Title of Invention	MODIFIED RELEASE PHARMACEUTICAL COMPOSITIONS AND PROCESS FOR THE PREPARATION THEREOF
Abstract	Novel method for preparation of drug 'Tamsulosin hydrochloride' in matrix form is disclosed.The drug is mixed with inert diluents and later embedding the mixture and a plasticiser into apolymer to form a matrix. Such preparation may be further enteric coated to give it enteric properties.

Full Text

FORM 2 THE PATENTS ACT, 1970 (39 of 1970) COMPLETE SPECIFICATION (See section 10) "MODIFIED RELEASE PHARMACEUTICAL COMPOSITIONS AND PROCESS FOR THE PREPARATION THEREOF" German Remedied Limited, a company incorporated under the Companies Act, 1956, of A- Shivsagar Estate, Dr. A. Besant Road, Worli, Mumbai-400 018, Maharashtra, India The following specification particularly describes and ascertains the nature of the invention and the manner in which it is to be performed: Field of invention The present invention relates to modified release compositions and a process for their preparation. More particularly, present invention relates to modified release composition for the drug tamsulosin hydrochloride in the form of tablets and a process for their preparation and use in treatment of benign prostate hypertrophy (BPH). Background of the invention Tamsulosin Hydrochloride is an alpha blocker used to relieve urinary retention in men with an enlarged prostate gland. Tamsulosin is used to treat the signs and symptoms of benign enlargement of the prostate (benign prostatic hyperplasia or BPH). The present invention i.e. a modified release preparation of tamsulosin hydrochloride is administered once daily giving better compliance. Prior Art US 6,395,300 discloses putting low aqueous solubility drugs in a porous matrix form which forms microparticles when the matrix is contacted with an aqueous medium. US 6,328,979 discloses a sustained-release pharmaceutical composition comprising an ionic pharmaceutically active substance and an ionic compound which has an opposite charge to that of the ionic pharmaceutically active substance and enhances the hydrophobic property of the ionic pharmaceutically active substance. US 6,248/363 iscloses a solid pharmaceutical.composition which includes a solid carrier, the solid carrier including a substrate and an encapsulation coat on the substrate. The encapsulation coat includes at least one ionic or non-ionic hydrophilic surfactant. Optionally, the encapsulation coat can include a pharmaceutical active ingredient, a lipophilic component such as a lipophilic surfactant or a triglyceride, or both a pharmaceutical active ingredient and a lipophilic component. Objects of the invention It is an object of the present invention to provide a pharmaceutical composition in the form of a tablet for use in benign prostatic hyperplasia. It is another object of the present invention to provide a pharmaceutical composition in the form of a tablet from which the active substance is released with a adjustable release profile i.e. as slow as required, but completely over a predetermined period of time. It is yet another object of the present invention to provide a pharmaceutical composition in the form of a tablet that protects the active substance from gastric fluids. It is still another object of the present invention to provide a composition which combines the slow release properties of a matrix formulation and gastric resistant properties of a polymer to modify the release of the drug. One more object of the present invention to provide a pharmaceutical composition giving same level of effective concentration in blood over a longer period of time reducing the frequency of dosages. The present invention overcomes the difficulties in preparation of modified release dosage form of Tamsulosin Hydrochloride. The present invention has following advantages over the existing prior art in the field: 1. Process for preparation of modified release tablets of tamsulosin hydrochloride is significantly shortened as compared to existing prior art. 2. Close and constant monitoring of the process not required. 3. Processing losses are considerably minimized. 4. Modified release tablets of tamsulosin hydrochloride under present invention can be prepared by using low cost conventional machinery. 5. Preparation of modified release tablets of tamsulosin hydrochloride under present invention reduces the cost of production. Summary of the invention The above and other objects of the invention are achieved by providing a composition in the form of a tablet that uses both a matrix and a coating polymer to modify the release of the drug. The process for preparing dosage form as described under prior art which is employed by companies like Glaxo Wellcome (Flomax MR Capsules), has following disadvantages among others: 1. Time for preparation (i.e. processing time) of dosage form is longer. 2. Process needs to be monitored closely for attaining desired results. 3. About 10 - 30% of loss of active drug (Tamsulosin Hydrochloride in this case) is incurred in processing of pellets. This invention has a particular application where it is desired to prevent the release in acidic environment and release the drug over a period of time in buffer. One of the important features of the present invention is that it combines the gastric resistant and sustained release properties of different polymers to modify the release of the drug to formulate a tablet of low dose drugs used in benign prostatic hyproplasia such as tamsulosin. The composition of the present invention is in the form of a tablet. The tablet core is in the form of a matrix containing the drug & comprises of either an insoluble and unswellable polymer which controls the drug release by diffusion or comprises of a swellable polymer which controls the drug release by diffusion and erosion. The operation of the present invention can be described as follows: In acidic medium the film coating provides a barrier and prevents the release of the drug. At higher pH (above pH 5.5) the film coating dissolves.' The core matrix in contact with the medium & the drug is released slowly over a period of time. The composition of the core can be altered to suit the solubility of the active ingredient. Detailed Description: The present invention provides a novel modified release pharmaceutical composition which comprises of a core matrix consisting of a mixture of a water insoluble non-permeable or water swellable polymer and at least an active ingredient dispersed in such core matrix, said core matrix being coated with an acid insoluble polymer such that upon administration, the acid insoluble polymer prevents the release of the drug in gastric fluids. The release rate of low dose drugs can be controlled by designing a matrix of acrylic acid copolymer(s) or cellulose ether(s) such as hydropropylmethyl cellulose to the extent of 5% to 30% by weight. The polymer is combined with other soluble &/ or insoluble excipients to improve compressibility and lubrication. Within the cores of this matrix, the active ingredients are dispersed. The water insoluble, non-swellable polymer is preferably a copolymer of acrylic and methacrylic acid esters. The water swellable polymer is preferably a cellulose ether such as hydroxypropylmethyl cellulose. This core is then coated with a film comprising of plasticizer(s), pigment, lubricant and an acid insoluble polymer. The coating polymer dissolves at higher pH and the release is then controlled in intestinal fluid by the matrix which releases the drug slowly over a period of time. The acid insoluble coating polymer may be methacrylic acid copolymer or hydroxypropylmethyl cellulose phthalate or polyvinyl acetate phthalate or cellulose acetate phthalate. The tablet core comprises of 0.2 to 0.4% of said active ingredients, 5 to 30% by weight of said polymer and balance comprising of excipients and additives. The amount of the acid insoluble, non-swellable polymer in said film coating suspension is from 2 to 10% by weight, preferably 7.0 % by weight. Fillers such as lactose, microcrystalline cellulose, starch, dibasic calcium phosphate or any other suitable filler can be added to the extent of 20% to 90% by weight. The resultant mixture may be converted into granules by use of either organic solvent like isopropyl alcohol or ethyl alcoh'ol or specially denatured spirit or acetone or mixture of purified water with organic solvent. Resultant granules are dried at a temperature less than or equal to 60°C. The granules may be and mixed with lubricants and glidants like talc, magnesium stearate, aerosil, colloidal silicon dioxide etc. The granules are then compressed at a hardness between 30 and 80N to form tablets. The tablets are then coated with an acid insoluble polymer soluuble at a higher pH (above 5, preferably above pH 5.5), 5 The inner core matrix The core matrix comprises of 5 to 30% of the polymer and from 0.2 to 0.4% of active ingredient. The percentage of other excipients can be adjusted accordingly. The polymer material chosen for the matrix may be either non swellable; insoluble such as acrylic acid copolymer or a swellable polymer such as hydroxypropylmethyl cellulose, while other polymers or waxes may also be used to retard the release. It is preferred that the retarding material is also bio-compatible. Coating Membrane The coating membrane is a barrier coat which protects the active ingredient matrix from the gastric fluids. It is basically an acid insoluble acrylic acid co-polymer. Phthelates such as polyvinyl acetate, cellulose acetate phthalate, hydroxypropylmethylcellulose phthlate can also be used. The preferred polymer is acrylic acid copolymer such as Methacrylic Acid Copolymer Type C (USP). A coating of about 5mg is applied to the surface area of approx. 121 mm2 and in that proportion. The shape preferred for coated pharmaceutical tablets is a circular biconvex tablet with diameter of about 6 mm, with weight of about 100 mg. The invention shows following characteristics - At least 90% of the active ingredient is released over a period of 8 hours in buffer of pH 6.8 and 7.2 which is demonstrated quantitatively by in-vitro models. The active principle has solubility practically independent of pH. The formulation shows stability during handling and storage. The following example(s) illustrate typical tablet manufactured according to the invention. Preparation of tablets of Tamsulosin Hydrochloride a) Typical preparation of solid matrix core. The composition for each core is given below. 7 Sr. No. Particulars 0.2 ma / tab. 0.4 ma /tab. 1 Tamsulosin Hydrochloride * 0.20 0.40 2 Hydroxypropylmethyl Cellulose IP (Methocel K-100) 15.00 15.00 3 Lactose IP 81.30 81.10 4 Talc IP 3.00 3.00 5 Magnesium Stearate IP 0.5 0.5 Weight 100 mg 100 mg Punch Diameter 6.0 mm 6.0 mm All excipients wherever applicable must comply with pharmacopoeial specifications. Tamsulosin is added on 100% assay basis and tablet weight is adjusted with lactose. Process can be described as follows :- Step I : Tamsulosin Hydrochloride of particle size less than 100 microns, Lactose and Hydroxypropylmethyl Cellulose are blended together in a suitable Mixer or a Granulator till a homogenous mix is obtained. Step II: A mixture of Isopropyl Alcohol and Purified Water is prepared (preferably 1:1). The blend as mentioned in step I is granulated and sized through 5 mm / 8 mm sieve in a suitable mill, dried at a temperature below 60°C using suitable driers and sized using 1/1.5/2 mm sieve in a suitable mill. Step III: The granules are mixed first with Talc followed by Magnesium Stearate using a suitable mixer or processor. The granules are compressed as follows :- Parameters 0.2 ma / 0.4 mg Diameter 6 mm Weight 100 mg Thickness 3.2-3.6 Diameter to thickness ratio 1.875- 1.67 Application of acid insoluble coating membrane Ingredients Quantity ma/ tablet Composition for 100 a of suspension (g) 20ma 40 ma 20 ma 40 mg Methacrylic Acid Copolymer Type C USNF 2.063 2.603 7.0 7.0 Dibutyl Phthalate * 0.495 0.495 1.68 1.68 Talc 1.586 1.586 5.4 5.4 Titanium Dioxide 0.766 0.856 2.59 2.9 Ferric oxide 0.9 — 0.31 — Isopropyl Alcohol q.s. Q.s. q. s. to 100 q. s. to 100 Coating deposited on tablet 5.0 mg / tablet * 5.0 mg / tablet * In place of Dibutyl Phthalate other plasticizers like Triacetin, etc. can also be used singly or in combination. The coating suspension was sprayed continuously with continuous drying. The release rates were determined by in-vitro models. The details are as follows :- The release rate is expressed in percent released, calculated as equivalent of Tamsulosin Hydrochloride released. The release rates of these batches have been monitored in buffers 6.8 and 7.2. The typical rate of release obtained over 8 hours is shown in graphical representation in the accompanying drawing. As routine checks of dissolution profile monitoring was done for 2 hr., 4 hr., 6 hr. and 8 hr. dissolution rates in buffer 6.8 Medium Time (hours) % Drug Release Limit pH 1.2 At 2.0 Nil NMT 10 % pH6.8 After 4.0 59.1 25 - 50 % pH6.8 After 6.0 84.0 55 - 85 % pH6.8 After 8.0 95.0 NLT 85 % pH6.8 After 12.0 98.1 NLT 90 % Within 8-12 hours the entire quantity of drug is released. We claim: 1. A composition for use in the treatment of benign prostate hyperplasia which comprises an active ingredient dispersed in a core matrix consisting of a polymer, excipients & /or additives wherein the said core matrix is further coated with acid insoluble polymer(s) such that upon administration, the said coating provides a barrier to gastric fluids and dissolves in intestinal fluids so that the said core matrix releases the drug over a period of time. 2. A composition as claimed in claim 1 wherein the active ingredient in the composition is an a1A receptor blocker such as Tamsulosin Hydrochloride. 3. A composition as claimed in claim 1 wherein the CIIA blocker is present in an amount of from 0.2 to 0.4% by weight of the composition. 4. A composition as claimed in claim 1 wherein the matrixing polymer is, a insoluble and non-swellable polymer. 5. A composition as claimed in claim 1 wherein the matrixing polymer is a swellable polymer. 6. A composition as claimed in claim 1 wherein the matrixing polymer is preferably a cellulose ether, more preferably hydroxypropylmethyl cellulose. 7. A composition as claimed in claim 1 wherein said core comprises of from 0.2 to 0.4% by weight of said active ingredients, from 5 to 30% by weight of said polymer(s), preferably around 15% and balance comprising of said excipients and additives and in a preferred embodiment 15% by weight of the said polymer. 8. A composition as claimed in claim 1 wherein the amount of said acid insoluble polymer in said coating is from 2 to 10% by weight, more preferably 7% by weight. 9. A composition as claimed in claim 1 wherein the said acid insoluble polymer in the said coating composition is selected from phthalates such as polyvinyl acetate phthalate, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate or methacrylic acid 11 copolymer(s) such as methacrylate and methacrylic acid copolymer type C USP. 10. A composition as claimed in claim 1 wherein the core mixture is granulated in presence of organic solvents such as isopropyl alcohol, ethyl alcohol, specially denatured spirit or acetone and purified water, either singly or in combination. 11. A composition as claimed as claim 1 wherein the granules are dried, sized and mixed with lubricants and glidants such as colloidal silicon dioxide, magnesium stearate and talc. 12. A composition as claimed in claim 1 wherein the composition contains fillers such as lactose, starch, microcrystalline cellulose or dicalcium phosphate, preferably lactose. 13. A composition as claimed in claim 1 wherein the composition is in the form of tablet. 14. A process for the preparation of a novel composition for use in the treatment of benign prostatic hyperplasia which comprises compressing a mixture of said polymer and / or other conventional additives and at least an active ingredient and coating said tablets with a coating composition comprising of an acid insoluble polymer. 15. A composition for use in the treatment of benign prostate hyperplasia substantially as described herein. GERMAN REMEDIES LIMITED No. 1025/MUM/2002 One Sheet pH 6.8 buffer pH 7.2 buffer 3 40.0 37.8 4 59.1 59.6 5 71.6 79.8 6 84.0 88.8 7 88.4 92.5 8 95.0 97.1 12 98.1 100.1 Dissolution Of Tamsulosin HCL in Buffers pH 6.8 & 7.2 90.0 ■ 80.0 SO.O 40.0 60.0 7 8 9 Time in Hours —•— pH 6.8 buffer —* pH 7.2 buffer Abstract: Novel method for preparation of drug 'Tamsulosin hydrochloride' in matrix form is disclosed. The drug is mixed with inert diluents and later embedding the mixture and a plasticiser into a polymer to form a matrix. Such preparation may be further enteric coated to give it enteric 5 properties.

Documents:

1025-mum-2002-abstract(25-11-2002).pdf

1025-mum-2002-abstract-(25-11-2002).doc

1025-mum-2002-abstract.doc

1025-mum-2002-abstract.pdf

1025-mum-2002-cancelled pages(24-11-2003).pdf

1025-mum-2002-claims.doc

1025-mum-2002-claims.pdf

1025-mum-2002-correspondence(6-6-2008).pdf

1025-mum-2002-correspondence(ipo)-(9-4-2008).pdf

1025-mum-2002-correspondence-received-ver-010304.pdf

1025-mum-2002-correspondence-received-ver-060906.pdf

1025-mum-2002-correspondence-received-ver-160103.pdf

1025-mum-2002-correspondence-received-ver-241103.pdf

1025-mum-2002-correspondence-received-ver-251102.pdf

1025-mum-2002-correspondence-received-ver-310103.pdf

1025-mum-2002-descripiton (complete).pdf

1025-mum-2002-descripiton (provisional).pdf

1025-mum-2002-drawing(24-11-2003).pdf

1025-mum-2002-form 1(25-3-2008).pdf

1025-mum-2002-form 1(5-3-2004).pdf

1025-mum-2002-form 18(8-9-2006).pdf

1025-mum-2002-form 2(granted)-(24-11-2003).pdf

1025-mum-2002-form 2(granted)-(25-11-2002).doc

1025-mum-2002-form 3(25-11-2002).pdf

1025-mum-2002-form 5(24-11-2003).pdf

1025-mum-2002-form 6(5-3-2004).pdf

1025-mum-2002-form-1.pdf

1025-mum-2002-form-18.pdf

1025-mum-2002-form-2-complete.pdf

1025-mum-2002-form-2-provisional.doc

1025-mum-2002-form-2-provisional.pdf

1025-mum-2002-form-26.pdf

1025-mum-2002-form-3.pdf

1025-mum-2002-form-5.pdf

1025-mum-2002-form-6.pdf

1025-mum-2002-power of authority(31-1-2003).pdf

1025-mum-2002-we claims(granted)-(25-11-2002).doc

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