellulose derivatives such us microcrystalline cellulose, dibasic calcium
phosphate, calcium sulfate, and mixtures thereof.
7 The process as claimed in claim 1, wherein part A and Part B granules contain a
disintegrant selected from a group of starches, silica, microcellulose, cross-linked
carboxymethylcellulose, cross-linked polyvinylpyrrolidone, ion exchange resins, clays
such as Bentonite, Veeghum, alginates, and a mixture thereof.
8 The process as claimed in claim 1, wherein part A and Part B granules contain a glidant
selected from a group of silica derivatives, talc, starch and mixtures thereof.
9 The process as claimed in claim 1, wherein part A and Part B granules contain a binder
selected from a group of starch paste, sorbitol, alginates, polyvinyl pyrrolidine,
hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose,
carboxymethylcellulose, methylcellulose, ethylcellulose, and mixtures thereof.
10 The process as claimed in claim 1, wherein part A and Part B granules contain a lubricant
selected from a group of metallic stearates, stearic acid, talc, polyethylene glycols, soluble
salts such as sodium chloride, sodium benzoate, sodium lauryl sulfate, spray dried
magnesium lauryl sulfate, boric acid and a mixture thereof.
11 A rapidly disintegrating, bioadhesive, pharmaceutical composition for topical application
obtained by the process as claimed in claim 1, wherein the said composition is non-
effervescent and comprises:
a. A specific high molecular weight polymeric agent which possesses the dual
properties of bioadhesion and bioactivity, thus acting both as drug and excipient
and is present in the concentration range of 10% to 40%; and
b. Pharmaceutical excipients.

Documents:

267-DEL-2003-Abstract-(09-11-2011).pdf

267-del-2003-abstract.pdf

267-DEL-2003-Claims-(09-11-2011).pdf

267-del-2003-Claims-(12-09-2012).pdf

267-del-2003-claims.pdf

267-DEL-2003-Correspondence Others-(09-11-2011).pdf

267-DEL-2003-Correspondence-Others-(10-11-2010).pdf

267-del-2003-Correspondence-Others-(12-09-2012).pdf

267-del-2003-correspondence-others.pdf

267-del-2003-correspondence-po.pdf

267-DEL-2003-Description (Complete)-(09-11-2011).pdf

267-del-2003-description (complete).pdf

267-del-2003-drawings.pdf

267-DEL-2003-Form-1-(09-11-2011).pdf

267-del-2003-form-1.pdf

267-del-2003-form-18.pdf

267-DEL-2003-Form-2-(09-11-2011).pdf

267-del-2003-form-2.pdf

267-del-2003-form-26.pdf

267-del-2003-form-3.pdf

267-DEL-2003-Form-5-(09-11-2011).pdf

267-del-2003-form-5.pdf

267-DEL-2003-GPA-(09-11-2011).pdf

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Patent Number

254997

Indian Patent Application Number

267/DEL/2003

PG Journal Number

03/2013

Publication Date

18-Jan-2013

Grant Date

12-Jan-2013

Date of Filing

10-Mar-2003

Name of Patentee

NATIONAL INSTITUTE OF PHARMACEUTICAL EDUCATION AND RESEARCH (NIPER)

Applicant Address

SECTOR 67, PHASE X, SAS NAGAR, MOHALI, DISTRICT ROPAR, PUNJAB 160 062, INDIA

Inventors:

#	Inventor's Name	Inventor's Address
1	SANJAY GARG	NATIONAL INSTITUTE OF PHARMACEUTICAL EDUCATION AND RESEARCH (NIPER), DEPARTMENT OF PHARMACEUTICS, SECTOR 67, PHASE X, S.A.S NAGAR, MOHALI,PUNJAB 160 062, INDIA
2	KAVITA VERMANI	H.NO.36, JAGDISH NAGAR, JWALAPUR, HARDWAR-249 407, UTTARANCHAL, INDIA
3	GUNGAN KOHLI	H.NO.B-25, KIRAN GARDEN, UTTAM NAGAR, NEW DELHI-110 059,INDIA
4	K.RAGHUPATHI	POST:DEVANOOR, MON:DHARMASAGAR, DIST.WARANGAL-506371, ANDHRA PRADESH, INDIA
5	KAUSTUBH R. TAMBWEKAR	TAMBWEKAR NIWAS 51, GOKHALE ROAD (SOUTH), DADAR (WEST), MUMBAI-400 028, MAHARASHTRA, INDIA
6	CHAMAN LAL KAUL	NATIONAL INSTITUTE OF PHARMACEUTICAL EDUCATION AND RESEARCH (NIPER), DEPARTMENT OF PHARMACEUTICS, SECTOR 67, PHASE X, S.A.S NAGAR, MOHALI,PUNJAB 160 062, INDIA

PCT International Classification Number

A61K 9/20

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA