WO2000069415A2 - Melt granulation - Google Patents
Melt granulation Download PDFInfo
- Publication number
- WO2000069415A2 WO2000069415A2 PCT/SI2000/000013 SI0000013W WO0069415A2 WO 2000069415 A2 WO2000069415 A2 WO 2000069415A2 SI 0000013 W SI0000013 W SI 0000013W WO 0069415 A2 WO0069415 A2 WO 0069415A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- pharmaceutical formulation
- formulation according
- clarithromycin
- prepared
- granulate
- Prior art date
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- 238000007909 melt granulation Methods 0.000 title claims abstract description 8
- 238000000576 coating method Methods 0.000 claims abstract description 16
- 239000011248 coating agent Substances 0.000 claims abstract description 15
- 238000000034 method Methods 0.000 claims abstract description 12
- AGOYDEPGAOXOCK-KCBOHYOISA-N clarithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@](C)([C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)OC)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 AGOYDEPGAOXOCK-KCBOHYOISA-N 0.000 claims description 31
- 229960002626 clarithromycin Drugs 0.000 claims description 31
- 239000008194 pharmaceutical composition Substances 0.000 claims description 23
- 238000002360 preparation method Methods 0.000 claims description 17
- 239000008187 granular material Substances 0.000 claims description 14
- 239000000725 suspension Substances 0.000 claims description 14
- 229920000642 polymer Polymers 0.000 claims description 8
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- 239000000126 substance Substances 0.000 claims description 7
- 239000000654 additive Substances 0.000 claims description 6
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- 238000002156 mixing Methods 0.000 claims description 6
- 235000000346 sugar Nutrition 0.000 claims description 6
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 5
- 239000002775 capsule Substances 0.000 claims description 4
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- VVQNEPGJFQJSBK-UHFFFAOYSA-N Methyl methacrylate Chemical compound COC(=O)C(C)=C VVQNEPGJFQJSBK-UHFFFAOYSA-N 0.000 claims description 3
- 239000002253 acid Substances 0.000 claims description 3
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- 235000003599 food sweetener Nutrition 0.000 claims description 3
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- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims description 2
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- 239000012730 sustained-release form Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- OULAJFUGPPVRBK-UHFFFAOYSA-N tetratriacontyl alcohol Natural products CCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCO OULAJFUGPPVRBK-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 229920003169 water-soluble polymer Polymers 0.000 description 1
- 238000005550 wet granulation Methods 0.000 description 1
- 239000000230 xanthan gum Substances 0.000 description 1
- 235000010493 xanthan gum Nutrition 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
- 229940082509 xanthan gum Drugs 0.000 description 1
Classifications
-
- 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
- A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
- A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
-
- 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
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1617—Organic compounds, e.g. phospholipids, fats
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5026—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
Definitions
- the present invention belongs to the field of pharmaceutical technology and discloses melt granulation.
- the present invention discloses a simple one-step process for coating clarithromycin or derivatives thereof by means of melt granulation in order to effectively cover their bitterness, as well as a new, patient- friendly oral pharmaceutical formulation suitable also for diabetics, which at the same time also enables variations in the rate and site of the release of the active component.
- Clarithromycin is a slightly basic, practically water-insoluble, acid-sensitive macrolide antibiotic with a very bitter taste that remains in the mouth for several hours after taking a therapeutical dose.
- the commercially available oral suspension with clarithromycin contains a considerable amount of sugar (which does not eliminate the bitter aftertaste), but it still has a relatively unpleasant taste. Moreover, the technology of the preparation thereof is a multistep one and hence expensive.
- the present invention arises from the need to prepare an oral suspension with clarithromycin or derivatives thereof, which will be tasty, effective and obtainable by means of a one-step process.
- Clarithromycin is a semi-synthetic antibiotic obtained by methylation of erythromycin in the lactone position C6. The synthesis is described in US 4,331,803 and US 4,672,109. It is active against gram-positive bacteria and, due to the broad spectrum of antimicrobial activity, it is used clinically. On the market it is available in the form of coated tablets, suspensions and prolonged-release tablets.
- JP 85/163823 discloses an oral medicament with clarithromycin, citric acid increasing the abso ⁇ tion of antibiotic in the alimentary tract, disintegrants, excipients and lubricants.
- EP 0277042 discloses an oral pharmaceutical formulation (also with macrolides) with an improved taste and having a coating of particular polymers (especially polyvinyl acetal diethylaminoacetate - AEA), soluble in gastric juice and with a mean particle diameter under 60 ⁇ m.
- US 4,808,411 discloses a pharmaceutical formulation with erythromycin or its derivatives and a carbomer, possibly in the form of ion-complex particles coated with a polymer, which can be suspended in a liquid carrier.
- JP 01-308,223 discloses the preparation of film-coated microgranules of a sustained- release medicament containing AEA and water in addition to clarithromycin.
- EP 0302370 and WO 90/08537 disclose improved oral pharmaceutical formulations (oil solution, suspension, emulsion) of erythromycin and derivatives to be filled into soft gelatine capsules with N-methyl-pyrrolidone.
- EP-B-0420992 discloses a process for the production of an oral pharmaceutical formulation (also with macrolides) with a masked taste, which comprises spraying a medicament suspension into a cold water solution of AEA.
- JP 02-279,622 discloses oral medicaments with AEA, prepared by a fine granulation of a medicament (clarithromycin) dispersed in a melted oil base (cacao butter), followed by suspending the fine particles in a water solution of AEA and spray-drying the suspension.
- AEA a fine granulation of a medicament (clarithromycin) dispersed in a melted oil base (cacao butter), followed by suspending the fine particles in a water solution of AEA and spray-drying the suspension.
- US 5,017,383 discloses a method for the production of a finely coated pharmaceutical formulation, which comprises mixing frozen particles of a liquid medium with a medicament (also with macrolides) and a coating in the form of a fine powder adhering onto the surface of the particles.
- JP 05-255,075 discloses melt granulation of macrolides, wherein the coating consists of polymers soluble in stomach (particularly Eudragit E), which are dispersed in compounds with a low melting point.
- the final granulation is performed by spraying.
- the final preparation of a dry syrup is accomplished by mixing granules with sugar and hydroxypropyl methyl cellulose (HPMC).
- US 5,599,556 and US 5,609,909 disclose the masking of the taste of encapsulated clarithromycin particles with prolamine coatings prior to the preparation of a suspension.
- WO 96/34628 discloses an oral pharmaceutical formulation (also with macrolides) for masking the taste (particularly a dry syrup), which contains a medicament with an unpleasant taste, a higher polymer soluble in stomach (particularly AEA and Eudragit E) and a monoglyceride with a low melting point (particularly glyceryl monostearate) in the stable crystal form ⁇ (transformed from the metastable form ⁇ by additional shaking at increased temperature), and a method of masking the taste.
- WO 97/16174 discloses a process of water granulation of a macrolide antibiotic with a carbomer (acrylic polymer).
- US 5,705,190 discloses a controlled-release solid oral pharmaceutical formulation (also of clarithromycin) containing a medicament weakly soluble in water, a water- soluble alginate salt, a complex salt of alginic acid with a metal cation and an organic carboxylic acid facilitating the dissolution of the medicament.
- US 5,707,646 discloses a pharmaceutical formulation (also with macrolides) for oral use (particularly a dry syrup) containing a medicament with an unpleasant taste, a functional polymer (particularly AEA or/and Eudragit E) in a substance with a melting point of 40-120 °C, a sugar alcohol (e.g. sorbitol) and a basic oxide (particularly MgO).
- a pharmaceutical formulation also with macrolides
- a dry syrup containing a medicament with an unpleasant taste
- a functional polymer particularly AEA or/and Eudragit E
- a sugar alcohol e.g. sorbitol
- a basic oxide particularly MgO
- WO 98/46239 discloses a delayed-release pharmaceutical formulation containing an erythromycin derivative and a hydrophilic water-soluble polymer, which in oral use has an improved taste profile and fewer gastrointestinal side effects in comparison with the common form.
- the preparation technology includes, inter alia, wet granulation, drying, sieving and milling processes.
- the aim of the present invention is a new oral pharmaceutical formulation with clarithromycin or derivatives thereof.
- clarithromycin which may be present alone or in a homogeneuos mixture with conventional adjuvants, with a lipid film- forming substance having a low melting point (below 100 °C).
- the granulate was prepared in the melt in a mixer-granulator, thus in one step and in one vessel without the use of any solvents. From the granulate various conventional final pharmaceutical formulations such as suspensions in concentrations of 125 mg/5 ml and 250 mg/5 ml, tablets or capsules can be prepared.
- the base for coating can be clarithromycin itself or its mixture with excipients such as lactose, calcium carbonate, sodium hydrogen phosphate, NaCl, citric acid, PEG or stomach-insoluble polymers such as Eudragit L or S (1:1 or 1 :2 copolymer of methacrylic acid and MMA), microcrystalline cellulose etc.
- excipients such as lactose, calcium carbonate, sodium hydrogen phosphate, NaCl, citric acid, PEG or stomach-insoluble polymers such as Eudragit L or S (1:1 or 1 :2 copolymer of methacrylic acid and MMA), microcrystalline cellulose etc.
- the weight ratio between clarithromycin and these excipients amounts from 5: 1 to 1 : 1.2
- lipid film-forming substance almost insoluble in water there can be used a higher fatty alcohol, preferably stearyl, cetostearyl or cetyl alcohol or a suitable acid such as stearic acid or a physical mixture or an ester of several such components e.g. stearyl stearate.
- a higher fatty alcohol preferably stearyl, cetostearyl or cetyl alcohol or a suitable acid such as stearic acid or a physical mixture or an ester of several such components e.g. stearyl stearate.
- the weight ratio between clarithromycin and these excipients amounts from 2: 1 to 1 :2.
- the melt granulation is performed in such a way that a mixture of clarithromycin (possibly with addition of adjuvants) and of the lipid for coating is heated in a granulator under mixing to the melting point of the lipid component and then the obtained granulate is slowly cooled.
- viscosity enhancers and stabilizers such as xanthan gum, guar gum, silica gel, magnesium aluminium silicate etc.
- sugar or sweetening agents such as aspartame, sodium saccharinate or erythritol, caramel, vanilla or fruit flavours and colouring agents can also be added.
- all the cited additives for the preparation of suspensions cannot cover the bitterness of clarithromycin by themselves.
- the pharmaceutical formulation of the present invention can be improved by using polyols instead of sugar, which makes it also suitable for diabetics.
- polyols instead of sugar
- e.g. xylitol and mannitol and their combinations with maltitol, maltol and sorbitol can be used.
- the present pharmaceutical formulation represents the only oral suspension with clarithromycin, which is not based on sugar (saccharose).
- Fatty alcohols such as stearyl alcohol possess, in proportion to their concentration, a delaying effect on the release of the active component from the pharmaceutical formulation. This property can be used for controlling the clarithromycin release rate and an oral suspension with delayed action can be prepared.
- a gastroresistant layer onto the granulate base from the melt, the site of clarithromycin release in the alimentary tract can be affected.
- Polymers forming a gastroresistant coating such as shellac, cellulose acetate phthalate, HPMC phthalate, ethylcellulose latex, polymethacrylates etc. can be used therefor.
- the preparation of the granulate was identical to that of Examples 1 or 2. Additionally, a gastroresistant coating was applied; for 200 mg of pellet cores the following dispersion was prepared:
- the preparation of the granulate was identical to the one of Examples 1 or 2. Additionally, a gastroresistant coating was applied; for 500 mg of pellet cores the following water dispersion was prepared: Eudragit L 30 D-55 48.612 mg triethyl citrate 0.893 mg talc 0.495 mg water 332.143 mg
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Biophysics (AREA)
- Molecular Biology (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Liquid Deposition Of Substances Of Which Semiconductor Devices Are Composed (AREA)
- Glanulating (AREA)
- Crystals, And After-Treatments Of Crystals (AREA)
Abstract
Description
Claims
Priority Applications (7)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
PL00351654A PL351654A1 (en) | 1999-05-19 | 2000-05-18 | Melt granulation |
EP00931886A EP1183013A2 (en) | 1999-05-19 | 2000-05-18 | Melt granulation |
SK1664-2001A SK16642001A3 (en) | 1999-05-19 | 2000-05-18 | Pharmaceutical formulation in granular form |
AU49697/00A AU4969700A (en) | 1999-05-19 | 2000-05-18 | Melt granulation |
EEP200100607A EE200100607A (en) | 1999-05-19 | 2000-05-18 | Pharmaceutical composition in granular form and a process for its preparation |
HR20010932A HRP20010932A2 (en) | 1999-05-19 | 2001-12-18 | Melt granulation |
BG106236A BG106236A (en) | 1999-05-19 | 2001-12-19 | Melt granulation |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
SI9900119A SI20244A (en) | 1999-05-19 | 1999-05-19 | Melt granulation |
SIP-9900119 | 1999-05-19 |
Publications (2)
Publication Number | Publication Date |
---|---|
WO2000069415A2 true WO2000069415A2 (en) | 2000-11-23 |
WO2000069415A3 WO2000069415A3 (en) | 2001-04-26 |
Family
ID=20432471
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/SI2000/000013 WO2000069415A2 (en) | 1999-05-19 | 2000-05-18 | Melt granulation |
Country Status (13)
Country | Link |
---|---|
EP (1) | EP1183013A2 (en) |
AU (1) | AU4969700A (en) |
BG (1) | BG106236A (en) |
CZ (1) | CZ20014133A3 (en) |
EE (1) | EE200100607A (en) |
HR (1) | HRP20010932A2 (en) |
HU (1) | HUP0201233A3 (en) |
PL (1) | PL351654A1 (en) |
RU (1) | RU2001134166A (en) |
SI (1) | SI20244A (en) |
SK (1) | SK16642001A3 (en) |
WO (1) | WO2000069415A2 (en) |
YU (1) | YU82001A (en) |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2001072284A1 (en) * | 2000-03-28 | 2001-10-04 | Biochemie Gesellschaft M.B.H. | Granulated particles with masked taste |
EP1333807A2 (en) * | 2000-10-13 | 2003-08-13 | Advancis Pharmaceuticals | Extended release erythromycin derivatives |
EP1484056A1 (en) * | 2002-02-21 | 2004-12-08 | Otsuka Pharmaceutical Co., Ltd. | Sustained release preparations and process for producing the same |
US7943585B2 (en) | 2003-12-22 | 2011-05-17 | Sandoz, Inc. | Extended release antibiotic composition |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1991019486A1 (en) * | 1990-06-14 | 1991-12-26 | Kalmo Enterprises, Inc. | Stable aqueous drug suspensions |
WO1993017667A1 (en) * | 1992-03-12 | 1993-09-16 | Taisho Pharmaceutical Co., Ltd. | Composition for oral preparations |
WO1994012157A1 (en) * | 1992-11-30 | 1994-06-09 | Kv Pharmaceutical Company | Tastemasked pharmaceutical materials |
WO2000061119A2 (en) * | 1999-04-09 | 2000-10-19 | Pharmaplus S.R.L. | A process for the microencapsulation of medicaments |
-
1999
- 1999-05-19 SI SI9900119A patent/SI20244A/en not_active IP Right Cessation
-
2000
- 2000-05-18 WO PCT/SI2000/000013 patent/WO2000069415A2/en not_active Application Discontinuation
- 2000-05-18 PL PL00351654A patent/PL351654A1/en not_active Application Discontinuation
- 2000-05-18 CZ CZ20014133A patent/CZ20014133A3/en unknown
- 2000-05-18 SK SK1664-2001A patent/SK16642001A3/en unknown
- 2000-05-18 AU AU49697/00A patent/AU4969700A/en not_active Abandoned
- 2000-05-18 RU RU2001134166/14A patent/RU2001134166A/en not_active Application Discontinuation
- 2000-05-18 EE EEP200100607A patent/EE200100607A/en unknown
- 2000-05-18 HU HU0201233A patent/HUP0201233A3/en unknown
- 2000-05-18 YU YU82001A patent/YU82001A/en unknown
- 2000-05-18 EP EP00931886A patent/EP1183013A2/en not_active Withdrawn
-
2001
- 2001-12-18 HR HR20010932A patent/HRP20010932A2/en not_active Application Discontinuation
- 2001-12-19 BG BG106236A patent/BG106236A/en unknown
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1991019486A1 (en) * | 1990-06-14 | 1991-12-26 | Kalmo Enterprises, Inc. | Stable aqueous drug suspensions |
WO1993017667A1 (en) * | 1992-03-12 | 1993-09-16 | Taisho Pharmaceutical Co., Ltd. | Composition for oral preparations |
WO1994012157A1 (en) * | 1992-11-30 | 1994-06-09 | Kv Pharmaceutical Company | Tastemasked pharmaceutical materials |
WO2000061119A2 (en) * | 1999-04-09 | 2000-10-19 | Pharmaplus S.R.L. | A process for the microencapsulation of medicaments |
Non-Patent Citations (2)
Title |
---|
S. EL-SHANAWANY: "Sustained release of nitrofurantoin frominert wax matrixes" JOURNAL OF CONTROLLED RELEASE, vol. 26, no. 1, 1 July 1993 (1993-07-01), pages 11-19, XP000377735 Amsterdam (NL) * |
S. ZGOULLI ET AL.: "Microencapsulation of erythromycin and clarithromycin using a spray-drying technique" JOURNAL OF MICROENCAPSULATION, vol. 16, no. 5, September 1999 (1999-09), pages 565-571, XP000834849 London (GB) * |
Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2001072284A1 (en) * | 2000-03-28 | 2001-10-04 | Biochemie Gesellschaft M.B.H. | Granulated particles with masked taste |
EP1333807A2 (en) * | 2000-10-13 | 2003-08-13 | Advancis Pharmaceuticals | Extended release erythromycin derivatives |
EP1333807A4 (en) * | 2000-10-13 | 2005-06-29 | Advancis Pharmaceuticals | Extended release erythromycin derivatives |
EP1484056A1 (en) * | 2002-02-21 | 2004-12-08 | Otsuka Pharmaceutical Co., Ltd. | Sustained release preparations and process for producing the same |
EP1484056A4 (en) * | 2002-02-21 | 2009-06-10 | Otsuka Pharma Co Ltd | Sustained release preparations and process for producing the same |
US7927628B2 (en) | 2002-02-21 | 2011-04-19 | Otsuka Pharmaceutical Co., Ltd. | Sustained release preparations and process for producing the same |
US7943585B2 (en) | 2003-12-22 | 2011-05-17 | Sandoz, Inc. | Extended release antibiotic composition |
Also Published As
Publication number | Publication date |
---|---|
SI20244A (en) | 2000-12-31 |
EE200100607A (en) | 2003-02-17 |
SK16642001A3 (en) | 2002-05-09 |
HUP0201233A3 (en) | 2003-10-28 |
YU82001A (en) | 2004-07-15 |
CZ20014133A3 (en) | 2002-03-13 |
BG106236A (en) | 2002-08-30 |
AU4969700A (en) | 2000-12-05 |
WO2000069415A3 (en) | 2001-04-26 |
HRP20010932A2 (en) | 2003-04-30 |
RU2001134166A (en) | 2003-08-27 |
EP1183013A2 (en) | 2002-03-06 |
PL351654A1 (en) | 2003-05-19 |
HUP0201233A2 (en) | 2002-08-28 |
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