Title of Invention

COMPOSITION FOR USE IN THE TREATMENT INTER ALIA, OF ASTHMA AND OTHER BRONCHIAL CONDITIONS AND PREPARATION THEREOF

Abstract

A Composition for use in the treatment inter alia, of asthma and other bronchial conditions is disclosed. The compositions comprises as active ingredients, a mixture of at least two Xanthine derivatives, the first Xanthine derivative being more soluble in water and being present in an amount of from 45 to 90% by wt and the second Xanthine derivative being less soluble in water and being present in an amount of from 10 to 55% by wt, from 1 to 10% by wt of excipients, additives and binders, said active ingredients and said additives being present in a matrix comprising essentially of hyroxypropylmethylcellulose (HPMC). Such that drug is released over 24 hours independent of the pH of the surrounding fluid.

Full Text

FORM 2 THE PATENTS ACT, 1970 (39 of 1970) COMPLETE SPECIFICATION (See Section 10; rule 13) "COMPOSITION FOR USE IN THE TREATMENT INTER ALIA, OF ASTHMA AND OTHER BRONCHIAL CONDITIONS AND PREPARATION THEREOF" We, CADILA HEALTHCARE LIMITED, a company incorporated under the Companies Act, 1956, of Zydus Tower, Satellite Cross Roads, Ahmedabad - 380 015, Gujarat, India, The following 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 matrix release pharmaceutical compositions and a process for the preparation thereof. More particularly, the present invention relates to sustained release matrix type compositions in the form of tablets and a process for the preparation thereof. More particularly, the present invention relates to sustained matrix release tablets for use in treatment of asthma and other respiratory tract problems and a process for the preparation thereof. In particular, the present invention relates to sustained release compositions in the form of a tablet for use in the treatment of asthma wherein a single tablet or capsule is capable of providing relief for a period of at least twenty-four hours. Background of the invention Theophylline and Etofylline have been conventionally used in the treatment of asthma. There is a plethora of prior art on the use of Theophylline and Etofylline for the treatment of asthma and COPD. There has also been the problem of striking a balance between increasing the bio-availabity of the drug into the system and controlling the release to the drug into system at such a rate that effective concentration of drug is maintained for a longer period avoiding high concentration of drug for a shorter period and thereby reducing the frequent intake of drug. Description of prior art Despite the above mentioned problems numerous attempts have been made to formulate Theophylline and Etofylline as a tablet which releases an initial burst of therapeutic agent, 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 carboxymethylcellulose, cellulose acetate phthlate, sodium carboxymethylcellulose, 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 2 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 undesirable ingredients, etc. Therefore, in order to strike a proper balance between increased bio availability and sustained release there is a constant ongoing research using various excipients. 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 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 appear 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 3 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 forms a highly viscous solution (hydrocolloid) or at least swells. With the prior 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 need for tablets, particularly 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. The intention was to achieve this aim by matrix, i.e. without release-slowing film coatings applied to the core. 4 " In addition there has been a need to develop a technique for simple and low cost production of these. As mentioned in said US Patent No. 6,290,990 it was intended that this take place in a continuous and one-stage process without previous mixing or pre-granulation of the components and without final spheronization or similar shaping/rounding of the after the production process." None of the prior art known to the applicants teach any pharmaceutical composition in the form of tablet or other similar form for treatment of asthma which is capable attaining release of Etofylline and Theophylline uniformly over 12 - 18 hrs. period independent of pH of medium to provide relief from asthma over 24 hrs. period. Furthermore, none of the prior art cited above or known to the applicants addresses the problem of the side effects associated with the active ingredient particularly, when the active ingredient is theophylline. The present invention attempts to obviate the disadvantages of the prior art by providing a novel matrix release composition, which preferably is in the form of a tablet. 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 yet another object of the present invention to provide a pharmaceutical composition, preferably, in the form a tablet for use in treatment of asthma, COPD and other bronchial problems. It is still another object of the present invention to provide a pharmaceutical composition, preferably, in the form a tablet for use in treatment of asthma, COPD and other bronchial problems which completely avoids the problems of side-effects associated with an active ingredient. It is still another object of the present invention to provide a pharmaceutical composition, preferably, in the form a tablet for use in treatment of asthma, COPD and other bronchial problems which is capable of attaining release of Etofylline and Theophylline uniformly over 18 - 24 hrs. period independent of pH of medium to 5 provide relief from asthma over 24 hrs. period, thus reducing the dosage of medication to just once a day. Summary of the invention The above and other objects of the invention are achieved by providing* a , novel composition in the form of a tablet or granules or pellets in a matrix essentially comprising of a high molecular weight Hydroxypropylmethylcellulose (HPMC), so that the release of drug takes place uniformly over 12 - 24, preferably 18 to 24 hrs. period independent of pH of medium. This gives relief from asthma over 24 hrs. period. This matrix does not pose any danger of intestinal obstruction during the passage of the matrix tablet through the digestive tract. The pharmaceutical composition of the present invention is preferably in the form of a tablet or like comprising essentially of a mixture of at least two xanthines derivatives, at least one of them being freely soluble in water and the other being only partially soluble in water. The tablet core comprises of a matrix of a high molecular weight Hydroxypropylmethylcellulose (HPMC), along with other excipients to improve compressibility and lubrication. Within the pores of this matrix, the active ingredients are dispersed. The core consists of active ingredient dispersed in the matrix formed by a polymer along with other suitable excipients. The polymer being used is swellable polymer and is thermodynamically compatible with dissolution medium and biological fluids that the glass transition temperature of the polymer is lower than the one encountered during experimental conditions. The release of bioactive ingredient is controlled by the diffusion of the drug from and through the swollen polymer structure under the countercurrent diffusion of water or biological fluids into the polymer. It has been suggested that the release rate of the drug is dependent on its solubility, diffusion coefficient porosity of the polymer matrix and the tortuosity of the path of drug molecules during diffusion. The diffusion follows the Fick"s law of diffusion under equlibrium conditions. However until complete swelling of the polymer has been achieved the equilibrium is not reached and diffusion does not follow Fick"s law of diffusion. Exact mathematical treatment of the release rates in such systems is difficult and empirically the fraction released can be represented by the following equation: Qt/Q = kt" Where Qt/Q represents the fraction of drug released, k is constant for the matrix and t is time. For those polymer, which do not show a time-lag during 6 swelling, have value of n= 1 and the release rate becomes a constant, indicating zero order release rate. For the system described above the release rate is proportional to the square root of time provided the surface area of the dosage form remains constant. With the very similar compositions and differing surface areas the release rates for the drugs change as illustrated in the Formulations A to C Accordingly, the present invention provides a novel composition for use in the treatment inter alia, of asthma and other bronchial conditions which comprises as active ingredients, a mixture of at least two Xanthine derivatives., the first Xanthine derivative being soluble in water and being present in an amount of from 45 to 90 % by wt and the second Xanthine derivative being less soluble in water and being present in an amount of from 10 to 55% by wt, from 1 to 10% by wt of excipients, said active ingredients and said additives being present in a matrix comprising essentially of Hydroxypropylmethylcellulose (HPMC). The present invention also relates to a process for the preparation of a novel composition for use in the treatment inter alia, of asthma and other bronchial conditions which comprises mixing active ingredients consisting of at least two Xanthine derivatives, the first Xanthine derivative being soluble in water and being present in an amount from 65 to 95 % by wt and the second Xanthine derivative being less soluble in water and being present in an amount of from 5 to 35% by wt, from 1 to 10% by wt of water soluble excipients, compressing said mixture in a matrix comprising essentially of hydroxypropylmethylcellulose (HPMC). Preferably, the viscosity of said Hydroxypropylmethylcellulose (HPMC) is in the range of 10,000 and 140,000 cp, more preferably around 100,000 cp. The molecular weight of HPMC should be between 15,000 and 45,000 preferably around 27,000. Preferably, said the first water soluble Xanthine derivative is Etofylline and the second Xanthine derivative is Theophylline. In a most preferred embodiment, Etofylline and Theophylline are present in a ratio of 77:23. In yet another preferred embodiment, said core comprises from 60 to 90% by wt of said active ingredients, from 5 to 25% by wt of said polymer and balance, comprising of said excipients and additives. 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. 7 In yet another embodiment, the mixture is granulated in the presence of organic solvents such as isopropyl alcohol, ethyl alcohol, specially denatured spirit or acetone or any mixture thereof. 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 conventional 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 etofylline and theophylline, which offer the following advantages: (1) Better solubility of theophylline in the presence of etofylline (2) Easier change over from one formulation to another because all the formulations contain the same ratio of the drugs. (3) Reduced risk of side effects because: (a) Theophylline and etofylline have not demonstrated cumulative toxicity in animal experiments, and, (b) Etofylline 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) combined with Etofylline in the ratio of 23:77 shows rapid dissolution and bio-availability as compared to Theophylline or Etofylline singularly. The release rate of such rapidly dissolving combination can be controlled, by designing a matrix of Hydroxypropyl methylcellulose (HPMC) having a viscosity in the range of 15,000 to 100,000cps which is an important feature of the invention. The typical viscosity of HPMC is in the range of 70,000 to 140,000cps, preferably 100,000cps. The mixture of Theophylline and Etofylline may be mixed with the polymer to the extent of 5-25%. 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 8 lubricants and gradients like talc, magnesium stearate, aerosil, etc. The drug may contain fillers such as Lactose, Starch, or even may be granulated without the aid of any fillers. According to the invention, sustained release tablets of Etofylline and Theophylline have been designed in a high molecular weight Hydroxypropylmethylcellulose (HPMC) matrix. The drugs Etofylline and Theophylline are released from this matrix uniformly in sustained manner over the period of 12 - 18 hrs. This release takes place independent of the pH of the surrounding medium. The matrix itself gets eroded into palpable, soft residues over the period of 12 - 18 hrs. Therefore, this matrix does not pose any danger of intestinal obstruction during the passage of the matrix tablet through the digestive tract. The amounts of Etofylline and Theophylline employed in the invention are from about 45 - 90 % Etofylline and 10-55 % Theophylline. The ratio should be most preferably, be 77:23. The compressed tablets will be capsule, oval, or round, or any other shape. The tablet matrix may include other excipients such as Lactose, Dibasic Calcium Phosphate, etc. and suitable binders like PVP, Natural Gums, etc. alongwith tablet lubricants such Talc, Magnesium Stearate, Stearic Acid or any other lubricant, etc. Hydroxypropylmethylcellulose (HPMC) has been used for retarding / sustaining the release of. Etofylline and Theophylline. (The molecular weight of HPMC should be between 15,000 and 45,000, preferably around 27,000.) Tablets may be prepared either by direct compression or by suitable granulation / drying process using aqueous or non-aqueous or partly aqueous (Hydroalcoholic) granulation process. Resultant granules are then dried sieved and suitably compressed into tablets. The tablets are compressed at the hardness between (70 to 120 N) (and then coated using a polymer solution in which Micronised Lactose or PEG (Poly Ethylene Glycol) is suspended. Tablets may be coated using conventional pan coating or in a fluid bed coating equipment or in an Accela cota type of equipment. The following examples illustrate typical delivery device manufactured according to the invention. The dosage form is a tablet Based on experiments conducted, the most preferred Etophyllin & Theophyllin ratio has been at 77:23. Both the drugs comply with the pharmacopoeial 9 specifications. Theophyllin can be used as Theophyllin anhydrous as well as theophyllin hydrated. However, the above mentioned ratio refers to hydrated theophyllin- When Theophyllin anhydrous is to be used, necessary corrections in the quantity should be made so as to be equivalent to Theophyllin hydrated. The corresponding weight of diluent Dibasic Calcium Phosphate is adjusted accordingly. In the below mentioned typical tablet core compositions, quantities of the drugs have been rounded off. 300 mg mg/tab 450 mg mg/tab 600 mg mg/tab 750 mg mg/tab Etophyllin 231.00 346.00 462 577.00 Theophyllin hydrated 69.00 104.00 138 173.00 Dibasic Calcium Phosphate (Dihydrate) 13.12 24.70 46.24 60.325 Hydroxypropylmethycellulos e 56.88 80.301 93.76 117.175 Magnesium Stearate 5.00 7.500 10 12.500 375 562.500 750 940 Punch Length: 14mm Width:6mm Thickness: 4.2-4.5 mm Length: 16mm Width:7mm Thickness: 4.9-5.2 mm Length: 17mm Width:7.75mm Thickness: 5.2-5.6 mm Length:20mm Width:9.5mm Thickness: 6.35-6.75 mm Typical Method of Manufacture: 1) Etofyllin, Theophyllin, Dibasic Calcium Phosphate and hydroxypropylmethycellulose are mixed together. 2) The resultant blend is granulated with the mixture of Isopropyl Alcohol and Purified Water in the ratio of 1:1. 3) Wet granules are graded and dried. 4) Dried granules are graded again and lubricated with Magnesium Stearate. 5) The lubricated granules are compressed. The release rates of the batches have been monitored at various pH at various time intervals as given below: 10 Time Period (hrs) Total time elapsed (hrs) Medium 1 - 0.1NHC1 1 2 pH 4.5 buffer 4 6 pH 6.9buffer 2 8 pH 7.2 buffer 4 12 pH 7.5 buffer The typical rate of release obtained over 8hrs. period is shown in graphical representation in graph as figure J . As routine checks of dissolution profile, 1 hr., 2 hr., 5hr., 8hr., & 12hr. dissolution rates using USP dissolution rate test apparatus 1. Is shown in Fig 2 The release rates obtained on 12 batches of 300 mg., 12 batches of 450 mg & 12 batches of 600 mg have been tabulated below: 300 mg. Dissolution profile: Time Media BN 101 BN 102 BN 103 BN 104 BN 105 BN 106 BN 107 BN 108 BN 109 BN 110 BN 111 BN 112 1 hr. limit (15-40%) 0.1N HC1 32 30 32 31 31 32 32 32 32 30 31 30 2 hr. limit (30-55%) pH 4.5 buffer 47 44 47 45 46 48 46 47 47 44 46 44 4 hr limit (45-75%) pH 6.9 buffer 69 66 68 68 68 69 66 68 67 65 69 66 5 hr. limit (55-85%) pH 6.9 buffer 76 74 76 74 76 77 77 76 76 73 77 73 8 hr. limit ( 12hr. limit ( 11 450mg. Dissolution profile: Time Media BN 101 BN 102 BN 103 BN 104 BN 105 BN 106 BN 107 BN 108 BN 109 BN 110 BN 111 BN 112 1 hr. limit (15-40%) 0.1N HC1 28 28 27 27 27 28 22 27 28 29 29 26 2 hr. limit (30-55%) pH 4.5 buffer 42 43 39 39 41 41 37 41 42 42 42 40 4 hr limit (45-75%) pH 6.9 buffer 61 64 57 58 62 60 50 60, 61 63 63 59 5 hr. limit (55-85%) pH 6.9 buffer 69 71 63 66 69 67 66 67 68 70 70 66 8 hr. limit ( 12hr. limit ( 600mg. Dissolution profile: Time Media BN 101 BN 102 BN 103 BN 104 BN 105 BN 106 BN 107 BN 108 BN 109 BN 110 BN 111 BN 112 1 hr. limit (15-40%) 0.1N HC1 25 25.9 26.5 25.6 26.L 25.6 24.9 22.5 25.3 24.8 25.7 27.2 2 hr. limit (30-55%) pH 4.5 buffer 37.6 39.5 39.4 38.6 39,5 38.2 35.5 33.2 37.4 36.7 38.9 40.7 4 hr limit (45-75%) pH 6.9 buffer 57 57.6 56.9 57.4 58.3 57.3 52.9 51.3 51.8 51.1 57.9 60.6 5 hr. limit (55-85%) pH 6.9 buffer 64 64.5 64.6 64.6 65.6 65 60.9 59.7 57.4 56.8 64.8 67.1 8 hr. limit ( 12hr. limit ( 12 750mg. Dissolution profile: Time Media BN 101 BN 102 BN 103 BN 104 BN 105 BN 106 BN 107 BN 108 BN 109 BN 110 BN 111 BN 112 1 hr. limit (15-40%) 0.1N HC1 26 28 27 26 28 28 25 26 28 29 26 26 2 hr. limit (30-55%) pH 4.5 buffer 40 43 39 40 42 40 39 41 41 41 40 40 4 hr limit (45-75%) pH 6.9 buffer 58 63 59 58 60 60 55 60 58 58 60 58 5 hr. limit (55-85%) pH 6.9 buffer 69 69 68 65 69 68 67 67 68 69 70 67 8 hr. limit ( 12hr. limit ( Preparation of the tablets of Etofylline and Theophylline anhydrous. The composition for each core for various strengths is given below: Formn C 300 mg mg/tab Formn. B 450 mg mg/tab Formn. A 600 mg mg/tab Formn. D 750 mg mg/tab Etophyllin 231.00 346.00 462.00 577.00 Theophyllin anhydrous 62.730 94.55 125.46 157.28 Calcium hydrogen Phosphate 19.400 34.149 58.78 76.045 Hydroxypropylmethycellul ose 56.880 80.301 93.76 117.175 Magnesium Stearate 5.000 7.500 10 12.500 375 562.5 750 940 Punch Length: 14mm Width:6mm Thickness: 4.2-4.5 mm Length: 16mm Width:7mm Thickness: 4.9-5.2 mm Length: 17mm Width:7.75mm Thickness: 5.2-5.6 mm Lengdi:20mm Width:9.5mm Thickness: 6.35-6.75 mm Typical method of manufacture (common to all the above three A, B, C 85 D formulations) 13 1) 2) 3) 4) 5) Etofylline, Theophylline and Calcium hydrogen phosphate and Hydroxypropylmethylcellulose are blended together in a Rapid Mixer Granulator or Planetary Mixer Granulator till a homogenous mixas obtained. A solvent mixture of isopropanol: water is prepared in l.1proportion weight basis. The blend as mentioned in I is granulated and sieved through 800mm NO. 10) sieve, dried and dry -graded through sieve (ASTM NO.20) 0.85 mm* The granules are mixed with Magnesium Stearate. The granules are compressed in tablet dosage form to confirm to dimensions as mentioned in the table (above). Release rates for various Formulations Time (hrs.) Frmn C: 300 mg Frmn B: 450mg Frmn A: 600 mg Frmn D: 750 mg Percentage of Drug release: 1 29.4 25.00 25.3 26.2 2 44.90 38.50 37.60 40.5 4 67.60 57.40 57.20 58.5 5 77.00 65.00 64.5 66.1 6 83.10 71.40 70.90 82.4 8 93.50 82.40 81.80 92.6 14 We Claim: 1. A composition for use in the treatment inter alia, of asthma and other bronchial conditions which comprises as active ingredients, a mixture of at least two Xanthine derivatives, the first Xanthine derivative being soluble in water and being present in an amount of from 45 to 90 % by wt and the second Xanthine derivative being less soluble in water and being present in an amount of from 10 to 55% by wt, from 1 to 10% by wt of excipients, additives and binders, said active ingredients and said additives being present in a matrix comprising essentially of hydroxypropylmethylcellulose (HPMC), such that drug is released over 24 hours independent of the pH of the surrounding fluid. 2. A composition as claimed in Claim 1 wherein the viscosity of said Hydroxypropylmethylcellulose (HPMC) is in the range of 10,000 and 140,000 cp, more preferably around 100,000 cp. 3. A composition as claimed in claim 1 or 2 wherein the molecular weight of said HPMC is between 15,000 and 45,000 more preferably, about 27,000. 4. A composition as claimed in any one of claims 1 to 3 wherein said the first water soluble Xanthine derivative is Etofylline and the second Xanthine derivative is Theophylline. 5. A composition as claimed in any preceding claim wherein said Etofylline and Theophylline are present in a ratio of 77:23. 6. A composition as claimed in any preceding claim wherein said active ingredients are present in an amount of from 60 to 90% by wt said polymer is present in amount of from from 5 to 25% by wt and balance, comprising of said excipients, binders and additives. 7. A composition as claimed in any preceding claim wherein the water soluble excipients and additives, which are same or different and are selected from the group consisting of lactose, Dibasic Calcium Phosphate, PEG, sucrose, mannitol, dextrose or citric acid. 8. A composition as claimed in any preceding claim wherein said binders are selected from HPMC, PVP or natural gums. 9. A composition as claimed in any preceding claim wherein the mixture is granulated in the presence of organic solvents selected from the group consisting of isopropyl alcohol, ethyl alcohol, denatured spirit or acetone or any mixture thereof. 15 10. A composition as claimed in any preceding claim wherein the granules are graded and mixed with lubricants and glidants/ gradients such as talc, magnesium stearate, or Aerosil. 11. A composition as claimed in any preceding claim wherein said conventional fillers are selected from starch or lactose. 12. A process for the preparation of a composition for use in the treatment inter alia, of asthma and other bronchial conditions which comprises mixing active ingredients consisting of at least two Xanthine derivatives, the first Xanthine derivative being soluble in water and being present in an amount from 65 to 95 % by wt and the second Xanthine derivative being less soluble in water and being present in an amount of from 5 to 35% by wt, from 1 to 10% by wt of water soluble excipients, compressing said mixture in a matrix comprising essentially of hydroxypropylmethylcellulose (HPMC). 13. A process as claimed in claim 12 wherein the mixture is converted into granules in the presence of organic solvents and / or water. 14. A process as claimed in claim 12 or 13 wherein the organic solvents are selected from isopropyl alcohol, ethyl alcohol, denatured spirit, acetone or a mixture of any of them. 15. A composition for use in the treatment inter alia, of asthma and other bronchial conditions substantially as herein described with reference to the foregoing Examples. 16. A process for the preparation of composition for use in the treatment inter alia, of asthma and other bronchial conditions substantially as herein described with reference to the foregoing Examples. 17. A process for the preparation of composition for use in the treatment inter alia, of asthma and other bronchial conditions substantially as herein described with reference to the accompanying drawings. SUBRAMANIAM) of SUBRAMANYAM, NATARAJ 8B ASSOCIATES ATTORNEY FOR THE APPLICANTS Dated this the 2nd day of July 2007 16

Documents:

183-mum-2002-cancelled pages(05-07-2007).pdf

183-mum-2002-claim(granted)-(05-07-2007).doc

183-mum-2002-claim(granted)-(05-07-2007).pdf

183-mum-2002-corredpondence(05-07-2007).pdf

183-mum-2002-corredpondence(ipo)-(19-12-2006).pdf

183-mum-2002-form 1(05-03-2004).pdf

183-mum-2002-form 1(05-07-2007).pdf

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

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

183-mum-2002-form 2(granted)-(05-07-2007).doc

183-mum-2002-form 2(granted)-(05-07-2007).pdf

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

183-mum-2002-form 5(22-01-2003).pdf

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

183-mum-2002-general power of authority(10-04-2002).pdf