Title of Invention	SUSTAINED RELEASE PHARMACEUTICAL COMPOSITIONS AND PROCESS FOR THE PREPARATION THEREOF
Abstract	A controlled release composition for use in the treatment, inter alia of asthma and other bronchial conditions is disclosed. The composition is in the form of a tablet and comprises of a core matrix consisting of a mixture of a water insoluble, non permeable and non swellable polymer and soluble excipients and/or other conventional additives, and at least an active ingredient disperesed in such core matrix, said core matrix being coated with said water insoluble, non permeable and non swellable polymer and soluble excipients, such that upon administration, the soluble excipients in said coating and said core matrix dissolve and create micropores on various layers thereby allowing entry of surrounding fluids therein and create channels for the release for the release of said active ingredients through said micropores.

Title of Invention

SUSTAINED RELEASE PHARMACEUTICAL COMPOSITIONS AND PROCESS FOR THE PREPARATION THEREOF

Abstract

A controlled release composition for use in the treatment, inter alia of asthma and other bronchial conditions is disclosed. The composition is in the form of a tablet and comprises of a core matrix consisting of a mixture of a water insoluble, non permeable and non swellable polymer and soluble excipients and/or other conventional additives, and at least an active ingredient disperesed in such core matrix, said core matrix being coated with said water insoluble, non permeable and non swellable polymer and soluble excipients, such that upon administration, the soluble excipients in said coating and said core matrix dissolve and create micropores on various layers thereby allowing entry of surrounding fluids therein and create channels for the release for the release of said active ingredients through said micropores.

Full Text	FORM 2 THE PATENTS ACT, 1970 (39 of 1970) COMPLETE SPECIFICATION (See Section 10; rule 13) "SUSTAINED RELEASE PHARMACEUTICAL COMPOSITIONS AND PROCESS FOR THE PREPARA TION THEREOF" ORIGINAL 182/MUMNP/2002 27/02/2002 GRANTED 7/9/2007 We, CADILA HEALTHCARE LIMITED, a company incorporated under the Companies Act, 1956, of Zydus Tower, Satellite Cross Roads, Ahmedabad - 380 015, Gujarat, India, The followingl specification describes the nature of the invention and the manner in which it is to be performed: Field of invention The present invention relates to sustained release compositions and a process for the preparation thereof. More particularly, present invention relates to sustained release compositions in the form of tablets and a process for the preparation of such sustained release tablets. More particularly, the present invention relates to sustained release polymer coated tablets for use in treatment of asthma and other respiratory tract problems and a process for the preparation thereof. The present invention has particular application where one of the active ingredients is highly soluble in water and the other active ingredient, if any, is less soluble in water. One of the important applications envisaged by the present invention relates to a mixture of Xanthine bronchodilators used for treatment, inter alia of asthma, wherein one of the ingredients of the mixture is highly soluble in water and the other ingredient is less soluble in water. the invention Background of There are several methods by which a highly soluble pharmaceutical substance or al drug is administered to a patient. One of the important factors which has to be borne in mind while administering such drugs is to ensure that there is no sudden burst of the drug into the system (known as dosage dumping): Towards this end, slow release formulations of different drugs for various indications have been envisaged in the art. However, the problem has always been that of striking a balance between maintaining a proper bio¬availability of the drug into the system and controlling the release to avoid an overdose of the drug into the system. This has been equally true in case of drugs used for treatment asthma and COPD, for example mixtures of Xanthine bronchodilators comprising of Theophylline and Etofyllin used for treatment, inter alia of asthma, wherein one of the ingredients of the mixture is highly soluble in water and the other ingredient is less soluble in water. Both Etofyllin and Theophylline have been conventionally used in the treatment of asthma. There is a plethora of prior art on their use for the treatment of asthma and COPD. While, both Etophylline and Theophylline have demonstrated excellent therapeutic activity in the treatment of asthma and COPD, their use has been limited due to the fact that the problem of striking a balance between a proper bio-availability of the drug into the system and controlling the release to avoid an overdose of the drug into the system remains. Description of prior art Despite the above mentioned problems numerous attempts have been made to formulate Theophylline as a tablet which releases an initial burst of Theophylline and thereafter releases it at an essentially constant rate. Conventionally various attempts have been made to achieve an initial burst of the active agent into the system followed by a constant rate of release but each suffers from some disadvantage or other. For example, U.S. Pat. Nos. 2,793,979 and 2,993,836 describe the use of waxes and lipids in the matrix tablet formulations. Ethylcellulose has been used in matrix formulations with polyethylene glycol (U.S. Pat. No. 3,039,933), with calcium stearate (U.S. Pat. No. 3,322,633) and with calcium sulfate (U.S. Pat. No. 3,632,739) among other ingredients. Other known matrix materials include Carboxyrnethylcellulose1, Cellulose acetate phthalate, Sodium Carboxyrnethylcellulose, gums, carbohydrates such as starch and sorbitol and the like. U.S. Pat No. 3,087,860 teaches the use of polymeric matrix materials such as methyl! acrylate methyl methacrylate, while, U.S. Pat. No. 2,987,445 teaches the use of various polymers and copolymers such as polyethylene, Polymethyl methacrylate and copolymers of methyl methacrylate and alkyl acrylates and the like. All of these various matrix formulations suffer from several disadvantages. The primary disadvantage is slowing of the release rate as a function of time. Other disadvantages include dumping of entire dose in the stomach, short life in the gastrointestinal tract, difficulty of manufacture, the inclusion of undesirable ingredients, etc In an attempt to overcome the above-mentioned disadvantages, US Patent No. 470284 teaches a long-acting matrix tablet formulation especially suited for acid soluble therapeutic agents. Accordingly, this patent discloses a pharmaceutical tablet which releases an initial burst of therapeutic agent and thereafter relea"ses the agent at an essentially constant rate comprising an acid soluble therapeutic agent in an insoluble matrix. The tablet essentially contains an acid insoluble base soluble pharmaceutically acceptable component selected from polymers jand fatty acids, a pharmaceutically acceptable, organic acid and at least one pharmaceutically acceptable excipient. The component and the acid are present in an amount of from about 1-25 percent by weight of total composition. This US Patent also suggests that the component may be a polymeric acid phthalate and the acid is a mono- or polycarboxylic acid, especially wherein the component is hydroxypropyl methylcellulose phthalate and the acid is citric acid. While, this patent essentially is directed towards trimazosin as the therapeutic agent and ethyl Cellulose, hydrogenated vegetable oil or mixtures thereof as the excipient, it also broadly suggests that Theophylline may be the therapeutic agent.. This patent however does not provide any specific details of polymer coated sustained release Theophylline tablets. Therefore, in order to strike a proper balance between increased bio¬availability and sustained release there is a constant ongoing research using various excipierits. Thus, U.S. Pat. No. 4,797,286 describes sustained release, orally administrable pharmaceutical formulations employing GELUCIRE to make a carrier matrix. The compositions were prepared by admixing a pharmaceutically active agent with molten GELUCIRE and then filling capsules with the admixture. A sustained release formulation containing captopril is described in U.S. Pat. No. 5,433,951. Various GELUCIRE compositions were employed according i, to the experimental descriptions to make captopril formulations, which were then used to fill hard gelatin capsules. Sustained release compositions of Theophylline have been described in U.S. Pat. No. 4,988,679. In this case, triglycerides of a medium chain length alkanoic acid or distilled acetylated monoglycerides, a liquid, high HLB polyglyceryl ester and colloidal silicon dioxide were employed to make a liquid sustained release composition. US Patent No. 6,171,615 discloses a means of making effective sustained release pharmaceutical compositions of Theophylline for delivery in a gelatin capsule by employing certain GELUCIRE excipients in combination with certain nucleation enhancers. The pharmaceutical compositions described in this study are particularly stable with respect to dissolution upon ageing. EP-A 240 904 and EP-A 240 906 disclose the extrusion of polymer melts, preferably of vinylpyrrolidone copolymers, which contain active substances. However, there is no mention in either of them of the adjustment of a particular profile of active substance release by means of polymer mixtures. In addition, the storage stability of the products produced in this way is in many cases low, and the release slowing effect appears to diminish with time. EP-B 204 596 describes the production of pellets by embedding an active substance in a matrix composed of at least one non-hydrophilic polymer and either a mixture of at least two lipid substances, of which one has polymer dissolving or -gelling properties and the other has lubricant properties, or one lipid substance which combines the two stated properties, with or without one or more additives selected from extenders and antistatic agents. These pellets however, suffer from serious disadvantages in that with higher amounts(i.e. above about 20%) of non-hydrophilic polymer the release takes place too quickly for a slow-release product, and with smaller amounts the release changes greatly on storage and is incomplete. US Patent No. 6,290,990 seeks to achieve the above-mentioned need by melt extrusion of certain polymer matrices which contain active substances and subsequent continuous shaping to produce slow-release pellets with high active substance content, even of active substances which are very readily soluble in water. According to this US Patent, it is possible to achieve release profiles which can be adjusted over wide ranges solely by the composition of the polymer matrix without diffusion-controlling polymer coatings and which have high storage stability; The basic principle of the polymer matrix according to US Patent No. 6,290,990 is a matrix, which is plasticized by a lipophilic substance and is composed of a polymer, which is insoluble in water and gastrointestinal fluids. The release profile is adjusted over wide ranges by incorporating into the matrix of insoluble polymer and lipophilic component a gel former, i.e., a polymer, which in water With the prior forms a highly viscous solution (hydrocolloid) or at least swells. art matrices, although the release of the active substance is controlled by the concentration of insoluble polymer, there is a risk that the administration form will disintegrate if the amount of polymer is too low, but the release of active substance may be incomplete if the amount of polymer is too large, since portions of the active substance are completely entrapped and unavailable. The addition, according to US Patent No. 6,290,990, of gel former breaks up the release-slowing matrix by swelling of this polymer, and the active substance is allowed to be completely released, which at times, could be a serious disadvantage. Thus, there has been a continuing need for tablets, preferably for pharmaceutical purposes, from which the active substance is released with an adjustable release profile, i.e., as slow as required, but completely over a predetermined period of time. However, none of the prior art cited above or known to the applicants addresses the above-mentioned problems, particularly those relating to striking a balance between maintaining a proper bio-availability of the drug into the system and controlling the release to avoid an overdose of the drug into the system particularly when the or one of the active ingredients is highly soluble in ii water and the other active ingredient is less soluble in water. The present invention attempts to obviate the disadvantages of the prior art by providing a novel controlled release composition in which a core consisting of active ingredient or ingredients, soluble excipients and. insoluble polymer is coated with film coating containing said polymer and excipients. Objects of the invention It is therefore, an object of the present invention to provide a composition, preferably for pharmaceutical purposes, from which the active substance is released with an adjustable release profile, i.e., as slow as required, but completely over a predetermined period of time. It is another object of the present invention to provide a composition, preferably for pharmaceutical purposes, which completely avoids the problem of "dose dumping associated with the prior art. It is an important object of the present invention to provide a pharmaceutical! composition, preferably, in the form of a tablet in which the active the or one of the active ingredients is highly soluble in water and other active ingredient, if any is less soluble in water. It is yet another object of the present invention to provide a pharmaceutical! composition, preferably, in the form of a tablet for use in treatment of asthma, COPD and other bronchial problems. It is yet another object of the present invention to provide a pharmaceutical! composition, preferably, in the form of a tablet for use in treatment of asthma, COPD and other bronchial problems which ensures zero order kinetics release rate. It is still another object of the present invention to provide a pharmaceutical composition, preferably, in the form of a tablet for use in treatment of a"sthma, COPD and other bronchial problems which avoids the problems of side-effects associated with an active ingredient and gives advantage of lower dose of active pharmaceutical ingredients giving same level of effective concentration in blood over a longer period of time reducing the frequent dosages. It is another object of the present invention to provide a pharmaceutical composition comprising of a mixture of two Xanthine bronchodilators, preferably, in the form of a tablet for use in treatment of asthma, COPD and other bronchial problems in which one of the ingredients of the mixture is highly soluble in water, for e.g., Etofyllin and the other ingredient is less soluble in water for e.g., Theophylline. Summary of the invention The above and other objects of the invention are achieved by providing a novel composition comprising of at least one pharmaceutically active substance which is freely soluble in water and optionally other pharmaceutically active substance which is only partially soluble in water. The composition is preferably in the form of a tablet. The tablet core comprises of an unswellable polymer insoluble in the dissolution medium, along with other soluble as well as insoluble excipients to improve compressibility and lubrication. Within the core of this matrix, the active ingredients are dispersed. This core is coated with the film comprising of freely soluble excipients, plasticizer, lubricants and same polymer that has no permeability for the drug or dissolution medium to allow their permeation. The sole mechanism for release is through the micropores on the surface of core, created by the soluble excipient in the coating solution. These micropores are instrumental in ensuring a sustained release of the active ingredient over a predetermined large period of time, at the same time preventing a sudden burst of drug release into the system. This invention has a particular application in respect of pharmaceutical compositions comprising of two active ingredients one of which is freely soluble in water and the other is less soluble in water. In a preferred embodiment, the present invention relates to pharmaceutical compositions for use in treatment of asthma, COPD and other bronchial conditions. Accordingly, the present invention provides a novel controlled release pharmaceutical composition which comprises of a core matrix consisting of a mixture of a water-insoluble, non permeable and non swellable polymer and soluble excipients and/or other conventional additives, and at least an active ingredient dispersed in such core matrix, said core matrix being coated with said water insoluble, non permeable and non swellable polymer and soluble excipients, such that upon administration, the soluble excipients in said coating and said core matrix dissolving and creating micropores on various layers thereby allowing entry of surrounding fluids therein and create channels for the release of said active ingredients through said micropores. In a preferred embodiment, composition comprises of two active ingredients one of which is highly soluble in water and other is less soluble in water. In yet another embodiment, said active ingredients consist of at least two Xanthine derivatives one of which is highly soluble in water and other is less soluble in water. The highly soluble Xanthine derivative is preferably Etofyllin and is present in an amount of from 65 to 95 % by wt of the composition. The less soluble Xanthine derivative is preferably Theophylline and present in an amount of from 5 to 35% by wt of said composition. The water; soluble excipients are preferably present in amount of from 1 to 10%by wt. The present invention also relates to a process for the preparation of said controlled release pharmaceutical composition, compressing a mixture of said a water insoluble lion permeable and non swellable polymer and soluble excipients and/or other conventional additives, and at least an active ingredient and coating said particles of said mixture in a coating composition comprising of an insoluble, non permeable and non swellable polymer and soluble additives, the soluble additive"s in said coating creating micropores on the surface, allowing entry of surrounding fluids therein and create channels for the release of said active ingredients through said micropores. Preferably, the composition is in the form of tablet. More preferably, the tablet consists of multiple coatings. In a most preferred embodiment, Etofyllin and Theophylline are present in a ratio of 77:23.; In another preferred embodiment, the composition of the present invention is a pharmaceutical composition in the form of polymer coated pellets. In yet another embodiment, the pellets are polymer coated micropellets in a capsule, preferably, a gelatin capsule. In another embodiment, said tablets or pellets comprise of a core comprising of said active ingredients, excipients and insoluble, non- permeable, non-swellable polymer and a sustained release coating consisting of a insoluble, non- permeable, non-swellable polymer and soluble additives. In yet another embodiment, same polymer is employed for coating as well as the core matrix. In yet another preferred embodiment, said core comprises of from 80 to 90% and in preferred embodiment 88.75% by wt of said active ingredients, from 1.75 to 15% by wt of said polymer and balance, comprising of said excipients and additives. In a preferred embodiment, said polymer is present in amount of 8 to 9 % by wt of said composition. The insoluble, non- permeable, non-swellable polymer is preferably an Acrylic acid, ;more preferably methacrylic acid copolymer preferably, Methacrylate and Methacrylic acid copolymer type B USP. In a preferred embodiment, the amount of said insoluble, non- permeable, non-swellable polymer in said coating composition is from 0.5 to 7 % by wt, more preferably, from 2.3 to 2.5% by wt. The water-soluble excipients and additives, which may be the same or different are selected from the group consisting of lactose, PEG, sucrose, mannitol, dextrose or citric acid. In yet another embodiment, the compressed mixture is dispersed in an organic solvent! selected from isopropyl alcohol, ethyl alcohol, specially denatured spirrd or acetone. In yet another embodiment, the compressed mixture is granulated in the presence of organic solvents such as isopropyl alcohol, ethyl alcohol, specially denatured spirit or acetone. In another embodiment, the granules are graded with lubricants and gradients such as talc, magnesium stearate, or Aerosil. In yet another embodiment, the composition optionally contains fillers such as, for example, starch or lactose Detailed description One of the important feature of the present invention is that it employs a mixture of at least two active ingredients, for example bronchodilators, preferably, Xanthine derivatives. Preferably, the Xanthine derivatives comprise of Etofyllin and Theophylline, which offer the following advantages: i! (1) Better solubility of Theophylline in the presence of Etofyllin (2) Easier change over from one formulation to another because all the formulations contain the same ratio of the drugs. (3) Reduced riskjof side effects because: (a) Theophylline and Etofyllin have not demonstrated cumulative toxicity in animal experiments, and, (b) Etofyllin is not converted into Theophylline as happens with many other Xanthine derivatives. This offers wider therapeutic window. By employing the composition of the present invention, a linear rate of release is obtained in acidic medium and the linearity relationship of concentration with time is established. Combination of Theophylline (hydrous or anhydrous) with Etofyllih in "the ratio of 23: 77 shows rapid dissolution and bio-availability as compared to Theophylline or Etofyllin singularly. The release rate of such rapidly dissolving combination can be controlled, by designing a matrix of Methacrylic Acid Copolymer Type B and the mixture of Theophylline and Etofyllin mixed with the polymer to the extent of 5-25% and in preferred embodiment to the extent of 7 to 15 %. The resultant mixture may be converted into granules by use of either organic solvent like isopropyl alcohol or ethyl alcohol or specially denatured spirit or acetone or the aqueous dispersion of polymer or the polymer solution in organic solvent. Resultant granules may be graded and mixed with lubricants and glidants like talc, magnesium stearate, aerosil, etc. The tablet may contain fillers such as Lactose, Starch, or even may be granulated without the aid of fillers. The tablets are compressed at a hardness between 20 and 80 N and then coated using a polymer solution in which Micronised Lactose or PEG (Poly Ethylene Glycol) lis suspended. Tablets may be coated using conventional pan coating or in a fluid bed coating equipment or in an Accela cota type of equipment. After curing, the tablets show uniform rate of release of drug. The important feature of the present invention relates is the preparation of sustained and constant release polymer coated tablet. The constant release rate regimen can be described by following expression: dQ = constant where dQ = release rate dt dt Q = amount released at time t i.e. Q = constant x t + c wherein c is a constant value, t is the time, d is the differential, and dQ s the amount of the active ingredient released so that dQ/dt which is the release rate remains constant. The above equation indicates that amount of released substance is a linear function of time. The pharmacologically active substance is a mixture of Xanthine bronchodilators with one of them being freely water soluble and the other being less water soluble. For example, Theophylline and Etofyllin can be combined in a range with Theophylline ranging between 5 to 35% and Etofyllin ranging between 95 to 65% and in a preferred embodiment in the ratio of 23:77 %. This extended release preparation produces its biological response over a longer period of time and permits reduction in number of daily doses. Although the system described and studied extensively here is a pharmaceutical system, the same principle can be extrapolated for application into other fields. The preferred embodiment of the present invention has been described in terms of a tablet. However, it can be formulated in other dosage forms as well, for example polymer coated micropellets in a gelatin capsule. The pharmacokinetic studies of this preparation have been carried out and its efficacy over the extended period of time, 12 hr., has been demonstrated. Being a bronchodilator, it provides an efficacious means to control bronchospasms with minimal side effects. The tablet consists of drugs and excipients and polymeric substance for example, a meth"acrylic acid copolymer Type B. The tablet is preferably, further The excipients in of the tablets. T channels for outf coated by the same polymer, as that is added in the matrix alongwith excipients. coating are water soluble and create micropores on the surface he surrounding fluid enters the tablet core and creates the ow of drug solution through micropores. The polymer chosen is insoluble and hence the matrix structure remains intact in acidic fluid. The particle size of the excipient, which creates micropores, is such that a large number of micropores are created on tablet surface, each having dimension of a few microns, thus preventing sudden release of drug from any particular portion of the tablet. Almost 80% of the drug is released by zero order kinetics and due to carefully controlled particle size of excipient in coating layer, the danger of release of active ingredient from any particular position on the tablet is minimum. As will be appreciated by persons skilled in the art, in zero order kinetics, the release process is independent of amount of drug released and does not change with time. The present invention also provides a process for preparation of sustained , release polymer coated tablet which in the presence of dissolution fluid releases biologically active principles at substantially constant rate, for an extended period of time. The tablet cores comprises of an insoluble and unswellable polymer, in the dissolution medium, along with other excipients to improve compressibility and lubrication. Within the pores of this matrix, the active ingredients are dispersed. This core is coated with the same polymer that has no permeability for the drug or dissolution medium to allow their permeation. The sole mechanism for release is through the pores on the surface of core, created by the soluble excipient in the coating solution. The process comprises of: - 1) mixing of the active principles and other excipients. This mixture is preferably, granulated by a solution of Methacrylic Acid Copolymer to 20# ASTM sieve size. ii) compressing the tablets on a compression machine to obtain the cores having hardnes.s of at least 30N and not more than 70N, measured on Schleuniger hardness tester. The punches of 8 to 12.5 mm diameter are used. iii) applying a release sustaining membrane on these cores. The membrane is preferably, formed by spraying a solution of Methacrylic Acid Copolymer, and Lactose or PEG or Sucrose or Mannitol, etc. The operation of the present device may be described as follows: -As the dissolution medium comes in contact with the coated tablet, the freely soluble excipient present in the coat dissolves instantaneously in the surrounding dissolution medium, creating numerous micropores on the surface of coat. It can be assumed that the coat would be multi layered and the soluble excipient present in each layer would create a continuous channel of pores. Description with reference to the accompanying drawings The novel operative aspect of the present invention may be now be described with refernce to the sole figure of the accompanying drawings wherein: Fig. 1 discloses a preferred embodiment of the tablet of the present invention having multiple layered coat. Referring to the Fig., the tablet is generally shown by the refrence numeral 1. The tablet 1 consists of a tablet core or core matrix 2 consisting of a mixture of a water insoluble, non permeable and non swellable polymer 6. and soluble excipients and/or other conventional additives 5. The active ingredients are dispersed in the core matrix 2. As can be seen from the figure, the core matrix is coated with several layers or coats 3 of water insoluble, non permeable and non swellable polymer 6 and soluble excipients 5. Upon administration, the soluble excipients 5 in said coating 3 and said core matrix 2 dissolve and create micropores on various layers thereby allowing entry of surrounding fluids therein and create channels 4 for the release of said active ingredients through said micropores. As can be easily appreciated, the molecules of active ingredients travel through channels within the cores and coat up to the micropores created on the surface of tablet coat. The rate of release is proportional to time i.e zero order. . Thus, a careful selection of polymer and excipients for:the core and the delivery rate controlling membranes creates the above-mentioned structure to give zero order release rate. The composition of the core can be altered to suit the solubility of the active ingredient. The inner core matrix The core matrix comprises of 1.75% to 15% of the polymer and from 80 to, 90 %, preferably, about 86 88 % active ingredients. The percentage of other excipients is adjusted accordingly. The polymer material chosen for the matrix as well as for the coating should be insoluble, nonswellable and non-permeable to the dissolution medium being used. The most preferred polymer used for the present invention is Methacrylic Acid Copolymer Type B USP, while other polymers are well within the scope of the invention. It is preferred that the polymer is also bio¬compatible. The soluble excipient added in the coating solution is a freely water soluble substance selected from Lactose, Dextrose, Sucrose, PEG, Citric Acid and the like. The role of this additive depends entirely upon its concentration relative to the polymer in the coating solution, its particle size and the solubility of active ingredients present in the core. The water soluble additive that is present in the core and coating membrane serves as a channel forming agent, allowing the active ingredient to be released. The dissolution of water soluble excipient increases porosity and dissolution of active ingredients and reaching of dissolution medium into the inner portions of the core is enhanced. Since the polymer is insoluble and unswellable or non-permeable, a highly soluble active ingredient also cannot alter the structure of the tablet but the porosity is increased rapidly. Release rate controlling membrane As discussed earlier the release rate controlling membrane consists of an insoluble, non-permeable and nonswellable polymer and a highly soluble t additive. This membrane can be visualized as a multi layered membrane. Each layer in the membrane will consist of polymer film with the particles of additive dispersed within this film. The size of these additive particles is very important, which does not affect the integrity of the film but allows creation of pores after its own dissolution. The distribution of these particles within each layer will be random. These pores will not be superimposed for these layers but it will create a tortuous channel network in this coated layer. These channels will have dimension approximate to the particle size of the additive. If this channel size is too large, it will cause damage to the integrity of the membrane and subsequently causing a non-uniform and erratic release of the active ingredient. A coating of about 4 mg is applied to the surface area of apprpx. 196.11 mm2 and in that proportion. The shape, as always preferred for the pharmaceutical tablets, is a biconvex tablet with diameter varying from 8.00 mm to 12.5 mm and the thickness varying from 3.6 mm to 6.0 mm correspondingly. The amount of active "I ingredients in the cores varies from 150 mg to 450 mg and the diameter to thickness ratio varies. It was also observed that the uniformity in the release rate is maintained by varying the proportion of soluble active ingredient in the sustained release coating to suit the ratio between surface area to the amount of active ingredient in the core. The process comprises of usual process described, with following steps: - a) mixing the active principle with the additives and granulating it with an organic solution of polymer. Drying and further lubricating the granules. b) compressing the granules of Step I to the hardness of not less than 30N and not more than 70N, measured on a Schleuniger Hardness Tester, on a suitable compression machine and appropriate dies and punches to get the required active ingredient quantity in each tablet. c) applying the sustained release coating on the cores. This process can be carried out in the, conventional coating pan of capacity from 1 to 170 kg depending on the; quantity of cores. This device shows following characteristics: - At least 80% of the active ingredient is released by the zero order kinetics over a period of 6 hours, which is demonstrated quantitatively by in vitro models. The release occurs over the entire surface of tablet and the shortcomings of the release through single orifice on the surface do not exist. The collapse of the matrix structure or destruction of membrane during the course of dissolution of active ingredient is extremely unlikely as the polymer chosen for matrix and membrane is completely insoluble and non swellable in dissolution medium. Even in the event of such rupture, the dose dumping does not occur, as the solid reservoir releases active principle at rate proportional, to the square root of time. The active principle has solubility practically independent of pH. The i polymer chosen dissolves above pH 7.5. The formulation shows remarkable stability and strength during handling and storage. It can even be sugar coated without any significant change in release rate profile. The following examples illustrate typical delivery device manufactured according to the invention. The dosage form is a tablet. Preparation of the tablets of Etofyllin and Theophylline. a) Typical preparation of solid matrix reservoir. The composition is given below : Corresponding quantities of Theophyllin (anhydrous) When Theophyllin anhydrous is used, corresponding adjustment in quantities of lactose is done. 31.820 62.730 94.550 Based on experimentation, Etofyllin and Theophyllin ratio has been kept at 77:23. Both the drugs i.e. Etofyllin and Theophyllin comply with the pharmacopoeial specifications. Typical Method of Manufacture : 1. Etofyllin, Theophyllin and Lactose are pulverised. 2. Etofyllin, Theophyllin and Lactose are mixed together. 3. Methacrylic Acid Copolymer Type B NF is dissolved in organic solvents like Isopropyl Alcohol, Acetone or SD Spirit, etc. along with plasticizer Dibutyl Pthalate. Other Plasticizers such as Triacetin, Triethyl Citrate, castor oil etc. can also be used. 4. The blend of Etofyllin and Theophyllin is wetted completely with the solution of Methacrylic Acid Copolymer Type B in organic solvent along with plasticizer. 5. Wet granules are graded and dried. 6. Dried granules are graded again and lubricated with Talc and Magnesium Stearate. 7. The lubricated granules are compressed at corresponding compression weight as shown above. 8. The tablets are further film coated with a solution of Methacrylic Acid Copolymer Type B in organic solvent such as IPA, Acetone, SD Spirit, etc. along with plasticizer such as Dibutyl Phthalate, Triacetin, Triethyl Citrate, etc. Micronised Lactose and Micronised Talc are suspended in this solution. Micronised Lactose dissolves in contact with the gastric fluid and then Theophyllin and Etofyllin are released at a controlled rate by diffusion and dissolution process. Micronised Talc prevents the tackiness in tablets during coating. Typically following would be the compositions in the film coating:- Film Coating Compositions Ingredient 150 mq Otv. (mq./tab.) 300 mq Otv. (mq./tab.) 450 mq Otv. (mq./tab.) Methacrylic Acid Co-polymer Type B 1.135 1.160 1.185 Lactose (Micronisecl) 2.181 2.040 1.900 Talc (Micronised) 0.456 0.389 0.254 Di-butyl Phthalate 0.228 0.232 0.237 Organic Solvents q.s. q.s. q.s. Film coated tablets can in turn be sugar coated using classical method. The release rates of the batches have been monitored in N/10 HCl. The typical rate of release obtained over 8 hrs. period is shown in graphical representation in Fig 1 of te accompanying drawings. As routine checks of dissolution profile, we have monitored 1 hr., 3 hr. and 6 hr. dissolution rates in N/10 HCl using USP dissolution rate test Apparatus I. The release rates obtained on 15 batches of 150 mg have been tabulated. 300 & 450 mg tablets also give similar rate of release as the composition of all three strengths is similar. The table as given below lists the rates of release of individual tablets. Based on the table the release profile in N/ 10 HCl in following range can be obtained. Etofyllin, Theophylline and Lactose are blended together in a Rapid Mixer Granulator or Planetary Mixer Granulator till a homogenous mix is obtained. A solution of polymer material in (for each tablet) 0.0408 ml of 6:4 isopropanol :acetone is prepared. The blend as mentioned in I is granulated and sieved through 2.00mm (ASTM NO. 10) sieve, dried and dry -graded through sieve (ASTM NO.20) 0.85 mm. The granules are mixed first with talc, followed by Magnesium Stearate. The granules are compressed in two following dosage forms. Application of release rate sustaining membrane Two different compositions of coating solutions are used for the two different matrix ;cores to achieve uniform release rates. * In place of Dibutylpthalate other plasticisers like Triacetin, etc. can also be used singly or in\| combination. In all the strengths the coating solution was sprayed continuously with continuous, drying. The release rates were determined by in vitro models. . The release rates were determined for reservoir matrices, sustained release coated tablets for both the strengths and sugar coated tablets for Strength I. The details are as follows :- Apparatus Dissolution Medium RPM Temperature USP XVI Type I 900 ml of 0. IN HCI 100 37°C The release rate is expressed in cumulative percentage released, calculated as equivalent of Theophylline release. Within 8 \|hrs. the entire quantity of drug is released and upto 6 hrs. the kinetics is strictly zero order and the release rate becomes slightly non-linear thereafter. Sustained release coated tablet Strength III Time % Release hrs. 1 22.55 3 49.70 6 78.21 We Claim: 1. A controlled release composition for use in the treatment, inter alia of asthma and other bronchial conditions, which comprises of a core matrix consisting of a mixture of a water insoluble, non permeable and non swellable polymer and soluble excipients and/or other conventional additives, and at least an active ingredient dispersed in such core matrix, said core matrix being coated with said water insoluble, non permeable and non swellable polymer and soluble excipients, such that upon administration the soluble excipients in said coating and said core matrix dissolve and create micropores on various layers thereby allowing entry of surrounding fluids therein and create channels for the release of said active ingredients through said micropores. i2. A composition as claimed in. Claim 1 wherein the active ingredients in the composition comprises of at least two Xanthine derivatives one of which is highly soluble [in water and other is less soluble in water. 3. A composition as claimed in Claim 2 wherein the highly soluble Xanthine derivative is Etofyllin and is present in an amount of from 65 to 95 % by weight of the composition and the less soluble Xanthine derivative is Theophylline and present in an amount of from 5 to 35% by weight of said composition and the water soluble excipients are preferably present in amount of from 1 to 10% by wt. 4. A composition as claimed in any preceding claim wherein said EtofyUin and Theophylline are present in a ratio of 77:23. 5. A composition as claimed in any preceding claim wherein the composition is in the form of tablet. 6. A composition as claimed in any preceding claim wherein the tablet consists of multiple coatings. 7. A composition as claimed in any one of claims 1 to 5 wherein said composition is in the form of polymer coated pellets. 8. A composition as claimed in claim 7 wherein the pellets are polymer coated micropellets in a capsule, preferably, a gelatin capsule. 9. A composition as claimed in claim 8 wherein said tablets or pellets comprise of a core comprising of said active ingredients, excipients and insoluble, non-permeable, non-swellable polymer and a sustained release coating consisting of a insoluble, jnon- permeable, non-swellable polymer and soluble additives. 10. A composition as claimed in any preceding claim wherein the same polymer is employed for coating as well as the core matrix. 11. A composition as claimed in any preceding claim wherein said core comprises of from 80 to 90%, preferably, 88.75% by wt of said active ingredients, from 1.75 to 15%, preferably 8 to 9 % by wt of said polymer and balance, comprising of said excipients and additives. 12. A composition as claimed in claim 11 wherein the insoluble, non- permeable, non-swellable polymer is preferably an Acrylic acid, more preferably methacrylic acid copolymer preferably, Methacrylate and Methacrylic acid copolymer type B USP. 13. A composition as claimed in claim 12 wherein the amount of said insoluble, non- permeable, non-swellable polymer in said coating composition is from 0.5 to 7 % by wt, more preferably, from 2.3 to 2.5% by wt. 14. A composition as claimed in claim 11 wherein the water-soluble excipients and additives, which is the same or different and are selected from the group consisting of lactose, PEG, sucrose, mannitol, dextrose or citric acid 15.A composition as claimed in any preceding claim wherein the composition optionally contains fillers such as, starch or lactose. 16. A process for the preparation of a novel composition for use in the treatment inter alia, of asthma and other bronchial conditions which comprises compressing a mixture of said a water insoluble non permeable and non swellable polymer and soluble excipients and/or other conventional additives, and at least an active ingredient and coating said particles of said mixture in a coating composition comprising of an insoluble, non permeable and non swellable polymer and soluble additives, the soluble additives in said coating creating micropores on the surface, allowing entry of surrounding fluids therein and create channels for the release of said active ingredients through said micropores. 17.A process as claimed in claim 16 wherein said compressed mixture is dispersed in an organic solvent selected from isopropyl alochol, ethyl alcohol, specially denatured spirit and acetone. 18.A process as! claimed in claims 17 wherein said compressed mixture is granulated. 19.A process as claimed in any one of claims 16 to 18 wherein the active ingredients comprises of at least two Xanthine derivatives one of which is highly soluble" in water and other is less soluble in water. 20. A process as claimed in Claim 19 wherein the highly soluble Xanthine derivative is Etofyllin and is present in an amount of from 65 to 95 % by weight of the composition and the less soluble Xanthine derivative is Theophylline and present in an amount of from 5 to 35% by weight of said composition and the water soluble excipients are preferably present in amount of from 1 to 10% by wt. 21. A process as claimed in claim 19 wherein said Etofyllin and Theophylline are present in a ratio of 77:23. 22. A process as claimed in any preceding claim wherein the same polymer is employed for coating as well as the core matrix. 23. A process as claimed in any one of claims 16 to 21 wherein said core comprises of! from 80 to 90% preferably, 88.75% by wt of said active ingredients, from 1.75 to 15%, preferably 8 to 9 % by wt of said polymer and balance, comprising of said excipients and additives. 24. A process as claimed in claim 22 wherein the insoluble, non- permeable, non-swellable polymer is preferably an Acrylic acid, more preferably methacrylic acid copolymer preferably, Methacrylate and Methacrylic acid copolymer type B USP. 25. A process as claimed in claim 16 wherein the amount of said insoluble, non- permeable, non-swellable polymer is from 0.5 to 7 % by wt, more preferably, from 2.3 to 2.5% by wt. 26. A process as claimed in claim 11 wherein the water-soluble excipients and additives, which may be the same or different are selected from the group consisting of lactose, PEG, sucrose, mannitol, dextrose or citric acid. 27.A controlled release composition for use in the treatment, inter alia of asthma and other bronchial conditions, substantially as herein described with reference to the foregoing examples. 28. A process for the preparation of a controlled release composition for use in the treatment, inter alia of asthma and other bronchial conditions, il substantially as herein described with reference to the foregoing examples. Dated this "the 24th day of February 2003 H.SUBRRAMANIAM OF SUBRAMANIAM NATARAJ & ASSOCIATES Attorny for the Applicants

Full Text

FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
COMPLETE SPECIFICATION
(See Section 10; rule 13)
"SUSTAINED RELEASE PHARMACEUTICAL COMPOSITIONS AND PROCESS FOR
THE PREPARA TION THEREOF"

ORIGINAL
182/MUMNP/2002
27/02/2002

GRANTED
7/9/2007

We, CADILA HEALTHCARE LIMITED, a company incorporated under the Companies
Act, 1956, of Zydus Tower, Satellite Cross Roads, Ahmedabad - 380 015, Gujarat,
India,
The followingl specification describes the nature of the invention and the manner in which it is to be performed:

Field of invention
The present invention relates to sustained release compositions and a
process for the preparation thereof. More particularly, present invention relates
to sustained release compositions in the form of tablets and a process for the
preparation of such sustained release tablets. More particularly, the present
invention relates to sustained release polymer coated tablets for use in treatment
of asthma and other respiratory tract problems and a process for the preparation
thereof. The present invention has particular application where one of the active
ingredients is highly soluble in water and the other active ingredient, if any, is
less soluble in water. One of the important applications envisaged by the present
invention relates to a mixture of Xanthine bronchodilators used for treatment,
inter alia of asthma, wherein one of the ingredients of the mixture is highly
soluble in water and the other ingredient is less soluble in water.

the invention
Background of
There are several methods by which a highly soluble pharmaceutical substance or al drug is administered to a patient. One of the important factors which has to be borne in mind while administering such drugs is to ensure that there is no sudden burst of the drug into the system (known as dosage dumping): Towards this end, slow release formulations of different drugs for various indications have been envisaged in the art. However, the problem has always been that of striking a balance between maintaining a proper bio¬availability of the drug into the system and controlling the release to avoid an overdose of the drug into the system. This has been equally true in case of drugs used for treatment asthma and COPD, for example mixtures of Xanthine bronchodilators comprising of Theophylline and Etofyllin used for treatment, inter alia of asthma, wherein one of the ingredients of the mixture is highly soluble in water and the other ingredient is less soluble in water.
Both Etofyllin and Theophylline have been conventionally used in the treatment of asthma. There is a plethora of prior art on their use for the treatment of asthma and COPD. While, both Etophylline and Theophylline have
demonstrated excellent therapeutic activity in the treatment of asthma and

COPD, their use has been limited due to the fact that the problem of striking a balance between a proper bio-availability of the drug into the system and controlling the release to avoid an overdose of the drug into the system remains.

Description of prior art

Despite the above mentioned problems numerous attempts have been made to formulate Theophylline as a tablet which releases an initial burst of Theophylline and thereafter releases it at an essentially constant rate. Conventionally various attempts have been made to achieve an initial burst of

the active agent

into the system followed by a constant rate of release but each

suffers from some disadvantage or other. For example, U.S. Pat. Nos. 2,793,979 and 2,993,836 describe the use of waxes and lipids in the matrix tablet formulations. Ethylcellulose has been used in matrix formulations with polyethylene glycol (U.S. Pat. No. 3,039,933), with calcium stearate (U.S. Pat. No. 3,322,633) and with calcium sulfate (U.S. Pat. No. 3,632,739) among other ingredients. Other known matrix materials include Carboxyrnethylcellulose1, Cellulose acetate phthalate, Sodium Carboxyrnethylcellulose, gums, carbohydrates such as starch and sorbitol and the like.
U.S. Pat No. 3,087,860 teaches the use of polymeric matrix materials
such as methyl! acrylate methyl methacrylate, while, U.S. Pat. No. 2,987,445
teaches the use of various polymers and copolymers such as polyethylene,
Polymethyl methacrylate and copolymers of methyl methacrylate and alkyl
acrylates and the like.
All of these various matrix formulations suffer from several disadvantages. The primary disadvantage is slowing of the release rate as a function of time. Other disadvantages include dumping of entire dose in the stomach, short life in the gastrointestinal tract, difficulty of manufacture, the inclusion of undesirable ingredients, etc
In an attempt to overcome the above-mentioned disadvantages, US Patent
No. 470284 teaches a long-acting matrix tablet formulation especially suited for
acid soluble therapeutic agents. Accordingly, this patent discloses a

pharmaceutical tablet which releases an initial burst of therapeutic agent and
thereafter relea"ses the agent at an essentially constant rate comprising an acid
soluble therapeutic agent in an insoluble matrix. The tablet essentially contains
an acid insoluble base soluble pharmaceutically acceptable component selected
from polymers jand fatty acids, a pharmaceutically acceptable, organic acid and
at least one pharmaceutically acceptable excipient. The component and the acid
are present in an amount of from about 1-25 percent by weight of total
composition.
This US Patent also suggests that the component may be a polymeric acid phthalate and the acid is a mono- or polycarboxylic acid, especially wherein the

component is hydroxypropyl methylcellulose phthalate and the acid is citric
acid.
While, this patent essentially is directed towards trimazosin as the therapeutic
agent and ethyl Cellulose, hydrogenated vegetable oil or mixtures thereof as the
excipient, it also broadly suggests that Theophylline may be the therapeutic
agent.. This patent however does not provide any specific details of polymer
coated sustained release Theophylline tablets.
Therefore, in order to strike a proper balance between increased bio¬availability and sustained release there is a constant ongoing research using various excipierits.
Thus, U.S. Pat. No. 4,797,286 describes sustained release, orally administrable pharmaceutical formulations employing GELUCIRE to make a carrier matrix. The compositions were prepared by admixing a pharmaceutically active agent with molten GELUCIRE and then filling capsules with the admixture.
A sustained release formulation containing captopril is described in U.S.
Pat. No. 5,433,951. Various GELUCIRE compositions were employed according
i,
to the experimental descriptions to make captopril formulations, which were then used to fill hard gelatin capsules.
Sustained release compositions of Theophylline have been described in U.S. Pat. No. 4,988,679. In this case, triglycerides of a medium chain length alkanoic acid or distilled acetylated monoglycerides, a liquid, high HLB polyglyceryl ester and colloidal silicon dioxide were employed to make a liquid sustained release composition.
US Patent No. 6,171,615 discloses a means of making effective sustained
release pharmaceutical compositions of Theophylline for delivery in a gelatin
capsule by employing certain GELUCIRE excipients in combination with certain
nucleation enhancers. The pharmaceutical compositions described in this study
are particularly stable with respect to dissolution upon ageing.
EP-A 240 904 and EP-A 240 906 disclose the extrusion of polymer melts, preferably of vinylpyrrolidone copolymers, which contain active substances. However, there is no mention in either of them of the adjustment of a particular profile of active substance release by means of polymer mixtures. In addition, the storage stability of the products produced in this way is in many cases low, and the release slowing effect appears to diminish with time.
EP-B 204 596 describes the production of pellets by embedding an active substance in a matrix composed of at least one non-hydrophilic polymer and

either a mixture of at least two lipid substances, of which one has polymer

dissolving or -gelling properties and the other has lubricant properties, or one lipid substance which combines the two stated properties, with or without one or more additives selected from extenders and antistatic agents. These pellets however, suffer from serious disadvantages in that with higher amounts(i.e. above about 20%) of non-hydrophilic polymer the release takes place too quickly
for a slow-release product, and with smaller amounts the release changes greatly
on storage and is incomplete.
US Patent No. 6,290,990 seeks to achieve the above-mentioned need by

melt extrusion of certain polymer matrices which contain active substances and subsequent continuous shaping to produce slow-release pellets with high active substance content, even of active substances which are very readily soluble in water. According to this US Patent, it is possible to achieve release profiles which can be adjusted over wide ranges solely by the composition of the polymer matrix without diffusion-controlling polymer coatings and which have high storage stability;
The basic principle of the polymer matrix according to US Patent No. 6,290,990 is a matrix, which is plasticized by a lipophilic substance and is
composed of a polymer, which is insoluble in water and gastrointestinal fluids.
The release profile is adjusted over wide ranges by incorporating into the matrix
of insoluble polymer and lipophilic component a gel former, i.e., a polymer,

which in water With the prior
forms a highly viscous solution (hydrocolloid) or at least swells.
art matrices, although the release of the active substance is
controlled by the concentration of insoluble polymer, there is a risk that the
administration form will disintegrate if the amount of polymer is too low, but the
release of active substance may be incomplete if the amount of polymer is too
large, since portions of the active substance are completely entrapped and
unavailable. The addition, according to US Patent No. 6,290,990, of gel former
breaks up the release-slowing matrix by swelling of this polymer, and the active
substance is allowed to be completely released, which at times, could be a
serious disadvantage.
Thus, there has been a continuing need for tablets, preferably for
pharmaceutical purposes, from which the active substance is released with an
adjustable release profile, i.e., as slow as required, but completely over a
predetermined period of time.
However, none of the prior art cited above or known to the applicants addresses the above-mentioned problems, particularly those relating to striking

a balance between maintaining a proper bio-availability of the drug into the system and controlling the release to avoid an overdose of the drug into the
system particularly when the or one of the active ingredients is highly soluble in
ii water and the other active ingredient is less soluble in water.
The present invention attempts to obviate the disadvantages of the prior
art by providing a novel controlled release composition in which a core
consisting of active ingredient or ingredients, soluble excipients and. insoluble
polymer is coated with film coating containing said polymer and excipients.
Objects of the invention
It is therefore, an object of the present invention to provide a composition,

preferably for pharmaceutical purposes, from which the active substance is
released with an adjustable release profile, i.e., as slow as required, but
completely over a predetermined period of time.
It is another object of the present invention to provide a composition,
preferably for pharmaceutical purposes, which completely avoids the problem of
"dose dumping associated with the prior art.
It is an important object of the present invention to provide a
pharmaceutical! composition, preferably, in the form of a tablet in which the
active the or one of the active ingredients is highly soluble in water and other
active ingredient, if any is less soluble in water.
It is yet another object of the present invention to provide a
pharmaceutical! composition, preferably, in the form of a tablet for use in
treatment of asthma, COPD and other bronchial problems.
It is yet another object of the present invention to provide a pharmaceutical! composition, preferably, in the form of a tablet for use in
treatment of asthma, COPD and other bronchial problems which ensures zero
order kinetics release rate.
It is still another object of the present invention to provide a
pharmaceutical composition, preferably, in the form of a tablet for use in
treatment of a"sthma, COPD and other bronchial problems which avoids the
problems of side-effects associated with an active ingredient and gives advantage
of lower dose of active pharmaceutical ingredients giving same level of effective
concentration in blood over a longer period of time reducing the frequent
dosages.
It is another object of the present invention to provide a pharmaceutical
composition comprising of a mixture of two Xanthine bronchodilators,

preferably, in the form of a tablet for use in treatment of asthma, COPD and other bronchial problems in which one of the ingredients of the mixture is highly soluble in water, for e.g., Etofyllin and the other ingredient is less soluble in water for e.g., Theophylline.
Summary of the invention
The above and other objects of the invention are achieved by providing a novel composition comprising of at least one pharmaceutically active substance

which is freely

soluble in water and optionally other pharmaceutically active

substance which is only partially soluble in water. The composition is preferably in the form of a tablet. The tablet core comprises of an unswellable polymer insoluble in the dissolution medium, along with other soluble as well as

insoluble excipients to improve compressibility and lubrication. Within the core of this matrix, the active ingredients are dispersed. This core is coated with the film comprising of freely soluble excipients, plasticizer, lubricants and same polymer that has no permeability for the drug or dissolution medium to allow their permeation. The sole mechanism for release is through the micropores on
the surface of core, created by the soluble excipient in the coating solution.

These micropores are instrumental in ensuring a sustained release of the active
ingredient over a predetermined large period of time, at the same time preventing
a sudden burst of drug release into the system. This invention has a particular
application in respect of pharmaceutical compositions comprising of two active
ingredients one of which is freely soluble in water and the other is less soluble in
water.
In a preferred embodiment, the present invention relates to pharmaceutical compositions for use in treatment of asthma, COPD and other bronchial conditions.
Accordingly, the present invention provides a novel controlled release pharmaceutical composition which comprises of a core matrix consisting of a mixture of a water-insoluble, non permeable and non swellable polymer and soluble excipients and/or other conventional additives, and at least an active ingredient dispersed in such core matrix, said core matrix being coated with said water insoluble, non permeable and non swellable polymer and soluble excipients, such that upon administration, the soluble excipients in said coating and said core matrix dissolving and creating micropores on various layers thereby allowing entry of surrounding fluids therein and create channels for the release of said active ingredients through said micropores.

In a preferred embodiment, composition comprises of two active ingredients one of which is highly soluble in water and other is less soluble in water.
In yet another embodiment, said active ingredients consist of at least two Xanthine derivatives one of which is highly soluble in water and other is less soluble in water.
The highly soluble Xanthine derivative is preferably Etofyllin and is
present in an amount of from 65 to 95 % by wt of the composition.
The less soluble Xanthine derivative is preferably Theophylline and present in an amount of from 5 to 35% by wt of said composition.

The water; soluble excipients are preferably present in amount of from 1 to 10%by wt.
The present invention also relates to a process for the preparation of said controlled release pharmaceutical composition, compressing a mixture of said a water insoluble lion permeable and non swellable polymer and soluble excipients and/or other conventional additives, and at least an active ingredient and coating said particles of said mixture in a coating composition comprising of an insoluble, non permeable and non swellable polymer and soluble additives, the soluble additive"s in said coating creating micropores on the surface, allowing entry of surrounding fluids therein and create channels for the release of said
active ingredients through said micropores.
Preferably, the composition is in the form of tablet. More preferably, the
tablet consists of multiple coatings.
In a most preferred embodiment, Etofyllin and Theophylline are present in a ratio of 77:23.;
In another preferred embodiment, the composition of the present invention is a pharmaceutical composition in the form of polymer coated pellets.
In yet another embodiment, the pellets are polymer coated micropellets in a capsule, preferably, a gelatin capsule.
In another embodiment, said tablets or pellets comprise of a core comprising of said active ingredients, excipients and insoluble, non- permeable, non-swellable polymer and a sustained release coating consisting of a insoluble, non- permeable, non-swellable polymer and soluble additives.
In yet another embodiment, same polymer is employed for coating as well as the core matrix.
In yet another preferred embodiment, said core comprises of from 80 to 90% and in preferred embodiment 88.75% by wt of said active ingredients, from

1.75 to 15% by wt of said polymer and balance, comprising of said excipients and additives. In a preferred embodiment, said polymer is present in amount of 8 to 9 % by wt of said composition.
The insoluble, non- permeable, non-swellable polymer is preferably an
Acrylic acid, ;more preferably methacrylic acid copolymer preferably,
Methacrylate and Methacrylic acid copolymer type B USP.
In a preferred embodiment, the amount of said insoluble, non- permeable,
non-swellable polymer in said coating composition is from 0.5 to 7 % by wt,
more preferably, from 2.3 to 2.5% by wt.
The water-soluble excipients and additives, which may be the same or

different are selected from the group consisting of lactose, PEG, sucrose,
mannitol, dextrose or citric acid.

In yet another embodiment, the compressed mixture is dispersed in an organic solvent! selected from isopropyl alcohol, ethyl alcohol, specially denatured spirrd or acetone.
In yet another embodiment, the compressed mixture is granulated in the presence of organic solvents such as isopropyl alcohol, ethyl alcohol, specially denatured spirit or acetone.
In another embodiment, the granules are graded with lubricants and gradients such as talc, magnesium stearate, or Aerosil.
In yet another embodiment, the composition optionally contains fillers such as, for example, starch or lactose Detailed description
One of the important feature of the present invention is that it employs a
mixture of at least two active ingredients, for example bronchodilators,
preferably, Xanthine derivatives. Preferably, the Xanthine derivatives comprise of
Etofyllin and Theophylline, which offer the following advantages: i!
(1) Better solubility of Theophylline in the presence of Etofyllin
(2) Easier change over from one formulation to another because all the
formulations contain the same ratio of the drugs.
(3) Reduced riskjof side effects because:
(a) Theophylline and Etofyllin have not demonstrated cumulative toxicity in animal experiments, and,
(b) Etofyllin is not converted into Theophylline as happens with many other Xanthine derivatives. This offers wider therapeutic window.

By employing the composition of the present invention, a linear rate of release is obtained in acidic medium and the linearity relationship of concentration with time is established.

Combination of Theophylline (hydrous or anhydrous) with Etofyllih in "the
ratio of 23: 77 shows rapid dissolution and bio-availability as compared to
Theophylline or Etofyllin singularly. The release rate of such rapidly dissolving combination can be controlled, by designing a matrix of Methacrylic Acid Copolymer Type B and the mixture of Theophylline and Etofyllin mixed with the polymer to the extent of 5-25% and in preferred embodiment to the extent of 7 to 15 %. The resultant mixture may be converted into granules by use of either
organic solvent like isopropyl alcohol or ethyl alcohol or specially denatured
spirit or acetone or the aqueous dispersion of polymer or the polymer solution in
organic solvent. Resultant granules may be graded and mixed with lubricants
and glidants like talc, magnesium stearate, aerosil, etc. The tablet may contain
fillers such as Lactose, Starch, or even may be granulated without the aid of
fillers.
The tablets are compressed at a hardness between 20 and 80 N and then
coated using a polymer solution in which Micronised Lactose or PEG (Poly
Ethylene Glycol) lis suspended. Tablets may be coated using conventional pan
coating or in a fluid bed coating equipment or in an Accela cota type of
equipment. After curing, the tablets show uniform rate of release of drug. The important feature of the present invention relates is the preparation
of sustained and constant release polymer coated tablet.
The constant release rate regimen can be described by following expression:

dQ = constant where dQ = release rate
dt dt
Q = amount released at time t
i.e. Q = constant x t + c
wherein c is a constant value, t is the time, d is the differential, and dQ s the
amount of the active ingredient released so that dQ/dt which is the release rate
remains constant.
The above equation indicates that amount of released substance is a linear function of time.
The pharmacologically active substance is a mixture of Xanthine bronchodilators with one of them being freely water soluble and the other being less water soluble. For example, Theophylline and Etofyllin can be combined in a range with Theophylline ranging between 5 to 35% and Etofyllin ranging between

95 to 65% and in a preferred embodiment in the ratio of 23:77 %. This extended release preparation produces its biological response over a longer period of time and permits reduction in number of daily doses. Although the system described
and studied extensively here is a pharmaceutical system, the same principle can

be extrapolated for application into other fields.

The preferred embodiment of the present invention has been described in
terms of a tablet. However, it can be formulated in other dosage forms as well,
for example polymer coated micropellets in a gelatin capsule. The
pharmacokinetic studies of this preparation have been carried out and its
efficacy over the extended period of time, 12 hr., has been demonstrated. Being a
bronchodilator, it provides an efficacious means to control bronchospasms with
minimal side effects. The tablet consists of drugs and excipients and polymeric substance for
example, a meth"acrylic acid copolymer Type B. The tablet is preferably, further
The excipients in of the tablets. T channels for outf
coated by the same polymer, as that is added in the matrix alongwith excipients.
coating are water soluble and create micropores on the surface he surrounding fluid enters the tablet core and creates the ow of drug solution through micropores. The polymer chosen is
insoluble and hence the matrix structure remains intact in acidic fluid. The
particle size of the excipient, which creates micropores, is such that a large
number of micropores are created on tablet surface, each having dimension of a
few microns, thus preventing sudden release of drug from any particular portion
of the tablet.
Almost 80% of the drug is released by zero order kinetics and due to
carefully controlled particle size of excipient in coating layer, the danger of
release of active ingredient from any particular position on the tablet is
minimum. As will be appreciated by persons skilled in the art, in zero order
kinetics, the release process is independent of amount of drug released and does
not change with time.
The present invention also provides a process for preparation of sustained ,
release polymer coated tablet which in the presence of dissolution fluid releases
biologically active principles at substantially constant rate, for an extended
period of time. The tablet cores comprises of an insoluble and unswellable
polymer, in the dissolution medium, along with other excipients to improve
compressibility and lubrication. Within the pores of this matrix, the active
ingredients are dispersed. This core is coated with the same polymer that has no
permeability for the drug or dissolution medium to allow their permeation. The

sole mechanism for release is through the pores on the surface of core, created by the soluble excipient in the coating solution.
The process comprises of: -
1) mixing of the active principles and other excipients. This mixture is

preferably, granulated by a solution of Methacrylic Acid Copolymer to 20# ASTM
sieve size.
ii) compressing the tablets on a compression machine to obtain the cores
having hardnes.s of at least 30N and not more than 70N, measured on Schleuniger hardness tester. The punches of 8 to 12.5 mm diameter are used. iii) applying a release sustaining membrane on these cores. The membrane is preferably, formed by spraying a solution of Methacrylic Acid Copolymer, and Lactose or PEG or Sucrose or Mannitol, etc.
The operation of the present device may be described as follows: -As the dissolution medium comes in contact with the coated tablet, the freely soluble excipient present in the coat dissolves instantaneously in the surrounding dissolution medium, creating numerous micropores on the surface of coat. It can be assumed that the coat would be multi layered and the soluble excipient present in each layer would create a continuous channel of pores. Description with reference to the accompanying drawings
The novel operative aspect of the present invention may be now be described with refernce to the sole figure of the accompanying drawings wherein:
Fig. 1 discloses a preferred embodiment of the tablet of the present invention having multiple layered coat.
Referring to the Fig., the tablet is generally shown by the refrence numeral
1. The tablet 1 consists of a tablet core or core matrix 2 consisting of a mixture
of a water insoluble, non permeable and non swellable polymer 6. and soluble
excipients and/or other conventional additives 5. The active ingredients are
dispersed in the core matrix 2. As can be seen from the figure, the core matrix is
coated with several layers or coats 3 of water insoluble, non permeable and non
swellable polymer 6 and soluble excipients 5. Upon administration, the soluble
excipients 5 in said coating 3 and said core matrix 2 dissolve and create
micropores on various layers thereby allowing entry of surrounding fluids
therein and create channels 4 for the release of said active ingredients through
said micropores.

As can be easily appreciated, the molecules of active ingredients travel through channels within the cores and coat up to the micropores created on the surface of tablet coat. The rate of release is proportional to time i.e zero order. .
Thus, a careful selection of polymer and excipients for:the core and the
delivery rate controlling membranes creates the above-mentioned structure to
give zero order release rate. The composition of the core can be altered to suit
the solubility of the active ingredient.
The inner core matrix
The core matrix comprises of 1.75% to 15% of the polymer and from 80
to, 90 %, preferably, about 86 88 % active ingredients. The percentage of other
excipients is adjusted accordingly.
The polymer material chosen for the matrix as well as for the coating
should be insoluble, nonswellable and non-permeable to the dissolution medium

being used. The most preferred polymer used for the present invention is Methacrylic Acid Copolymer Type B USP, while other polymers are well within

the scope of the invention. It is preferred that the polymer is also bio¬compatible.
The soluble excipient added in the coating solution is a freely water soluble substance selected from Lactose, Dextrose, Sucrose, PEG, Citric Acid and the like. The role of this additive depends entirely upon its concentration

relative to the polymer in the coating solution, its particle size and the solubility

of active ingredients present in the core. The water soluble additive that is present in the core and coating membrane serves as a channel forming agent, allowing the active ingredient to be released. The dissolution of water soluble excipient increases porosity and dissolution of active ingredients and reaching of dissolution medium into the inner portions of the core is enhanced. Since the polymer is insoluble and unswellable or non-permeable, a highly soluble active ingredient also cannot alter the structure of the tablet but the porosity is increased rapidly.
Release rate controlling membrane
As discussed earlier the release rate controlling membrane consists of an
insoluble, non-permeable and nonswellable polymer and a highly soluble
t
additive. This membrane can be visualized as a multi layered membrane. Each layer in the membrane will consist of polymer film with the particles of additive dispersed within this film. The size of these additive particles is very important, which does not affect the integrity of the film but allows creation of pores after its own dissolution. The distribution of these particles within each layer will be

random. These pores will not be superimposed for these layers but it will create a tortuous channel network in this coated layer. These channels will have dimension approximate to the particle size of the additive. If this channel size is too large, it will cause damage to the integrity of the membrane and subsequently causing a non-uniform and erratic release of the active ingredient. A coating of about 4 mg is applied to the surface area of apprpx. 196.11 mm2 and in that proportion.
The shape, as always preferred for the pharmaceutical tablets, is a biconvex tablet with diameter varying from 8.00 mm to 12.5 mm and the
thickness varying from 3.6 mm to 6.0 mm correspondingly. The amount of active
"I ingredients in the cores varies from 150 mg to 450 mg and the diameter to
thickness ratio varies. It was also observed that the uniformity in the release rate
is maintained by varying the proportion of soluble active ingredient in the
sustained release coating to suit the ratio between surface area to the amount of
active ingredient in the core.
The process comprises of usual process described, with following steps: -
a) mixing the active principle with the additives and granulating it with an organic solution of polymer. Drying and further lubricating the granules.
b) compressing the granules of Step I to the hardness of not less than 30N and not more than 70N, measured on a Schleuniger Hardness Tester, on a suitable compression machine and appropriate dies and punches to get the required active ingredient quantity in each tablet.
c) applying the sustained release coating on the cores. This process can be
carried out in the, conventional coating pan of capacity from 1 to 170 kg
depending on the; quantity of cores.
This device shows following characteristics: -

At least 80% of the active ingredient is released by the zero order kinetics over a period of 6 hours, which is demonstrated quantitatively by in vitro models. The release occurs over the entire surface of tablet and the shortcomings of the release through single orifice on the surface do not exist. The collapse of the
matrix structure or destruction of membrane during the course of dissolution of

active ingredient is extremely unlikely as the polymer chosen for matrix and

membrane is completely insoluble and non swellable in dissolution medium. Even in the event of such rupture, the dose dumping does not occur, as the solid reservoir releases active principle at rate proportional, to the square root of time.
The active principle has solubility practically independent of pH. The
i
polymer chosen dissolves above pH 7.5. The formulation shows remarkable

stability and strength during handling and storage. It can even be sugar coated without any significant change in release rate profile.
The following examples illustrate typical delivery device manufactured according to the invention. The dosage form is a tablet.
Preparation of the tablets of Etofyllin and Theophylline.
a) Typical preparation of solid matrix reservoir. The composition is given
below :

Corresponding quantities of Theophyllin
(anhydrous)
When Theophyllin anhydrous is used, corresponding adjustment in quantities of lactose is done.

31.820

62.730

94.550

Based on experimentation, Etofyllin and Theophyllin ratio has been kept at 77:23. Both the drugs i.e. Etofyllin and Theophyllin comply with the pharmacopoeial specifications.
Typical Method of Manufacture :
1. Etofyllin, Theophyllin and Lactose are pulverised.
2. Etofyllin, Theophyllin and Lactose are mixed together.

3. Methacrylic Acid Copolymer Type B NF is dissolved in organic solvents
like Isopropyl Alcohol, Acetone or SD Spirit, etc. along with plasticizer
Dibutyl Pthalate. Other Plasticizers such as Triacetin, Triethyl Citrate,
castor oil etc. can also be used.

4. The blend of Etofyllin and Theophyllin is wetted completely with the
solution of Methacrylic Acid Copolymer Type B in organic solvent along
with plasticizer.
5. Wet granules are graded and dried.

6. Dried granules are graded again and lubricated with Talc and Magnesium
Stearate.
7. The lubricated granules are compressed at corresponding compression weight as shown above.
8. The tablets are further film coated with a solution of Methacrylic Acid Copolymer Type B in organic solvent such as IPA, Acetone, SD Spirit, etc. along with plasticizer such as Dibutyl Phthalate, Triacetin, Triethyl Citrate, etc. Micronised Lactose and Micronised Talc are suspended in
this solution. Micronised Lactose dissolves in contact with the gastric
fluid and then Theophyllin and Etofyllin are released at a controlled rate
by diffusion and dissolution process. Micronised Talc prevents the
tackiness in tablets during coating.
Typically following would be the compositions in the film coating:-

Film Coating Compositions
Ingredient 150 mq Otv. (mq./tab.) 300 mq Otv. (mq./tab.) 450 mq Otv. (mq./tab.)
Methacrylic Acid Co-polymer Type B 1.135 1.160 1.185
Lactose (Micronisecl) 2.181 2.040 1.900
Talc (Micronised) 0.456 0.389 0.254
Di-butyl Phthalate 0.228 0.232 0.237
Organic Solvents q.s. q.s. q.s.

Film coated tablets can in turn be sugar coated using classical method.
The release rates of the batches have been monitored in N/10 HCl. The typical rate of release obtained over 8 hrs. period is shown in graphical representation in Fig 1 of te accompanying drawings.
As routine checks of dissolution profile, we have monitored 1 hr., 3 hr. and 6 hr. dissolution rates in N/10 HCl using USP dissolution rate test Apparatus I. The release rates obtained on 15 batches of 150 mg have been tabulated. 300 & 450 mg tablets also give similar rate of release as the composition of all three strengths is similar.
The table as given below lists the rates of release of individual tablets.

Based on the table the release profile in N/ 10 HCl in following range can be
obtained.

Etofyllin, Theophylline and Lactose are blended together in a Rapid Mixer Granulator or Planetary Mixer Granulator till a homogenous mix is obtained.
A solution of polymer material in (for each tablet) 0.0408 ml of 6:4
isopropanol :acetone is prepared. The blend as mentioned in I is granulated and
sieved through 2.00mm (ASTM NO. 10) sieve, dried and dry -graded through
sieve (ASTM NO.20) 0.85 mm.
The granules are mixed first with talc, followed by Magnesium Stearate.
The granules are compressed in two following dosage forms.

Application of release rate sustaining membrane
Two different compositions of coating solutions are used for the two different matrix ;cores to achieve uniform release rates.

* In place of Dibutylpthalate other plasticisers like Triacetin, etc. can also be
used singly or in| combination.

In all the strengths the coating solution was sprayed continuously with continuous, drying.

The release rates were determined by in vitro models.
.
The release rates were determined for reservoir matrices, sustained
release coated tablets for both the strengths and sugar coated tablets for

Strength I.
The details are as follows :-

Apparatus Dissolution Medium RPM Temperature
USP XVI Type I 900 ml of 0. IN HCI 100 37°C
The release rate is expressed in cumulative percentage released, calculated as equivalent of Theophylline release.

Within 8 |hrs. the entire quantity of drug is released and upto 6 hrs. the kinetics is strictly zero order and the release rate becomes slightly non-linear thereafter.
Sustained release coated tablet Strength III

Time % Release
hrs.
1 22.55
3 49.70
6 78.21

We Claim:
1. A controlled release composition for use in the treatment, inter alia of
asthma and other bronchial conditions, which comprises of a core matrix
consisting of a mixture of a water insoluble, non permeable and non
swellable polymer and soluble excipients and/or other conventional
additives, and at least an active ingredient dispersed in such core matrix,
said core matrix being coated with said water insoluble, non permeable and
non swellable polymer and soluble excipients, such that upon
administration the soluble excipients in said coating and said core matrix
dissolve and create micropores on various layers thereby allowing entry of
surrounding fluids therein and create channels for the release of said active
ingredients through said micropores.

i2. A composition as claimed in. Claim 1 wherein the active ingredients in the
composition comprises of at least two Xanthine derivatives one of which is highly soluble [in water and other is less soluble in water.
3. A composition as claimed in Claim 2 wherein the highly soluble Xanthine derivative is Etofyllin and is present in an amount of from 65 to 95 % by weight of the composition and the less soluble Xanthine derivative is Theophylline and present in an amount of from 5 to 35% by weight of said composition and the water soluble excipients are preferably present in amount of from 1 to 10% by wt.
4. A composition as claimed in any preceding claim wherein said EtofyUin and Theophylline are present in a ratio of 77:23.
5. A composition as claimed in any preceding claim wherein the composition is
in the form of tablet.
6. A composition as claimed in any preceding claim wherein the tablet consists of multiple coatings.
7. A composition as claimed in any one of claims 1 to 5 wherein said composition is in the form of polymer coated pellets.

8. A composition as claimed in claim 7 wherein the pellets are polymer coated micropellets in a capsule, preferably, a gelatin capsule.
9. A composition as claimed in claim 8 wherein said tablets or pellets comprise of a core comprising of said active ingredients, excipients and insoluble, non-permeable, non-swellable polymer and a sustained release coating consisting of a insoluble, jnon- permeable, non-swellable polymer and soluble additives.

10. A composition as claimed in any preceding claim wherein the same polymer is employed for coating as well as the core matrix.
11. A composition as claimed in any preceding claim wherein said core comprises of from 80 to 90%, preferably, 88.75% by wt of said active ingredients, from 1.75 to 15%, preferably 8 to 9 % by wt of said polymer and balance, comprising of said excipients and additives.
12. A composition as claimed in claim 11 wherein the insoluble, non- permeable, non-swellable polymer is preferably an Acrylic acid, more preferably methacrylic acid copolymer preferably, Methacrylate and Methacrylic acid copolymer type B USP.

13. A composition as claimed in claim 12 wherein the amount of said insoluble, non- permeable, non-swellable polymer in said coating composition is from 0.5 to 7 % by wt, more preferably, from 2.3 to 2.5% by wt.
14. A composition as claimed in claim 11 wherein the water-soluble excipients and additives, which is the same or different and are selected from the group consisting of lactose, PEG, sucrose, mannitol, dextrose or citric acid
15.A composition as claimed in any preceding claim wherein the composition optionally contains fillers such as, starch or lactose.
16. A process for the preparation of a novel composition for use in the treatment inter alia, of asthma and other bronchial conditions which comprises compressing a mixture of said a water insoluble non permeable and non swellable polymer and soluble excipients and/or other conventional additives, and at least an active ingredient and coating said particles of said

mixture in a coating composition comprising of an insoluble, non permeable and non swellable polymer and soluble additives, the soluble additives in
said coating creating micropores on the surface, allowing entry of

surrounding fluids therein and create channels for the release of said active
ingredients through said micropores.
17.A process as claimed in claim 16 wherein said compressed mixture is dispersed in an organic solvent selected from isopropyl alochol, ethyl alcohol, specially denatured spirit and acetone.
18.A process as! claimed in claims 17 wherein said compressed mixture is granulated.
19.A process as claimed in any one of claims 16 to 18 wherein the active ingredients comprises of at least two Xanthine derivatives one of which is highly soluble" in water and other is less soluble in water.
20. A process as claimed in Claim 19 wherein the highly soluble Xanthine
derivative is Etofyllin and is present in an amount of from 65 to 95 % by
weight of the composition and the less soluble Xanthine derivative is
Theophylline and present in an amount of from 5 to 35% by weight of said
composition and the water soluble excipients are preferably present in
amount of from 1 to 10% by wt.
21. A process as claimed in claim 19 wherein said Etofyllin and Theophylline are
present in a ratio of 77:23.
22. A process as claimed in any preceding claim wherein the same polymer is
employed for coating as well as the core matrix.

23. A process as claimed in any one of claims 16 to 21 wherein said core
comprises of! from 80 to 90% preferably, 88.75% by wt of said active
ingredients, from 1.75 to 15%, preferably 8 to 9 % by wt of said polymer and
balance, comprising of said excipients and additives.

24. A process as claimed in claim 22 wherein the insoluble, non- permeable, non-swellable polymer is preferably an Acrylic acid, more preferably methacrylic acid copolymer preferably, Methacrylate and Methacrylic acid copolymer type B USP.
25. A process as claimed in claim 16 wherein the amount of said insoluble,
non- permeable, non-swellable polymer is from 0.5 to 7 % by wt, more
preferably, from 2.3 to 2.5% by wt.
26. A process as claimed in claim 11 wherein the water-soluble excipients and
additives, which may be the same or different are selected from the group
consisting of lactose, PEG, sucrose, mannitol, dextrose or citric acid.
27.A controlled release composition for use in the treatment, inter alia of asthma and other bronchial conditions, substantially as herein described with reference to the foregoing examples.
28. A process for the preparation of a controlled release composition for use in
the treatment, inter alia of asthma and other bronchial conditions,
il substantially as herein described with reference to the foregoing examples.
Dated this "the 24th day of February 2003
H.SUBRRAMANIAM OF SUBRAMANIAM NATARAJ & ASSOCIATES
Attorny for the Applicants

Documents:

182-mum-2002-cancelled pages(07-09-2007).pdf

182-mum-2002-claims(granted)-(07-09-2007).doc

182-mum-2002-claims(granted)-(07-09-2007).pdf

182-mum-2002-correapondence(12-03-2008).pdf

182-mum-2002-correapondence(ipo)-(04-03-2008).pdf

182-mum-2002-drawing(07-09-2007).pdf

182-mum-2002-form 1(08-03-2004).pdf

182-mum-2002-form 1(10-04-2002).pdf

182-mum-2002-form 1(27-02-2002).pdf

182-mum-2002-form 18(29-12-2005).pdf

182-mum-2002-form 2(granted)-(07-09-2007).pdf

182-mum-2002-form 3(27-02-2002).pdf

182-mum-2002-form 5(25-02-2003).pdf

182-mum-2002-form 6(08-03-2004).pdf

182-mum-2002-petition no 281(08-03-2004).pdf

182-mum-2002-power of attorney(10-04-2002).pdf

182-mum-2002-power of attorney(27-04-2004).pdf

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Patent Number

216386

Indian Patent Application Number

182/MUM/2002

PG Journal Number

13/2008

Publication Date

28-Mar-2008

Grant Date

12-Mar-2008

Date of Filing

27-Feb-2002

Name of Patentee

CADILA HEALTHCARE LIMITED

Applicant Address

ZYDUS TOWER, SATELLITE CROSS ROADS, AHMEDABAD 380 015

Inventors:

#	Inventor's Name	Inventor's Address
1	JANI RAJENDRAKUMAR HARIPRASAD	GERMAN REMEDIES LIMITED, A- SHIVASAGAR ESTATE, DR. A. BESANT ROAD, WORLI, MUMBAI 400 018
2	DURVE RAVINDRA SADASHIV	M.Vasanji Road, Andheri(E), Worli, Mumbai-400093
3	PATANKAR HARSHAD	M.Vasanji Road, Andheri(E), Worli,Mumbai-400093

PCT International Classification Number

A61K47/48

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA