JP2006512358A - Tamsulosin controlled release pharmaceutical composition - Google Patents

Abstract

The present invention relates to a pharmaceutical composition with controlled release of tamsulosin or a pharmaceutically acceptable salt thereof. In particular, the present invention relates to a preparation of individual drugs or combined drugs having controlled release containing a spherical nucleus obtained by adding a controlled release preparation to a mixture of tamsulosin and a spheronizing agent.

Description

  The technical field of the present invention relates to a controlled release pharmaceutical composition of tamsulosin or a pharmaceutically usable salt thereof. In particular, the present invention relates to controlled-release individual or combined drugs comprising spherical nuclei obtained by adding a controlled release agent to a mixture of tamsulosin and a spheronizing agent. The invention also relates to the manufacture of such medicaments.

  The need for improved clinical outcomes of modified release drugs has been described in the prior art. This is particularly important in drugs that have a short half-life, specific area absorption, gastrointestinal disorders, or other side effects at high plasma concentrations. One common improved drug release method is the use of a monolithic structure designed to have improved release characteristics. Monolithic structures include osmotic drug delivery systems, biological erodible or non-erodible matrix structures, and the like.

  Currently, the majority of modified release drugs that are formulated are monolithic structures, but this has significant drawbacks. Oversupply can be caused by intentional or accidental delivery system failure. Oversupply can lead to poisoning symptoms and fatal consequences for some compounds. Furthermore, the release of relatively many monolithic structures from the stomach is affected by the presence or absence of food and the type of food consumed.

  Because of these disadvantages, conversion from monolithic structures to complex drugs where individual drugs have improved release characteristics is underway. The final dosage form consists of a complex drug pressed into a tablet form or packed into a capsule or bag. When administered, individual drug components are freely dispersed in the gastrointestinal tract, preventing partial concentration of drugs that can cause inflammation of the gastrointestinal mucosa. In addition, since each component unit constituting this structure is small, the dosage form is independent of fluctuations in the drainage time from the stomach of the patient.

  The surface area of the composite dosage form is large, facilitating complete and uniform absorption, minimizing peak plasma fluctuations and reducing the potential for side effects. A further advantage is that the drug is freely distributed through the gastrointestinal tract, so that the absorption variability is reduced, the dissolution properties are reproducible and a high concentration of the active substance in the gastrointestinal tract can be prevented.

  Drug release from complex drugs with such controlled release is controlled by either dissolution or erosion of the coating by enzymatic or pH processes. The erodible coating involves the use of enteric polymers that dissolve in the intestine.

The method for producing a combined drug includes the following methods:

(A) extrusion spheronization method (b) wet granulation method (c) dry granulation method: The dry granulation method mainly includes the following two steps:
1. Strike process 2. Roller pressing process

  The extrusion / spheronization method is a multi-step process for producing uniform size microparticles. Used mainly for the production of double particles suitable for controlled release or delayed release. This process increases volume density, improves fluid properties, and reduces dust problems due to low density finely divided fluid excipient powders. The general process includes separate steps: a wet massing step, a subsequent step of extruding the wet mass into a cylindrical body, followed by a step of sphering the cylindrical body. The extrusion process includes a step of passing the wet mass through a mold and forming it into a cylinder having a uniform diameter. Extruded cylinders are cut with similar lengths. These cylinders are formed into spherical particles in an apparatus including a bowl with a fixed side wall and a bottom plate or disk that rotates at high speed. This spheronization is due to friction generated by collision between the fine particles and the fine particles and the apparatus. This step requires a spheronizing agent to assist in spheronization.

Tamsulosin, 5-[(2R) -2-[[2- (2-ethoxy-phenoxy) ethyl] amino] propyl] -2-methoxybenzenesulfonamide, is selective for α ₁ receptors in the prostate of the human body α ₁ -Adrenoceptor blocker. EP 34432 and US Pat. No. 4,731,478 are disclosed as pharmaceutically active substances having alpha-adrenergic blocking activity that are effective in the treatment of heart failure and benign prostatic hyperplasia.

  According to the pharmacokinetic study of tamsulosin, it is absorbed from the intestine and is almost completely biologically active.

  U.S. Pat. No. 4,772,475 discloses an oral drug controlled release combination drug, wherein each drug comprises a granulated product of a controlled release agent, a physiologically active substance and a drug forming substance. This patent emphasizes that the drug-forming substance (crystalline cellulose) must be at least 50% by weight or more. The drug of the present invention has a high physical strength, and the dissolution rate can be controlled without an enteric coating.

  However, because tamsulosin is absorbed from the intestine, the aim is to develop a composition that can gradually release the drug in the intestine where the drug is completely absorbed.

  It has been discovered that enteric coated tamsulosin controlled release drugs can provide release at a desired site. Controlled release compositions can be made with up to 50% w / w spheronizing agent.

  A controlled release pharmaceutical composition of tamsulosin comprising a spherical nucleus is provided. The core contains tamsulosin, approximately 10% to 45% w / w spheronizing agent, rate controlling polymer, enteric coating outer layer and the like. An enteric coating is provided to cover the nucleus.

  The core can include sugar, non-pareil seed, microcrystalline cellulose, celphere, silicon dioxide sand, glass, plastic, polystyrene, hydroxypropyl methylcellulose, and the like. Sugars can include glucose, mannitol, lactose, xylitol, dextrose and sucrose. The core can include non-soluble materials, soluble materials, and expandable materials.

  Examples of pharmaceutical compositions are produced by a spheronization process. A spheronizing agent is microcrystalline cellulose. Tamsulosin can include free radicals, pharmaceutically available salts and tamsulosin isomers. Pharmaceutically available salts of tamsulosin can include hydrochloride, hydroiodide, hydrobromide, and hydrogen fumarate. For example, the pharmaceutically available salt of tamsulosin may be the hydrochloride salt. The pharmaceutical composition can comprise from about 0.03% to about 0.33% by weight of a tamsulosin concentrate.

  Rate control polymers can include enteric polymers, water-insoluble polymers, water-soluble polymers, alkali metal salts of higher fatty acids, waxes and mixtures thereof. The rate controlling polymer can be present in the pharmaceutical composition at a concentration of about 20% to 90% by weight.

  Enteric polymers can include hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, methacrylic acid and ethyl acrylate copolymers. In particular, enteric polymers can include methacrylic acid and ethyl acrylate copolymers.

  Waxes can include hydroxylated vegetable oils, long chain fatty acid esters, long chain fatty acids and mixtures thereof. The wax can include glyceryl monostearate and stearic acid.

  The water-soluble polymer can include polyvinyl pyrrolidone, hydroxypropyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, methyl cellulose, and mixtures thereof.

  The water-insoluble polymer may include ethyl cellulose, cellulose acetate, a methacrylic acid-acrylic acid copolymer having a quaternary ammonia group, and a mixture thereof.

  Alkali metal salts of higher fatty acids can include magnesium stearate, zinc stearate, calcium stearate and mixtures thereof. In particular, the alkali metal salt of a higher fatty acid can contain magnesium stearate.

  The spherical core can include one or more drug-usable excipients. Pharmaceutically available excipients can include plasticizers, diluents, colorants, and fragrances.

  Enteric coatings can include hydroxypropyl methylcellulose phthalate, polyvinyl phthalate, cellulose acetate phthalate, copolymers of acrylic acid and methacrylic acid, and mixtures thereof. Enteric coatings can also include alkalizing agents, plasticizers, tackifiers and opacifiers.

  The pharmaceutical composition is formulated into capsules, bags, and tablets.

  According to another embodiment, a process for producing a tamsulosin controlled release pharmaceutical composition is provided. The process includes providing a sphere nucleus comprising tamsulosin, a spheronizing agent, and one or more rate controlling polymers, and coating the sphere nucleus with an enteric polymer. The core can be produced by extrusion spheronization. The extrusion spheronization process consists of a granulation step of tamsulosin, a spheronizing agent and a rate controlling polymer, an extrusion step of the granulation mixture, a spheronization step of the resulting extrudate, a drying step of the resulting sphere core, these sphere nuclei Coating with an enteric polymer.

  Tamsulosin can include tamsulosin free radicals, pharmaceutically usable salts and isomers. The pharmaceutically acceptable salt of tamsulosin may be hydrochloride, hydroiodide, hydrobromide or hydrogen fumarate. In one example, the pharmaceutically available salt of tamsulosin may be the hydrochloride salt. The pharmaceutical composition can comprise from about 0.03% to about 0.33% by weight of a tamsulosin concentrate.

  The rate control agent may include an enteric polymer, a water-insoluble polymer, a water-soluble polymer, an alkali metal salt of a higher fatty acid, a wax and a mixture thereof at a concentration of about 20% to 90% by weight of the composition.

  Enteric polymers can include hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, methacrylic acid and ethyl acrylate copolymers. In particular, enteric polymers can include methacrylic acid and ethyl acrylate copolymers.

  Waxes can include hydroxylated vegetable oils, long chain fatty acid esters, long chain fatty acids and mixtures thereof. In particular, the wax can include glyceryl monostearate and stearic acid.

  The water-soluble polymer can include polyvinyl pyrrolidone, hydroxypropyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, methyl cellulose, and mixtures thereof.

  The water-insoluble polymer may include ethyl cellulose, cellulose acetate, a methacrylic acid-acrylic acid copolymer having a quaternary ammonia group, and a mixture thereof.

  Alkali metal salts of higher fatty acids can include magnesium stearate, zinc stearate, calcium stearate and mixtures thereof. In particular, the alkali metal salt of a higher fatty acid can contain magnesium stearate.

  The spherical core can include one or more drug-usable excipients. Pharmaceutically available excipients can include plasticizers, diluents, colorants, and fragrances.

  The enteric polymer can include hydroxypropyl methylcellulose phthalate, polyvinyl phthalate, cellulose acetate phthalate, copolymers of acrylic acid and methacrylic acid, and mixtures thereof. The enteric coating can also include alkalizing agents, plasticizers, viscosity modifiers, and opacifiers.

  The pharmaceutical composition is formulated into capsules, bags, and tablets.

  According to yet another embodiment, a process for producing a controlled release pharmaceutical composition of tamsulosin is provided. This step comprises granulating a tamsulosin and spheronizing agent with one or more diffused rate controlling polymers, extruding the granulated product using an extrusion device, and forming the resulting extrudate into a spherical core. To spheronize and to coat the resulting sphere core.

  Tamsulosin can include free radicals, pharmaceutically acceptable salts and isomers of tamsulosin. Pharmaceutically available salts of tamsulosin can include hydrochloride, hydroiodide, hydrobromide, and hydrogen fumarate. For example, the pharmaceutically available salt of tamsulosin may be the hydrochloride salt. The pharmaceutical composition can comprise from about 0.03% to about 0.33% by weight of a tamsulosin concentrate.

  Rate control agents can include enteric polymers, water-insoluble polymers, water-soluble polymers, alkali metal salts of higher fatty acids, waxes, and mixtures thereof at a concentration of about 20% to 90% by weight of the composition. .

  Enteric polymers can include hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, methacrylic acid and ethyl acrylate copolymers. In particular, enteric polymers can include methacrylic acid and ethyl acrylate copolymers.

  Waxes can include hydroxylated vegetable oils, long chain fatty acid esters, long chain fatty acids and mixtures thereof. In particular, the wax can include glyceryl monostearate and stearic acid.

  The water-soluble polymer can include polyvinyl pyrrolidone, hydroxypropyl cellulose, carboxymethyl cellulose sodium, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, methyl cellulose, and mixtures thereof.

  The water-insoluble polymer may include ethyl cellulose, cellulose acetate, a methacrylic acid-acrylic acid copolymer having a quaternary ammonia group, and a mixture thereof.

  Alkali metal salts of higher fatty acids can include magnesium stearate, zinc stearate, calcium stearate and mixtures thereof. In particular, the alkali metal salt of a higher fatty acid can contain magnesium stearate.

  The spherical core can include one or more drug-usable excipients. Pharmaceutically available excipients can include plasticizers, diluents, colorants, and fragrances.

  Enteric coatings can include hydroxypropyl methylcellulose phthalate, polyvinyl phthalate, cellulose acetate phthalate, copolymers of acrylic acid and methacrylic acid, and mixtures thereof. The enteric coating can also include an alkalinizing agent, a plasticizer, an adhesion modifier and an opacifier.

  The pharmaceutical composition is formulated into capsules, bags, and tablets.

  In yet another embodiment, a method of manufacturing a controlled release drug composition includes providing a core with a coating, forming an individual drug, and forming a dosage form by combining one or more individual drugs.

  Examples of methods of manufacturing a controlled release combination drug dosage form can include one or more of the features described below, and can include any one or more of the features described above. The step of combining one or more individual drugs can include the step of packing the individual drugs in a capsule or bag, or the step of pressing the individual drugs into a tablet.

  In yet another embodiment, a method for treating benign prostatic hyperplasia is provided. The method includes a dosing step of a tamsulosin controlled release pharmaceutical composition comprising a spherical nucleus. The core includes tamsulosin, about 10% w / w to about 45% w / w spheronizing agent, and one or more rate controlling polymers. The core is then coated with an enteric coating.

  Embodiments can include one or more of the aforementioned features. Details of embodiments of the invention are described below. Other properties, objects and advantages of the invention will be apparent from the description and claims.

  The present invention relates to a controlled release individual drug or combination drug comprising an enteric coated sphere nucleus in which the nucleus comprises tamsulosin, a spheronizing agent of about 10% w / w to about 45% w / w and a rate controlling polymer.

  “Spherical” is a common term in pharmaceutical technology and means a spherical granule having a diameter of approximately 0.1 mm to 2.5 mm.

  Tamsulosin can include tamsulosin free radicals, pharmaceutically usable salts or isomers. Pharmaceutically available salts can include hydrochloride, hydroiodide, hydrobromide, hydrogen fumarate. Tamsulosin comprises about 0.03% to about 0.33% by weight of the composition.

  The spheronizing agent can include any drug-usable substance that is spheronized with the active substance sphere to form a sphere nucleus. The most common spheronizing agent is microcrystalline cellulose. Examples of microcrystalline cellulose that can be used include Avicel PH101 or Avicel PH102 from FMC Corporation. The spheronizing agent can be present in the range of about 10% to about 45% by weight of the formulation.

  Rate control agents can include enteric polymers, water-insoluble polymers, water-soluble polymers, alkaline metal salts of higher fatty acids, waxes, and mixtures thereof.

  Suitable enteric polymers include hydroxypropyl methylcellulose acetate phthalate, hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate phthalate, polymethyl acrylate and copolymers of acrylic acid and methacrylic acid (sold under the trademark Eudragit), for example Eudragit L30D-55 (diffused anionic aqueous polymer of methacrylic acid-ethyl acrylate copolymer), Eudragit L100-55 (spray-dried Eudragit L30D-55 that can be reduced as an aqueous diffuser), Eudragit L100 (pH 6. Anionic polymer powder that dissolves at 0 or higher) and Eudragit S100 (anionic polymer powder that dissolves at pH 7.0 or higher) (Conventional).

  Suitable waxes include hydroxylated vegetable oils, long chain fatty acid esters, stearic acid and oleic acid, long chain fatty acids of mixtures thereof, and the like.

  Suitable water-insoluble polymers include ethyl cellulose, cellulose acetate, copolymers of polyethylene and vinyl acetate, methyl methacrylate methacrylate with quaternary ammonia groups sold under trademarks such as Eudragit RL, Eudragit RS and Eudragit NE Including copolymers.

  Suitable alkaline metal salts of higher fatty acids include magnesium stearate, zinc stearate, calcium stearate.

  Suitable water soluble polymers can include polyvinyl pyrrolidone, sodium carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, methylcellulose and mixtures thereof.

  The rate controlling polymer can comprise from about 20% to about 90% by weight of the formulation. The rate controlling polymer of the present invention can also act as a binder and can be added, dissolved or diffused into a suitable solvent system, and the resulting solution or diffuse can then be used to granulate the active agent. Is done. The resulting granule mass is then processed in an extrusion or spheronization step. This method allows the rate controlling polymer to more effectively delay drug release.

  Optionally, in addition to the active agent, spheronizing agent, and rate controlling polymer, the sphere core can also include other drug-available excipients. Other pharmaceutically available excipients for use herein include plasticizers, diluents, colorants and fragrances.

  Suitable diluents include lactose, starch, sugar alcohol, sucrose and mixtures thereof.

The controlled release composition according to the present invention is manufactured in the following steps.
a. Tamsulosin, spheronizing agent and rate controlling polymer are granulated with water.
b. The resulting granule mixture is extruded.
c. The resulting extrudate is spheronized until sphere nuclei are formed.

  Alternatively, the granulation process in step a) may be performed while diffusing the rate controlling polymer.

  The extrusion process can be performed with any extrusion device such as a screw feed extrusion device, a gravity-feed extrusion device such as a cylindrical roll or a gear roll, and a piston-feed extrusion device.

  The pharmaceutical composition according to the present invention further comprises an enteric coating so as to cover the spherical core. The coating does not substantially dissolve in the acidic environment of the stomach and dissolves well over time in a controlled release state in the intestine.

  Examples of enteric coatings include neutralized hydroxypropyl methylcellulose phthalate (HPMCP) coating, beeswax, glyceryl monostearate, shellac and cellulose, shellac and stearic acid; methacrylic acid and methacrylic acid methyl ester (Eudragit, trade name) And neutralized copolymers of polymethacrylates containing metallic stearates.

  Conventional enteric coatings such as polyvinyl acetate phthalate, cellulose acetate phthalate, cellulose acetate succinate may be utilized.

  Most substances in enteric coatings are acidic and therefore chemically unstable when contacted with an active substance. This can be prevented by using suitable alkalizing agents such as sodium hydroxide, potassium hydroxide, calcium carbonate, sodium carboxymethylcellulose, magnesium oxide and magnesium hydroxide. The enteric coating can also include plasticizers of citrate, triacetin, diethyl phthalate, dibutyl phthalate, polyethylene glycol, propylene glycol, glycerin, tributyl citrate. Enteric coatings can also contain anti-adhesives or tack modifiers as inert adjuvants to stabilize the coating process. Suitable tack modifiers can include talc, kaolin or anhydrous colloidal silica. The coating can include an opacifier such as titanium dioxide.

  The enteric coating layer can be formed on the surface of the spherical core by a conventional coating method such as fluidized coating or pan coating.

  The composition according to the present invention can be packed into capsules, bags or pressed into tablets using conventional pharmaceutical techniques. The improved combined drug system described above is further illustrated in the following examples. These examples are illustrative of the techniques, compositions and concepts described herein and are not intended to limit the invention.

Manufacturing steps:
1. Tamsulosin hydrochloride is dissolved in water, and the resulting solution is used for granulation of microcrystalline cellulose in a mixer.
2. The granule of Step 1 is dried at 60 ° C. in a liquid bed dryer, and sieved to obtain fine particles having a size of approximately 600 μm or less.
3. Sieve magnesium stearate / glyceryl monostearate / stearic acid and starch to obtain a fine particle having a size of 600 μm or less, and mix it with the granule of Step 2 in a mixer.
4). The step 3 mixture is granulated with a diffused methacrylic acid-ethyl acrylate copolymer (Eudragit L30D55) in a rotary mixer grinder. In Example 3, the same mixture is further granulated with a 10% solution of povidone in water.
5. The granulate from step 4 is extruded through a tube with an inner diameter of 1 mm.
6). The extrudate from step 5 is spheronized with a spheronizer equipped with a 3.25 mm pitch plate.
7). The spherical core obtained in Step 6 is dried at 60 ° C. for 1 hour in a liquid bed dryer.
8). The enteric coating material is diffused in water to produce a diffusion enteric coating of Eudragit L100: 55.
9. Coat the spherical nuclei of step 7 with the diffuse of step 8 to add a weight of approximately 3.33% w / w.
10. Pack the coated nuclei from step 9 into capsules.

  In order to examine the in vitro release of tamsulosin, the capsule obtained in Example 1 was compared with the FLOMAX capsule (containing 0.4 mg tamsulosin manufactured by Boehringer Ingelheim). Dissolution experiments were performed using USP apparatus II in 500 ml of pH 6.8 phosphate buffer at 50 rpm. The results are shown in Table 1.

表４：ＵＳＰ溶解装置ＩＩ／５００ｍｌ・ｐＨ６．８燐酸バッファ／５０ｒｐｍを使用した、カプセルからのタムスロシン体外放出性データ（実施例１のもの）と、ＦＬＯＭＡＸカプセル（Ｂｏｅｈｒｉｎｇｅｒ Ｉｎｇｅｌｈｅｉｍ製）との比較

Table 4: Comparison of tamsulosin extracorporeal release data from capsules (from Example 1) and FLOMAX capsules (Boehringer Ingelheim) using USP dissolution apparatus II / 500 ml pH 6.8 phosphate buffer / 50 rpm

  Although the features of the present invention have been described using examples, it goes without saying that improvements and combinations can be made without departing from the essence of the present invention. Further, specific combinations thereof are not described in the claims, but do not limit the scope of the present invention.

Claims (71)

Tamsulosin controlled release pharmaceutical composition comprising: (a) i. Tamsulosin ii. Approximately 10% w / w to 45% w / w spheronizing agent iii. A spherical core containing one or more rate controlling polymers;
(B) an enteric coating covering the sphere core;
A pharmaceutical composition comprising:   The composition according to claim 1, wherein the tamsulosin comprises a tamsulosin free radical, a pharmaceutically usable salt and an isomer.   The composition of claim 2, wherein the pharmaceutically acceptable salt of tamsulosin includes hydrochloride, hydroiodide, hydrobromic acid and hydrogen fumarate.   The composition of claim 3, wherein the pharmaceutically acceptable salt of tamsulosin is hydrochloride.   The composition of claim 1, wherein the composition comprises from about 0.03% to about 0.33% by weight tamsulosin concentrate.   The composition according to claim 1, wherein the spheronizing agent is microcrystalline cellulose.   The composition according to claim 1, wherein the rate controlling polymer comprises an enteric polymer, a water-insoluble polymer, an alkaline metal salt of a water-soluble polymer higher fatty acid, a wax, and a mixture thereof.   The composition of claim 1, wherein the composition comprises from about 20% to about 90% by weight of a rate controlling polymer.   8. The composition according to claim 7, wherein the enteric polymer includes hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, and a copolymer of methacrylic acid and ethyl acrylate.   The composition of claim 9, wherein the enteric polymer comprises one or more copolymers of methacrylic acid and ethyl acrylate.   8. The composition according to claim 7, wherein the wax comprises a hydroxylated vegetable oil, an ester of a long chain fatty acid, a long chain fatty acid, and a mixture thereof.   The composition according to claim 11, wherein the wax is glyceryl monostearate.   The composition according to claim 11, wherein the wax is stearic acid.   The composition according to claim 7, wherein the water-soluble polymer includes polyvinylpyrrolidone, hydroxypropylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, methylcellulose, and a mixture thereof.   The composition according to claim 7, wherein the water-insoluble polymer includes ethyl cellulose, cellulose acetate, a methacrylic acid-acrylic acid copolymer having a quaternary ammonia group, and a mixture thereof.   8. The composition according to claim 7, wherein the alkaline metal salt of a higher fatty acid includes magnesium stearate, zinc stearate, calcium stearate, and a mixture thereof.   The composition according to claim 16, wherein the alkaline metal salt of a higher fatty acid is magnesium stearate.   The composition of claim 1, wherein the spherical nucleus comprises one or more pharmaceutically usable excipients.   The composition according to claim 18, wherein the pharmaceutically usable excipient includes a plasticizer, a diluent, a colorant and a fragrance.   The composition according to claim 1, wherein the enteric coating layer comprises hydroxypropyl methylcellulose phthalate, polyvinyl phthalate, cellulose acetate phthalate, a copolymer of acrylic acid and methacrylic acid, and a mixture thereof.   The composition according to claim 20, wherein the enteric coating contains an alkalizing agent, a plasticizer, a viscosity modifier, and an opacifier.   The composition according to claim 1, wherein the composition is in the form of a capsule, a bag or a tablet. A method for producing a tamsulosin controlled release pharmaceutical composition comprising the steps of:
(A) granulating tamsulosin, spheronizing agent and one or more rate controlling polymers to obtain a granule mixture;
(B) extruding the granule mixture to obtain an extrudate;
(C) spheroidizing the extrudate to obtain a spherical core;
(D) drying the spherical core;
(E) coating the spherical core with an enteric polymer;
A method for producing a pharmaceutical composition, comprising:   25. The method of claim 24, wherein tamsulosin comprises tamsulosin free radicals, pharmaceutically usable salts and isomers.   25. The method of claim 24, wherein the pharmaceutically acceptable salts of tamsulosin include hydrochloride, hydroiodide, hydrobromide and hydrogen fumarate.   26. A method according to claim 25, characterized in that the pharmaceutically acceptable salt of tamsulosin is hydrochloride.   24. The method of claim 23, wherein the pharmaceutical composition comprises from about 0.03% to about 0.33% by weight tamsulosin concentrate.   24. The method of claim 23, wherein the spheroid is microcrystalline cellulose.   24. The method of claim 23, wherein the rate controlling polymer comprises an enteric polymer, a water insoluble polymer, a water soluble polymer, an alkaline metal salt of a higher fatty acid, a wax, and mixtures thereof.   24. The method of claim 23, wherein the pharmaceutical composition comprises from about 20% to about 90% by weight of a rate controlling polymer concentrate.   30. The method of claim 29, wherein the enteric polymer comprises hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, a copolymer of methacrylic acid and ethyl acrylate.   32. The method of claim 31, wherein the enteric polymer comprises a copolymer of methacrylic acid and ethyl acrylate.   30. The method of claim 29, wherein the wax comprises hydroxylated vegetable oil, esters of long chain fatty acids, long chain fatty acids, and mixtures thereof.   34. The method of claim 33, wherein the wax is glyceryl monostearate.   34. A method according to claim 33, wherein the wax is stearic acid.   30. The method of claim 29, wherein the water-soluble polymer includes polyvinylpyrrolidone, hydroxypropylcellulose, carboxymethylcellulose sodium, hydroxypropylmethylcellulose, hydroxyethylcellulose, methylcellulose, and mixtures thereof.   30. The method of claim 29, wherein the water-insoluble polymer includes ethyl cellulose, cellulose acetate, methacrylic acid-acrylic acid copolymers having quaternary ammonium groups, and mixtures thereof.   30. The method of claim 29, wherein the alkaline metal salt of a higher fatty acid is magnesium stearate, zinc stearate, calcium stearate and mixtures thereof.   40. The method of claim 38, wherein the alkaline metal salt of the higher fatty acid is magnesium stearate.   24. The method of claim 23, wherein the spherical nucleus comprises one or more pharmaceutically available excipients.   41. The method of claim 40, wherein the pharmaceutically usable excipient comprises a plasticizer, diluent, colorant or fragrance.   24. The method of claim 23, wherein the enteric coating comprises an enteric polymer.   43. The method of claim 42, wherein the enteric polymer includes hydroxypropyl methylcellulose phthalate, polyvinyl phthalate, cellulose acetate phthalate, a copolymer of acrylic acid and methacrylic acid, and mixtures thereof.   43. The method of claim 42, wherein the enteric coating comprises an alkalinizing agent, a plasticizer, a viscosity modifier, and an opacifier.   The method according to claim 23, wherein the composition is a capsule, a bag or a tablet. A method for producing a tamsulosin controlled release pharmaceutical composition comprising the steps of:
(A) granulating tamsulosin and spheronizing agent with one or more diffused rate controlling polymers to obtain granules;
(B) extruding the granule with an extrusion device to form an extrudate;
(C) spheronizing the extrudate until a spherical core is formed;
(D) coating the spherical core with an enteric polymer;
The manufacturing method characterized by including.   49. The method of claim 46, wherein tamsulosin comprises tamsulosin free radicals, pharmaceutically usable salts and isomers.   48. The method of claim 47, wherein pharmaceutically acceptable salts of tamsulosin include hydrochloride, hydroiodide, hydrobromide, and hydrogen fumarate.   49. The method of claim 48, wherein the pharmaceutically acceptable salt of tamsulosin is hydrochloride.   49. The method of claim 46, wherein the pharmaceutical composition comprises from about 0.03% to about 0.33% by weight tamsulosin concentrate.   The method of claim 46, wherein the spheronizing agent is microcrystalline cellulose.   The method of claim 46, wherein the rate controlling polymer comprises an enteric polymer, a water-insoluble polymer, a water-soluble polymer, an alkaline metal salt of a higher fatty acid, a wax, and a mixture thereof.   47. The method of claim 46, wherein the pharmaceutical composition comprises from about 20% to about 90% by weight of a rate controlling polymer concentrate.   53. The method of claim 52, wherein the enteric polymer comprises hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, a copolymer of methacrylic acid and ethyl acrylate.   55. The method of claim 54, wherein the enteric polymer comprises a copolymer of methacrylic acid and ethyl acrylate.   53. The method of claim 52, wherein the wax includes a hydroxylated vegetable oil, an ester of a long chain fatty acid, a long chain fatty acid, and mixtures thereof.   57. The method of claim 56, wherein the wax is glyceryl monostearate.   57. The method of claim 56, wherein the wax is stearic acid.   53. The method of claim 52, wherein the water soluble polymer includes polyvinyl pyrrolidone, hydroxypropyl cellulose, carboxymethyl cellulose sodium, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, methyl cellulose, and mixtures thereof.   53. The method according to claim 52, wherein the water-insoluble polymer includes ethyl cellulose, cellulose acetate, a copolymer of methacrylic acid and acrylic acid having a quaternary ammonium group, and a mixture thereof.   53. The method of claim 52, wherein the alkaline metal salt of the higher fatty acid is magnesium stearate, zinc stearate, calcium stearate, and mixtures thereof.   62. The method of claim 61, wherein the alkaline metal salt of the higher fatty acid is magnesium stearate.   49. The method of claim 46, wherein the spherical nucleus comprises one or more pharmaceutically available excipients.   64. The method of claim 63, wherein the pharmaceutically usable excipient comprises a plasticizer, a diluent, a colorant and a fragrance.   49. The method of claim 46, wherein the enteric coating comprises an enteric polymer.   66. The method of claim 65, wherein the enteric polymer includes hydroxypropyl methylcellulose phthalate, polyvinyl phthalate, cellulose acetate phthalate, a copolymer of acrylic acid and methacrylic acid, and mixtures thereof.   The method of claim 46, wherein the enteric coating includes an alkalinizing agent, a plasticizer, a viscosity modifier, and an opacifier.   The method according to claim 46, wherein the composition is a capsule, a bag or a tablet. A method for treating benign prostatic hyperplasia comprising the step of administering a controlled release pharmaceutical composition of tamsulosin, the composition comprising:
(A) i. Tamsulosin ii. From about 10% w / w to about 45% w / w spheronizing agent iii. A rate controlling polymer;
A spherical nucleus containing
(B) an enteric coating covering the sphere core;
A method comprising the steps of: A controlled release drug composition comprising one or more individual drugs, the individual drug comprising:
(A) i. Tamsulosin,
ii. About 10% w / w to about 45% w / w spheronizing agent;
iii. Speed control polymer,
A spherical nucleus containing
(B) an enteric coating covering the sphere core;
A pharmaceutical composition comprising:   The composition according to claim 70, wherein the composition is a capsule, a bag or a tablet.