WO2005023225A1 - Cilostazol adsorbate - Google Patents
Cilostazol adsorbate Download PDFInfo
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- WO2005023225A1 WO2005023225A1 PCT/IB2004/002866 IB2004002866W WO2005023225A1 WO 2005023225 A1 WO2005023225 A1 WO 2005023225A1 IB 2004002866 W IB2004002866 W IB 2004002866W WO 2005023225 A1 WO2005023225 A1 WO 2005023225A1
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- WIPO (PCT)
- Prior art keywords
- cilostazol
- pharmaceutical composition
- adsorbate
- solvent
- inert
- Prior art date
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1682—Processes
- A61K9/1694—Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
Abstract
The invention relates to cilostazol adsorbates, and processes for their preparation. It also relates to oral pharmaceutical compositions that include the cilostazol adsorbate.
Description
CILOSTAZOL ADSORBATE Field of the Invention The technical field of the invention relates to cilostazol adsorbates, and processes for their preparation. It also relates to oral pharmaceutical compositions that include the cilostazol adsorbate. Background of the Invention Chemically, cilostazol, 6-[4-(l-cyclohexyl-lH-tetrazol-5-yl) butoxy]-3,4- dihydrocarbostyrl. It not only shows a high platelet aggregation suppression action but also various other kinds of medical actions such as phosphodiesterase inhibition action, an anti-ulcer action, a hypotensive action and an anti-phlogistic action. Therefore, cilostazol is widely used as thrombolytic drug, cerebral circulation improving drug, anti-phlogistic drug, anti-ulcer drug, hypotensive drug, drug for asthma, phosphodiesterase inhibitor and the like. Cilostazol is practically insoluble in water, and its bioavailability from pharmaceutical compositions is considered to be dissolution rate limited. Well-defined approaches addressing the solubility problem of cilostazol, are therefore needed to improve the dissolution rate, and consequently to achieve the desired bioavailability and therapeutic effects. Prior art approaches are mainly directed to micronization of cilostazol, prior to use in pharmaceutical compositions, as an aid to improve dissolution. For example, WO
00/57881 discloses a cilostazol preparation, which comprises cilostazol having an average particle diameter of about 3 μm or less into a suspending and/or solubilizing agent having capability of dissolving cilostazol even at lower portion of digestive tract. WO 96/21448 discloses a resin particle having a particle size of not greater than 2000μm, which comprises an ethylene vinyl alcohol copolymer and 5 to 10% by weight of cilostazol. The resin particle, upon being administered orally allows the concentration of cilostazol in blood to be kept constant over an extended period of time. Summary of the Invention However, there still exists a need for alternate approaches, which would be economically feasible and less time consuming. The inventors have now discovered that
adsorption of cilostazol on inert carriers to form adsorbates, would provide dosage form with improved rates of dissolution. In one general aspect there is provided cilostazol adsorbates. The cilostazol adsorbates include cilostazol adsorbed on inert carrier. The inert carriers may include one or more of polymeric carriers like cellulose derivatives such as microcrystalline cellulose, hydroxypropyl cellulose, hydroxy propyl methyl cellulose; starches such as maize, rice, corn and potato starch; super disintegrants such as croscarmellose sodium (Ac-Disol), sodium starch glycolate, and crospovidone; polyvinyl alcohol; polyvinyl pyrrolidone; solid grades of polyethylene glycols; and non- polymeric carriers like lactose and cyclodextrins. The inert carrier may also be commercially available inert carriers comprising the above inert carrier material such as non-pareil seed, celphere, and the like, hi particular, the super disintegrants, mannitol, polyvinyl pyrrolidone, polyethylene glycol, microcrystalline cellulose, sucrose may be used. The ratio of cilostazol to inert carrier may vary from about 1 : 0.1 to about 1 : 10 by weight. In another general aspect there is provided a process of preparing a cilostazol adsorbate. The process includes the steps of layering on an inert carrier a solution of cilostazol in a solvent; drying; and optionally milling. another general aspect there is provided a process of preparing a cilostazol adsorbate. The process includes the steps of dissolving or suspending cilostazol and an inert carrier in a solvent; evaporating the solvent to give a residue; and optionally milling the resultant residue. In another general aspect there is provided a process of preparing a cilostazol adsorbate. The process includes the steps of dissolving or suspending cilostazol and an inert carrier in a solvent; adding a miscible anti-solvent to precipitate out cilostazol coated carriers; and optionally milling the precipitate. one general aspect there is provided a pharmaceutical composition that includes cilostazol adsorbate and one or more pharmaceutically acceptable inert excipients. The one or more pharmaceutically acceptable inert excipients may be selected from the group consisting of wetting agents, diluents, crystal modifiers, binders, disintegrants, coloring agents, flavoring agents, stabilizers, lubricants/glidants and plasticizers.
h another general aspect there is provided a process for preparing a pharmaceutical composition of cilostazol. The process includes the steps of combining cilostazol adsorbate and one or more pharmaceutical acceptable inert excipients, and processing into a solid dosage form. In another general aspect there is provided a modified release pharmaceutical composition that includes cilostazol adsorbate, rate controlling polymer, and one or more pharmaceutically acceptable inert excipients. In another aspect there is provided a process for preparing a modified release pharmaceutical composition of cilostazol. The process includes the steps of combining cilostazol adsorbate, rate controlling polymer and one or more pharmaceutical inert excipients, and processing into a solid dosage form. The composition may be formulated in the form of granules filled in capsule, tablet or other suitable dosage form. The tablet formulation may further be coated. In another general aspect there is provided a method of treating intermittent claudication by administering a pharmaceutical composition to a mammal in need thereof. The pharmaceutical composition includes cilostazol adsorbate and one or more pharmaceutical inert excipients. i another general aspect there is provided a method of treating intermittent claudication by administering a modified release pharmaceutical composition to a mammal in need thereof. The modified release pharmaceutical composition includes cilostazol adsorbate, rate controlling polymer, and one or more pharmaceutically acceptable inert excipients. The details of one or more embodiments of the inventions are set forth in the description below. Other features and advantages of the inventions will be apparent from the description and the claims. Detailed Description of the Invention The inventors have found that improved dissolution characteristics, and consequently improved bioavailability can be achieved by pharmaceutical compositions that include cilostazol adsorbates. The cilostazol adsorbates can be prepared by adsorption of cilostazol on inert carriers. On oral administration, the cilostazol is released from the adsorbates into the surrounding media, in a highly dispersed form, enhancing dissolution.
The preparation of adsorbates maintains the particulate nature throughout processing and storage, until it is released in the dissolution media/ gastrointestinal fluids. It also helps to achieve the reproducible results. The term "cilostazol" as used herein includes cilostazol and its pharmaceutically acceptable salts. The term "cilostazol adsorbate" as used herein refers to particles of cilostazol or its phannaceutically acceptable salts that are closely associated with the carrier in clusters. However, it is not essential that all of the particles of cilostazol or its pharmaceutically salts may actually be in contact with the carrier particle. The term "inert carrier" as used herein refers to an organic material having an external surface area on which cilostazol can be adsorbed from solution in fine particle form. Examples of inert carriers include polymeric carriers like cellulose derivatives such as microcrystalline cellulose, hydroxypropyl cellulose, hydroxy propyl methyl cellulose; starches such as maize, rice, corn and potato starch; super disintegrants such as croscarmellose sodium (Ac-Disol), sodium starch glycolate, and crospovidone; polyvinyl alcohol; polyvinyl pyrrolidone; solid grades of polyethylene glycols; and non-polymeric carriers like lactose and cyclodextrins. The inert carrier may also be commercially available inert carriers comprising the above inert carrier material such as non-pareil seed, celphere, and the like. In particular, the super disintegrants, mannitol, polyvinyl pyrrolidone, polyethylene glycol, microcrystalline cellulose, sucrose may be used. The ratio of cilostazol to inert carrier may vary from about 1 :0.1 to about 1 :10 by weight. The invention further includes a process of preparing cilostazol adsorbates. In general, the process includes dissolving cilostazol in a solvent to form a solution, and layering the solution on an inert carrier, according to the techniques known in the art, for example, dip coating, spray coating, and compression coating. The coated inert carriers may then be milled to form the adsorbates. In one aspect, cilostazol adsorbate may be prepared by dissolving cilostazol in a solvent to form a solution, adding inert carrier into the solution to form a suspension, evaporating the solvent to get a residue, drying the resulting residue and milling. In one aspect, cilostazol adsorbate may be prepared by a) dissolving cilostazol in a solvent to form a solution,
b) adding inert carriers to the solvent to form a suspension, c) combining the solution of step a) and suspension of step b) to form a suspension, d) evaporating the solvent of suspension of step c) to get a residue, and e) drying the resulting residue and milling. The solvent used to prepare cilostazol solution or inert carrier suspension may be the same or even different. The solution and suspension may be combined in either order; or they may be simultaneously combined into a separate container with constant stirring. In particular, they may be combined by adding the suspension into the solution. h one aspect, the cilostazol adsorbate may be prepared by dissolving cilostazol in a solvent to form a solution, adding inert carrier into the solution to form a suspension, adding a miscible anti-solvent to precipitate out cilostazol coated carriers, and drying and milling the precipitate. The adsorbates prepared in any of the aspects above, may further include one or more pharmaceutically acceptable excipients such as binders, crystal modifiers, wetting agents, and the like. Suitable solvents for dissolving or suspending cilostazol and carrier include one or more organic solvents, including, for example, ethanol, methanol, isopropanol, tertiary butanol, acetone, dimethyl sulfoxide, dimethylfomiamide, tertahydrofuran, methylene chloride, chloroform, triethylamine, pyridine, ethyl acetate, acetonitrile and the mixtures thereof. Examples of anti-solvents include one or more of aqueous and/or non-aqueous solvents such as methanol, isopropyl alcohol and water. The residue obtained on drying of the solvent, or the precipitate separated on addition of anti-solvent may be dried using conventional drying methods such as spray drying, filtration, freeze-drying. In particular, spray drying maybe used. Milling of the dried cilostazol adsorbates may be carried out in conventional milling equipments, such as cad mill, air-jet mill, multi mill and the like. The cilostazol adsorbate prepared by any of the processes above may be used as such or combined with other pharmaceutically acceptable inert excipients to form pharmaceutical compositions formulated as solid dosage forms such as tablet, capsule,
granule and the like. The pharmaceutical composition may be prepared as a conventional immediate release dosage form, or a modified release dosage form. The modified release dosage form in addition to above may also include one or more rate-controlling polymers. The term "modified release dosage form" as used herein includes any modified release formulation intended for slow release such as sustained release, controlled release, delayed release, timed release etc.; capable of modifying and controlling the release of cilostazol up to a period of about 24 hours. Examples of rate-controlling polymers include one or more of cellulose derivatives, alginic acid derivatives methacrylic acid derivatives, waxes, polysaccharides, alkylene oxides and the like. In one aspect, the pharmaceutical composition of cilostazol may be prepared by a process that includes the steps of: blending cilostazol adsorbate with pharmaceutically acceptable inert excipients; optionally granulating the blend; lubricating the blend/granules and processing into a solid dosage form. In another aspect, modified release pharmaceutical composition of cilostazol may be prepared by a process comprising the steps of: blending cilostazol adsorbate, rate- controlling polymer and pharmaceutically acceptable inert excipients; optionally granulating the blend; lubricating the blend/granules and processing into a solid dosage form. Cilostazol adsorbates may be granulated with the pharmaceutically excipients using any of the conventional methods used in the art including wet granulation, dry granulation, and extrusion-spheronization. hi the wet granulation method, the dry solids (active ingredients, filler, disintegrant, etc.) are blended and moistened with the binder solution and then the agglomerates or granules are built up of the moistened solids. Wet massing is continued until a desired homogeneous particle size has been achieved whereupon the granulated product is dried to form dried granules. The dried granules are blended with lubricants and, optionally, a disintegrant and the blend then is compressed into tablets or filled into hard gelatin capsules. hi the dry granulation method, the active ingredient can be compacted alone or together with other pharmaceutically acceptable excipients. The granules then are mixed with extragranular excipients and compressed into tablets or filled into hard gelatin capsules.
Thus, the cilostazol dosage forms can be a tablet dosage form prepared by compression of granules of active ingredient and pharmaceutically acceptable excipients obtained by the wet granulation method or the dry granulation method. The cilostazol dosage forms also can be a capsule prepared by filling granules of active ingredient and pharmaceutically acceptable excipients obtained by the wet granulation method or the dry granulation method in a hard gelatin capsule. Examples of pharmaceutically acceptable inert excipients include wetting agents, diluents, crystal modifiers, binders, disintegrants, coloring agents, flavoring agents, stabilizers, lubricants/glidants and plasticizers. Examples of wetting agents may include both ionic and non-ionic wetting agents.
These include polyethylene glycols; polyoxyethylene - polyoxypropylene block copolymers known as "poloxamer"; polyglycerin fatty acid ester such as decaglyceryl monolaurate and decaglyceryl monomyristate, polyoxyethylene sorbitan fatty acid ester such as polyoxyethylene sorbitan monooleate, polyethylene glycol fatty acid ester such as polyoxyethylene monosterate, polyoxyethylene alkyl ether such as poluoxyethylene lauryl ether; polyoxyethylene castor oil and hardened castor oil, such as polyoxyethylene hardened castor oil; sucrose ester of fatty acid such as sucrose state ester and sucrose palmitate ester and alkyl sulfate salt such as sodium lauryl sulfate and magnesium lauryl sulfate; sodium caproate, sodium glycocholate, soy lecithin, sodium stearyl fumarate, propylene glycol alginate, octyl sulfosuccinate disodium, palmitoyl carnitine; and the like, h particular, poloxamer (available in trade name of Lutrol) is used. Examples of diluents include calcium carbonate, calcium phosphate-dibasic, calcium phosphate-tribasic, calcium sulfate, cellulose-microcrystalline, cellulose powdered, dextrates, dextrins, dextrose excipients, fructose, kaolin, lactitol, lactose, mannitol, sorbitol, starch pregelatinized, sucrose, sugar compressible, sugar confectioners and the like and combinations thereof Suitable crystal modifiers may include one or more of polyethylene glycol, poly vinyl pyrrolidone and the like. Suitable binders may include one or more of polyvinyl pyrrolidone, methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, gelatin, gum Arabic, ethyl cellulose, polyvinyl alcohol, pullulan, pregelatinized starch, agar, tragacanth, sodium alginate, propylene glycol and the like.
Suitable disintegrants may include one or more of microcrystalline cellulose, croscarmellose sodium, crospovidone, carboxymethyl starch sodium, sodium starch glycollate and the like. Suitable lubricants and glidants may include one or more of colloidal anhydrous silica, stearic acid, magnesium stearate, calcium stearate, talc, hydrogenated castor oil, sucrose esters of fatty acid, microcrystalline wax, yellow beeswax, white beeswax and the like. Suitable plasticizers may include one or more of polyethylene glycol, triethyl citrate, triacetin, diethyl phthalate, dibutyl sebacate, and the like. Suitable stabilizers may include one or more of antioxidants, buffers, acids and the like. The colors may be selected from any FDA approved colors for oral use. The solid dosage form may be further coated with one or more functional and/or non-functional layers comprising film-forming materials. Examples of film forming material may include water soluble coating materials of celluloses such as hydroxy propyl cellulose, hydroxy propyl methyl cellulose, hydroxyethyl cellulose, methyl hydroxy ethyl cellulose; enteric coating material of celluloses such as hydroxy propyl methyl cellulose phthalate, hydroxy propyl methyl cellulose acetate succinate, and cellulose acetate phthalate; and other enteric film coating materials such as methacrylic acid copolymer, shellac and the like. The invention is further illustrated by the following examples but they should not be construed as limiting the scope of the invention any way.
Cilostazol Adsorbate
Example 1 :
Cilostazol adsorbate Example 14:
Procedure: 1. Cilostazol was dissolved in methanol (at 65°C) with constant stirring. 2. To the solution formed in step 1, other excipients were added with constant stirring. 3. The resultant suspension was stirred at room temperature, and filtered under vacuum. 4. The material collected on the filter was dried overnight, and crushed to obtain cilostazol adsorbate.
Cilostazol tablet Example 15:
Procedure: Same as in Example 4. In vitro dissolution study Procedure: Same as in Example 9. The results of the study are listed below.
Cilostazol adsorbate Example 16:
Procedure:
Same as in Example 9. The results of the study are listed below.
Claims
We claim:1. A pharmaceutical composition comprising cilostazol adsorbate and one or more pharmaceutically acceptable inert excipients.
2. The pharmaceutical composition of claim 1 , wherein the cilostazol adsorbate comprises cilostazol adsorbed on inert carrier.
3. The pharmaceutical composition of claim 2, wherein cilostazol adsorbate comprises pharmaceutically acceptable salts of cilostazol.
4. The pharmaceutical composition of claim 2, wherein the inert carrier comprises one or more of polymeric carriers like cellulose derivatives, starches, super disintegrants, polyvinyl alcohol, polyvinyl pyrrolidone, solid grades of polyethylene glycols, and non-polymeric carriers.
5. The pharmaceutical composition of claim 4, wherein the cellulose derivatives comprise one or more of microcrystalline cellulose, hydroxypropyl cellulose, and hydroxypropyl methyl cellulose.
6. The pharmaceutical composition of claim 4, wherein the starch comprises one or more of maize, rice, corn, and potato starch.
7. The pharmaceutical composition of claim 4, wherein the super disintegrant comprises one or more of croscarmellose sodium, sodium starch glycolote, and crospovidone.
8. The pharmaceutical composition of claim 4, wherein the non-polymeric carriers comprise one or both of lactose and cyclodextrins.
9. The pharmaceutical composition of claim 4, wherein the inert carrier is mannitol, polyvinyl pyrrolidone, polyethylene glycol, microcrystalline cellulose, sucrose, or super disintegrant.
10. The pharmaceutical composition of claim 2, wherein the weight ratio of cilostazol and inert carrier may vary from about 1:0.1 to about 1:10.
11. The pharmaceutical composition of claim 1 , wherein the pharmaceutically acceptable inert excipients comprise one or more of wetting agents, diluents, crystal modifiers, binders, disintegrants, coloring agents, flavoring agents, stabilizers, lubricants/glidants and plasticizers.
12. The pharmaceutical composition of claim 1, wherein the composition is a tablet, capsule or granule.
13. The pharmaceutical composition of claim 12, wherein the composition is a tablet.
14. The pharmaceutical composition of claim 13, wherein the tablet is coated.
15. A process for preparing a cilostazol adsorbate, the process comprising the steps of layering on an inert carrier a solution of cilostazol in a solvent, followed by drying and optionally milling.
16. The process of claim 15, wherein the layering on inert carriers is done by dip coating or spray coating technique.
17. The process of claim 16, wherein the layering on inert carriers is done by spray coating technique.
18. A process for preparing a cilostazol adsorbate, the process comprising the steps of dissolving or suspending cilostazol and an inert carrier in a solvent, evaporating the solvent to get a residue, and optionally milling the resultant residue.
19. A process for preparing a cilostazol adsorbate, the process comprising the steps of dissolving or suspending cilostazol and an inert carrier in a solvent, adding a miscible anti-solvent to precipitate out cilostazol coated carriers, and optionally milling the precipitate.
20. The process of claim 18 or 19, wherein the cilostazol is dissolved in a solvent to fonn a solution, and inert carrier is suspended into the solution.
21. The process of claim 18 or 19, wherein the cilostazol is dissolved in a solvent to form a solution, inert carrier is suspended in a solvent to form a suspension separately, and then combined together.
22. The process of claim 21 , wherein the solvent used to prepare the solution of cilostazol and the suspension of inert carrier is same.
23. The process of claim 21, wherein the solvent used to prepare the solution of cilostazol and the suspension of inert carrier is different.
24. The process of claim 15, 18, or 19, wherein the solvent comprises one or more of ethanol, methanol, isopropanol, tertiary butanol, acetone, dimethyl sulfoxide, dimethyl formamide, tertahydrofuran, methylene chloride, chloroform, triethylamine, pyridine, ethylacetate, and acetonitrile.
25. The process of claim 24, wherein the solvent comprises one or both of methylene chloride and methanol.
26. The process of claim 19, wherein the anti-solvent comprises one or more of methanol, isopropyl alcohol, and water.
27. A modified release pharmaceutical composition comprising cilostazol adsorbate, rate controlling polymer, and one or more pharmaceutically acceptable inert excipients.
28. The pharmaceutical composition of claim 27, wherein the rate controlling polymer comprises one or more of cellulose derivatives, alginic acid derivatives, methacrylic acid derivatives, waxes, polysaccharides, and alkylene oxides.
29. The pharmaceutical composition of claim 27, wherein the pharmaceutically acceptable inert excipients comprise one or more of wetting agents, diluents, crystal modifiers, binders, disintegrants, coloring agents, flavoring agents, stabilizers, lubricants/glidants and plasticizers.
30. A process for preparing a pharmaceutical composition, the process comprising the steps of combining cilostazol adsorbate and one or more pharmaceutical acceptable inert excipients, and processing into a solid dosage fonn.
31. A process for preparing a modified release pharmaceutical composition, the process comprising the steps of combining cilostazol adsorbate, rate-controlling polymer and one or more pharmaceutical inert excipients, and processing into a solid dosage form.
32. The process of claim 30 or 31, wherein the solid dosage form is a tablet, capsule or granules.
33. The process of claim 32, wherein the solid dosage form is a tablet.
34. The process of claim 32, wherein the dosage form is prepared by wet or dry granulation, or extrusion-spheronization technique.
35. The process of claim 34, wherein the dosage form is prepared by wet granulation.
36. The process of claim 30 or 31 , wherein the pharmaceutically acceptable inert excipients comprise one or more of wetting agents, diluents, crystal modifiers, binders, disintegrants, coloring agents, flavoring agents, stabilizers, lubricants/glidants and plasticizers.
37. A method of treating intermittent claudication by administering a pharmaceutical composition to a mammal in need thereof, the pharmaceutical composition comprisisng cilostazol adsorbate, and one or more pharmaceutically acceptable excipients.
38. A method of treating intermittent claudication by administering a modified release pharmaceutical composition to a mammal in need thereof, the modified release pharmaceutical composition comprisisng cilostazol adsorbate, rate controlling polymer, and one or more pharmaceutically acceptable excipients.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN1107/DEL/2003 | 2003-09-05 | ||
| IN1107DE2003 | 2003-09-05 |
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| Publication Number | Publication Date |
|---|---|
| WO2005023225A1 true WO2005023225A1 (en) | 2005-03-17 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/IB2004/002866 WO2005023225A1 (en) | 2003-09-05 | 2004-09-03 | Cilostazol adsorbate |
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Cited By (2)
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| WO2008100106A1 (en) * | 2007-02-16 | 2008-08-21 | Amorepacific Corporation | Controlled release preparation containing cilostazoland process for the preparation thereof |
| TWI501789B (en) * | 2008-05-15 | 2015-10-01 | Otsuka Pharma Co Ltd | A solid pharmaceutical formulation |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008100106A1 (en) * | 2007-02-16 | 2008-08-21 | Amorepacific Corporation | Controlled release preparation containing cilostazoland process for the preparation thereof |
| EP2124891A1 (en) * | 2007-02-16 | 2009-12-02 | Amorepacific Corporation | Controlled release preparation containing cilostazoland process for the preparation thereof |
| JP2010519200A (en) * | 2007-02-16 | 2010-06-03 | アモーレパシフィック コーポレイション | Controlled release formulation containing cilostazol and method for producing the same |
| EP2124891A4 (en) * | 2007-02-16 | 2013-05-29 | Amorepacific Corp | Controlled release preparation containing cilostazoland process for the preparation thereof |
| TWI501789B (en) * | 2008-05-15 | 2015-10-01 | Otsuka Pharma Co Ltd | A solid pharmaceutical formulation |
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