CA2540965A1 - Process for preparing clopidogrel compositions - Google Patents
Process for preparing clopidogrel compositions Download PDFInfo
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- CA2540965A1 CA2540965A1 CA002540965A CA2540965A CA2540965A1 CA 2540965 A1 CA2540965 A1 CA 2540965A1 CA 002540965 A CA002540965 A CA 002540965A CA 2540965 A CA2540965 A CA 2540965A CA 2540965 A1 CA2540965 A1 CA 2540965A1
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- clopidogrel
- granules
- particles
- aggregates
- composition
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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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- 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
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
-
- 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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
-
- 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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- 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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
-
- 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
-
- 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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
- A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
Abstract
This invention provides a composition suitable for oral administration comprising clopidogrel in pharmaceutically acceptable salt form which composition comprises : a polymer coating selected from a polyvinyl acetate or a polyvinyl alcohol, and a hydrophobic component comprising a hydrogenated vegetable oil, wherein the salt is selected from mesylate, hydrobromide, hydroiodide and hydrochloride, and wherein the clopidogrel is in the form of coated particles, granules or agglomerates. In another aspect, the invention provides a process for preparing tablets comprising clopidogrel in pharmaceutically acceptable salt form which process comprises a) compacting the clopidrogrel with anhydrous or substantially anhydrous components so as to form aggregates, b) breaking down the aggregates so as to form granules or particles, c) optionally mixing the granules or particles with at least one further component, and d) compacting or compressing the granules or particles thus formed into tablets, wherein the clopidogrel is used in mesylate, hydrobromide, hydroiodide, or hydrochloride form, and the process further comprises mixing a moisture scavenger with the aggregates, granules or particles. A granule- or particle-coating step may be included after step b) or step c) when present and before step d).
Description
Process for t~ret~arin~ clonido~rel compositions This invention relates to pharmaceutical compositions comprising clopidogrel and to processes for preparing such compositions.
Clopidogrel is a known anti-thrombotic agent which inhibits platelet aggregation. See Merck Index, 12~ Edition, entry 2457. Clopidogrel is administered currently in the form of the biphosphate salt as a film-coated tablet.
Some clopidogrel salts are known to exhibit difficulties in formulation. The present applicants have found that clopidogrel in base or salt form, e.g. as mesylate or hydrochloride, is problematic to formulate for example as a tablet, and attribute this principally to hygroscopicity. Furthermore, the applicants have found that clopidogrel tablets suffer from degradation on storage.
The present applicants have sought to overcome the problems of hitherto known clopidogrel compositions.
In one aspect, therefore, this invention provides a composition suitable for oral administration comprising clopidogrel in base or pharmaceutically acceptable salt form which composition comprises a polymer coating.
The polymer coating may comprise a polyvinyl acetate or a polyvinyl alcohol.
In this and other aspects of the invention described below, when in salt form clopidogrel may be selected from mesylate, hydroiodide, hydrobromide and hydrochloride.
In another aspect this invention provides a composition suitable for oral administration comprising clopidogrel in base or pharmaceutically acceptable salt form which composition comprises a hydrophobic component.
Suitable hydrophobic components include hydrogenated vegetable oils.
The hydrophobic component-containing compositions of this invention may comprise a polymer coating, e.g. a polyvinyl acetate or a polyvinyl alcohol. In a preferred aspect, the hydrophobic component, when present, is not coated.
In another aspect, this invention provides clopidogrel in form of coated particles, granules or agglomerates.
In a further aspect, this invention provides a composition suitable for oral administration comprising clopidogrel in base or pharmaceutically acceptable salt form wherein the clopidogrel is in the form of coated particles, granules or agglomerates.
In a preferred aspect, this invention provides a composition suitable for oral administration comprising clopidogrel in pharmaceutically acceptable salt form which composition comprises - a polymer coating selected from a polyvinyl acetate or a polyvinyl alcohol, and - a hydrophobic component comprising a hydrogenated vegetable oil, wherein the salt is selected from mesylate, hydrobromide, hydroiodide and hydrochloride, and wherein the clopidogrel is in the form of coated particles, granules or agglomerates.
The particle-, granule- or agglomerate-coating may comprise a hydrophobic polymer, e.g. a polyvinyl acetate or a polyvinyl alcohol, a hydrogenated vegetable oil or a cyclodextrin.
Preferred polymer coatings employed in the compositions of this invention are selected from celluose acetate, polymethacrylates for example Eudragit E or Eudragit NE
30 D, and ethylcellulose.
Suitable vegetable oils include hydrogenated cottonseed oil e.g. those available commercially as Lubritab or Sterotex; hydrogenated palm oil, e.g. available as Softisan 154 or Dynasan P60; hydrogenated soyabean oil such as that available as Sterotex HM.
The hydrophobic component may be selected from cetyl alcohol, cetostearyl alcohol, cholesterol, gyceryl monostearate, glyceryl monooleate, glyceryl palmitostearate and stearic acid.
The cyclodextrin may comprise an alpha-, beta- or gamma-cyclodextrin.
The compositions of this invention herein described may be administered in form of a tablet, sachet, or hard or soft gelatine capsule. Coated tablets are preferred.
In the compositions of the invention, the clopidogrel may be present in an amount of up to SO% by weight, for example 10 to 45%, e.g. 20 to 40%, e.g. 25 to 35% by weight, based on the total weight of the composition.
Thus components of the compositions of this invention may include:
- a sugar, e.g. a lactose, in an amount when present of up to 60% by weight, for example 20 to 50%, e.g. 25 to 40% by weight based on the total weight of the composition. Lactose DCL 11 is a suitable grade in the compositions of this invention;
- a microcrystalline cellulose in an amount when present of up to 40% by weight, for example S to 35%, e.g. 8 to 25%, e.g. 10 to 20% by weight based on the total weight of the composition. Avicel PH 112 is an appropriate grade for use in the compositions of this invention;
- a starch in an amount when present of up to 40% by weight, for example 5 to 35%, e.g. 8 to 20%, e.g. 10 to 17% by weight based on the total weight of the composition.
Starch 1500 LM is an appropriate grade for use in the compositions of this invention;
- a dessicant for example milled anhydrous silica, available commercially under the trade mark Syloid AL; this component when present may be in an amount of up to 8 %
by weight of the composition, e.g. 0.5 to 6%, e.g. 1 to 4% by weight;
- the hydrogenated vegetable oil when present in an amount of up to about 15 %
by weight, e.g. 1 to 10%, e.g. 2 to 7% by weight, based on the weight of the composition.
Such oils are commercially available for example under the trade mark Sterotex;
- the polymer coating, when present, in an amount of up to about 10 % by weight, e.g. 2 to 8%, e.g. 4 to 6 % by weight, based on the weight of the composition. Such coatings are available commercially for example under the trade mark Opadry AMB;
- a filler in an amount when present of up to 80% by weight, for example 5 to 75%, e.g.
to 65%, e.g. 15 to SO% by weight based on the total weight of the composition.
Mannitol and xylitol are examples of suitable fillers in compositions of this invention.
Other components may include titanium dioxide, a hydroxypropyl methylcellulose,.a hydroxyl propylcellulose and a propylene glycol.
The compositions of this invention are more straightforward to formulate than hitherto known compositions. The applicants have found that processability of the components in forming, e.g.. tablets, is easier than for known processes for making solid clopidogrel compositions.
The compositions of this invention are storage-stable. Thus no or negligible degradation is observed on storage at ambient conditions over periods of days, weeks and months.
The clopidogrel employed in the compositions and processes of this invention may be in racemate form, in form of a partially- or wholly-enriched diastereomer. Thus the clopidogrel may be in form of a pure or substantially pure diastereomer, e.g.
> 90% e.g.
93%, 94%, 95% or > 95%, e.g. 96%, 97% or greater diastereomer as determined using known methods.
In another aspect, this invention provides a process for preparing tablets comprising clopidogrel in base or pharmaceutically acceptable salt form which process comprises a) compacting the clopidrogrel with anhydrous or substantially~anhydrous components so as to form aggregates, b) breaking down the aggregates so as to form granules or particles, c) optionally mixing the granules or particles with at least one further component, and d) compacting or compressing the granules or particles thus formed into tablets.
Compaction may be carried out for example using a roller compactor.
The present applicants understand roller compaction to be a form of high-pressure agglomeration. Thus a roller press exerts a mechanical pressure on a powder or other dry bulk material while forced between, for example, two or more counter-rotating rollers. The conditions within the roller compactor are typically such that the material is compressed into compacts which are subsequently passed through a mill to produce granules.
The applicants have found that a Fitzpatrick Chilsonator compactor is a suitable commercially available compactor for roller compaction. Thus the roller speed may be between 1 and 10 rpm, e.g. 2 to 8 such as 3, 4 or 5 r.p.m. Roller pressures applied to the material may be between 300 and 800 pounds per square inch (psi), e.g. 350 (24.60 kg/cm2) to 700 (49.21 kg/cm2), such as 500 (35.13 kglcmz), 550 or 600 psi.
The desiccant, e.g. anhydrous silica, may be mixed with the aggregates or granules.
This improves stability and flow of the processed mixture.
A hydrophobic lubricant, e.g. hydrogenated vegetable oil, may be added. This provides improved stability over that observed using conventional lubricants.
The process may be carried out in a low- or ultra-low humidity environment.
The applicants have found that the compacted blend resulting from process step a) may be milled to granules or particles by screening through a comminuting mill, for example an oscillating granulator, quadrocomill or hammer mill. Thus step b) serves to break the aggregates down in size.
In a preferred aspect, process step b) may be carried out so as to form granules with a small or negligible proportion of particles. Thus the output from step b) may amount to 80% or more granules by weight in a granule/particle mixture, e.g. 85%, 90%, 95% or greater e.g. 98%, 99% or 100% granules.
In a further aspect this invention provides a process for preparing coated clopidogrel particles or granules which process comprises preparing a solution of clopidogrel and the polymer, hydrogenated vegetable oil, or cyclodextrin, in a suitable solvent medium and spray-drying the solution.
The solvent medium may comprise an aqueous or organic solvent or mixture of organic solvents. When an aqueous medium is employed, this may containing up to 100 %
by weight water, e.g. S to 80%, e.g. 10 to 60% by weight.
The thus coated or encapsulated particles or granules may be further processed, for example into tablets using compaction or compression.
Coating of the clopidogrel particles may be achieved using a fluidised bed, e.g. a Wurster, or by water-in-oil or oil-in-water phase separation or coacervation encapsulation methods.
In a further aspect, therefore, coating of the clopidogrel granules or particles may be carried out after process step b) or step c) if present and before step d).
Without being bound to a particular theoretical mechanism of action, the applicants believe that the hydrophobic polymer may establish an effective moisture barrier around the particles or tablets.
Typical dimensions observed using known methods of particles used in this invention range from 50 microns to 150 microns. 75 % of the granules of this invention may be in the size range 100 microns to S00 microns, and 75% of the agglomerates of this invention may be in the size range 500 microns to 2000 microns.
A preferred aspect of the invention is a clopidogrel composition as herein described in form of a coated particle, granule, agglomerate or tablet, wherein the coating is free of or substantially free of HPMC.
Clopidogrel may be administered at a dose of l0mg, 25mg, SOmg, 60 mg, 75mg or 100mg drug substance based on clopidogrel base, depending on the patient s body weight and other circumstances. This dose may be daily. When administered in tablet form, the tablet weight may be for example SO mg, 100mg, 150 mg, 200 mg or 300 mg in total.
Clopidogrel base, mesylate and hydroiodide are sourced from the Torrent company.
Clopidogrel hydrochloride may be prepared by processes analogous to those disclosed in published patent applications EP 0 281 459 and WO 98/51682.
Clopidogrel hydrobromide may be prepared by passing HBr gas through an organic solution of clopidogrel base, e.g. in toluene, at ambient temperature.
Clopidogrel hydrobromide salt precipitates and may be filtered and washed, e.g. with an organic solvent such as toluene. The wet cake of the salt may be dried under vacuum at elevated temperature, for example 50 to 80°C, e.g. 70 to 75°C, to provide clopidogrel HBr as an off-white solid.
In another aspect, this invention provides a composition or process substantially as herein described with reference to the examples. In a further aspect, this invention provides compositions produced using the processes of this invention. The compositions, e.g. tablets, produced by the processes of this invention may be free of or substantially free of HPMC.
Following is a description by way of example only of compositions and processes of this invention.
Example 1 Com onents Relative amounts 300 m tablet Clo ido rel mes 30-32 % wlw of com osition94 m late Lactose DCL 11 40-50 % w/w of com osition122 m Avicel PH 112 10-20 % w/w of com osition30 m Starch 1500 LM 10-15 % w/w of com osition30 m S loid AL1-FP 1-5 % w/w of com osition12 m Sterotex ~ 3-5 % w/w of composition12 mg ~
The components (all anhydrous) are mixed together, processed using dry roller compaction into aggregates, compacted to granules and formed into tablets.
Processing takes place in a low-humidity environment. 1000 tablets are prepared and divided into lots each of 100 tablets. All ten lots are stored at ambient conditions and inspected at daily intervals.
No degradation is detected by visual inspection after 10 days. Negligible degradation is observed after two months.
Example 2 Example 1 is repeated using clopidogrel hydroiodide in place of the mesylate, using molar equivalent to 75 mg clopidogrel base. Stable tablets are produced.
Example 3 Example 1 is repeated using clopidogrel hydrochloride in place of the mesylate using molar equivalent to 75 mg clopidogrel base. Stable tablets are produced.
Example 4 Com onents Relative amounts 300 m tablet Clo ido rel mes late 30-32 % w/w of com osition95 m Lactose DCL 11 40-50 % w/w of com osition115 m Avicel PH 112 10-20 % w/w of com osition32 m Starch 1500 LM 10-15 % w/w of com osition30 m S loid AL 1 -FP 1-5 % w/w of com osition6 m Sterotex 3-S % w/w of com osition10 m Opadry AMB - - 4-6 % w/w of composition12 mg ~
The anhydrous components are mixed together, processed in analogous manner to that in Example 1 and formed into tablets. The tablets are coated using Opadry AMB.
1000 tablets are prepared and divided into 10 lots each of 100 tablets. All ten lots are stored at ambient conditions and inspected at daily intervals. No degradation is detected by visual inspection after 10 days. Negligible degradation isobserved after one month.
Example S
Example 4 is repeated using clopidogrel hydroiodide in place of the mesylate.
The molar equivalent to 75 mg clopidogrel base is used. Stable tablets are produced.
Example 6 Example 4 is repeated using clopidogrel hydrochloride (molar equivalent to 75 mg base) in place of the mesylate. Stable tablets are produced.
Compositions containing mannitol as a tiller are prepared in the following Examples 7 and 9 to 12.
Examples 7a to c Coin onents M /tab Example Example Example 7 a 7b 7c Clo ido rel mes late 99.7 99.7 99.7 Mannitol 10&.8 143.8 53.8 Microcrystalline 70.5 40.5 11S.S
cellulose(Avicel PH 112) Low substituted 12.0 6.0 20 hydroxypropyl cellulose (L-HPC 11) Pol eth lene 1 col 6000 6.0 6.0 6.0 Sterotex S.0 4.0 5.0 O adr AMB 12.0 12.0 12.0 99.7 mg clopidogrel mesylate are equivalent to 7S mg clopidogrel base.
Composition 7a:
The clopidogrel salt is blended with mannitol, microcrystalline cellulose and part of the low substituted hydroxypropylcellulose. The blend is compacted using a Fitzpatrick Chilsonator roller compactor. The compacts are then milled into granules by screening through an oscillating granulator comminuting mill. The granules are blended with part of microcrystalline cellulose, low substituted hydroxypropylcellulose, mannitol, PEG
6000 and Sterotex. The blend is compressed into tablets using a Korsch rotary compressor. The tablets are then coated with Opadry AMB in a Hicoater perforated coating pan.
An analogous procedure is used to prepare compositions 7b and 7c.
Example 8~ Clopido~rel hydrobromide To a solution of 100 g clopidogrel base in 1000 ml toluene is passed hydrogen bromide gas for 1 S minutes at ambient temperature. Clopidogrel HBr precipitates. The precipitated clopidogrel.HBr salt is filtered and washed with S00 ml toluene.
The wet cake of the salt is dried under vacuum at 70 to 75°C overnight to give clopidogrel.HBr as an off-white solid.
Yield: 8 8.1 g ( 70 % ) Examples 9a to c Com onents M /tab Example Example Example 9a 9b 9c Clo ido rel h drobromide93.9 93.9 93.9 Mannitol 112.6 149.6 59.6 Microcrystalline 70.5 40.5 115.5 cellulose(Avicel PH 112) Low substituted 12.0 6.0 20 hydroxypropyl cellulose (L-HPC 11) Pol eth lens 1 col 6000 6.0 6.0 6.0 Sterotex 5.0 4.0 5.0 O dar AMB 12.0 12.0 12.0 93.9 mg clopidogrel hydrobromide are equivalent to 75 mg clopidogrel base.
Compositions 9a to 9c are prepared in analogous manner to that for 7a.
Examples 10a to 10c Com onents M tab Example Example Example 10a 10b 10c Clo ido rel h droiodide 104.9 104.9 104.9 Mannitol 101.7 138.6 48.6 Microcrystalline 70. S 40.5 115.5 cellulose(Avicel PH 112) Low substituted 12.0 6.0 20 hydroxypropyl cellulose (L-HPC 11) Pol eth lens 1 col 6000 6.0 6.0 6.0 Sterotex S.0 4.0 5.0 O adr AMB 12.0 12.0 12.0 104.9 mg clopidogrel hydroiodide are equivalent to 75 mg clopidogrel base.
Compositions 10a to 10c are prepared in analogous manner to that for 7a.
Examples 11a to 11c Com onents M /tab Example Example Example 11a 11b 11c Clo ido rel h drochloride83.5 83.5 83.5 Mannitol 123.0 160 70 Microcrystalline 70.5 40.5 115.5 cellulose(Avicel PH 112) Low substituted 12.0 6.0 20 hydroxypropyl cellulose (L-HPC 11) .
00 6.0 6.0 6.0 1 col 60 Pol eth lene _ 5.0 4.0 5.0 Sterotex O adr AMB 12.0 12.0 12.0 83.5 mg clopidogrel hydrochloride are equivalent to 75 mg clopidogrel base.
The compositions 11a to 11c are prepared in analogous manner to 7a above.
Examples 12a and 12b~ clopidogrel HCl tablets Com onents M tab _ Exam 1e 12b Exam 1e 12a Clopidogrel hydrochloride83.51 83.51 (e uiv. clo ido rel 75 m ) Mannitol 13 8 13 8 Microcrystalline cellulose43 43 (Avicel PH 112) Low substituted hydroxypropyl20 20 cellulose (L-HPC 11 ) Pol eth lene 1 co16000 7.5 7.5 H dro enated ve etable 6 oil O adr AMB 7.2 H dro ro lmeth lcellulose 7.2 Iron oxide red s s Titanium dioxide s s "qs": quantity sufficient to achieve desired shade or colour The compositions are prepared in analogous manner to that in Example 7a above, with the omission of Opadry AMB coating in the formulation of Example 12b. The tablet composition of Example 12a exhibits enhanced stability over that of Example 12b.
The process of this invention, including the use of roller compaction, serves to provide more stable and robust clopidogrel compositions than hitherto known compositions.
This allows economies such as elimination of more expensive packaging materials.
The compositions are reproducible, straightforward and economic to manufacture. In particular the invention provides more stable solid oral dosage forms of clopidogrel-mesylate, -hydroiodide and -hydrochloride.
Clopidogrel is a known anti-thrombotic agent which inhibits platelet aggregation. See Merck Index, 12~ Edition, entry 2457. Clopidogrel is administered currently in the form of the biphosphate salt as a film-coated tablet.
Some clopidogrel salts are known to exhibit difficulties in formulation. The present applicants have found that clopidogrel in base or salt form, e.g. as mesylate or hydrochloride, is problematic to formulate for example as a tablet, and attribute this principally to hygroscopicity. Furthermore, the applicants have found that clopidogrel tablets suffer from degradation on storage.
The present applicants have sought to overcome the problems of hitherto known clopidogrel compositions.
In one aspect, therefore, this invention provides a composition suitable for oral administration comprising clopidogrel in base or pharmaceutically acceptable salt form which composition comprises a polymer coating.
The polymer coating may comprise a polyvinyl acetate or a polyvinyl alcohol.
In this and other aspects of the invention described below, when in salt form clopidogrel may be selected from mesylate, hydroiodide, hydrobromide and hydrochloride.
In another aspect this invention provides a composition suitable for oral administration comprising clopidogrel in base or pharmaceutically acceptable salt form which composition comprises a hydrophobic component.
Suitable hydrophobic components include hydrogenated vegetable oils.
The hydrophobic component-containing compositions of this invention may comprise a polymer coating, e.g. a polyvinyl acetate or a polyvinyl alcohol. In a preferred aspect, the hydrophobic component, when present, is not coated.
In another aspect, this invention provides clopidogrel in form of coated particles, granules or agglomerates.
In a further aspect, this invention provides a composition suitable for oral administration comprising clopidogrel in base or pharmaceutically acceptable salt form wherein the clopidogrel is in the form of coated particles, granules or agglomerates.
In a preferred aspect, this invention provides a composition suitable for oral administration comprising clopidogrel in pharmaceutically acceptable salt form which composition comprises - a polymer coating selected from a polyvinyl acetate or a polyvinyl alcohol, and - a hydrophobic component comprising a hydrogenated vegetable oil, wherein the salt is selected from mesylate, hydrobromide, hydroiodide and hydrochloride, and wherein the clopidogrel is in the form of coated particles, granules or agglomerates.
The particle-, granule- or agglomerate-coating may comprise a hydrophobic polymer, e.g. a polyvinyl acetate or a polyvinyl alcohol, a hydrogenated vegetable oil or a cyclodextrin.
Preferred polymer coatings employed in the compositions of this invention are selected from celluose acetate, polymethacrylates for example Eudragit E or Eudragit NE
30 D, and ethylcellulose.
Suitable vegetable oils include hydrogenated cottonseed oil e.g. those available commercially as Lubritab or Sterotex; hydrogenated palm oil, e.g. available as Softisan 154 or Dynasan P60; hydrogenated soyabean oil such as that available as Sterotex HM.
The hydrophobic component may be selected from cetyl alcohol, cetostearyl alcohol, cholesterol, gyceryl monostearate, glyceryl monooleate, glyceryl palmitostearate and stearic acid.
The cyclodextrin may comprise an alpha-, beta- or gamma-cyclodextrin.
The compositions of this invention herein described may be administered in form of a tablet, sachet, or hard or soft gelatine capsule. Coated tablets are preferred.
In the compositions of the invention, the clopidogrel may be present in an amount of up to SO% by weight, for example 10 to 45%, e.g. 20 to 40%, e.g. 25 to 35% by weight, based on the total weight of the composition.
Thus components of the compositions of this invention may include:
- a sugar, e.g. a lactose, in an amount when present of up to 60% by weight, for example 20 to 50%, e.g. 25 to 40% by weight based on the total weight of the composition. Lactose DCL 11 is a suitable grade in the compositions of this invention;
- a microcrystalline cellulose in an amount when present of up to 40% by weight, for example S to 35%, e.g. 8 to 25%, e.g. 10 to 20% by weight based on the total weight of the composition. Avicel PH 112 is an appropriate grade for use in the compositions of this invention;
- a starch in an amount when present of up to 40% by weight, for example 5 to 35%, e.g. 8 to 20%, e.g. 10 to 17% by weight based on the total weight of the composition.
Starch 1500 LM is an appropriate grade for use in the compositions of this invention;
- a dessicant for example milled anhydrous silica, available commercially under the trade mark Syloid AL; this component when present may be in an amount of up to 8 %
by weight of the composition, e.g. 0.5 to 6%, e.g. 1 to 4% by weight;
- the hydrogenated vegetable oil when present in an amount of up to about 15 %
by weight, e.g. 1 to 10%, e.g. 2 to 7% by weight, based on the weight of the composition.
Such oils are commercially available for example under the trade mark Sterotex;
- the polymer coating, when present, in an amount of up to about 10 % by weight, e.g. 2 to 8%, e.g. 4 to 6 % by weight, based on the weight of the composition. Such coatings are available commercially for example under the trade mark Opadry AMB;
- a filler in an amount when present of up to 80% by weight, for example 5 to 75%, e.g.
to 65%, e.g. 15 to SO% by weight based on the total weight of the composition.
Mannitol and xylitol are examples of suitable fillers in compositions of this invention.
Other components may include titanium dioxide, a hydroxypropyl methylcellulose,.a hydroxyl propylcellulose and a propylene glycol.
The compositions of this invention are more straightforward to formulate than hitherto known compositions. The applicants have found that processability of the components in forming, e.g.. tablets, is easier than for known processes for making solid clopidogrel compositions.
The compositions of this invention are storage-stable. Thus no or negligible degradation is observed on storage at ambient conditions over periods of days, weeks and months.
The clopidogrel employed in the compositions and processes of this invention may be in racemate form, in form of a partially- or wholly-enriched diastereomer. Thus the clopidogrel may be in form of a pure or substantially pure diastereomer, e.g.
> 90% e.g.
93%, 94%, 95% or > 95%, e.g. 96%, 97% or greater diastereomer as determined using known methods.
In another aspect, this invention provides a process for preparing tablets comprising clopidogrel in base or pharmaceutically acceptable salt form which process comprises a) compacting the clopidrogrel with anhydrous or substantially~anhydrous components so as to form aggregates, b) breaking down the aggregates so as to form granules or particles, c) optionally mixing the granules or particles with at least one further component, and d) compacting or compressing the granules or particles thus formed into tablets.
Compaction may be carried out for example using a roller compactor.
The present applicants understand roller compaction to be a form of high-pressure agglomeration. Thus a roller press exerts a mechanical pressure on a powder or other dry bulk material while forced between, for example, two or more counter-rotating rollers. The conditions within the roller compactor are typically such that the material is compressed into compacts which are subsequently passed through a mill to produce granules.
The applicants have found that a Fitzpatrick Chilsonator compactor is a suitable commercially available compactor for roller compaction. Thus the roller speed may be between 1 and 10 rpm, e.g. 2 to 8 such as 3, 4 or 5 r.p.m. Roller pressures applied to the material may be between 300 and 800 pounds per square inch (psi), e.g. 350 (24.60 kg/cm2) to 700 (49.21 kg/cm2), such as 500 (35.13 kglcmz), 550 or 600 psi.
The desiccant, e.g. anhydrous silica, may be mixed with the aggregates or granules.
This improves stability and flow of the processed mixture.
A hydrophobic lubricant, e.g. hydrogenated vegetable oil, may be added. This provides improved stability over that observed using conventional lubricants.
The process may be carried out in a low- or ultra-low humidity environment.
The applicants have found that the compacted blend resulting from process step a) may be milled to granules or particles by screening through a comminuting mill, for example an oscillating granulator, quadrocomill or hammer mill. Thus step b) serves to break the aggregates down in size.
In a preferred aspect, process step b) may be carried out so as to form granules with a small or negligible proportion of particles. Thus the output from step b) may amount to 80% or more granules by weight in a granule/particle mixture, e.g. 85%, 90%, 95% or greater e.g. 98%, 99% or 100% granules.
In a further aspect this invention provides a process for preparing coated clopidogrel particles or granules which process comprises preparing a solution of clopidogrel and the polymer, hydrogenated vegetable oil, or cyclodextrin, in a suitable solvent medium and spray-drying the solution.
The solvent medium may comprise an aqueous or organic solvent or mixture of organic solvents. When an aqueous medium is employed, this may containing up to 100 %
by weight water, e.g. S to 80%, e.g. 10 to 60% by weight.
The thus coated or encapsulated particles or granules may be further processed, for example into tablets using compaction or compression.
Coating of the clopidogrel particles may be achieved using a fluidised bed, e.g. a Wurster, or by water-in-oil or oil-in-water phase separation or coacervation encapsulation methods.
In a further aspect, therefore, coating of the clopidogrel granules or particles may be carried out after process step b) or step c) if present and before step d).
Without being bound to a particular theoretical mechanism of action, the applicants believe that the hydrophobic polymer may establish an effective moisture barrier around the particles or tablets.
Typical dimensions observed using known methods of particles used in this invention range from 50 microns to 150 microns. 75 % of the granules of this invention may be in the size range 100 microns to S00 microns, and 75% of the agglomerates of this invention may be in the size range 500 microns to 2000 microns.
A preferred aspect of the invention is a clopidogrel composition as herein described in form of a coated particle, granule, agglomerate or tablet, wherein the coating is free of or substantially free of HPMC.
Clopidogrel may be administered at a dose of l0mg, 25mg, SOmg, 60 mg, 75mg or 100mg drug substance based on clopidogrel base, depending on the patient s body weight and other circumstances. This dose may be daily. When administered in tablet form, the tablet weight may be for example SO mg, 100mg, 150 mg, 200 mg or 300 mg in total.
Clopidogrel base, mesylate and hydroiodide are sourced from the Torrent company.
Clopidogrel hydrochloride may be prepared by processes analogous to those disclosed in published patent applications EP 0 281 459 and WO 98/51682.
Clopidogrel hydrobromide may be prepared by passing HBr gas through an organic solution of clopidogrel base, e.g. in toluene, at ambient temperature.
Clopidogrel hydrobromide salt precipitates and may be filtered and washed, e.g. with an organic solvent such as toluene. The wet cake of the salt may be dried under vacuum at elevated temperature, for example 50 to 80°C, e.g. 70 to 75°C, to provide clopidogrel HBr as an off-white solid.
In another aspect, this invention provides a composition or process substantially as herein described with reference to the examples. In a further aspect, this invention provides compositions produced using the processes of this invention. The compositions, e.g. tablets, produced by the processes of this invention may be free of or substantially free of HPMC.
Following is a description by way of example only of compositions and processes of this invention.
Example 1 Com onents Relative amounts 300 m tablet Clo ido rel mes 30-32 % wlw of com osition94 m late Lactose DCL 11 40-50 % w/w of com osition122 m Avicel PH 112 10-20 % w/w of com osition30 m Starch 1500 LM 10-15 % w/w of com osition30 m S loid AL1-FP 1-5 % w/w of com osition12 m Sterotex ~ 3-5 % w/w of composition12 mg ~
The components (all anhydrous) are mixed together, processed using dry roller compaction into aggregates, compacted to granules and formed into tablets.
Processing takes place in a low-humidity environment. 1000 tablets are prepared and divided into lots each of 100 tablets. All ten lots are stored at ambient conditions and inspected at daily intervals.
No degradation is detected by visual inspection after 10 days. Negligible degradation is observed after two months.
Example 2 Example 1 is repeated using clopidogrel hydroiodide in place of the mesylate, using molar equivalent to 75 mg clopidogrel base. Stable tablets are produced.
Example 3 Example 1 is repeated using clopidogrel hydrochloride in place of the mesylate using molar equivalent to 75 mg clopidogrel base. Stable tablets are produced.
Example 4 Com onents Relative amounts 300 m tablet Clo ido rel mes late 30-32 % w/w of com osition95 m Lactose DCL 11 40-50 % w/w of com osition115 m Avicel PH 112 10-20 % w/w of com osition32 m Starch 1500 LM 10-15 % w/w of com osition30 m S loid AL 1 -FP 1-5 % w/w of com osition6 m Sterotex 3-S % w/w of com osition10 m Opadry AMB - - 4-6 % w/w of composition12 mg ~
The anhydrous components are mixed together, processed in analogous manner to that in Example 1 and formed into tablets. The tablets are coated using Opadry AMB.
1000 tablets are prepared and divided into 10 lots each of 100 tablets. All ten lots are stored at ambient conditions and inspected at daily intervals. No degradation is detected by visual inspection after 10 days. Negligible degradation isobserved after one month.
Example S
Example 4 is repeated using clopidogrel hydroiodide in place of the mesylate.
The molar equivalent to 75 mg clopidogrel base is used. Stable tablets are produced.
Example 6 Example 4 is repeated using clopidogrel hydrochloride (molar equivalent to 75 mg base) in place of the mesylate. Stable tablets are produced.
Compositions containing mannitol as a tiller are prepared in the following Examples 7 and 9 to 12.
Examples 7a to c Coin onents M /tab Example Example Example 7 a 7b 7c Clo ido rel mes late 99.7 99.7 99.7 Mannitol 10&.8 143.8 53.8 Microcrystalline 70.5 40.5 11S.S
cellulose(Avicel PH 112) Low substituted 12.0 6.0 20 hydroxypropyl cellulose (L-HPC 11) Pol eth lene 1 col 6000 6.0 6.0 6.0 Sterotex S.0 4.0 5.0 O adr AMB 12.0 12.0 12.0 99.7 mg clopidogrel mesylate are equivalent to 7S mg clopidogrel base.
Composition 7a:
The clopidogrel salt is blended with mannitol, microcrystalline cellulose and part of the low substituted hydroxypropylcellulose. The blend is compacted using a Fitzpatrick Chilsonator roller compactor. The compacts are then milled into granules by screening through an oscillating granulator comminuting mill. The granules are blended with part of microcrystalline cellulose, low substituted hydroxypropylcellulose, mannitol, PEG
6000 and Sterotex. The blend is compressed into tablets using a Korsch rotary compressor. The tablets are then coated with Opadry AMB in a Hicoater perforated coating pan.
An analogous procedure is used to prepare compositions 7b and 7c.
Example 8~ Clopido~rel hydrobromide To a solution of 100 g clopidogrel base in 1000 ml toluene is passed hydrogen bromide gas for 1 S minutes at ambient temperature. Clopidogrel HBr precipitates. The precipitated clopidogrel.HBr salt is filtered and washed with S00 ml toluene.
The wet cake of the salt is dried under vacuum at 70 to 75°C overnight to give clopidogrel.HBr as an off-white solid.
Yield: 8 8.1 g ( 70 % ) Examples 9a to c Com onents M /tab Example Example Example 9a 9b 9c Clo ido rel h drobromide93.9 93.9 93.9 Mannitol 112.6 149.6 59.6 Microcrystalline 70.5 40.5 115.5 cellulose(Avicel PH 112) Low substituted 12.0 6.0 20 hydroxypropyl cellulose (L-HPC 11) Pol eth lens 1 col 6000 6.0 6.0 6.0 Sterotex 5.0 4.0 5.0 O dar AMB 12.0 12.0 12.0 93.9 mg clopidogrel hydrobromide are equivalent to 75 mg clopidogrel base.
Compositions 9a to 9c are prepared in analogous manner to that for 7a.
Examples 10a to 10c Com onents M tab Example Example Example 10a 10b 10c Clo ido rel h droiodide 104.9 104.9 104.9 Mannitol 101.7 138.6 48.6 Microcrystalline 70. S 40.5 115.5 cellulose(Avicel PH 112) Low substituted 12.0 6.0 20 hydroxypropyl cellulose (L-HPC 11) Pol eth lens 1 col 6000 6.0 6.0 6.0 Sterotex S.0 4.0 5.0 O adr AMB 12.0 12.0 12.0 104.9 mg clopidogrel hydroiodide are equivalent to 75 mg clopidogrel base.
Compositions 10a to 10c are prepared in analogous manner to that for 7a.
Examples 11a to 11c Com onents M /tab Example Example Example 11a 11b 11c Clo ido rel h drochloride83.5 83.5 83.5 Mannitol 123.0 160 70 Microcrystalline 70.5 40.5 115.5 cellulose(Avicel PH 112) Low substituted 12.0 6.0 20 hydroxypropyl cellulose (L-HPC 11) .
00 6.0 6.0 6.0 1 col 60 Pol eth lene _ 5.0 4.0 5.0 Sterotex O adr AMB 12.0 12.0 12.0 83.5 mg clopidogrel hydrochloride are equivalent to 75 mg clopidogrel base.
The compositions 11a to 11c are prepared in analogous manner to 7a above.
Examples 12a and 12b~ clopidogrel HCl tablets Com onents M tab _ Exam 1e 12b Exam 1e 12a Clopidogrel hydrochloride83.51 83.51 (e uiv. clo ido rel 75 m ) Mannitol 13 8 13 8 Microcrystalline cellulose43 43 (Avicel PH 112) Low substituted hydroxypropyl20 20 cellulose (L-HPC 11 ) Pol eth lene 1 co16000 7.5 7.5 H dro enated ve etable 6 oil O adr AMB 7.2 H dro ro lmeth lcellulose 7.2 Iron oxide red s s Titanium dioxide s s "qs": quantity sufficient to achieve desired shade or colour The compositions are prepared in analogous manner to that in Example 7a above, with the omission of Opadry AMB coating in the formulation of Example 12b. The tablet composition of Example 12a exhibits enhanced stability over that of Example 12b.
The process of this invention, including the use of roller compaction, serves to provide more stable and robust clopidogrel compositions than hitherto known compositions.
This allows economies such as elimination of more expensive packaging materials.
The compositions are reproducible, straightforward and economic to manufacture. In particular the invention provides more stable solid oral dosage forms of clopidogrel-mesylate, -hydroiodide and -hydrochloride.
Claims (11)
1. A composition suitable for oral administration comprising clopidogrel in pharmaceutically acceptable salt form which composition comprises - a polymer coating selected from a polyvinyl acetate or a polyvinyl alcohol, and - a hydrophobic component comprising a hydrogenated vegetable oil, wherein the salt is selected from mesylate, hydrobromide, hydroiodide and hydrochloride, and wherein the clopidogrel is in the form of coated particles, granules or agglomerates.
2. A composition as claimed in claim 1 in form of a tablet, sachet or capsule.
3. A composition as claimed in claim 1 or claim 2 wherein the coated particles, granules or agglomerates are free of or substantially free of HPMC.
4. A process for preparing tablets comprising clopidogrel in pharmaceutically acceptable salt form which process comprises a) compacting the clopidrogrel with anhydrous or substantially anhydrous components so as to form aggregates, b) breaking down the aggregates so as to form granules or particles, c) optionally mixing the granules or particles with at least one further component, and d) compacting or compressing the granules or particles thus formed into tablets, wherein the clopidogrel is used in mesylate, hydrobromide, hydroiodide, or hydrochloride form, and the process further comprises mixing a moisture scavenger with the aggregates, granules or particles.
5. A process as claimed in claim 4 further comprising addition of a hydrophobic lubricant.
6. A process as claimed in claim 4 or 5 carried out in a low- or ultra-low humidity environment.
7. A process as claimed in any one of claims 4 to 6 wherein step a) is carried out using roller compaction.
8. A process as claimed in any one of claims 4 to 7 which process further comprises a granule- or particle-coating step after step b) or step c) when present and before step d).
9. A process as claimed in claim 8 wherein the coating is carried out using a hydrophobic polymer, a hydrogenated vegetable oil or a cyclodextrin.
10. A tablet prepared by the process of any one of claims 4 to 9.
11. A tablet as claimed in claim 10 which is free of or substantially free of HPMC.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB0325603.9 | 2003-11-03 | ||
| GBGB0325603.9A GB0325603D0 (en) | 2003-11-03 | 2003-11-03 | Organic compounds |
| PCT/EP2004/012437 WO2005048992A1 (en) | 2003-11-03 | 2004-11-03 | Process for preparing clopidogrel compositions |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2540965A1 true CA2540965A1 (en) | 2005-06-02 |
Family
ID=29725839
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002540965A Abandoned CA2540965A1 (en) | 2003-11-03 | 2004-11-03 | Process for preparing clopidogrel compositions |
Country Status (8)
| Country | Link |
|---|---|
| EP (1) | EP1682096A1 (en) |
| JP (1) | JP2007527414A (en) |
| CN (1) | CN101848705A (en) |
| AU (1) | AU2004290511A1 (en) |
| BR (1) | BRPI0416109A (en) |
| CA (1) | CA2540965A1 (en) |
| GB (1) | GB0325603D0 (en) |
| WO (1) | WO2005048992A1 (en) |
Families Citing this family (24)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005070464A2 (en) * | 2004-01-21 | 2005-08-04 | Biofarma Ilac Sanayi Ve Ticaret A.S. | A tablet formulation of clopidogrel bisulphate |
| CN1997648A (en) * | 2004-04-20 | 2007-07-11 | 赛诺菲-安万特 | Polymorphic forms of methyl(+)-(S)-alpha-(2-chlorophenyl)-6,7-dihydrothieno[3,2-C]pyridine-5(4H) acetate hydrobromide, clopidrogel hydrobromide |
| BRPI0510008A (en) | 2004-04-20 | 2007-09-18 | Sanofi Aventis | clopidogrel salt and polymorphic forms of this |
| TW200640932A (en) * | 2005-02-24 | 2006-12-01 | Teva Pharma | Clopidogrel base suitable for pharmaceutical formulation and preparation thereof |
| DE202005013839U1 (en) * | 2005-09-01 | 2005-10-27 | Helm Ag | Tablet containing monobasic acid salt of clopidogrel, useful for preventing thromboembolic events, e.g. stroke or myocardial infarction, contains no ionic or basic auxiliaries or polyethylene glycol |
| WO2007054968A2 (en) * | 2005-09-20 | 2007-05-18 | Torrent Pahrmaceuticals Limited | Novel pharmaceutical compositions of clopidogrel mesylate |
| IS2385B (en) * | 2006-02-10 | 2008-07-15 | Actavis Group Hf. | Clopidogrel bisulfate pharmaceutical compositions |
| CZ298349B6 (en) * | 2006-03-09 | 2007-09-05 | Zentiva, A. S | Hydrogen bromide clopidogrel pharmaceutical composition |
| JP2009532462A (en) * | 2006-04-05 | 2009-09-10 | カディラ・ヘルスケア・リミテッド | Modified release clopidogrel formulation |
| DK1847258T4 (en) | 2006-04-13 | 2013-04-15 | Acino Pharma Ag | Partial glycerides as lubricant for pharmaceutical compositions containing thieno [3,2-c] pyridine derivatives |
| EP1847259B8 (en) * | 2006-04-13 | 2010-04-14 | RIEMSER Specialty Production GmbH | Compositions comprising thieno[2,3-c]pyridine derivatives as active agents with poloxamers as lubricants |
| WO2007128476A1 (en) * | 2006-05-04 | 2007-11-15 | Sandoz Ag | Pharmaceutical compositions containing clopidogrel hydrochloride |
| KR20080055356A (en) * | 2006-12-15 | 2008-06-19 | 에스케이케미칼주식회사 | Inclusion complex of clopidogrel and beta-cyclodextrin |
| KR20080055355A (en) * | 2006-12-15 | 2008-06-19 | 에스케이케미칼주식회사 | Inclusion complex of clopidogrel and beta-cyclodextrin |
| EP1970054A3 (en) | 2007-03-14 | 2009-06-03 | Ranbaxy Laboratories Limited | Clopidogrel tablets |
| EP2148655B1 (en) * | 2007-04-20 | 2013-02-27 | Wockhardt Limited | Pharmaceutical compositions of clopidogrel |
| EP2095815B1 (en) * | 2008-02-26 | 2011-10-26 | Laboratorios Lesvi, S.L. | Pharmaceutical formulations containing clopidogrel |
| EP2107061A1 (en) | 2008-04-02 | 2009-10-07 | Krka Tovarna Zdravil, D.D., Novo Mesto | Process for the preparation of optically enriched clopidogrel |
| DE602008002820D1 (en) | 2008-04-25 | 2010-11-11 | Sandoz Ag | Hydrogen sulfate of 2-acetoxy-5- (α-cyclopropylcarbonyl-2-fluorobenzyl) -4,5,6,7-tetrahydrothienoÄ3,2-cpyridine and its preparation |
| EA024980B1 (en) | 2009-02-17 | 2016-11-30 | КРКА, д.д., НОВО МЕСТО | Dosage forms comprising prasugrel base or its pharmaceutically acceptable acid addition salts and processes for their preparation |
| JP2013032289A (en) * | 2009-10-28 | 2013-02-14 | Daiichi Sankyo Co Ltd | Wax stable formulation |
| ES2363964B1 (en) | 2009-11-20 | 2012-08-22 | Gp Pharm, S.A. | CAPSULES OF PHARMACEUTICAL ACTIVE PRINCIPLES AND ESTERS OF POLYINSATURATED FATTY ACIDS. |
| CN101766573B (en) | 2010-02-05 | 2013-02-13 | 上海安必生制药技术有限公司 | Preparation process of clopidogrel bisulfate solid preparation |
| CN101851247B (en) * | 2010-06-04 | 2013-05-29 | 浙江华海药业股份有限公司 | Composition containing clopidogrel bisulfate crystal particles |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2363053C (en) * | 2001-11-09 | 2011-01-25 | Bernard Charles Sherman | Clopidogrel bisulfate tablet formulation |
| EP1606231A1 (en) * | 2003-02-03 | 2005-12-21 | Nadkarni, Sunil Sadanand | Process for preparation of clopidogrel, its salts and pharmaceutical compositions |
-
2003
- 2003-11-03 GB GBGB0325603.9A patent/GB0325603D0/en not_active Ceased
-
2004
- 2004-11-03 JP JP2006537245A patent/JP2007527414A/en not_active Withdrawn
- 2004-11-03 EP EP04797570A patent/EP1682096A1/en not_active Withdrawn
- 2004-11-03 WO PCT/EP2004/012437 patent/WO2005048992A1/en not_active Application Discontinuation
- 2004-11-03 BR BRPI0416109-2A patent/BRPI0416109A/en not_active Application Discontinuation
- 2004-11-03 CN CN200480032288A patent/CN101848705A/en active Pending
- 2004-11-03 AU AU2004290511A patent/AU2004290511A1/en not_active Abandoned
- 2004-11-03 CA CA002540965A patent/CA2540965A1/en not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| WO2005048992A1 (en) | 2005-06-02 |
| JP2007527414A (en) | 2007-09-27 |
| AU2004290511A1 (en) | 2005-06-02 |
| GB0325603D0 (en) | 2003-12-10 |
| CN101848705A (en) | 2010-09-29 |
| EP1682096A1 (en) | 2006-07-26 |
| BRPI0416109A (en) | 2007-01-02 |
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