CN101848705A - Process for preparing clopidogrel compositions - Google Patents

Process for preparing clopidogrel compositions Download PDF

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Publication number
CN101848705A
CN101848705A CN200480032288A CN200480032288A CN101848705A CN 101848705 A CN101848705 A CN 101848705A CN 200480032288 A CN200480032288 A CN 200480032288A CN 200480032288 A CN200480032288 A CN 200480032288A CN 101848705 A CN101848705 A CN 101848705A
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China
Prior art keywords
clopidogrel
granule
tablet
compositions
microgranule
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Pending
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CN200480032288A
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Chinese (zh)
Inventor
R·巴拉特拉杰恩
P·哈尔卡尔
S·罗伊
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Sandoz AG
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Sandoz AG
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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

The preparation method of clopidogrel composition
The present invention relates to comprise the pharmaceutical composition of clopidogrel and prepare this method for compositions.
Clopidogrel is a kind of antithrombotic agents of known inhibition platelet aggregation.Consult " Merck index " the 12nd edition the 2457th.Clopidogrel is used with the thin membrane coated tablet of hydrophosphate form at present.
The salt of known some clopidogrel has difficulties in the preparation process.The applicant has been found that: the alkali of clopidogrel or salt form such as mesylate or hydrochlorate, when for example being mixed with tablet, have problems, and this mainly is because hygroscopicity.In addition, the applicant finds that the clopidogrel tablet is degraded in storage process.
The applicant has managed to overcome the problem of known clopidogrel composition up to now.
Therefore, on the one hand, the invention provides and be suitable for Orally administered, as to comprise the clopidogrel of alkali or pharmaceutical acceptable salt compositions, said composition comprises polymer coating.
Polymer coating can comprise polyvinyl acetate or polyvinyl alcohol.
At aspect this and other aspects of the following stated of the present invention, when being salt form, clopidogrel can be selected from mesylate, hydriodate, hydrobromate and hydrochlorate.
On the other hand, the invention provides and be suitable for Orally administered, as to comprise the clopidogrel of alkali or pharmaceutical acceptable salt compositions, said composition comprises hydrophobic components.
Suitable hydrophobic components comprises hydrogenated vegetable oil.
The compositions that comprises hydrophobic components of the present invention can comprise polymer coating, as polyvinyl acetate or polyvinyl alcohol.Aspect preferred, when hydrophobic components exists not by coating.
On the other hand, the invention provides the clopidogrel of coated particle (particle), granule (granule) or agglomerate (agglomerate) form.
Advance on the one hand, the invention provides and be suitable for Orally administered, as to comprise the clopidogrel of alkali or pharmaceutical acceptable salt compositions, wherein clopidogrel is coated particle, granule or agglomerate.
Aspect preferred, the invention provides the compositions that is suitable for Orally administered, as to comprise pharmaceutical acceptable salt clopidogrel, said composition comprises:
-be selected from polyvinyl acetate or polyvinyl alcohol polymer coating and
-comprise the hydrophobic components of hydrogenated vegetable oil,
Wherein said salt is selected from mesylate, hydrobromate, hydriodate and hydrochlorate, and wherein clopidogrel is coated particle, granule or agglomerate.
Microgranule, granule or agglomerate coating can comprise hydrophobic polymer, as polyvinyl acetate or polyvinyl alcohol, and hydrogenated vegetable oil or cyclodextrin.
The preferred polymers coating that is adopted in the present composition is selected from cellulose acetate, polymethacrylates such as Eudragit E or Eudragit NE 30D, and ethyl cellulose.
Suitable vegetable oil comprises cotmar, as commercially available Lubritab that gets or Sterotex; Hydrogenated palm oil is as utilizing Softisan 154 or Dynasan P60; Hydrogenated soybean oil is as utilizing Sterotex HM.
Hydrophobic components can be selected from spermol, cetostearyl alcohol, cholesterol, glyceryl monostearate, glycerin mono-fatty acid ester, Palmic acid tristerin (glyceryl palmitostearate) and stearic acid.
Cyclodextrin can comprise α, β or γ cyclodextrin.
Compositions of the present invention described here can be used with the form of tablet, medicine bag or hard or Perle.Preferred coated tablet.
In compositions of the present invention, based on the gross weight of compositions, the content of clopidogrel can reach 50% by weight, and for example by weight 10 to 45%, for example 20 to 40%, for example 25 to 35%.
Thus, the component of the present composition can comprise:
-sugar, as lactose, its content reaches 60% by weight based on the gross weight of compositions when existing, and for example by weight 20 to 50%, for example 25 to 45%.In the present composition, lactose DCL 11 is the ranks that suit;
-microcrystalline Cellulose, its content reaches 40% by weight based on the gross weight of compositions when existing, and for example by weight 5 to 35%, for example 8 to 25%, for example 10 to 20%.Avicel PH 112 is the suitable ranks that are used for the present composition;
-starch, its content reaches 40% by weight based on the gross weight of compositions when existing, and for example by weight 5 to 35%, for example 8 to 20%, for example 10 to 17%.Starch 1500LM is the suitable rank that is used for the present composition;
-desiccant, the anhydride silica of Fen Suiing for example is with commercially available the getting of trade mark Syloid AL; Content when this component exists can reach 8% of composition weight, and for example by weight 0.5 to 6%, for example 1 to 4%;
-hydrogenated vegetable oil, when existing its content reach by weight based on the weight of compositions about 15%, for example by weight 1 to 10%, for example 2 to 7%.This class oil for example gets so that trade mark Sterotex is commercially available;
-polymer coating, when existing its content reach by weight based on the weight of compositions about 10%, for example by weight 2 to 8%, for example 4 to 6%.This class coating is for example with commercially available the getting of trade mark Opadry AMB;
-filler, its content reaches 80% by weight based on the gross weight of compositions when existing, and for example by weight 5 to 75%, for example 10 to 65%, for example 15 to 50%.Mannitol and xylitol are the examples of suitable filler in the present composition.
Other components can comprise titanium dioxide, hydroxypropyl emthylcellulose, hydroxypropyl cellulose and propylene glycol.
The more hitherto known compositions of the preparation of the present composition is more direct.The applicant has been found that: it is more easy that the processing characteristics of each component in forming tablet for example prepares the known method of solid clopidogrel composition.
Composition stores of the present invention is stable.Therefore, store a couple of days, several weeks or several months, do not observe degraded or observed degraded and can ignore in environmental condition.
The clopidogrel that uses in the compositions and methods of the invention can be the diastereomer form of racemic object form, part or all of enrichment.Therefore, clopidogrel can be pure or pure basically diastereomer form, for example＞90%, for example 93%, 94%, 95% or＞95%, for example 96%, 97% or more diastereomer, as determining with known method.
On the other hand, the invention provides the preparation method of the tablet of the clopidogrel that comprises alkali or pharmaceutical acceptable salt, this method comprises:
A) clopidogrel and anhydrous or anhydrous basically component are compressed to form aggregation;
B) aggregation is cracked to form granule or microgranule;
C) optional with granule or microgranule mixes with at least a other components and
D) granule or microgranule are compressed or compress, thereby form tablet.
Compress and to carry out with for example roll-type compacting machine.
The applicant understands: it is a kind of high pressure agglomerated form that roll-type compresses.Therefore, roll squeezer applies mechanical pressure to powder or other dried bulk materials, forces it to pass through between the roller of two or more reverse rotations simultaneously.Condition in the roll-type compacting machine makes that usually material is compressed into compact, make subsequently its by pulverizer with the preparation granule.
The applicant has been found that: Fitzpatrick Chilsonator compacting machine is to be suitable for the commercially available compacting machine that roll-type compresses.Thus, the speed of roller can be between 1 to 10rpm, and for example 2 to 8 as 3,4 or 5rpm.The roller pressure that puts on material can be per square inch 300 to 800 pounds (psi), 350 (24.60kg/cm for example 2) to 700 (49.21kg/cm 2), as 500 (35.13kg/cm 2), 550 or 600psi.
Desiccant such as anhydride silica can mix with aggregation or granule.This has improved the stable and mobile of institute's process mixture.
Can add hydrophobic lubricant, for example hydrogenated vegetable oil.This provides with respect to the stability of using the viewed improvement of traditional lubrication agent.
Described method can be carried out under low humidity or ultralow humidity environment.
The applicant finds: derive from the method step mixture that compresses a) and sieve by pulverizer and can be ground into granule or microgranule, for example oscillating granulator, quadrocomill or beater grinder.Thus, step b) is used for aggregation cracked.
Aspect preferred, can carry out method step b), to form the wherein little or negligible granule of ratio of microgranule.Thus, in the product of step b), the granule in granule/particle mixture can reach by weight 80% or higher, and for example 85%, 90%, 95%, or higher, 98%, 99% or 100% granule for example.
Advance on the one hand, the invention provides the coated particle or the particulate method of preparation clopidogrel, this method comprises preparation clopidogrel and polymer, hydrogenated vegetable oil or cyclodextrin solution and this solution of spray drying in the suitable solvent medium.
Solvent medium can comprise the mixture of aqueous or organic solvent or organic solvent.As adopt aqueous medium, then can contain and reach 100% water by weight, for example by weight 5 to 80%, for example 10 to 60%.
So the microgranule of coating or encapsulation or granule can further use and compress or compression method is processed into for example tablet.
The coating of clopidogrel microgranule can or pass through Water-In-Oil or oil-in-water phase separation method or the realization of coagulation encapsulation method with fluid bed such as Wurster.
Therefore, on the other hand, the coating of clopidogrel granule or microgranule can be at method step b) or the step c) when existing after and step d) carry out before.
Do not limit by specific theory action mechanism, the applicant believes: hydrophobic polymer can be set up effective damp proof barrier around microgranule or tablet.
The typical sizes of the microgranule that uses among the present invention with the known method observation is 50 microns to 150 microns.The particulate size of the present invention of 75% can be 100 microns to 500 microns, and the size of 75% agglomerate of the present invention can be 500 microns to 2000 microns.
The preferred aspect of the present invention is the clopidogrel composition of coated particle, granule, agglomerate or tablet form described herein, and wherein coating does not contain or is substantially free of hydroxypropyl emthylcellulose (HPMC).
Depend on body weight and other situations of patient, can use the clopidogrel of counting 10mg, 25mg, 50mg, 60mg, 75mg or 100mg drug dose with clopidogrel base.But this dosage is used every day.When using with tablet form, sheet heavily can be and for example amounts to 50mg, 100mg, 150mg, 200mg or 300mg.
The alkali of clopidogrel, mesylate and hydriodate are from Torrent company.
The hydrochloric acid clopidogrel can by with disclosed patent application EP 0281459 and WO 98/51682 in similarly method preparation.
The hydrobromic acid clopidogrel can by at room temperature HBr gas is fed clopidogrel base for example the organic solution in toluene prepare.Clopidogrel hydrobromate produces precipitation, it can be filtered and for example use organic solvent such as toluene wash.Wet salt filter cake can obtain the hydrobromic acid clopidogrel in the temperature of vacuum, rising, for example 50 to 80 ℃, 70 to 75 ℃ of dryings for example, is the off-white color solid.
On the other hand, the invention provides basically as described compositions of this paper reference example or method.On the other hand, the invention provides the compositions of using method preparation of the present invention.Compositions such as tablet by the inventive method preparation can not contain or be substantially free of HPMC.
Below illustrate the compositions and methods of the invention.
Embodiment 1
Component Relative quantity The 300mg tablet
The methanesulfonic acid clopidogrel The 30-32%w/w of compositions ??94mg
Lactose DCL 11 The 40-50%w/w of compositions ??122mg
??Avicel?PH?112 The 10-20%w/w of compositions ??30mg
Starch 1500LM The 10-15%w/w of compositions ??30mg
??Syloid?AL?1-FP The 1-5%w/w of compositions ??12mg
??Sterotex The 3-5%w/w of compositions ??12mg
Component (all anhydrous) is mixed, utilize dry method rolling to be processed into aggregation, be pressed into granule and make tablet.Processing is carried out under low-humidity environment.Make 1000, be divided into 10 batches, 100 every batch.Be stored under the environmental condition and inspection every day with all 10 batches.
Degraded is not found in visual examination after 10 days.Observed degraded can be ignored after 2 months.
Embodiment 2
Use the hydroiodic acid clopidogrel to replace the methanesulfonic acid clopidogrel, repeat embodiment 1, use the mole that is equivalent to the 75mg clopidogrel base.Make stable tablet.
Embodiment 3
Use the hydrochloric acid clopidogrel to replace the methanesulfonic acid clopidogrel, repeat embodiment 1, use the mole that is equivalent to the 75mg clopidogrel base.Make stable tablet.
Embodiment 4
Component Relative quantity The 300mg tablet
The methanesulfonic acid clopidogrel The 30-32%w/w of compositions ??95mg
Lactose DCL 11 The 40-50%w/w of compositions ??115mg
Component Relative quantity The 300mg tablet
??Avicel?PH?112 The 10-20%w/w of compositions ??32mg
Starch 1500LM The 10-15%w/w of compositions ??30mg
??Syloid?AL?1-FP The 1-5%w/w of compositions ??6mg
??Sterotex The 3-5%w/w of compositions ??10mg
??Opadry?AMB The compositions of 4-6%w/w ??12mg
Anhydrous components is mixed, handle, form tablet in mode similar to Example 1.Tablet Opadry AMB coating.
Make 1000, be divided into 10 batches, 100 every batch.Be stored under the environmental condition and inspection every day with all 10 batches.Degraded is not found in visual examination after 10 days.Observed degraded can be ignored after 1 month.
Embodiment 5
Use the hydroiodic acid clopidogrel to replace the methanesulfonic acid clopidogrel, repeat embodiment 4.Use is equivalent to the mole of 75mg clopidogrel base.Make stable tablet.
Embodiment 6
Use hydrochloric acid clopidogrel (mole is equivalent to the alkali of 75mg) to replace the methanesulfonic acid clopidogrel, repeat embodiment 4, make stable tablet.
The following example 7 and embodiment 9 to 12 have prepared and have comprised the compositions of mannitol as filler.
Embodiment 7a to c
Figure G04832288520060515D000071
99.7mg the methanesulfonic acid clopidogrel is equivalent to the 75mg clopidogrel base.
Compositions 7a:
Clopidogrel salt is mixed with mannitol, microcrystalline Cellulose and part low-substituted hydroxypropyl cellulose.Mixture compresses with Fitzpatrick Chilsonator roll squeezer.Sieve by the oscillating granulator pulverizer then, compact is ground into granule.Granule is mixed with part microcrystalline Cellulose, low-substituted hydroxypropyl cellulose, mannitol, PEG 6000 and Sterotex.Mixture is compressed into tablet with the Korsch rotary tablet machine.Then tablet is used Opadry AMB coating in Hicoater porous coating pan.
Similarly method is used to prepare compositions 7b and 7c.
Embodiment 8: the hydrobromic acid clopidogrel
In the solution of 100g clopidogrel base in 1000ml toluene, fed bromize hydrogen gas 15 minutes at ambient temperature.The hydrobromic acid clopidogrel produces precipitation.The sedimentary clopidogrel hydrobromate of institute is filtered and uses the 500ml toluene wash.Wet salt filter cake is spent the night at 70 to 75 ℃ of vacuum dryings, obtain the hydrobromic acid clopidogrel, be the off-white color solid.Yield: 88.1g (70%).
Embodiment 9a to c
Figure G04832288520060515D000081
93.9mg the hydrobromic acid clopidogrel is equivalent to the 75mg clopidogrel base.
Prepare compositions 9a to 9c in the mode that is similar to 7a.
Embodiment 10a to 10c
104.9mg the hydroiodic acid clopidogrel is equivalent to the 75mg clopidogrel base.
Prepare compositions 10a to 10c in the mode that is similar to 7a.
Embodiment 11a to 11c
Figure G04832288520060515D000092
83.5mg the hydrochloric acid clopidogrel is equivalent to the 75mg clopidogrel base.
Prepare compositions 11a to 11c in the mode that is similar to above-mentioned 7a.
Embodiment 12a and 12b: hydrochloric acid clopidogrel sheet
Figure G04832288520060515D000101
" qs ": the amount that is enough to reach required colourity or color
Prepare compositions in the mode that is similar to the foregoing description 7a, in the preparation of embodiment 12b, omit Opadry AMB coating.The tablet composition of embodiment 12a strengthens than the stability of embodiment 12b.
Comprise the inventive method of using roll-in method, be used to provide more known compositions more stable and more firm clopidogrel composition.This is more economical, as need not more expensive packaging material.Said composition favorable reproducibility, direct, preparation economy.Particularly, the invention provides the solid oral dosage form of more stable methanesulfonic acid clopidogrel, hydroiodic acid clopidogrel and hydrochloric acid clopidogrel.

Claims (11)

1. comprise pharmaceutical acceptable salt clopidogrel, be suitable for Orally administered compositions, said composition comprises
-be selected from polyvinyl acetate or polyvinyl alcohol polymer coating and
-comprise the hydrophobic components of hydrogenated vegetable oil,
Wherein said salt is selected from mesylate, hydrobromate, hydriodate and hydrochlorate, and wherein clopidogrel is coated particle, granule or agglomerate.
2. compositions as claimed in claim 1 is tablet, medicine bag or capsule form.
3. compositions as claimed in claim 1 or 2, wherein coated particle, granule or agglomerate do not contain or do not contain substantially HPMC.
4. comprise the preparation method of tablet of the clopidogrel of pharmaceutical acceptable salt, this method comprises
A) clopidogrel is compressed to form aggregation with anhydrous or anhydrous basically component;
B) aggregation is cracked to form granule or microgranule;
C) optional granule or microgranule are mixed with at least a other components; With
D) granule or microgranule are compressed or compress, thereby form tablet;
Wherein use mesylate, hydrobromate, hydriodate or the hydrochloride form of clopidogrel, this method also comprises mixes moisture scavenger with aggregation, granule or microgranule.
5. method as claimed in claim 4 also comprises the adding hydrophobic lubricant.
6. as claim 4 or 5 described methods, under the environment of low or ultralow humidity, carry out.
7. as any one described method in the claim 4 to 6, wherein step a) is carried out with roll-in method.
8. as any one described method in the claim 4 to 7, this method also be included in step b) or the step c) when existing after and step d) before to the coating steps of granule or microgranule.
9. method as claimed in claim 8, coating wherein use hydrophobic polymer, hydrogenated vegetable oil or cyclodextrin to carry out.
10. pass through the tablet of any one described method preparation in the claim 4 to 9.
11. tablet as claimed in claim 10, it does not contain or does not contain substantially HPMC.
CN200480032288A 2003-11-03 2004-11-03 Process for preparing clopidogrel compositions Pending CN101848705A (en)

Applications Claiming Priority (2)

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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

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