Title of Invention	AN IMPROVED PHARMACEUTICAL FORMULATION CONTAINING TAMSULOSIN SALT AND A PROCESS FOR ITS PREPARATION
Abstract	This application discloses a modified release pharmaceutical formulation in oral dosage form comprising a solution of Tamsulosin Hcl or pharmaceutically acceptable salts thereof in Polyvinyl pyrrolidone and / or β-cyclodextrin containing a solublising agent, an emulsifiying agent, a binder and a solvent and forming into pellets, using sugar spheres as the base, the coated pellets having a further polymer coating, the polymer coated pellets having an enteric coating of a polymer, plasticizers, wetting agent, antitacking agent and solvents which are encapsulated in hard gelatin capsules. This application also discloses a process for the preparation of the said formulation. The formulation is useful for the treatment of benign prostatic hyperplasia (BPH).

Title of Invention

AN IMPROVED PHARMACEUTICAL FORMULATION CONTAINING TAMSULOSIN SALT AND A PROCESS FOR ITS PREPARATION

Abstract

This application discloses a modified release pharmaceutical formulation in oral dosage form comprising a solution of Tamsulosin Hcl or pharmaceutically acceptable salts thereof in Polyvinyl pyrrolidone and / or β-cyclodextrin containing a solublising agent, an emulsifiying agent, a binder and a solvent and forming into pellets, using sugar spheres as the base, the coated pellets having a further polymer coating, the polymer coated pellets having an enteric coating of a polymer, plasticizers, wetting agent, antitacking agent and solvents which are encapsulated in hard gelatin capsules. This application also discloses a process for the preparation of the said formulation. The formulation is useful for the treatment of benign prostatic hyperplasia (BPH).

Full Text	Technical Field This invention relates to an improved process for the preparation of Tamsulosin hydrochloride . Tamsulosin hydrochloride is an antagonist of alpha lA adrenoceptors in the prostate. Tamsulosin Hcl is (-)-[R]-5,4,2-[2-(0-ethoxy phenoxy) ethyl] amino propyl -2- methoxy benzene sulfonamide monohydrochloride. The empirical formula of Tamsulosin Hcl is C20H28N205S. Hcl. The molecular weight of Tamsulosin Hcl is 444.98. Tamsulosin Hcl is indicated in the treatment of the signs and symptoms of benigh prostatic hyperplasia (BPH). It aids in relaxing the smooth muscles in bladder neck and prostate resulting in an improvement in urine flow rate and a reduction in symptoms of BPH. The recommended daily dosage is 0.4mg. Background and prior art US Patent no 4,772,475 details a pharmaceutical controlled release individual unit or multiple units formulation in which the individual unit comprises a granulation product obtained by adding a release controlling agent to a mixture of a physiologically active substance and units-forming substance(s) and granulating and resultant mixture, said granulation product (granules) being substantially not disintegrated but gradually releasing the physiologically active substance in the gastrointestinal tract. The release controlling agent used is a methacrylic acid- ethyl acrylate copolymer or mixtures of said copolymer and ethyl cellulose. Examples of the formulation containing Tamsulosin Hydrochloride were given. The results of dissolution rates of the compositions exemplified in 21 Examples were provided in the patent .On a detailed study of these Examples it is observed that: In 6 Examples eudragit L30D-55 has been used as the release controlling agent(A) In 4 Examples same eudragit has been used as the release controlling agent but in addition magnesium stearate was also used (B) In 3 Examples ethyl cellulose has been used as the release controlling agent (C), & In another 6 Examples water has been used as the release controlling agent. In all the above cases the dissolution rate percentage were given. But in 10 cases only dissolution rate was provided for 2 hours, of the 10 examples, 3 samples showing more than 90% release, 2 samples showing release between 61% and 66.2% 1 sample showing 57.6% and 3 samples showing 41.7% to 44.8% all the values at the end of 2nd hour of dissolution study. Such a high degree of variation in dissolution rate and release of more than 90% drug at the end of 2nd hour in three out of 10 samples may be caused due to lack of uniform geometry of the resultant granulation of the active ingredients and also may not qualify for the formation of a controUed-release dosage form. The combination of acrylic acid polymers and their copolymers with celluloses may lead to inconsistent release profiles. WO Patent no 03 / 039531 Al discloses a pharmaceutical tablet comprising a tablet matrix having dispersed therein 0.1 to 10mg of Tamsulosin or a pharmaceutically acceptable salt thereof, and optionally having an enteric coating over said martix, wherein said tablet is a modified release tablet and has a dissolution profile such that in each of the media, simulated intestinal fluid (SIF), fasting state simulated intestinal fluid (FaSSIF) and fed state simulated intestinal fluid (FeSSIF) said tablet releasing not more than 60% of said Tamsulosin at 2 hours elapsed time in USP2 (a type of dissolution testing as per US Pharmacopeia.) apparatus using 500 ml of said media at 50-100 rpm paddle speed. The patent also provides data on the release of Tamsulosin in at the end of 30 minutes, 2 hours and 6 hours in Simulated gastric fluid(SGF) media and Simulated intestinal fluid.(SIF) media. In the book on sustained and controlled- release drug delivery systems by Gwen M. Jantzen and Joseph R.Robinson, the authors commented that in the case of the matrix based dosage form, " cracking of the matrix material can cause unwanted release". In their book on Novel drug delivery and its therapeutic application edited by L.F.Prescott and W.S.Nimmo, while commenting upon the relative merits of single and multi-particulate systems, the authors opined that" multiple units can have the following advantages; 1) they are less influenced by food (gastric emptying) than single units. 2) the individual units are normally well distributed in the gastrointestinal tract if taken after or together with food, and by spreading in this way the risk of local high concentrations of released drug is reduced. 3) there may be fewer problems with stenosis or obstruction caused by gastrointestinal pathology and 4) dose adjustment may well be easier. On the other hand the advantages of controlled release dosage form are reduction in drug blood level fluctuations, reduction in drug frequency, enhanced patient convenience and compliance and reduction in adverse side effects and normal food intake. It is well known that release of the active ingredient from a matrix based system depends on the availability of adequate amount of gastric fluids. As Tamsulosin is a sparingly soluble drug, the absence of a proper liquid content available throughout its dissolution time, may pose problems of a continuous drug availability. EP no 1088551 mentions various dosage forms that can be made using Tamsulosin as active agent. The active agent is mixed with diluents, other additives like binders, lubricants, a disintegrating agent, a stabilizer, a solublising aid, a plasticiser, and a colouring agent and compressing them into tablets for achieving a sustained release preparation. This approach suffers from the same disadvantages as stated above. The JP no 2001114679 discloses a medicine containing Tamsulosin for the treatment of lower urinary tract diseases with pharmaceutically acceptable salt as an active ingredient which contains tamsulosin or its sah permitted pharmaceutically as an active principle. Tamsulosin is mixed with inactive diluent like lactose, a mannitol, a microcrystal cellulose, grape sugar, starch, a polyvinyl pyrrolidone and magnesium aluminium silicate in a solid tablet. It contains solublizing agent like hydroxypropylcellulose and hydroxyproylmethyl cellulose, a magnesium stearate, a calcium stearate, a polyethylene glycol, starch, lubricant like talk and stabilizing agent like lactose, glutamic acid or an aspartic acid. The invention is a self-sustaining discharge type gradual release tablet. It is obtained by coating a tablet, a granule, a fine grain agent and a capsule by conventional method . The JP No 2000080032 discloses a composition for oral administration containing tamsulosin Hcl and its dosage forms particular for the treatment of eccrisis obstacle treatment agent especially accompanying the neurogenic bladder. . This composition contains tamsulosin or tamsulosin Hcl as an active ingredient, mixed with inactive diluent lactose, mannitol, grape sugar, a microcrystal cellulose, starch, a polyvinyl pyrrolidone, magnesium aluminium silicate in a solid tablet with solublizing agent, binder, additives, like hydroxypropyl methylcellulose, hydroxypropylcellulose, magnesium stearate, a calcium stearate, polyethylene glycol, starch, lubricant like talc, disintegrator like a calcium carboxymethyl cellulose, stabilizing agent like a lactose, glutamic acid or an aspartic acid a plasticizer like a triacetin, titanium oxide and a colouring agent like iron sesquioxide according to a conventional method. Tablet or the pilule as occasion demands with the film of glycocalyx such as cane sugar, gelatin, agar, hydroxypropylcellusle , Hydroxy propyl methylcellulose phthalate or the enteric nature matter. The composition is self-sustaining discharge type gradual release tablet., or granule, a fine-grain capsule form. The daily dose of the composition in ordinary cases is about 0.1-0.8mg, most preferably 0.2-0.4mg the active ingredient per adult when the tamsulosin hydrochloride is orally administered, and the daily dose is administered once after the meal. None of the prior art described above addresses the problem of improving the solubility of Tamsulosin and then controlling the release of the drug in a gradual manner by diffusion, so that the modified release dosage form presents a graded release profile over a period in excess of 4 hours, wherein at the end of the 4th hour, at least 70% of the drug gets released. Accordingly the present invention relates to a drug delivery system for administering tamsulosin as an oral dosage form for treating conditions such as benign prostatic hypertrophy (BPH). Objectives of the Invention Therefore the main objective of the present invention is to provide a pharmaceutical composition containing Tamsulosin Hydrochloride useful for the sustained release of the active ingredient. Another objective of the present invention is to provide a drug delivery system for the oral administration of Tamsulosin Hydrochloride. Still another objective of the present invention is to provide a drug delivery system for administering Tamsulosin Hydrochloride orally which releases the drug over a period of time, in excess of 4 hours. Yet another objective of the present invention is to provide a drug formulation wherein consistency of the drug release is provided by designing the process by layering the drug as a soluble complex on non-pareil seeds, a separate polymer coating for controlled release, and a second coating with enteric polymer for targetted drug release. Yet another objective of the present invention is to provide a drug formulation wherein the unit dosage drug is contained in ready to dissolve in multiple reservoirs. Another objective of the present invention is to provide a drug delivery system containing Tamsulosin Hydrochloride wherein the unit dosage of the drug is contained in is ready to dissolve multiple reservoirs where the release of the drug from the multiple reservoirs is controlled by a diffusion process. Yet another objective of the present invention is to prepare hard gelatin capsules, containing Tamsulosin Hydrochloride each capsule containing a unit dose of the drug as multiple reservoirs. Still another objective of the present invention is to provide a method of preparing a formulation containing Tamsulosin Hydrochloride which can be administered orally. Detailed description Tamsulosin Hcl is only slightly soluble in water. The effect of solubilising agents on increasing the solubility of Tamsulosin HCL was assessed with two materials, poly vinyl pyrrolidone (PVPK -30) and cyclodextrin. Initially 200mg Tamsulosin HCL was dissolved in 100ml of demineralised water. Addition of any further drug did not result in any increased solubility of the drug, indicating the saturation of the drug in water. In another experiment, 5 gm of PVPK-30 was dissolved in 100 ml of demineralised water and 200 mg of Tamsulosin Hcl was added to this solution. The drug showed complete dissolution. Another 100 mg of Tamsulosin Hcl was added to this solution. The drug was completely soluble in this solution. Upon addition of another 100 mg of Tamsulosin Hcl, however some crystals remained. It was concluded that PVPK-30 was helping the dissolution of Tamsulosin Hcl atleast by 50%. In another experiment 1.0 gm of cyclodextrin was dissolved in 100 ml of demineralised water. To this solution, 200 mg Tamsulosin Hcl was added and the drug dissolved. To this solution, 300 mg of Tamsulosin Hci was added in increments of lOOmg. Upto 400 mg of Tamsulosin Hcl could be dissolved in this solution and a few crystals remained with 500 mg total drug. It was concluded that addition of 1% B- cyclodextrin was able to improve the dissolution of Tamsulosin Hcl by atleast 100%. This exciting prospect of improved solubility of Tamsulosin Hcl in the presence of Polyvinyl pyrrolidone / cyclodextrin was successfully worked out. Initially the drug and the solublising agent along with an emulsifier are dissolved in a solvent mixture of alcoholic and aqueous media. The drug, as it is in a completely dissolved state, is layered on to sugar spheres in a conventional way, resulting in a drug solubiliser complex. ( Tamsulosin with polyvinyl pyrrolidone and cyclodextrin ) in a very fine particulate deposit. Accordingly, the present invention provides an improved release pharmaceutical formulation useful for treatment of benign prostatic hyperplasia which comprises a core of sugar spheres having a coating of a solution of Tamsulosin Hcl or a pharmaceutically acceptable salts thereof in Polyvinyl pyrrolidone and / or β-cyclodextrin containing a solublising agent, an emulsifiying agent, a binder and a solvent in the form of pellets, the spheres also having a coating of ethyl cellulose polymer and a further coating of an enteric polymer containing, plasticizers, antitacking agent and a solvent. The formulation may be in pellet or capsule form .The formulation of the invention ensures release of the drug at predefined rates in such a way that drug is available for bio-absorbtion even at the end of 4 hour and having good stability and useful for the treatment of Benign prostatic hyperplasia. The present invention also provides a process for the preparation of the above said improved release pharmaceutical formulation containing Tamsulosin Hydrochloride in an oral dosage form which comprises I. preparing a solid solution of Tamsulosin Hcl or a pharmaceutically acceptable salts thereof in Polyvinyl pyrrolidone and / or 13-cyclodextrin containing a solublising agent, an emulsifiying agent, a binder and a solvent and forming info pellets. II. impregnating the above solution on to sugar spheres. III. coating the resulting drug loaded pellets with a polymer coating layer IV. providing the polymer coated pellets with a coating of an enteric polymer, containing plasticizers, wetting agent, antitacking agent and a solvent and if desired. V. encapsulating the enteric coated pellets in hard gelatin capsules. The pellets or the capsules so prepared upon coming into contact with gastro intestinal fluids readily dissolves and readily diffuse through the polymer system loaded, on the drug loaded pellets. The polymer system acts as a controlled release membrane and allows diffusion of the drug through it at a predefined rate. A gastric resistant coat over the polymer coated pellets ensures that the gradual release of the drug takes place in the small intestine where its absorption is best. The predefined dissolution rates of Tamsulosin Hcl are worked out in such a way as to ensure less than 10% drug release at the end of 2 hours in the gastric medium and then subsequently shifting to pH 6.8 buffer to ensure that at the end of 1st hour, the drug release is between 35 to 55%, at the end of 2nd hour the drug release is between 50 to 70% and at the end of 4th hour, the drug releases not less than 70%, thereby ensuring an adequate amount of drug available for bio-absorption. The amount of sugar spheres used in the drug coating may be in the range of 700 to 950 mg per gram of the composition and more preferably the amount ranges from 750 to 900 mg per gram of the composition. The amount of Tamsulosin or its pharmaceutically acceptable salts used in the composition may be in the range of 1.0 mg to 10.0 mg per gram of the composition, preferably in the range of 2.0 mg to 4.0 mg per gram of the composition. Examples of useful tamsulosin pharmaceutically acceptable salts includes Tamsulosin Hydrochloride, Tamsulosin Hydrobromide, Tamsulosin methane sulfonate, Tamsulosin tosylate. Tamsulosin besylate, Tamsulosin acetate, Tamsulosin maleate, Tamsulosin tartarate and Tamsulosin citrate. The Hydrochloride salt is preferred. The solublising agent used in the formulation may be selected from cyclodextrins 3-hydroxy proply- beta cyclodextrin, di methyl beta cyclodextrin, 2- hydroxy propyl-beta cyclodextrin and beta cyclodextrin and the like, and Polyvinyl pyrrolidone, lecithin and the like or mixture thereof The amount of solublising agent used ranges from 1.00 to 10.00 mg per gram of the composition, more preferably 2.00 to 8.00 mg per gram of the composition. The emulsifying agent used in the formulation may be selected from anionic or non-ionic surfactants such as sodium lauryl sulphate, polyethylene-propylene glycol copolymer (Poloxamer), polyoxy ethylene alkyl ethers (cetomacrogol-1000), polyoxy ethylene castrol oil derivatives ( Cremophor RH60, Cremophor RH40), Poly oxy ethylene sorbital fatty acid esters (Poly sorbit-20, Poly sorbit-40, Poly sorbit-60, Poly sorbit-80), polyoxyethylene stearates (Macrogol- stearate), polyvinyl alcohol and the like and their mixture thereof .The amount of emulsifying agent employed in the drug coating , ranges from 0.01 to 10.00 mg per gram, preferably 0.02 to 8.00 mg per gram of the composition. The binder in the drug formulation may be selected from various grade of polyvinyl pyrrolidone and their molecular weight ranging from 2,500 to 30,00,000 and the preferred grade is polyvinyl pyrrolidone K-30 having molecular weight of 50,000. The amount of binder employed in the drug coating, ranges from 10.00 to 80.00 mg per gram, preferably 20.00 to 60.00 mg per gram of the composition. The solvents used in the formulation in the step (ii) may be selected from isopropyl alcohol, acetone, water and the like and preferably a mixture of isopropyl alcohol and water. The polymer used for the polymer coating is one or more polymers comprising of ethyl cellulose, hydroxyethyl cellulose, polyvinyl acetate phthalate and hydroxy propyl methyl cellulose acetate succinate The amount of polymer ranges from 20.0 mg to 100.0 mg, preferably 25.0 mg to 85.0 mg per gram of the composition. The plastisizer used in the polymer coating may be selected from diethyl phthalate, di butyl phthalate, triacetin, polyethylene glycol 4000 and the like .The amount of plastisizer employed in the polymer coating ranges from 2.00 to 25.00 mg per gram, more preferably 2.50 to 20.00 mg per gram of the composition. The anti-tacking agent used in the polymer coating may be selected from talc, magnesium stearate and the like or a mixture thereof The amount of anti-tacking agent used ranges from 1.0 mg to 15.0 mg, preferably 2.0 mg to 10.0 mg per gram of the composition. The solvent used in the Polymer coating stage may be selected from isopropyl alcohol, ethyl alcohol, acetone, water and the like or a mixture thereof The polymer used in the enteric coating may be selected from hydroxy propyl methyl cellulose phthalate, hydroxy propyl methyl cellulose acetate succinate, polyvinyl acetate phthalate, and the like. The amount of polymer used in the enteric coating ranges from 30.00 to 160.00 mg per gram of the composition , more preferably 40.00 to 140.00 mg per gram of the composition. For the enteric coating , the plasticizer may be selected from diethyl phthalate, di butyl phthalate, cetyl alcohol, poly ethylene glycol-4000, triethyl citrate, triacetin and the like. The amount of plasticizer used in the enteric coating ranges from 3.00 to 30.00 mg per gram of the composition, more preferably 4.00 to 25.00 mg per gram of the composition. The anti-tacking agent used in the enteric coating may be selected from talc,magnesium stearate and the like or a mixture thereof The amount of anti-tacking agent used in the enteric coating ranges from 4.0 mg to 16.0 mg per gram of the composition, more prefereably 5.0 to 12.0 mg per gram of the composition. The solvent used in the enteric coating may be selected from iso-propyl alcohol, ethyl alcohol, acetone, water and the like or a mixture thereof The enteric coated pellets may be filled into hard gelatin capsules in a conventional manner and may be packed into moisture resistant primary pack followed by secondary pack. The invention is explained in detail in the Examples given below which are provided by way of illustration only and therefore should not be construed to limit the scope of the invention. Example I Stage I:- Drug Coating Ingredients Quantity mg/ gm of pellets Tamsulosin Hydrochloride 2.290 Sugar spheres (18/22#) 835.000 Sodium Lauryl sulphate 0.040 Polyvinyl pyrrolidone K-30 41.740 Isopropyl alcohol * 164.000 Water* 136.000 * Solvents used in the process, but present only in negligible quantities in the final composition. Tamsulosin HCL was dissolved in a mixture of isopropyl alcohol and water. Sodium lauryl sulphate and polyvinyl pyrroHdone K-30 were added to this drug solution and the resultant liquid passed through colloid mill. Sugar spheres ( 18 / 22#) were loaded into a side vented coating pan and the drug solution was layered on to the sugar spheres . The resultant drug pellets were dried in the same coating pan. Stage II - Polymer Coating Ingredients Quantity mg/ gm of pellets Drug loaded pellets prepared by step(i) 879.000 Ethyl cellulose 30.700 Diethyl phthalate 3.070 Talc 3.070 * Iso propyl alcohol 483.000 * Solvent used in the process, but present only in negligible quantities in the final composition. Ethyl cellulose and diethyl phthalate were dissolved in Isopropyl alcohol and talc added to it. This suspension was passed through colloid mill and coated on to the drug pellets obtained from step (i) . The polymer coated drug pellets were dried in the same coating pan. Stage in - Enteric coating Ingredients Quantity mg/ gm of pellets Polymer coated pellets obtained in step(ii) 913.00 Diethyl phthalate 5.92 Cetyl alcohol 13.23 Hydroxy propyl methyl cellulose phthalate 59.20 Talc 5.92 * Iso propyl alcohol 580.00 * Acetone 580.00 * Solvent used in the process, but present only in negligible quantities in the final composition. Hydroxy propyl methyl cellulose phthalate, diethyl phthalate, and cetyl alchol were dissolved in a mixture of Isopropyl alcohol and acetone to which talc was added. The suspension was passed through colloid mill and coated onto the polymer coated pellets, obtained by step(ii) . The enteric coated pellets were dried in the same coating pan. The enteric coated pellets were filled into size '1' hard gelatin capsules depending on the drug content of the pellets. Non pareil seeds were used to adjust the balance of fill weight of 290 mg. The filled capsules were packed in High density Poly ethylene Containers / Blister strips. Example 2 Stage I:- Drug Coating Ingredients Quantity mg/ gm of pellets Tamsulosin Hydrochloride 2.290 Sugar spheres ( 18 /22#) 828.000 Sodium Lauryl sulphate 0.040 Polyvinyl pyrrolidone K-30 36.000 P-cy clodextrin 7.300 Isopropyl alcohol * 164.000 Water* 136.000 * Solvents used in the process, but present only in negligible quantities in the final composition. Tamsulosin HCL and p-cyclodextrin were dissolved in a mixture of isopropyl alcohol and water. Sodium lauryl sulphate and polyvinyl pyrrolidone K-30 were added to this drug complex and the resultant liquid passed through colloid mill. Sugar spheres ( 18 / 22#) were loaded into a fluidised bed coating appratus and the drug solution was layered onto these spheres. The resultant drug pellets were dried in the same equipment. Stage II - Polymer Coating Ingredients Quantity mg/ gm of pellets Drug loaded pellets obtained in step(i) 882.00 Ethyl cellulose 30.70 Diethyl phthalate 3.070 Talc 3.070 Iso propyl alcohol 483.000 Solvents used in the process, but present only in negligible quantities in the final composition. Ethyl cellulose, and Diethyl phthalate were dissolved in Isopropyl alcohol and talc was added to it. This suspension was passed through colloid mill and coated on to the drug pellets , obtained in step(i) in the same fluidised bed coating apparatus. The polymer coated drug pellets were dried in the same equipment. Stage III- Enteric coating:- Ingredients Quantity mg/ gm of pellets Polymer coated pellets obtained in step(ii) 915.00 Diethyl phthalate 5.92 Cetyl alcohol 13.23 Hydroxy propyl methyl cellulose phthalate 59.20 Talc 5.920 * Isopropyl alcohol 580.00 * Acetone 580.00 * Solvents used in the process, but present only in negligible quantities in the final composition. Hydroxy propyl methyl cellulose phthalate, diethyl phthalate, and cetyl alcohol were dissolved in a mixture of isopropyl alcohol and acetone to which talc was added. The suspension was passed through colloid mill and coated onto the polymer coated pellets, obtained from stage II, in a fluidised bed coating apparatus. The enteric coated pellets were dried in the same coating pan. The enteric coated pellets were filled into size ' 1' hard gelatin capsules depending on the drug content of the pellets. Non-pareil seeds were used to adjust the balance of fill weight of 290 mg. The filled capsules were packed in Hydroxy propyl methyl cellulose Containers / Blister strips. Example 3 Stage I:- Drug Coating Ingredients Quantity mg/ gm of pellets Tamsulosin Hydrochloride 2.290 Sugar spheres ( 18 /22#) 830.000 Sodium Lauryl sulphate 0.040 Polyvinyl pyrrolidone K-30 36.000 2-hydroxy propyl- P-cyclodextrin 8.000 Isopropyl alcohol * 164.000 Water* 136.000 * Solvents used in the process, but present only in negligible quantities in the final composition. Tamsulosin HCL and 2-hydroxy propyl- P-cyclodextrin were dissolved in a mixture of isopropyl alcohol and water. Sodium lauryl sulphate and polyvinyl pyrrolidone K-30 were added to this drug complex and the resultant liquid passed through colloid mill Sugar spheres ( 18 / 22#) were loaded into a fluidised bed coating appratus and the drug solution was layered onto these spheres. The resultant drug pellets were dried in the same equipment. Stage II - Polymer Coating Ingredients Quantity mg/ gm of pellets Drug loaded pellets obtained in step(ii) 885.00 Ethyl cellulose 30,70 Dibutyl phthalate 3.070 Talc 3.070 Iso propyl alcohol 483.000 Solvents used in the process, but present only in negligible quantities in the final composition. Ethyl cellulose, Dibutyl phthalate were dissolved in Isopropyl alcohol and talc was added to it. This suspension was passed through colloid mill and coated on to the drug pellets , obtained in step(i)in the same fluidised bed coating apparatus. The polymer coated drug pellets were dried in the same equipment. Stage III- Enteric coating:- Ingredients Quantity mg/ gm of pellets Polymer coated pellets obtained in step(ii) 913.00 Diethyl phthalate 7.00 Cetyl alcohol 13.23 Polyvinyl acetate phthalate 70.00 Talc 7.00 * Ethanol (95%) 580.00 * Acetone 580.00 * Solvents used in the process, but present only in negligible quantities in the final composition. Polyvinyl acetate phthalate, dibutyl phthalate, and cetyl alcohol were dissolved in a mixture of ethanol and acetone to which talc was added. The suspension was passed through colloid mill and coated onto the polymer coated pellets, obtained in step (ii) in a fluidised bed coating apparatus. The enteric coated pellets were dried in the same coating pan. The enteric coated pellets were filled into size ' 1 ' hard gelatin capsules depending on the drug content of the pellets. Non-pareil seeds were used to adjust the balance of fill weight of 290 mg. The filled capsules were packed in High density Poly ethylene Containers / Blister strips. Example 4 Stage I:- Drug Coating Ingredients Quantity mg/ gm of pellets Tamsulosin Hydrochloride 2.290 Sugar spheres ( 18 /22#) 833.000 Sodium Lauryl sulphate 0.040 Polyvinyl pyrrolidone K-30 36.000 Di methyl β-cyclodextrin 7.800 Isopropyl alcohol * 164.000 Water* 136.000 * Solvents used in the process, but present only in negligible quantities in the final composition. Tamsulosin HCL and Di methyl β-cyclodextrin were dissolved in a mixture of isopropyl alcohol and water. Sodium lauryl sulphate and polyvinyl pyrrolidone K-30 were added to this drug complex and the resultant liquid passed through colloid mill. Sugar spheres (18 / 22#) were loaded into a fluidised bed coating appratus and the drug solution was layered onto these speheres. The resultant drug pellets were dried in the same equipment. Stage II - Polymer Coating Ingredients Quantity mg/ gm of pellets Drug loaded pellets obtained in step(i) 886.000 Hydroxy ethyl cellulose 42.000 Poly vinyl acetate phthalate aq dispersion(sureteric)42.000 (as solid content) Triacefin 20.000 Talc 10.000 Water 500.000 Hydroxy ethyl cellulose and Triacetin were dissolved in water and Poly vinyl acetate phthalate aq dispersion(sureteric) and talc were added to it. This suspension was passed through colloid mill and coated on to the dnig pellets , obtained in step(i) in the same fluidised bed coating apparatus. The polymer coated drug pellets were dried in the same equipment. Stage in- Enteric coating:- Ingredients Quantity mg/ gm of pellets Polymer coated pellets obtained in step(ii) 915.0 Polyethylene glycol 4000 13.0 Polyvinyl acetate phthalate aq solution (Sureteric) 60.0 (as solid content) Talc 12.0 Water 250.0 Polyethylene glycol 4000 was dissolved in water and polyvinyl acetate phthalate aqueous dispersion and talc were added. The suspension was passed through colloid mill and coated onto the polymer coated pellets, obtained from stage II, in a fluidised bed coating apparatus. The enteric coated pellets were dried in the same coating pan. The enteric coated pellets were filled into size ' 1 ' hard gelatin capsules depending on the drug content of the pellets. Non-pareil seeds were used to adjust the balance of fill weight of 290 mg. The filled capsules were packed in High density Poly ethylene Containers / Blister strips. Example 5 Stage I:- Drug Coating Ingredients Quantity mg/ gm of pellets Tamsulosin Hydrochloride 2.29 Sugar spheres (18 /22#) 828,00 Polyethylene- Propylene glycol copolymer 4.00 Polyvinyl pyrrolidone K-30 36.00 3- hydroxy propyl-P-cyclodextrin 8. 00 Isopropyl alcohol * 164.00 Water* 136.00 * Solvents used in the process, but present only in negligible quantities in the final composition. Tamsulosin HCL and 3-hydroxy propyl-p-cyclodextrin were dissolved in a mixture of isopropyl alcohol and water. Polyethylene-Propylene glycol copolymer (polxamer) and polyvinyl pyrrolidone K-30 were added to this drug complex and the resultant liquid passed through colloid mill. Sugar spheres (18 / 22#) were loaded into a fluidised bed coating appratus and the drug solution was layered onto these spheres. The resultant drug pellets were dried in the same equipment. Stage II - Polymer Coating Ingredients Quantity mg/ gm of pellets Drug loaded pellets obtained in step(i) 922.00 Hydroxy ethyl cellulose 68.00 Triacetin 7,00 Talc 3.00 Water 800.00 Hydroxy ethyl cellulose and Triacetin were dissolved in water and talc was added to it. This suspension was passed through colloid mill and coated on to the drug pellets , obtained in step(i) in the same fluidised bed coating apparatus. The polymer coated drug pellets were dried in the same equipment. Stage III- Enteric coating:- Ingredients Quantity mg/ gm of pellets Polymer coated pellets obtained in step(ii) 900.00 Triethyl citrate 18.00 Hydroxypropyl methyl cellulose acetate succinate-LF 70.00 Sodium lauryl sulphate 2.00 Talc 10.00 Water* 1000.00 * Solvent used in the process, but present only in negligible quantities in the final composition. Sodium lauryl sulphate and triethyl citrate were dissolved in water to which talc and Hydroxypropyl methyl cellulose acetate succinate-LF were added. The suspension was passed through colloid mill and coated onto the polymer coated pellets, obtained in step(ii) , in a fluidised bed coating apparatus. The enteric coated pellets were dried in the same coating pan. The enteric coated pellets were filled into size ' 1 ' hard gelatin capsules depending on the drug content of the pellets. Non-pareil seeds were used to adjust the balance of fill weight of 290 mg. The filled capsules were packed in High density Poly ethylene Containers / Blister strips. Example 6 Stage I:- Drug Coating Ingredients Quantity mg/ gm of pellets Tamsulosin Hydrochloride 2.290 Sugar spheres ( 18 /22#) 828.000 Polyoxyethylene castor oil dertivatives - (Cremophor RH40) 2.50 Polyvinyl pyrrolidone K-30 36.000 p-cyclodextrin 7.300 Isopropyl alcohol * 164.000 Water* 136.000 * Solvents used in the process, but present only in negligible quantities in the final composition. Tamsulosin HCL and P-cyclodextrin were dissolved in a mixture of isopropyl alcohol and water. Cremophor RH40 (polyoxyethylene castor oil derivative) and polyvinyl pyrrolidone K-30 were added to this drug complex and the resultant liquid passed through colloid mill. Sugar spheres ( 18 / 22#) were loaded into a fluidised bed coating appratus and the drug solution was layered onto these spheres. The resultant drug pellets were dried in the same equipment. Stage II - Polymer Coating Ingredients Quantity mg/ gm of pellets Drug loaded pellets obtained in step (i) 840.00 Hydroxy ethyl cellulose 50.00 Hydroxy propyl methyl cellulose acetate succinate 90.00 Sodium lauryl sulphate 3.00 Triacetain 14.00 Talc 3.00 Water 1500.00 * Solvents used in the process, but present only in negligible quantities in the final composition. Hydroxy ethylcellulose, Triacetin, Sodium lauryl sulphate were dissolved in water and talc and hydroxy propyl methyl cellulose acetate succinate were added to it. This suspension was passed through colloid mill and coated on to the drug pellets , obtained in step(i) in the same fluidised bed coating apparatus. The polymer coated drug pellets were dried in the same equipment. Stage III- Enteric coating:- Ingredients Quantity mg/ gm of pellets Polymer coated pellets obtained in step(ii) 847.00 Triacetin 13.00 Hydroxy propyl methyl cellulose acetate succinate 130.00 Sodium lauryl sulphate 4.00 Talc 6.00 Water* 1500.00 * Solvent used in the process, but present only in negligible quantities in the final composition. Triacetin and sodium lauryl sulphate were dissolved in water to which talc and hydroxy propyl methyl cellulose acetate succinate were added. The suspension was passed through colloid mill and coated onto the polymer coated pellets, obtained in step(ii), in a fluidised bed coating apparatus. The enteric coated pellets were dried in the same coating pan. The enteric coated pellets were filled into size ' 1 ' hard gelatin capsules depending on the drug content of the pellets. Non-pareil seeds were used to adjust the balance of fill weight of 290 mg. The filled capsules were packed in High density Poly ethylene Containers / Blister strips. Dissolution studies were conducted on the six compositions prepared according to the processes described in the Examples 1 to 6, using USP type I, rpm 100 and 500 ml as the medium using 1.2 pH buffer(USP) for 2 hours followed by 6.8 pH buffer (USP) for 4 hours thereafter. The results are tabulated below Each Value represents the average release from six baskets. The overall data shows a high degree of consistency in the dissolution performance, ensuring the release of the drug at the site of its maximum absorption,ie,in the small intestine. The results confirm to the prior set dissolution limits of a) less than 10% release in the gastric pH at the end of 2 hours b) 35-55% release at the end of 1st hour in the Ph 6.8 buffer. c) 50-70% release at the end of 2nd hour in the pH 6.8 buffer. d) Not less than 70% release at the end of 4 hours in the pH 6.8 buffer. Advantages of the invention:- 1) Drug release is not influenced by the poor solubility of Tamsulosin Hcl. A single point control of the drug release is achieved through polymer coating. 2) Reduction in stenosis or obstruction caused by gastro-intestine pathology. 3) Even modified release of the drug has the individual units are well distributed in the gastro intestinal track. 4) They are less influenced by the food (gastric emptying). 5) Dose adjustment is easier. We claim, 1. An improved release pharamceutical composition useful for treatment of benign prostatic hyperplasia which comprises a core of sugar spheres having a coating of a solution of Tamsulosin Hcl or pharmaceutically acceptable salts thereof in Polyvinyl pyrrolidone and / or β-cyclodextrin containing a solublising agent, an emulsifiying agent, a binder and a solvent in the form of pellets , the spheres also having a coating of one or more of ethyl cellulose, Hydroxy ethyl cellulose, polyvinyl acetate phthalate and hydroxypropyl methyl cellulose acetate succinate polymers and a further coating of an enteric polymer containing , plasticizers, wetting agent, antitacking agent and a solvent. 2. A pharmaceutical composition as claimed in claim l wherein the composition is in the form of capsules. 3. An improved composition as claimed in claim 1 & 2 wherein the active pharmaceutical agent used is selected from pharmaceutically acceptable tamsulosin salts such as Tamsulosin Hydrochloride, Tamsulosin Hydrbromide, Tamsulosin methane sulfonate, Tamsulosin tosylate, Tamsulosin besylate, Tamsulosin acetate, Tamsulosin maleate, Tamsulosin tartarate and Tamsulosin citrate, preferably Tamsulosin Hydrochloride. 4. An improved as claimed in claims 1 to 3 wherein the amount of the active pharmaceutical agent used is in the range of 1.0 mg to 10.0 mg per gram of the composition, preferably in the range of 2.0 mg to 4,0 mg per gram of the composition. 5. An improved composition as claimed in claims 1 to 4 wherein the amount of sugar spheres used in the core ranges from 700 to 950 mg per gram of the composition , preferably the amount ranges from 750 to 900 mg per gram of the composition, 6. An improved as claimed in claims 1 to 5 wherein the solublising agent used formation of the drug solution is selected from cyclodextrins 3-hydroxy proply- beta cyclodextrin, di methyl beta cyclodextrin, 2- hydroxy propyl-beta cyclodextrin and beta cyclodextrin and the like, and Polyvinyl pyrrolidone, lecithin and the like or mixture thereof 7. An improved composition as claimed in claims 1 to 6 wherein the amount of solublising agent used for the formation of the drug solution ranges from LOO to 10.00 mg per gram of the composition, preferably 2.00 to 8.00 mg per gram of the composition. 8. An improved composition as claimed in claims 1 to 7 wherein the emulsifying agent used for the formation of the drug solution is selected from anionic or non-ionic surfactants such as sodium lauryl sulphate, polyethylene-propylene glycol copolymer (Poloxamer), polyoxy ethylene alkyl ethers (cetomacrogol-1000), polyoxy ethylene castrol oil derivatives ( Cremophor RH60, Cremophor RH40), Polyoxy ethylene sorbital fatty acid esters (Poly sorbit-20. Poly sorbit-40, Poly sorbit-60, Poly sorbit-80), polyoxyethylene stearates (Macrogol- stearate), polyvinyl alcohol and the like and their mixture thereof 9. An improved composition as claimed in claims 1 to 8 wherein the amount of emulsifying agent employed for the formulation of the drug solution , ranges from 0.01 to 10.00 mg per gram, preferably 0.02 to 8.00 mg per gram of the composition. 10. An improved composition as claimed in claims 1 to 9 wherein the binder used for the formation of the drug solution is selected from various grade of polyvinyl pyrrolidone and their molecular weight ranging from 2,500 to 30,00,000 and the prefered grade is polyvinyl pyrrolidone K-30 having molecular weight of 50,000. 11. An improved composition as claimed in claims 1 to 10 wherein the amount of binder employed for the formation of the drug solution ranges from 10.00 to 80.00 mg per gram, preferably 20.00 to 60.00 mg per gram of the composition. 12. An improved composition as claimed in claims 1 tol 1 wherein the solvents used for the formation of the drug solution is selected from isopropyl alcohol, acetone, water and the like and preferably a mixture of isopropyl alcohol and water. 13. An improved composition as claimed in claims 1 to 12 wherein the polymer used for the polymer coating is one or more polymers comprising of ethyl cellulose, Hydroxy ethyl cellulose, polyvinyl acetate phthalate and hydroxy propyl methyl cellulose acetate succinate and its amount ranges from 20.0 mg to 100.0 mg, preferably 25.0 mg to 85.0 mg per gram of the composition. 14. An improved composition as claimed in claims 1 to 13 wherein the plastisizer used in the polymer composition is selected from diethyl phthalate, dibutyl phthalate, triacetin, polyethylene glycol 4000 and the like. 15. An improved composition as claimed in claims 1 to 14 wherein the amount of plastisizer employed in the polymer composition ranges from 2.00 to 25.00 mg per gram, preferably 2.50 to 20.00 mg per gram of the composition. 16. An improved composition as claimed in claims 1 to l5 wherein the anti-tacking agent used in the polymer composition is selected from talc, magnesium stearate and the like or a mixture thereof 17. An improved composition as claimed in claims 1 to 16 wherein the amount of anti-tacking agent used ranges from 1.0 mg to 15.0 mg, preferably 2.0 mg to 10,0 mg per gram of the composition. 18. An improved composition as claimed in claims 1 to 17 wherein the solvent used in the polymer composition is selected from isopropyl alcohol, acetone, ethyl alcohol, water and the like or a mixture thereof 19. An improved composition as claimed in claims 1 to 18 wherein the polymer used for the enteric coating is selected from hydroxy propyl methyl cellulose phthalate, hydroxy propyl methyl cellulose acetate succinate, polyvinyl acetate phthalate, and the like. 20. An improved composition as claimed in claims 1 to 19 wherein the amount of polymer used for the enteric coating ranges from 30.00 to 160.00 mg per gram of the composition, preferably 40.00 to 140.00 mg per gram of the composition. 21. An improved composition as claimed in claims 1 to 20 wherein, the plasticizer used for the enteric coating is selected from diethyl phthalate, di butyl phthalate, cetyl alcohol, poly ethylene glycol 4000, triethyl citrate, triacetin and the like. 22. An improved composition as claimed in claims 1 to 21 wherein the amount of plasticizer used for the enteric coating ranges from 3.00 to 30.00 mg per gram of the composition, preferably 4.00 to 25,00 mg per gram of the composition. 23. An improved composition as claimed in claims 1 to 22 wherein the anti-tacking agent used for the enteric coating is selected from talc, magnesium stearate and the like or a mixture thereof 24. An improved composition as claimed in claims 1 to 23 wherein the amount of anti- tacking agent used for the enteric coating ranges from 4.0 mg to 16.0 mg per gram of the composition, prefereably 5.0 to 12.0 mg per gram of the composition. 25. An improved composition as claimed in claims 1 to 24 wherein the solvent used for the enteric coating is selected from iso-propyl alcohol, ethyl alcohol, acetone, water and the like or a mixture thereof 26. A process for the preparation of an improved release pharmaceutical composition useful for treating benign prostatic hyperplasia (BPH) as claimed in claims 1 to 25 which comprises :- i. Preparing a solution of Tamsulosin Hcl or a pharmaceutically acceptable salts thereof in Polyvinyl pyrrolidone and / or β-cyclodextrin containing a solublising agent, an emulsifiying agent, a binder and a solvent and forming into pellets. ii. Impregnating the above solution obtained on to sugar spheres. iii. coating the drug loaded pellets with one or more polymers comprising of ethyl cellulose. Hydroxy ethyl cellulose, polyvinyl acetate phthalate and hydroxypropyl methyl cellulose acetate succinate in a medium of water, isopropylalcohol, ethyl alcohol, acetone or a mixture thereof iv. Coating the polymer coated pellets with an enteric polymer containing plasticizers, antitacking agent and a solvent and if desired. V. Encapsulating the enteric coated pellets in hard gelatin capsules. 27. A process as claimed in claim 26 wherein the active pharmaceutical agent used is selected from pharmaceutically acceptable tamsulosin salts such as Tamsulosin Hydrochloride, Tamsulosin Hydrbromide, Tamsulosin methane sulfonate, Tamsulosin tosylate, Tamsulosin besylate, Tamsulosin acetate, Tamsulosin maleate, Tamsulosin tartarate and Tamsulosin citrate, preferably Tamsulosin Hydrochloride. 28. A process as claimed in claims 26 & 27 wherein the amount of the active pharmaceutical agent used is in the range of 1.0 mg to 10.0 mg per gram of the composition, preferably in the range of 2.0 mg to 4.0 mg per gram of the composition 29. A process as claimed in claims 26 to 28 wherein the amount of sugar spheres in the drug coating is in the range of 700 to 950 mg per gram of the composition, preferably the amount ranges from 750 to 900 mg per gram of the composition. 30. A process as claimed in claims 26 to 29 wherein the solublising agent used for forming the solution of the drug is selected from cyclodextrins 3-hydroxy proply-beta cyclodextrin, di methyl beta cyclodextrin, 2- hydroxy propyl-beta cyclodextrin and beta cyclodextrin and the like, and Polyvinyl pyrrolidone, lecithin and the like or mixture thereof 31. A process as claimed in claims 26 to 30 wherein the amount of solublising agent used ranges from 1.00 to 10.00 mg per gram of the composition, preferably 2.00 to 8.00 mg per gram of the composition. 32. A process as claimed in claims 26 to 31 wherein the emulsifying agent used for the formation of the drug solution is selected from anionic or non-ionic surfactants such as sodium lauryl sulphate, polyethylene-propylene glycol copolymer (Poloxamer), polyoxy ethylene alkyl ethers (cetomacrogol-1000), polyoxy ethylene castrol oil derivatives ( Cremophor RH60, Cremophor RH40), Polyoxy ethylene sorbital fatty acid esters (Poly sorbit-20, Poly sorbit-40, Poly sorbit-60. Poly sorbit-80), polyoxyethylene stearates (Macrogol- stearate), polyvinyl alcohol and the like and their mixture thereof 33. A process as claimed in claims 26 to 32 wherein the amount of emulsifying agent employed ranges from 0.01 to 10,00 mg per gram, preferably 0.02 to 8.00 mg per gram of the composition. 34. A process as claimed in claims 26 to 33 wherein the binder used in the formation of the drug solution is selected from various grade of polyvinyl pyrrolidone and their molecular weight ranging from 2,500 to 30,00,000 and the prefered grade is polyvinyl pyrrolidone K-30 having molecular weight of 50,000. 35. A process as claimed in claims 26 to 34 wherein the amount of binder employed in the drug coating, ranges from 10.00 to 80.00 mg per gram, preferably 20.00 to 60.00 mg per gram of the composition. 36. A process as claimed in claims 26 to 35 wherein the solvents used in the formation of drug solution is selected from isopropyl alcohol, acetone, water and the like and preferably a mixture of isopropyl alcohol and water. 37. A process as claimed in claims 26 to 36 wherein the amount of ethyl cellulose, Hydroxy ethyl cellulose, polyvinyl acetate phthalate, hydroxy propyl methyl cellulose acetate succinate used in step (iv) ranges from 20.0 mg to 100.0 mg, preferably 25.0 mg to 85.0 mg per gram of the composition. 38. A process as claimed in claims 26 to 37 wherein the plastisizer used in the polymer coating in step (iii) is selected from diethyl phthalate, di butyl phthalate, triacetin, polyethylene glycol 4000 and the like. 39. A process as claimed in claims 26 to 38 wherein the amount of plastisizer employed in the polymer coating in step (iii) ranges from 2.00 to 25.00 mg per gram, preferably 2.50 to 20.00 mg per gram of the composition. 40. A process as claimed in claims 26 to 39 wherein the anti-tacking agent used in the polymer coating in step (iii) is selected from talc, magnesium stearate and the like or a mixture thereof 41. A process as claimed in claims 26 to 40 wherein the amount of anti-tacking agent used in step(iii) ranges from 1.0 mg to 15.0 mg, preferably 2.0 mg to 10.0 mg per gram of the composition. 42. A process as claimed in claims 26 to 41 wherein the solvent in the polymer coating in step(iv) is selected from isopropyl alcohol, acetone, ethyl alcohol, water and the like or a mixture thereof. 43. A process as claimed in claims 26 to 42 wherein the polymer used in the enteric coating in step( iv) is selected from hydroxy propyl methyl cellulose phthalate, hydroxy propyl methyl cellulose acetate succinate, polyvinyl acetate phthalate, and the like. 44. A process as claimed in claims 26 to 43 wherein the amount of polymer used in the enteric coating in step(iv) ranges from 30.00 to 160.00 mg per gram of the composition, preferably 40.00 to 140.00 mg per gram of the composition. 45. A process as claimed in claims 26 to 44 wherein, the plasticizer used in for the enteric coating is step(iv) is selected from diethyl phthalate, di butyl phthalate, cetyl alcohol, poly ethylene glycol 4000, triethyl citrate, triacetin and the like. 46. A process as claimed in claims 26 to 45 wherein the amount of plasticizer used in the enteric coating in step(iv) ranges from 3.00 to 30.00 mg per gram of the composition, preferably 4.00 to 25.00 mg per gram of the composition. 47. A process as claimed in claims 26 to 46 wherein the anti-tacking agent used in the enteric coating in step(iv) is selected from talc, magnesium stearate and the like or a mixture thereof 48. A process as claimed in claims 26 to 47 wherein the amount of anti-tacking agent used in the enteric coating in the step(iv) ranges from 4.0 mg to 16.0 mg per gram of the composition, prefereably 5.0 to 12.0 mg per gram of the composition. 49. A process as claimed in claims 26 to 48 wherein the solvent used in the enteric coating in step(iv) is selected from iso-propyl alcohol, ethyl alcohol, acetone, water and the like or a mixture thereof 50. An improved pharmaceutical composition in the form of pellets or hard gelatin capsule useful for treatment of Benign prostatic hyperplasia substantially as herein described with reference to the Examples 1 to 6. 51. A process for the preparation of an improved and modified pharmaceutical composition in the form of pellets or hard gelatin capsule useful for treatment of benign prostatic hyperplasia (BPH) substantially as herein described with reference to the Examples 1 to 6.

Full Text

Technical Field
This invention relates to an improved process for the preparation of Tamsulosin hydrochloride . Tamsulosin hydrochloride is an antagonist of alpha lA adrenoceptors in the prostate. Tamsulosin Hcl is (-)-[R]-5,4,2-[2-(0-ethoxy phenoxy) ethyl] amino propyl -2- methoxy benzene sulfonamide monohydrochloride. The empirical formula of Tamsulosin Hcl is C20H28N205S. Hcl. The molecular weight of Tamsulosin Hcl is 444.98. Tamsulosin Hcl is indicated in the treatment of the signs and symptoms of benigh prostatic hyperplasia (BPH). It aids in relaxing the smooth muscles in bladder neck and prostate resulting in an improvement in urine flow rate and a reduction in symptoms of BPH. The recommended daily dosage is 0.4mg.
Background and prior art
US Patent no 4,772,475 details a pharmaceutical controlled release individual unit or multiple units formulation in which the individual unit comprises a granulation product obtained by adding a release controlling agent to a mixture of a physiologically active substance and units-forming substance(s) and granulating and resultant mixture, said granulation product (granules) being substantially not disintegrated but gradually releasing the physiologically active substance in the gastrointestinal tract. The release controlling agent used is a methacrylic acid- ethyl acrylate copolymer or mixtures of said copolymer and ethyl cellulose. Examples of the formulation containing Tamsulosin Hydrochloride were given. The results of dissolution rates of the compositions exemplified in 21 Examples were provided in the patent .On a detailed study of these Examples it is observed that:
In 6 Examples eudragit L30D-55 has been used as the release controlling agent(A) In 4 Examples same eudragit has been used as the release controlling agent but in addition magnesium stearate was also used (B)
In 3 Examples ethyl cellulose has been used as the release controlling agent (C), & In another 6 Examples water has been used as the release controlling agent.

In all the above cases the dissolution rate percentage were given. But in 10 cases only dissolution rate was provided for 2 hours, of the 10 examples, 3 samples showing more than 90% release,
2 samples showing release between 61% and 66.2% 1 sample showing 57.6% and
3 samples showing 41.7% to 44.8%
all the values at the end of 2nd hour of dissolution study.
Such a high degree of variation in dissolution rate and release of more than 90% drug at the end of 2nd hour in three out of 10 samples may be caused due to lack of uniform geometry of the resultant granulation of the active ingredients and also may not qualify for the formation of a controUed-release dosage form.
The combination of acrylic acid polymers and their copolymers with celluloses may lead to inconsistent release profiles.
WO Patent no 03 / 039531 Al discloses a pharmaceutical tablet comprising a tablet matrix having dispersed therein 0.1 to 10mg of Tamsulosin or a pharmaceutically acceptable salt thereof, and optionally having an enteric coating over said martix, wherein said tablet is a modified release tablet and has a dissolution profile such that in each of the media, simulated intestinal fluid (SIF), fasting state simulated intestinal fluid (FaSSIF) and fed state simulated intestinal fluid (FeSSIF) said tablet releasing not more than 60% of said Tamsulosin at 2 hours elapsed time in USP2 (a type of dissolution testing as per US Pharmacopeia.) apparatus using 500 ml of said media at 50-100 rpm paddle speed. The patent also provides data on the release of Tamsulosin in at the end of 30 minutes, 2 hours and 6 hours in Simulated gastric fluid(SGF) media and Simulated intestinal fluid.(SIF) media.

In the book on sustained and controlled- release drug delivery systems by Gwen M. Jantzen and Joseph R.Robinson, the authors commented that in the case of the matrix based dosage form, " cracking of the matrix material can cause unwanted release".
In their book on Novel drug delivery and its therapeutic application edited by L.F.Prescott and W.S.Nimmo, while commenting upon the relative merits of single and multi-particulate systems, the authors opined that" multiple units can have the following advantages;
1) they are less influenced by food (gastric emptying) than single units.
2) the individual units are normally well distributed in the gastrointestinal tract if taken after or together with food, and by spreading in this way the risk of local high concentrations of released drug is reduced.
3) there may be fewer problems with stenosis or obstruction caused by gastrointestinal pathology and
4) dose adjustment may well be easier.
On the other hand the advantages of controlled release dosage form are reduction in drug blood level fluctuations, reduction in drug frequency, enhanced patient convenience and compliance and reduction in adverse side effects and normal food intake.
It is well known that release of the active ingredient from a matrix based system depends on the availability of adequate amount of gastric fluids. As Tamsulosin is a sparingly soluble drug, the absence of a proper liquid content available throughout its dissolution time, may pose problems of a continuous drug availability.
EP no 1088551 mentions various dosage forms that can be made using Tamsulosin as active agent. The active agent is mixed with diluents, other additives like binders, lubricants, a disintegrating agent, a stabilizer, a solublising aid, a plasticiser, and a

colouring agent and compressing them into tablets for achieving a sustained release preparation. This approach suffers from the same disadvantages as stated above.
The JP no 2001114679 discloses a medicine containing Tamsulosin for the treatment of lower urinary tract diseases with pharmaceutically acceptable salt as an active ingredient which contains tamsulosin or its sah permitted pharmaceutically as an active principle. Tamsulosin is mixed with inactive diluent like lactose, a mannitol, a microcrystal cellulose, grape sugar, starch, a polyvinyl pyrrolidone and magnesium aluminium silicate in a solid tablet. It contains solublizing agent like hydroxypropylcellulose and hydroxyproylmethyl cellulose, a magnesium stearate, a calcium stearate, a polyethylene glycol, starch, lubricant like talk and stabilizing agent like lactose, glutamic acid or an aspartic acid.
The invention is a self-sustaining discharge type gradual release tablet. It is obtained by coating a tablet, a granule, a fine grain agent and a capsule by conventional method .
The JP No 2000080032 discloses a composition for oral administration containing tamsulosin Hcl and its dosage forms particular for the treatment of eccrisis obstacle treatment agent especially accompanying the neurogenic bladder. . This composition contains tamsulosin or tamsulosin Hcl as an active ingredient, mixed with inactive diluent lactose, mannitol, grape sugar, a microcrystal cellulose, starch, a polyvinyl pyrrolidone, magnesium aluminium silicate in a solid tablet with solublizing agent, binder, additives, like hydroxypropyl methylcellulose, hydroxypropylcellulose, magnesium stearate, a calcium stearate, polyethylene glycol, starch, lubricant like talc, disintegrator like a calcium carboxymethyl cellulose, stabilizing agent like a lactose, glutamic acid or an aspartic acid a plasticizer like a triacetin, titanium oxide and a colouring agent like iron sesquioxide according to a conventional method. Tablet or the pilule as occasion demands with the film of glycocalyx such as cane sugar, gelatin, agar, hydroxypropylcellusle , Hydroxy propyl methylcellulose phthalate or the enteric nature matter. The composition is self-sustaining discharge type gradual release tablet., or granule, a fine-grain capsule form. The daily dose of the composition in ordinary cases is

about 0.1-0.8mg, most preferably 0.2-0.4mg the active ingredient per adult when the tamsulosin hydrochloride is orally administered, and the daily dose is administered once after the meal.
None of the prior art described above addresses the problem of improving the solubility of Tamsulosin and then controlling the release of the drug in a gradual manner by diffusion, so that the modified release dosage form presents a graded release profile over a period in excess of 4 hours, wherein at the end of the 4th hour, at least 70% of the drug gets released. Accordingly the present invention relates to a drug delivery system for administering tamsulosin as an oral dosage form for treating conditions such as benign prostatic hypertrophy (BPH).
Objectives of the Invention
Therefore the main objective of the present invention is to provide a pharmaceutical composition containing Tamsulosin Hydrochloride useful for the sustained release of the active ingredient.
Another objective of the present invention is to provide a drug delivery system for the oral administration of Tamsulosin Hydrochloride.
Still another objective of the present invention is to provide a drug delivery system for administering Tamsulosin Hydrochloride orally which releases the drug over a period of time, in excess of 4 hours.
Yet another objective of the present invention is to provide a drug formulation wherein consistency of the drug release is provided by designing the process by layering the drug as a soluble complex on non-pareil seeds, a separate polymer coating for controlled release, and a second coating with enteric polymer for targetted drug release.

Yet another objective of the present invention is to provide a drug formulation wherein the unit dosage drug is contained in ready to dissolve in multiple reservoirs.
Another objective of the present invention is to provide a drug delivery system containing Tamsulosin Hydrochloride wherein the unit dosage of the drug is contained in is ready to dissolve multiple reservoirs where the release of the drug from the multiple reservoirs is controlled by a diffusion process.
Yet another objective of the present invention is to prepare hard gelatin capsules, containing Tamsulosin Hydrochloride each capsule containing a unit dose of the drug as multiple reservoirs.
Still another objective of the present invention is to provide a method of preparing a formulation containing Tamsulosin Hydrochloride which can be administered orally.
Detailed description
Tamsulosin Hcl is only slightly soluble in water. The effect of solubilising agents on increasing the solubility of Tamsulosin HCL was assessed with two materials, poly vinyl pyrrolidone (PVPK -30) and cyclodextrin. Initially 200mg Tamsulosin HCL was dissolved in 100ml of demineralised water. Addition of any further drug did not result in any increased solubility of the drug, indicating the saturation of the drug in water. In another experiment, 5 gm of PVPK-30 was dissolved in 100 ml of demineralised water and 200 mg of Tamsulosin Hcl was added to this solution. The drug showed complete dissolution. Another 100 mg of Tamsulosin Hcl was added to this solution. The drug was completely soluble in this solution. Upon addition of another 100 mg of Tamsulosin Hcl, however some crystals remained. It was concluded that PVPK-30 was helping the dissolution of Tamsulosin Hcl atleast by 50%.
In another experiment 1.0 gm of cyclodextrin was dissolved in 100 ml of demineralised water. To this solution, 200 mg Tamsulosin Hcl was added and the drug dissolved. To

this solution, 300 mg of Tamsulosin Hci was added in increments of lOOmg. Upto 400 mg of Tamsulosin Hcl could be dissolved in this solution and a few crystals remained with 500 mg total drug. It was concluded that addition of 1% B- cyclodextrin was able to improve the dissolution of Tamsulosin Hcl by atleast 100%.
This exciting prospect of improved solubility of Tamsulosin Hcl in the presence of Polyvinyl pyrrolidone / cyclodextrin was successfully worked out. Initially the drug and the solublising agent along with an emulsifier are dissolved in a solvent mixture of alcoholic and aqueous media. The drug, as it is in a completely dissolved state, is layered on to sugar spheres in a conventional way, resulting in a drug solubiliser complex. ( Tamsulosin with polyvinyl pyrrolidone and cyclodextrin ) in a very fine particulate deposit.
Accordingly, the present invention provides an improved release pharmaceutical formulation useful for treatment of benign prostatic hyperplasia which comprises a core of sugar spheres having a coating of a solution of Tamsulosin Hcl or a pharmaceutically acceptable salts thereof in Polyvinyl pyrrolidone and / or β-cyclodextrin containing a solublising agent, an emulsifiying agent, a binder and a solvent in the form of pellets, the spheres also having a coating of ethyl cellulose polymer and a further coating of an enteric polymer containing, plasticizers, antitacking agent and a solvent.
The formulation may be in pellet or capsule form .The formulation of the invention ensures release of the drug at predefined rates in such a way that drug is available for bio-absorbtion even at the end of 4 hour and having good stability and useful for the treatment of Benign prostatic hyperplasia.
The present invention also provides a process for the preparation of the above said improved release pharmaceutical formulation containing Tamsulosin Hydrochloride in an oral dosage form which comprises
I. preparing a solid solution of Tamsulosin Hcl or a pharmaceutically acceptable
salts thereof in Polyvinyl pyrrolidone and / or 13-cyclodextrin containing a

solublising agent, an emulsifiying agent, a binder and a solvent and forming info pellets.
II. impregnating the above solution on to sugar spheres.
III. coating the resulting drug loaded pellets with a polymer coating layer
IV. providing the polymer coated pellets with a coating of an enteric polymer, containing plasticizers, wetting agent, antitacking agent and a solvent and if desired.
V. encapsulating the enteric coated pellets in hard gelatin capsules.
The pellets or the capsules so prepared upon coming into contact with gastro intestinal fluids readily dissolves and readily diffuse through the polymer system loaded, on the drug loaded pellets. The polymer system acts as a controlled release membrane and allows diffusion of the drug through it at a predefined rate. A gastric resistant coat over the polymer coated pellets ensures that the gradual release of the drug takes place in the small intestine where its absorption is best. The predefined dissolution rates of Tamsulosin Hcl are worked out in such a way as to ensure less than 10% drug release at the end of 2 hours in the gastric medium and then subsequently shifting to pH 6.8 buffer to ensure that at the end of 1st hour, the drug release is between 35 to 55%, at the end of 2nd hour the drug release is between 50 to 70% and at the end of 4th hour, the drug releases not less than 70%, thereby ensuring an adequate amount of drug available for bio-absorption.
The amount of sugar spheres used in the drug coating may be in the range of 700 to 950 mg per gram of the composition and more preferably the amount ranges from 750 to 900 mg per gram of the composition.
The amount of Tamsulosin or its pharmaceutically acceptable salts used in the composition may be in the range of 1.0 mg to 10.0 mg per gram of the composition, preferably in the range of 2.0 mg to 4.0 mg per gram of the composition. Examples of useful tamsulosin pharmaceutically acceptable salts includes Tamsulosin Hydrochloride, Tamsulosin Hydrobromide, Tamsulosin methane sulfonate, Tamsulosin tosylate.

Tamsulosin besylate, Tamsulosin acetate, Tamsulosin maleate, Tamsulosin tartarate and Tamsulosin citrate. The Hydrochloride salt is preferred.
The solublising agent used in the formulation may be selected from cyclodextrins 3-hydroxy proply- beta cyclodextrin, di methyl beta cyclodextrin, 2- hydroxy propyl-beta cyclodextrin and beta cyclodextrin and the like, and Polyvinyl pyrrolidone, lecithin and the like or mixture thereof The amount of solublising agent used ranges from 1.00 to 10.00 mg per gram of the composition, more preferably 2.00 to 8.00 mg per gram of the composition.
The emulsifying agent used in the formulation may be selected from anionic or non-ionic surfactants such as sodium lauryl sulphate, polyethylene-propylene glycol copolymer (Poloxamer), polyoxy ethylene alkyl ethers (cetomacrogol-1000), polyoxy ethylene castrol oil derivatives ( Cremophor RH60, Cremophor RH40), Poly oxy ethylene sorbital fatty acid esters (Poly sorbit-20, Poly sorbit-40, Poly sorbit-60, Poly sorbit-80), polyoxyethylene stearates (Macrogol- stearate), polyvinyl alcohol and the like and their mixture thereof .The amount of emulsifying agent employed in the drug coating , ranges from 0.01 to 10.00 mg per gram, preferably 0.02 to 8.00 mg per gram of the composition.
The binder in the drug formulation may be selected from various grade of polyvinyl pyrrolidone and their molecular weight ranging from 2,500 to 30,00,000 and the preferred grade is polyvinyl pyrrolidone K-30 having molecular weight of 50,000. The amount of binder employed in the drug coating, ranges from 10.00 to 80.00 mg per gram, preferably 20.00 to 60.00 mg per gram of the composition.
The solvents used in the formulation in the step (ii) may be selected from isopropyl alcohol, acetone, water and the like and preferably a mixture of isopropyl alcohol and
water.

The polymer used for the polymer coating is one or more polymers comprising of ethyl cellulose, hydroxyethyl cellulose, polyvinyl acetate phthalate and hydroxy propyl methyl cellulose acetate succinate
The amount of polymer ranges from 20.0 mg to 100.0 mg, preferably 25.0 mg to 85.0 mg per gram of the composition.
The plastisizer used in the polymer coating may be selected from diethyl phthalate, di butyl phthalate, triacetin, polyethylene glycol 4000 and the like .The amount of plastisizer employed in the polymer coating ranges from 2.00 to 25.00 mg per gram, more preferably 2.50 to 20.00 mg per gram of the composition.
The anti-tacking agent used in the polymer coating may be selected from talc, magnesium stearate and the like or a mixture thereof The amount of anti-tacking agent used ranges from 1.0 mg to 15.0 mg, preferably 2.0 mg to 10.0 mg per gram of the composition.
The solvent used in the Polymer coating stage may be selected from isopropyl alcohol, ethyl alcohol, acetone, water and the like or a mixture thereof
The polymer used in the enteric coating may be selected from hydroxy propyl methyl cellulose phthalate, hydroxy propyl methyl cellulose acetate succinate, polyvinyl acetate phthalate, and the like. The amount of polymer used in the enteric coating ranges from 30.00 to 160.00 mg per gram of the composition , more preferably 40.00 to 140.00 mg per gram of the composition.
For the enteric coating , the plasticizer may be selected from diethyl phthalate, di butyl phthalate, cetyl alcohol, poly ethylene glycol-4000, triethyl citrate, triacetin and the like. The amount of plasticizer used in the enteric coating ranges from 3.00 to 30.00 mg per gram of the composition, more preferably 4.00 to 25.00 mg per gram of the composition.
The anti-tacking agent used in the enteric coating may be selected from talc,magnesium stearate and the like or a mixture thereof The amount of anti-tacking agent used in the

enteric coating ranges from 4.0 mg to 16.0 mg per gram of the composition, more prefereably 5.0 to 12.0 mg per gram of the composition.
The solvent used in the enteric coating may be selected from iso-propyl alcohol, ethyl alcohol, acetone, water and the like or a mixture thereof
The enteric coated pellets may be filled into hard gelatin capsules in a conventional
manner and may be packed into moisture resistant primary pack followed by secondary
pack.
The invention is explained in detail in the Examples given below which are provided by
way of illustration only and therefore should not be construed to limit the scope of the
invention.
Example I
Stage I:- Drug Coating
Ingredients Quantity mg/ gm of pellets
Tamsulosin Hydrochloride 2.290
Sugar spheres (18/22#) 835.000
Sodium Lauryl sulphate 0.040
Polyvinyl pyrrolidone K-30 41.740
Isopropyl alcohol * 164.000
Water* 136.000
* Solvents used in the process, but present only in negligible quantities in the final
composition.
Tamsulosin HCL was dissolved in a mixture of isopropyl alcohol and water. Sodium
lauryl sulphate and polyvinyl pyrroHdone K-30 were added to this drug solution and the
resultant liquid passed through colloid mill. Sugar spheres ( 18 / 22#) were loaded into a
side vented coating pan and the drug solution was layered on to the sugar spheres . The
resultant drug pellets were dried in the same coating pan.
Stage II - Polymer Coating

Ingredients Quantity mg/ gm of pellets
Drug loaded pellets prepared by step(i) 879.000
Ethyl cellulose 30.700
Diethyl phthalate 3.070
Talc 3.070
* Iso propyl alcohol 483.000
* Solvent used in the process, but present only in negligible quantities in the final
composition.
Ethyl cellulose and diethyl phthalate were dissolved in Isopropyl alcohol and talc added
to it. This suspension was passed through colloid mill and coated on to the drug pellets
obtained from step (i) . The polymer coated drug pellets were dried in the same coating
pan.
Stage in - Enteric coating
Ingredients Quantity mg/ gm of pellets
Polymer coated pellets obtained in step(ii) 913.00
Diethyl phthalate 5.92
Cetyl alcohol 13.23
Hydroxy propyl methyl cellulose phthalate 59.20
Talc 5.92
* Iso propyl alcohol 580.00
* Acetone 580.00
* Solvent used in the process, but present only in negligible quantities in the final
composition.
Hydroxy propyl methyl cellulose phthalate, diethyl phthalate, and cetyl alchol were dissolved in a mixture of Isopropyl alcohol and acetone to which talc was added. The suspension was passed through colloid mill and coated onto the polymer coated pellets, obtained by step(ii) . The enteric coated pellets were dried in the same coating pan. The enteric coated pellets were filled into size '1' hard gelatin capsules depending on the drug content of the pellets. Non pareil seeds were used to adjust the balance of fill weight of 290 mg. The filled capsules were packed in High density Poly ethylene Containers / Blister strips.
Example 2

Stage I:- Drug Coating
Ingredients Quantity mg/ gm of pellets
Tamsulosin Hydrochloride 2.290
Sugar spheres ( 18 /22#) 828.000
Sodium Lauryl sulphate 0.040
Polyvinyl pyrrolidone K-30 36.000
P-cy clodextrin 7.300
Isopropyl alcohol * 164.000
Water* 136.000
* Solvents used in the process, but present only in negligible quantities in the final
composition.
Tamsulosin HCL and p-cyclodextrin were dissolved in a mixture of isopropyl alcohol and water. Sodium lauryl sulphate and polyvinyl pyrrolidone K-30 were added to this drug complex and the resultant liquid passed through colloid mill. Sugar spheres ( 18 / 22#) were loaded into a fluidised bed coating appratus and the drug solution was layered onto these spheres. The resultant drug pellets were dried in the same equipment.
Stage II - Polymer Coating
Ingredients Quantity mg/ gm of pellets
Drug loaded pellets obtained in step(i) 882.00
Ethyl cellulose 30.70
Diethyl phthalate 3.070
Talc 3.070
*Iso propyl alcohol 483.000
* Solvents used in the process, but present only in negligible quantities in the final
composition.
Ethyl cellulose, and Diethyl phthalate were dissolved in Isopropyl alcohol and talc was
added to it. This suspension was passed through colloid mill and coated on to the drug
pellets , obtained in step(i) in the same fluidised bed coating apparatus. The polymer
coated drug pellets were dried in the same equipment.
Stage III- Enteric coating:-
Ingredients Quantity mg/ gm of pellets
Polymer coated pellets obtained in step(ii) 915.00
Diethyl phthalate 5.92
Cetyl alcohol 13.23

Hydroxy propyl methyl cellulose phthalate 59.20
Talc 5.920
* Isopropyl alcohol 580.00
* Acetone 580.00
* Solvents used in the process, but present only in negligible quantities in the final
composition.
Hydroxy propyl methyl cellulose phthalate, diethyl phthalate, and cetyl alcohol were dissolved in a mixture of isopropyl alcohol and acetone to which talc was added. The suspension was passed through colloid mill and coated onto the polymer coated pellets, obtained from stage II, in a fluidised bed coating apparatus. The enteric coated pellets were dried in the same coating pan.
The enteric coated pellets were filled into size ' 1' hard gelatin capsules depending on the drug content of the pellets. Non-pareil seeds were used to adjust the balance of fill weight of 290 mg. The filled capsules were packed in Hydroxy propyl methyl cellulose Containers / Blister strips.
Example 3
Stage I:- Drug Coating
Ingredients Quantity mg/ gm of pellets
Tamsulosin Hydrochloride 2.290
Sugar spheres ( 18 /22#) 830.000
Sodium Lauryl sulphate 0.040
Polyvinyl pyrrolidone K-30 36.000
2-hydroxy propyl- P-cyclodextrin 8.000
Isopropyl alcohol * 164.000
Water* 136.000
* Solvents used in the process, but present only in negligible quantities in the final
composition.
Tamsulosin HCL and 2-hydroxy propyl- P-cyclodextrin were dissolved in a mixture of isopropyl alcohol and water. Sodium lauryl sulphate and polyvinyl pyrrolidone K-30 were added to this drug complex and the resultant liquid passed through colloid mill

Sugar spheres ( 18 / 22#) were loaded into a fluidised bed coating appratus and the drug solution was layered onto these spheres. The resultant drug pellets were dried in the same equipment.
Stage II - Polymer Coating
Ingredients Quantity mg/ gm of pellets
Drug loaded pellets obtained in step(ii) 885.00
Ethyl cellulose 30,70
Dibutyl phthalate 3.070
Talc 3.070
*Iso propyl alcohol 483.000
* Solvents used in the process, but present only in negligible quantities in the final
composition.
Ethyl cellulose, Dibutyl phthalate were dissolved in Isopropyl alcohol and talc was added to it. This suspension was passed through colloid mill and coated on to the drug pellets , obtained in step(i)in the same fluidised bed coating apparatus. The polymer coated drug pellets were dried in the same equipment.
Stage III- Enteric coating:-
Ingredients Quantity mg/ gm of pellets
Polymer coated pellets obtained in step(ii) 913.00
Diethyl phthalate 7.00
Cetyl alcohol 13.23
Polyvinyl acetate phthalate 70.00
Talc 7.00
* Ethanol (95%) 580.00
* Acetone 580.00
* Solvents used in the process, but present only in negligible quantities in the final
composition.
Polyvinyl acetate phthalate, dibutyl phthalate, and cetyl alcohol were dissolved in a mixture of ethanol and acetone to which talc was added. The suspension was passed through colloid mill and coated onto the polymer coated pellets, obtained in step (ii) in a fluidised bed coating apparatus. The enteric coated pellets were dried in the same coating pan.

The enteric coated pellets were filled into size ' 1 ' hard gelatin capsules depending on the drug content of the pellets. Non-pareil seeds were used to adjust the balance of fill weight of 290 mg. The filled capsules were packed in High density Poly ethylene Containers / Blister strips.
Example 4
Stage I:- Drug Coating
Ingredients Quantity mg/ gm of pellets
Tamsulosin Hydrochloride 2.290
Sugar spheres ( 18 /22#) 833.000
Sodium Lauryl sulphate 0.040
Polyvinyl pyrrolidone K-30 36.000
Di methyl β-cyclodextrin 7.800
Isopropyl alcohol * 164.000
Water* 136.000
* Solvents used in the process, but present only in negligible quantities in the final
composition.
Tamsulosin HCL and Di methyl β-cyclodextrin were dissolved in a mixture of isopropyl
alcohol and water. Sodium lauryl sulphate and polyvinyl pyrrolidone K-30 were added to
this drug complex and the resultant liquid passed through colloid mill. Sugar spheres (18
/ 22#) were loaded into a fluidised bed coating appratus and the drug solution was
layered onto these speheres. The resultant drug pellets were dried in the same equipment.
Stage II - Polymer Coating
Ingredients Quantity mg/ gm of pellets
Drug loaded pellets obtained in step(i) 886.000
Hydroxy ethyl cellulose 42.000
Poly vinyl acetate phthalate aq dispersion(sureteric)42.000 (as solid content)
Triacefin 20.000
Talc 10.000
Water 500.000
Hydroxy ethyl cellulose and Triacetin were dissolved in water and Poly vinyl acetate phthalate aq dispersion(sureteric) and talc were added to it. This suspension was passed

through colloid mill and coated on to the dnig pellets , obtained in step(i) in the same fluidised bed coating apparatus. The polymer coated drug pellets were dried in the same equipment.
Stage in- Enteric coating:-
Ingredients Quantity mg/ gm of pellets
Polymer coated pellets obtained in step(ii) 915.0
Polyethylene glycol 4000 13.0
Polyvinyl acetate phthalate aq solution (Sureteric) 60.0 (as solid content)
Talc 12.0
Water 250.0
Polyethylene glycol 4000 was dissolved in water and polyvinyl acetate phthalate aqueous dispersion and talc were added. The suspension was passed through colloid mill and coated onto the polymer coated pellets, obtained from stage II, in a fluidised bed coating apparatus. The enteric coated pellets were dried in the same coating pan.
The enteric coated pellets were filled into size ' 1 ' hard gelatin capsules depending on the drug content of the pellets. Non-pareil seeds were used to adjust the balance of fill weight of 290 mg. The filled capsules were packed in High density Poly ethylene Containers / Blister strips.
Example 5
Stage I:- Drug Coating
Ingredients Quantity mg/ gm of pellets
Tamsulosin Hydrochloride 2.29
Sugar spheres (18 /22#) 828,00
Polyethylene- Propylene glycol copolymer 4.00
Polyvinyl pyrrolidone K-30 36.00
3- hydroxy propyl-P-cyclodextrin 8. 00
Isopropyl alcohol * 164.00
Water* 136.00
* Solvents used in the process, but present only in negligible quantities in the final composition.

Tamsulosin HCL and 3-hydroxy propyl-p-cyclodextrin were dissolved in a mixture of
isopropyl alcohol and water. Polyethylene-Propylene glycol copolymer (polxamer) and
polyvinyl pyrrolidone K-30 were added to this drug complex and the resultant liquid
passed through colloid mill.
Sugar spheres (18 / 22#) were loaded into a fluidised bed coating appratus and the drug
solution was layered onto these spheres. The resultant drug pellets were dried in the same
equipment.
Stage II - Polymer Coating
Ingredients Quantity mg/ gm of pellets
Drug loaded pellets obtained in step(i) 922.00
Hydroxy ethyl cellulose 68.00
Triacetin 7,00
Talc 3.00
Water 800.00
Hydroxy ethyl cellulose and Triacetin were dissolved in water and talc was added to it. This suspension was passed through colloid mill and coated on to the drug pellets , obtained in step(i) in the same fluidised bed coating apparatus. The polymer coated drug pellets were dried in the same equipment.
Stage III- Enteric coating:-
Ingredients Quantity mg/ gm of pellets
Polymer coated pellets obtained in step(ii) 900.00
Triethyl citrate 18.00
Hydroxypropyl methyl cellulose acetate succinate-LF 70.00
Sodium lauryl sulphate 2.00
Talc 10.00
Water* 1000.00
* Solvent used in the process, but present only in negligible quantities in the final
composition.
Sodium lauryl sulphate and triethyl citrate were dissolved in water to which talc and
Hydroxypropyl methyl cellulose acetate succinate-LF were added. The suspension was
passed through colloid mill and coated onto the polymer coated pellets, obtained in

step(ii) , in a fluidised bed coating apparatus. The enteric coated pellets were dried in the same coating pan.
The enteric coated pellets were filled into size ' 1 ' hard gelatin capsules depending on the drug content of the pellets. Non-pareil seeds were used to adjust the balance of fill weight of 290 mg. The filled capsules were packed in High density Poly ethylene Containers / Blister strips.
Example 6
Stage I:- Drug Coating
Ingredients Quantity mg/ gm of pellets
Tamsulosin Hydrochloride 2.290
Sugar spheres ( 18 /22#) 828.000
Polyoxyethylene castor oil dertivatives -
(Cremophor RH40) 2.50
Polyvinyl pyrrolidone K-30 36.000
p-cyclodextrin 7.300
Isopropyl alcohol * 164.000
Water* 136.000
* Solvents used in the process, but present only in negligible quantities in the final
composition.
Tamsulosin HCL and P-cyclodextrin were dissolved in a mixture of isopropyl alcohol
and water. Cremophor RH40 (polyoxyethylene castor oil derivative) and polyvinyl
pyrrolidone K-30 were added to this drug complex and the resultant liquid passed
through colloid mill.
Sugar spheres ( 18 / 22#) were loaded into a fluidised bed coating appratus and the drug
solution was layered onto these spheres. The resultant drug pellets were dried in the same
equipment.
Stage II - Polymer Coating
Ingredients Quantity mg/ gm of pellets
Drug loaded pellets obtained in step (i) 840.00
Hydroxy ethyl cellulose 50.00
Hydroxy propyl methyl cellulose acetate succinate 90.00
Sodium lauryl sulphate 3.00

Triacetain 14.00
Talc 3.00
Water 1500.00
* Solvents used in the process, but present only in negligible quantities in the final
composition.
Hydroxy ethylcellulose, Triacetin, Sodium lauryl sulphate were dissolved in water and
talc and hydroxy propyl methyl cellulose acetate succinate were added to it. This
suspension was passed through colloid mill and coated on to the drug pellets , obtained
in step(i) in the same fluidised bed coating apparatus. The polymer coated drug pellets
were dried in the same equipment.
Stage III- Enteric coating:-
Ingredients Quantity mg/ gm of pellets
Polymer coated pellets obtained in step(ii) 847.00
Triacetin 13.00
Hydroxy propyl methyl cellulose acetate succinate 130.00
Sodium lauryl sulphate 4.00
Talc 6.00
Water* 1500.00
* Solvent used in the process, but present only in negligible quantities in the final
composition.
Triacetin and sodium lauryl sulphate were dissolved in water to which talc and hydroxy propyl methyl cellulose acetate succinate were added. The suspension was passed through colloid mill and coated onto the polymer coated pellets, obtained in step(ii), in a fluidised bed coating apparatus. The enteric coated pellets were dried in the same coating pan.
The enteric coated pellets were filled into size ' 1 ' hard gelatin capsules depending on the drug content of the pellets. Non-pareil seeds were used to adjust the balance of fill weight of 290 mg. The filled capsules were packed in High density Poly ethylene Containers / Blister strips.
Dissolution studies were conducted on the six compositions prepared according to the processes described in the Examples 1 to 6, using USP type I, rpm 100 and 500 ml as the

medium using 1.2 pH buffer(USP) for 2 hours followed by 6.8 pH buffer (USP) for 4
hours thereafter.
The results are tabulated below

Each Value represents the average release from six baskets. The overall data shows a high degree of consistency in the dissolution performance, ensuring the release of the drug at the site of its maximum absorption,ie,in the small intestine.
The results confirm to the prior set dissolution limits of
a) less than 10% release in the gastric pH at the end of 2 hours
b) 35-55% release at the end of 1st hour in the Ph 6.8 buffer.
c) 50-70% release at the end of 2nd hour in the pH 6.8 buffer.
d) Not less than 70% release at the end of 4 hours in the pH 6.8 buffer.
Advantages of the invention:-
1) Drug release is not influenced by the poor solubility of Tamsulosin Hcl. A single
point control of the drug release is achieved through polymer coating.
2) Reduction in stenosis or obstruction caused by gastro-intestine pathology.
3) Even modified release of the drug has the individual units are well distributed in the
gastro intestinal track.
4) They are less influenced by the food (gastric emptying).
5) Dose adjustment is easier.

We claim,
1. An improved release pharamceutical composition useful for treatment of benign prostatic hyperplasia which comprises a core of sugar spheres having a coating of a solution of Tamsulosin Hcl or pharmaceutically acceptable salts thereof in Polyvinyl pyrrolidone and / or β-cyclodextrin containing a solublising agent, an emulsifiying agent, a binder and a solvent in the form of pellets , the spheres also having a coating of one or more of ethyl cellulose, Hydroxy ethyl cellulose, polyvinyl acetate phthalate and hydroxypropyl methyl cellulose acetate succinate polymers and a further coating of an enteric polymer containing , plasticizers, wetting agent, antitacking agent and a solvent.
2. A pharmaceutical composition as claimed in claim l wherein the composition is in the form of capsules.
3. An improved composition as claimed in claim 1 & 2 wherein the active
pharmaceutical agent used is selected from pharmaceutically acceptable tamsulosin
salts such as Tamsulosin Hydrochloride, Tamsulosin Hydrbromide, Tamsulosin
methane sulfonate, Tamsulosin tosylate, Tamsulosin besylate, Tamsulosin acetate,
Tamsulosin maleate, Tamsulosin tartarate and Tamsulosin citrate, preferably
Tamsulosin Hydrochloride.
4. An improved as claimed in claims 1 to 3 wherein the amount of the active pharmaceutical agent used is in the range of 1.0 mg to 10.0 mg per gram of the composition, preferably in the range of 2.0 mg to 4,0 mg per gram of the composition.
5. An improved composition as claimed in claims 1 to 4 wherein the amount of sugar spheres used in the core ranges from 700 to 950 mg per gram of the composition , preferably the amount ranges from 750 to 900 mg per gram of the composition,
6. An improved as claimed in claims 1 to 5 wherein the solublising agent used formation of the drug solution is selected from cyclodextrins 3-hydroxy proply- beta cyclodextrin, di methyl beta cyclodextrin, 2- hydroxy propyl-beta cyclodextrin and beta cyclodextrin and the like, and Polyvinyl pyrrolidone, lecithin and the like or mixture thereof

7. An improved composition as claimed in claims 1 to 6 wherein the amount of solublising agent used for the formation of the drug solution ranges from LOO to 10.00 mg per gram of the composition, preferably 2.00 to 8.00 mg per gram of the composition.
8. An improved composition as claimed in claims 1 to 7 wherein the emulsifying agent used for the formation of the drug solution is selected from anionic or non-ionic surfactants such as sodium lauryl sulphate, polyethylene-propylene glycol copolymer (Poloxamer), polyoxy ethylene alkyl ethers (cetomacrogol-1000), polyoxy ethylene castrol oil derivatives ( Cremophor RH60, Cremophor RH40), Polyoxy ethylene sorbital fatty acid esters (Poly sorbit-20. Poly sorbit-40, Poly sorbit-60, Poly sorbit-80), polyoxyethylene stearates (Macrogol- stearate), polyvinyl alcohol and the like and their mixture thereof
9. An improved composition as claimed in claims 1 to 8 wherein the amount of emulsifying agent employed for the formulation of the drug solution , ranges from 0.01 to 10.00 mg per gram, preferably 0.02 to 8.00 mg per gram of the composition.
10. An improved composition as claimed in claims 1 to 9 wherein the binder used for the formation of the drug solution is selected from various grade of polyvinyl pyrrolidone and their molecular weight ranging from 2,500 to 30,00,000 and the prefered grade is polyvinyl pyrrolidone K-30 having molecular weight of 50,000.

11. An improved composition as claimed in claims 1 to 10 wherein the amount of binder employed for the formation of the drug solution ranges from 10.00 to 80.00 mg per gram, preferably 20.00 to 60.00 mg per gram of the composition.
12. An improved composition as claimed in claims 1 tol 1 wherein the solvents used for the formation of the drug solution is selected from isopropyl alcohol, acetone, water and the like and preferably a mixture of isopropyl alcohol and water.
13. An improved composition as claimed in claims 1 to 12 wherein the polymer used for the polymer coating is one or more polymers comprising of ethyl cellulose, Hydroxy ethyl cellulose, polyvinyl acetate phthalate and hydroxy propyl methyl cellulose acetate succinate and its amount ranges from 20.0 mg to 100.0 mg, preferably 25.0 mg to 85.0 mg per gram of the composition.

14. An improved composition as claimed in claims 1 to 13 wherein the plastisizer used
in the polymer composition is selected from diethyl phthalate, dibutyl phthalate,
triacetin, polyethylene glycol 4000 and the like.
15. An improved composition as claimed in claims 1 to 14 wherein the amount of plastisizer employed in the polymer composition ranges from 2.00 to 25.00 mg per gram, preferably 2.50 to 20.00 mg per gram of the composition.
16. An improved composition as claimed in claims 1 to l5 wherein the anti-tacking agent used in the polymer composition is selected from talc, magnesium stearate and the like or a mixture thereof
17. An improved composition as claimed in claims 1 to 16 wherein the amount of anti-tacking agent used ranges from 1.0 mg to 15.0 mg, preferably 2.0 mg to 10,0 mg per gram of the composition.
18. An improved composition as claimed in claims 1 to 17 wherein the solvent used in the polymer composition is selected from isopropyl alcohol, acetone, ethyl alcohol, water and the like or a mixture thereof

19. An improved composition as claimed in claims 1 to 18 wherein the polymer used for the enteric coating is selected from hydroxy propyl methyl cellulose phthalate, hydroxy propyl methyl cellulose acetate succinate, polyvinyl acetate phthalate, and the like.
20. An improved composition as claimed in claims 1 to 19 wherein the amount of polymer used for the enteric coating ranges from 30.00 to 160.00 mg per gram of the composition, preferably 40.00 to 140.00 mg per gram of the composition.
21. An improved composition as claimed in claims 1 to 20 wherein, the plasticizer used for the enteric coating is selected from diethyl phthalate, di butyl phthalate, cetyl alcohol, poly ethylene glycol 4000, triethyl citrate, triacetin and the like.

22. An improved composition as claimed in claims 1 to 21 wherein the amount of plasticizer used for the enteric coating ranges from 3.00 to 30.00 mg per gram of the composition, preferably 4.00 to 25,00 mg per gram of the composition.
23. An improved composition as claimed in claims 1 to 22 wherein the anti-tacking agent used for the enteric coating is selected from talc, magnesium stearate and the like or a mixture thereof

24. An improved composition as claimed in claims 1 to 23 wherein the amount of anti-
tacking agent used for the enteric coating ranges from 4.0 mg to 16.0 mg per gram of
the composition, prefereably 5.0 to 12.0 mg per gram of the composition.
25. An improved composition as claimed in claims 1 to 24 wherein the solvent used for the enteric coating is selected from iso-propyl alcohol, ethyl alcohol, acetone, water and the like or a mixture thereof
26. A process for the preparation of an improved release pharmaceutical composition useful for treating benign prostatic hyperplasia (BPH) as claimed in claims 1 to 25 which comprises :-
i. Preparing a solution of Tamsulosin Hcl or a pharmaceutically acceptable salts thereof in Polyvinyl pyrrolidone and / or β-cyclodextrin containing a solublising agent, an emulsifiying agent, a binder and a solvent and forming into pellets.
ii. Impregnating the above solution obtained on to sugar spheres.
iii. coating the drug loaded pellets with one or more polymers comprising of ethyl cellulose. Hydroxy ethyl cellulose, polyvinyl acetate phthalate and hydroxypropyl methyl cellulose acetate succinate in a medium of water, isopropylalcohol, ethyl alcohol, acetone or a mixture thereof
iv. Coating the polymer coated pellets with an enteric polymer containing plasticizers, antitacking agent and a solvent and if desired.
V. Encapsulating the enteric coated pellets in hard gelatin capsules.
27. A process as claimed in claim 26 wherein the active pharmaceutical agent used is
selected from pharmaceutically acceptable tamsulosin salts such as Tamsulosin
Hydrochloride, Tamsulosin Hydrbromide, Tamsulosin methane sulfonate,
Tamsulosin tosylate, Tamsulosin besylate, Tamsulosin acetate, Tamsulosin maleate,
Tamsulosin tartarate and Tamsulosin citrate, preferably Tamsulosin Hydrochloride.
28. A process as claimed in claims 26 & 27 wherein the amount of the active
pharmaceutical agent used is in the range of 1.0 mg to 10.0 mg per gram of the
composition, preferably in the range of 2.0 mg to 4.0 mg per gram of the composition

29. A process as claimed in claims 26 to 28 wherein the amount of sugar spheres in the drug coating is in the range of 700 to 950 mg per gram of the composition, preferably the amount ranges from 750 to 900 mg per gram of the composition.
30. A process as claimed in claims 26 to 29 wherein the solublising agent used for forming the solution of the drug is selected from cyclodextrins 3-hydroxy proply-beta cyclodextrin, di methyl beta cyclodextrin, 2- hydroxy propyl-beta cyclodextrin and beta cyclodextrin and the like, and Polyvinyl pyrrolidone, lecithin and the like or mixture thereof
31. A process as claimed in claims 26 to 30 wherein the amount of solublising agent used ranges from 1.00 to 10.00 mg per gram of the composition, preferably 2.00 to 8.00 mg per gram of the composition.
32. A process as claimed in claims 26 to 31 wherein the emulsifying agent used for the
formation of the drug solution is selected from anionic or non-ionic surfactants such
as sodium lauryl sulphate, polyethylene-propylene glycol copolymer (Poloxamer),
polyoxy ethylene alkyl ethers (cetomacrogol-1000), polyoxy ethylene castrol oil
derivatives ( Cremophor RH60, Cremophor RH40), Polyoxy ethylene sorbital fatty
acid esters (Poly sorbit-20, Poly sorbit-40, Poly sorbit-60. Poly sorbit-80),
polyoxyethylene stearates (Macrogol- stearate), polyvinyl alcohol and the like and
their mixture thereof
33. A process as claimed in claims 26 to 32 wherein the amount of emulsifying agent
employed ranges from 0.01 to 10,00 mg per gram, preferably 0.02 to 8.00 mg per
gram of the composition.
34. A process as claimed in claims 26 to 33 wherein the binder used in the formation of the drug solution is selected from various grade of polyvinyl pyrrolidone and their molecular weight ranging from 2,500 to 30,00,000 and the prefered grade is polyvinyl pyrrolidone K-30 having molecular weight of 50,000.
35. A process as claimed in claims 26 to 34 wherein the amount of binder employed in the drug coating, ranges from 10.00 to 80.00 mg per gram, preferably 20.00 to 60.00 mg per gram of the composition.

36. A process as claimed in claims 26 to 35 wherein the solvents used in the formation of drug solution is selected from isopropyl alcohol, acetone, water and the like and preferably a mixture of isopropyl alcohol and water.
37. A process as claimed in claims 26 to 36 wherein the amount of ethyl cellulose, Hydroxy ethyl cellulose, polyvinyl acetate phthalate, hydroxy propyl methyl cellulose acetate succinate used in step (iv) ranges from 20.0 mg to 100.0 mg, preferably 25.0 mg to 85.0 mg per gram of the composition.
38. A process as claimed in claims 26 to 37 wherein the plastisizer used in the polymer coating in step (iii) is selected from diethyl phthalate, di butyl phthalate, triacetin, polyethylene glycol 4000 and the like.
39. A process as claimed in claims 26 to 38 wherein the amount of plastisizer employed in the polymer coating in step (iii) ranges from 2.00 to 25.00 mg per gram, preferably 2.50 to 20.00 mg per gram of the composition.

40. A process as claimed in claims 26 to 39 wherein the anti-tacking agent used in the polymer coating in step (iii) is selected from talc, magnesium stearate and the like or a mixture thereof
41. A process as claimed in claims 26 to 40 wherein the amount of anti-tacking agent used in step(iii) ranges from 1.0 mg to 15.0 mg, preferably 2.0 mg to 10.0 mg per gram of the composition.
42. A process as claimed in claims 26 to 41 wherein the solvent in the polymer coating
in step(iv) is selected from isopropyl alcohol, acetone, ethyl alcohol, water and the
like or a mixture thereof.
43. A process as claimed in claims 26 to 42 wherein the polymer used in the enteric coating in step( iv) is selected from hydroxy propyl methyl cellulose phthalate, hydroxy propyl methyl cellulose acetate succinate, polyvinyl acetate phthalate, and the like.
44. A process as claimed in claims 26 to 43 wherein the amount of polymer used in the enteric coating in step(iv) ranges from 30.00 to 160.00 mg per gram of the composition, preferably 40.00 to 140.00 mg per gram of the composition.

45. A process as claimed in claims 26 to 44 wherein, the plasticizer used in for the
enteric coating is step(iv) is selected from diethyl phthalate, di butyl phthalate, cetyl
alcohol, poly ethylene glycol 4000, triethyl citrate, triacetin and the like.
46. A process as claimed in claims 26 to 45 wherein the amount of plasticizer used in
the enteric coating in step(iv) ranges from 3.00 to 30.00 mg per gram of the
composition, preferably 4.00 to 25.00 mg per gram of the composition.
47. A process as claimed in claims 26 to 46 wherein the anti-tacking agent used in the enteric coating in step(iv) is selected from talc, magnesium stearate and the like or a mixture thereof
48. A process as claimed in claims 26 to 47 wherein the amount of anti-tacking agent used in the enteric coating in the step(iv) ranges from 4.0 mg to 16.0 mg per gram of the composition, prefereably 5.0 to 12.0 mg per gram of the composition.
49. A process as claimed in claims 26 to 48 wherein the solvent used in the enteric
coating in step(iv) is selected from iso-propyl alcohol, ethyl alcohol, acetone, water
and the like or a mixture thereof
50. An improved pharmaceutical composition in the form of pellets or hard gelatin
capsule useful for treatment of Benign prostatic hyperplasia substantially as herein
described with reference to the Examples 1 to 6.
51. A process for the preparation of an improved and modified pharmaceutical
composition in the form of pellets or hard gelatin capsule useful for treatment of
benign prostatic hyperplasia (BPH) substantially as herein described with reference to
the Examples 1 to 6.

Documents:

983-che-2003-abstract.pdf

983-che-2003-claims filed.pdf

983-che-2003-claims granted.pdf

983-che-2003-correspondnece-others.pdf

983-che-2003-correspondnece-po.pdf

983-che-2003-description(complete)filed.pdf

983-che-2003-description(complete)granted.pdf

983-che-2003-form 1.pdf

983-che-2003-form 19.pdf

983-che-2003-form 3.pdf

983-che-2003-form 5.pdf

983-che-2003-pct.pdf

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Patent Number

211847

Indian Patent Application Number

983/CHE/2003

PG Journal Number

02/2008

Publication Date

11-Jan-2008

Grant Date

13-Nov-2007

Date of Filing

03-Dec-2003

Name of Patentee

M/S. NATCO PHARMA LIMITED

Applicant Address

NATCO HOUSE, ROAD NO. 2, BANJARA HILLS, HYDERABAD - 500 033

Inventors:

#	Inventor's Name	Inventor's Address
1	PODILI KHADGAPATHI	NATCO PHARMA LTD, NATCO HOUSE, ROAD NO. 2, BANJARA HILLS, HYDERABAD - 500 033,
2	VENKAIAH CHOWDARY NANNAPANENI	NATCO PHARMA LTD, NATCO HOUSE, ROAD NO. 2, BANJARA HILLS, HYDERABAD - 500 033,

PCT International Classification Number

A61K 9/00

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA