CN102697752A - Medicinal composition of pharmaceutically-acceptable salt containing clopidogrel and preparation method thereof - Google Patents
Medicinal composition of pharmaceutically-acceptable salt containing clopidogrel and preparation method thereof Download PDFInfo
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Abstract
The invention discloses a medicinal composition of a pharmaceutically-acceptable salt, i.e., (+)-(s)-alpha-(2-chlorphenyl)-6,7-dihydrothieno-[3,2-c]pyridine-5(4H) and a preparation method thereof. According to the medicinal composition, the limitations of polycrystalline types and electrostatic properties of bulk pharmaceuticals on the preparation of solid oral preparations with stable product quality and high bioavailability are broken through. A medicinal composition and an appropriate medicinal medium construct a novel medicinal composition creatively, so that possible adverse effects of crystal transformation caused in the preparation process of bulk pharmaceuticals on the product quality and a clinical treatment effect are eliminated completely, and the bioavailability is enhanced remarkably. The medicinal composition is suitable for industrially preparing soft capsules or liquid hard capsules.
Description
Technical field
The invention belongs to medical technical field, relate to pharmaceutical composition that comprises the acceptable salt of clopidogrel pharmacy and preparation method thereof.Described compositions has thoroughly been eliminated the adverse effect that the clopidogrel pharmaceutically acceptable salt brings therapeutic effect and product quality because of polymorphic, and bioavailability is improved, production technology suitability for industrialized production preferably.
Background technology
Sulfur hydracid clopidogrel is the medicament for resisting platelet aggregation of new generation by French Sai Nuofei drugmaker (Sanofi) development, and clopidogrel must could produce active metabolite and then performance antiplatelet focussing force after the CYP450 enzymatic conversion.Its active metabolite is alternative suppress adenosine diphosphate (ADP) (ADP) with it platelet receptor combine and by the activation of the glycoprotein GP II b/ III a complex of ADP mediation, the inhibition platelet is gathered.Except that ADP, clopidogrel can also suppress the platelet aggregation of other agonist induction through blocking the amplification of the platelet activation that is caused by the ADP that discharges.Be used to prevent and treat the circulation disorder of the heart, brain and other tremulous pulsies that cause because of the high coherent condition of platelet clinically.This product took the lead in getting into multinational markets such as Europe, North America, Australia, Singapore subsequently in U.S.'s listing in March, 1998, went on the market in China August calendar year 2001, and commodity are called Bo Liwei, and clinical practice at present is comparatively extensive.
The chemistry of clopidogrel is called (+)-(s)-α-(2-chlorphenyl)-6, the 7-dihydro-thiophene also-[3,2-c] pyridines-5 (4H) methyl acetate, its structural formula is following:
Because of clopidogrel base is an oily liquids, and solvent is residual too high in the preparation process, is difficult to satisfy the pharmacopeia requirement residual to solvent, thus often itself and pharmaceutically acceptable acid reaction are processed corresponding salt, to satisfy the pharmaceuticals industry requirement.
Hydrochlorate, sulfur hydrogen salt, hydrobromate and the taurocholate of clopidogrel are specifically disclosed in US4847265.
The method for preparing of sulfur hydracid clopidogrel and the crystal formation I that is obtained are disclosed in the EP281459 patent the earliest.
WO99/65915 also discloses crystal form II of sulfur hydracid clopidogrel and preparation method thereof.
U.S.2003/0114479 discloses crystalline form III, IV, V and the armorphous method for preparing of sulfur hydracid clopidogrel.
U.S.2003/0225129 discloses crystalline form III, IV, V, VI and the armorphous method for preparing of sulfur hydracid clopidogrel.
WO2005/080890 then discloses crystal form A, B, C, D, E, the F of hydrobromic acid clopidogrel; The method for preparing of the salt of two kinds of novel crystal forms A of (+)-(S)-LOMAR PWA EINECS 246-676-2 clopidogrel, B and benzenesulfonic acid clopidogrel, p-methyl benzenesulfonic acid clopidogrel and oxalic acid clopidogrel.
WO2005/103059 then discloses (+)-(S)-α-(2-chlorphenyl)-6, and the 7-dihydro-thiophene is [3,2-C] pyridines-5 (4H) methyl acetate naphthalene-1 also, and the 5-disulfonate exists multiple crystal formation Preparation method and uses such as A, B, C, D, E, F.
WO2008/134600 then discloses and has comprised the clopidogrel that the form with free alkali or the acceptable salt of its pharmacy exists and the compositions of sulfo group alkane ether ring dextrin (SAE-CD).
Can know that from present open source information the salt of clopidogrel exists polymorphism.With sulfur hydracid clopidogrel is example, because of its intermolecular arrangement mode difference, the present known 6 kinds of crystal formations that have; Extensive use then is crystalline form I and crystal form II clinically, and the II type has tangible fusing point and melting range, and its fusing point is 175～177 ℃; And the I type does not have tangible melting range, has only first fusing point, and its first fusing point is more than 180 ℃; Fine melt can change with condition, reaches as high as 199 ℃.Crystalline form I can change crystal form II under certain condition, and it is then relatively more difficult to be transformed into crystalline form I to crystal form II.The powder of crystal form II than the powder of crystalline form I finer and close be with still less static, so be more suitable for the production of solid preparation, matching the raw material that Norfin, Inc prepares Bo Liwei at present is exactly crystal form II.
Clopidogrel is because of containing ester bond in its structure, therefore granulating with some adjuvant (like magnesium stearate etc.) or dry run in cause quick degraded, cause selection of lubricants to be restricted, bring lot of challenges to solid preparation.Although 4591592 of U.S. Pat disclose the method that prevents the degraded of sulfur hydracid clopidogrel; Comprise and use ascorbic acid, fumaric acid, benzoic acid, citric acid, tartaric acid etc.; But true effect is still undesirable, new challenge that the while has also been given preparation process band.
The particle surface of clopidogrel pharmaceutically acceptable salt is prone to be adsorbed on the metal surface because of having static, is rubbed and then is bonded in rapidly on drift and the mould when pushing, and causes sticking and then cause unilateral irregularly that end product quality is poor.In addition, the crystal formation of clopidogrel salt also possibly cause crystal formation to change because of processes such as granulation, drying, tablettings, and then influences the dissolution characteristics of clopidogrel, and bioavailability also changes thereupon, finally influences clinical therapeutic efficacy.This is choosing of the maximum that in the solid preparation production process, runs into of clopidogrel salt just.
Chinese patent 201010106188.X then discloses a kind of method for preparing of sulfur hydracid clopidogrel tablet, through adding micropowder silica gel as antiplastering aid/coverture, reaches the sticking phenomenon that reduces in the punching course, to improve yield rate.But micropowder silica gel is to the dustproof of mixing of materials and tabletting process and prevent that layering from having brought new challenge.In addition; Regulation is except that the oikocryst type in the sulfur hydracid clopidogrel tablet at present, and the amount of other crystal formation must not surpass 5%, therefore how to control regardless of production process; Still can take place producing or be stored in the brilliant phenomenon of process transfer, thereby bring significant impact to product quality and clinical efficacy.
In sum; Open source literature shows; Because of the clopidogrel pharmaceutically acceptable salt exists polymorphous reason, processing technique such as pulverizing, wet granulation, oven dry, tabletting and storage are the principal elements of changeing brilliant, therefore press for the new pharmaceutical composition of exploitation clopidogrel pharmaceutically acceptable salt; The adverse effect of bringing to product quality because of polymorphic and static factor with thorough solution, thus guarantee that clinical efficacy is stable.
Summary of the invention
The present invention has broken through the polymorphic of clopidogrel pharmaceutically acceptable salt and the restriction that static characteristic brings to the preparation that preparation quality is stable, bioavailability is high.Through creatively itself and suitable pharmaceutically acceptable medium being formed new pharmaceutical composition; The adverse effect that the salt (below be referred to as active component) of thoroughly having eliminated clopidogrel possibly bring product quality and clinical therapeutic efficacy because of the commentaries on classics crystalline substance due to the preparation process, bioavailability also significantly improves.This pharmaceutical composition suitability for industrialized is prepared into soft capsule or liquid hard capsule.
In development process; The inventor has studied the clopidogrel pharmaceutically acceptable salt; Like the dissolubility in the pharmaceutically acceptable Auxiliary Liquid Material under 20 ℃ such as sulfur hydrogen salt, hydrochlorate, taurocholate, hydrobromate, citrate, benzene sulfonate, benzene methanesulfonic acid salt; Adopt to place behind the ultrasonic 2h and spend the night, detect then.See table 1 for details.
The dissolution characteristics of the main pharmaceutically acceptable salt of table 1 clopidogrel in different medium
Annotate: poloxamer (Poloxamer)
*Refer under the room temperature and to be the polyoxypropylene of liquid-polyoxyethylene glycol copolymer
Tween (Tween)
*Refer to a kind of or combination in any between four in 20,40,60,80.
Based on above-mentioned research, further to have studied under the different medium combined situation, the stability study of the pharmaceutical composition of clopidogrel pharmaceutically acceptable salt under different temperatures seen table 2.
Table 2 pharmaceutical composition is the fluid stability study under conventional storage requirement
Through to the fluid stability of pharmaceutical composition under dissolubility and the different temperatures of clopidogrel pharmaceutically acceptable salt in different medium, change the research of crystalline substance or crystallize; Make suspension if find compositions; Then active component need carry out micronization processes to reduce particulate sedimentation velocity; Otherwise layering appears in compositions easily, causes fluid unstable.But because of active component material in micronization process is squeezed and produces a large amount of heat; The crystal formation of a spot of active component is changed; Although it is relatively stable with the pharmaceutical composition hydrodynamics that vegetable oil or single PEG form; Possibly not cause the unfavorable factor of changeing brilliant among the preparation technology but get rid of fully yet, be unfavorable for the quick stripping of active component with vegetable oil as disperse medium simultaneously.
And be the pharmaceutical composition of main medium preparation with PEG; Active component then is dissolved in the medium with molecularity, has thoroughly got rid of the unfavorable factor of changeing crystallize in crystalline substance or the storage process, composition stable; Thereby the crystal formation and the static difficult problem of the salt solid preparation of the high-quality clopidogrel of puzzlement preparation have creatively been solved; Constant product quality in the shelf life, peak time obviously shortens, and has improved the pharmaceutical composition bioavailability.
The invention provides the pharmaceutical composition of clopidogrel pharmaceutically acceptable salt, wherein acceptable salt of clopidogrel pharmacy and medium shared mass percent in compositions is respectively 1.4%-10% and 90%-98.6%.
Medium in the pharmaceutical composition comprises solvent, cosolvent and surfactant, and wherein solvent is a Polyethylene Glycol, and its molecular weight is between 200 ~ 800 dalton, and the mass ratio of the salt of Polyethylene Glycol and clopidogrel is 8-68: 1.
Cosolvent then is selected from ethanol, propylene glycol, and a kind of or combination in any in the glycerol, the mass percent of cosolvent in medium is 2-15%
Surfactant is selected from a kind of or combination in any of (a)-(h), but is not limited to cited surfactant, and the mass percent of surfactant in medium is 0.1-5%:
(a) reactant of natural or castor oil hydrogenated and oxirane;
(b) tween;
(c) polyoxyethylene fatty acid;
(d) polyoxyethylene-polyoxypropylene copolymer and block copolymer (poloxamer), preferred poloxamer 188;
(e) saturated C
10-C
22Substituted (such as hydroxyl) the polyoxyethylene monoesters of fatty acid, like Solutol
HS-15 etc.;
(f) polyoxyethylene alkyl ether is like Brij
35 etc.;
(g) polyethylene glycol glycerol base fatty acid ester is like TGMS-15 etc.;
(h) C of sucrose
12-C
18Fatty acid ester, like monoleate of sucrose etc.
The clopidogrel pharmaceutically acceptable salt can be selected from but be not limited to following cited example: (+)-(S)-sulfur hydracid clopidogrel, (+)-(S)-hydrobromic acid clopidogrel, (+)-(S)-LOMAR PWA EINECS 246-676-2 clopidogrel, (+)-(S)-benzenesulfonic acid clopidogrel, (+)-(S)-p-methyl benzenesulfonic acid clopidogrel, (+)-(S)-oxalic acid clopidogrel, (+)-(S)-hydrochloric acid clopidogrel, (+)-(S)-citric acid clopidogrel, (+)-(S)-malic acid clopidogrel etc.
Suitable soft capsule or the liquid hard capsule of being prepared into of pharmaceutical composition of the present invention.The preparation process is following:
According to prescription, the clopidogrel pharmaceutically acceptable salt to be mixed with other medium, heated and stirred makes its dissolving, and mixing filters, the compacting capsule, drying, letter sorting, check, packing promptly get soft capsule, and the content water content is 4%-14% in its finished product.
Or according to prescription, the clopidogrel pharmaceutically acceptable salt is mixed with other medium, heated and stirred makes its dissolving, mixing, and fill is in hard capsule, and sealing, letter sorting, check, packing promptly get liquid hard capsule.
Soft capsule or liquid hard capsule according to this method preparation were investigated through intermediate experiment condition (experiment condition is 30 ℃ ± 2 ℃, RH65% ± 5%) in 1 year by a definite date; Indexs such as outward appearance, content, related substance all do not have significant change, and product meets 2010 editions " relevant regulations of Chinese pharmacopoeia.The soft capsule that with PEG400 is diluent media is an example, investigates the result and sees table 3 for details.The product that utilizes the present invention to prepare is compared with the listing tablet, has thoroughly eliminated the specific (special) requirements of preparation to the crude drug crystal formation, does not change crystalline substance or crystallize in the course of processing and the storage process and takes place, thereby make product quality homogeneity obtain abundant assurance.
To of the comparative study of the oral pharmaceutical composition of the present invention of rat with existing listing product pharmacokinetics test.
Test method: get 6 of healthy male domesticated dogs, be divided into 2 groups at random, per os gives pharmaceutical composition of the present invention and listing tablet respectively, and dosage is 75mg.In 0.08,0.17,0.34,0.5,0.75,1,1.5,2,2.5,3,4,6,8,12, the 24h veins of upper extremity is got blood system from blood plasma after the administration, adopts the liquid chromatography-tandem mass spectrometry method to measure blood drug level, sees table 4, accompanying drawing 1.
Result of study shows that the peak time tmax of clopidogrel is respectively 0.34 ± 0.1h and 1.9 ± 0.6 h in soft capsule and the reference preparation.
CMax also has remarkable difference, and the bioavailability of soft capsule is apparently higher than the tablet that goes on the market.Reason is that active component is dissolved in the medium with the individual molecule form in the soft capsule; Saved the course of dissolution of active component in the tablet, so after the soft capsule disintegrate, active component passes through intestinal absorption rapidly; Rapid-action and bioavailability is high; Thereby guaranteed clinical therapeutic efficacy, obviously be superior to the product that prior art makes, realized the major technological breakthrough of clopidogrel oral formulations.
The sample stability experimental data relatively under table 3 acceleration environment
Different time points determination of plasma concentration behind table 4 rat oral gavage
The pharmaceutical composition of clopidogrel pharmaceutically acceptable salt of the present invention, received beyond thought effect: in production process and storage process, not seeing changes crystalline substance or crystallize, constant product quality; The bioavailability of pharmaceutical composition significantly improves, and peak time obviously shortens, and blood drug level is high.This pharmaceutical composition is suitable to be prepared into soft capsule or liquid hard capsule, can realize large-scale industrial production.
The specific embodiment
Embodiment 1 sulfur hydracid clopidogrel preparation of soft capsule
Prescription is formed as follows: (g)
Sulfur hydracid clopidogrel 24.46
PEG400 842
1,2-propylene glycol 150
TW80 8.5
1024.96g processes 1000 soft capsules altogether.
Preparation technology: take by weighing the PEG400,1 of recipe quantity, 2-propylene glycol, TW80 add in the dissolving tank, under 45-70 ℃ condition, mix; Medicine is crossed 60 mesh sieves, take by weighing the sulfur hydracid clopidogrel (crystal formation is not limit) of recipe quantity, add in the blending agent; After treating medicine dissolution, filter and change medicine liquid tank, 30-38 ℃ of insulation over to; Connect encapsulating machine, be pressed into soft capsule, drying; The qualified back packing of quality testing, labeling, packing promptly get sulfur hydracid clopidogrel soft capsule.
Embodiment 2 sulfur hydracid clopidogrel preparation of soft capsule
Prescription is formed as follows: (g)
Sulfur hydracid clopidogrel 24.46
PEG200 716
1,2-propylene glycol 80
Ethanol 7
HS-15 0.8
828.26g processes 1000 soft capsules altogether.
Preparation technology: take by weighing the PEG200,1 of recipe quantity, 2-propylene glycol, ethanol, HS-15 add in the dissolving tank, under 45-70 ℃ condition, stir and make it mix homogeneously; Medicine is crossed 60 mesh sieves, take by weighing the sulfur hydracid clopidogrel (crystal formation is not limit) of recipe quantity, add in the blending agent; After treating medicine dissolution, filter and change medicine liquid tank, 30-38 ℃ of insulation over to; Connect encapsulating machine, be pressed into soft capsule, drying; The qualified back packing of quality testing, labeling, packing promptly get sulfur hydracid clopidogrel soft capsule.
Embodiment 3 hydrobromic acid clopidogrel preparation of soft capsule
Prescription is formed as follows: (g)
Hydrobromic acid clopidogrel 23.80
PEG600 500
1,2-propylene glycol 50
Tween 80 29
602.8g processes 1000 soft capsules altogether.
Preparation technology: take by weighing the PEG600,1 of recipe quantity, 2-propylene glycol, Tween 80 add in the dissolving tank, under 45-70 ℃ condition, stir and make it mix homogeneously; Medicine is crossed 60 mesh sieves, take by weighing the hydrobromic acid clopidogrel (crystal formation is not limit) of recipe quantity, add in the blending agent; After treating medicine dissolution, filter and change medicine liquid tank, 30-38 ℃ of insulation over to; Connect encapsulating machine, be pressed into soft capsule, drying; The qualified back packing of quality testing, labeling, packing promptly get hydrobromic acid clopidogrel soft capsule finished product.
Embodiment 4 citric acid clopidogrel preparation of soft capsule
Prescription is formed as follows: (g)
Citric acid clopidogrel 60.5
PEG800 890
Glycerol 29
Ethanol 29
HS-15 18
1026.5g processes 1000 soft capsules altogether.
Preparation technology: take by weighing PEG800, glycerol, ethanol, the HS-15 of recipe quantity, add in the dissolving tank, under 45-70 ℃ condition, stir and make it mix homogeneously; Medicine is crossed 60 mesh sieves, take by weighing the citric acid clopidogrel (crystal formation is not limit) of recipe quantity, add in the blending agent; After treating medicine dissolution, filter and change medicine liquid tank, 30-38 ℃ of insulation over to; Connect encapsulating machine, be pressed into soft capsule, drying; The qualified back packing of quality testing, labeling, packing promptly get citric acid clopidogrel soft capsule finished product.
The preparation of embodiment 5 hydrochloric acid clopidogrel liquid hard capsules
Prescription is formed as follows: (g)
Hydrochloric acid clopidogrel 84.3
PEG400 700
1,2-propylene glycol 28
Ethanol 28
POLOXAMER188 8
Polyoxyethylene castor oil 19
867.3g processes 1000 soft capsules altogether.
Preparation technology: take by weighing the PEG400,1 of recipe quantity, 2-propylene glycol, ethanol, POLOXAMER188, polyoxyethylene castor oil add in the dissolving tank, under 45-70 ℃ condition, stir and make it mix homogeneously; Medicine is crossed 60 mesh sieves, take by weighing the hydrochloric acid clopidogrel (crystal formation is not limit) of recipe quantity, add in the blending agent; After treating medicine dissolution, filter and change medicine liquid tank, 30-38 ℃ of insulation over to; Connect the capsule filling and sealing machine, filling, sealing, letter sorting, check, packing promptly get liquid hard.
Embodiment 6 sulfur hydracid clopidogrel preparation of soft capsule
Prescription is formed as follows: (g)
Sulfur hydracid clopidogrel 48.938
PEG400 930
1,2-propylene glycol 50
HS-15 20
1048.938g processes 1000 soft capsules altogether.
Preparation technology: take by weighing the PEG400,1 of recipe quantity, 2-propylene glycol, HS-15 add in the dissolving tank, under 45-70 ℃ condition, stir and make it mix homogeneously; Medicine is crossed 60 mesh sieves, take by weighing the sulfur hydracid clopidogrel (crystal formation is not limit) of recipe quantity, add in the blending agent; After treating medicine dissolution, filter and change medicine liquid tank, 30-38 ℃ of insulation over to; Connect encapsulating machine, be pressed into soft capsule, drying; The qualified back packing of quality testing, labeling, packing promptly get the soft capsule finished product.
Embodiment 7 sulfur hydracid clopidogrel preparation of soft capsule
Prescription is formed as follows: (g)
Sulfur hydracid clopidogrel 97.875
PEG400 880
1,2-propylene glycol 100
Tween 80 15
1102.875g processes 1000 soft capsules altogether.
Preparation technology: take by weighing the PEG400,1 of recipe quantity, 2-propylene glycol, TW80, ethanol add in the dissolving tank, under 45-70 ℃ condition, mix; Medicine is crossed 60 mesh sieves, take by weighing the sulfur hydracid clopidogrel (crystal formation is not limit) of recipe quantity, add in the blending agent; After treating medicine dissolution, filter and change medicine liquid tank, 30-38 ℃ of insulation over to; Connect encapsulating machine, be pressed into soft capsule, drying; The qualified back packing of quality testing, labeling, packing promptly get sulfur hydracid clopidogrel soft capsule.
Embodiment 8 sulfur hydracid clopidogrel preparation of soft capsule
Prescription is formed as follows: (g)
Sulfur hydracid clopidogrel 24.46
PEG400 880
1,2-propylene glycol 105
Brij
35 1
1010.46g processes 1000 soft capsules altogether.
Preparation technology: the PEG400,1 that takes by weighing recipe quantity; 2-propylene glycol, Brij
35; Add in the dissolving tank, under 45-70 ℃ condition, stir and make it mix homogeneously; Medicine is crossed 60 mesh sieves, take by weighing the sulfur hydracid clopidogrel (crystal formation is not limit) of recipe quantity, add in the blending agent; After treating medicine dissolution, filter and change medicine liquid tank, 30-38 ℃ of insulation over to; Connect encapsulating machine, be pressed into soft capsule, drying; The qualified back packing of quality testing, labeling, packing promptly get sulfur hydracid clopidogrel soft capsule.
Embodiment 9 sulfur hydracid clopidogrel preparation of soft capsule
Prescription is formed as follows: (g)
Sulfur hydracid clopidogrel 24.46
PEG400 815
1,2-propylene glycol 105
TGMS-15 25
984.46g processes 1000 soft capsules altogether.
Preparation technology: take by weighing the PEG400,1 of recipe quantity, 2-propylene glycol, TGMS-15 add in the dissolving tank, under 45-70 ℃ condition, stir and make it mix homogeneously; Medicine is crossed 60 mesh sieves, take by weighing the sulfur hydracid clopidogrel (crystal formation is not limit) of recipe quantity, add in the blending agent; After treating medicine dissolution, filter and change medicine liquid tank, 30-38 ℃ of insulation over to; Connect encapsulating machine, be pressed into soft capsule, drying; The qualified back packing of quality testing, labeling, packing promptly get sulfur hydracid clopidogrel soft capsule.
Prescription is formed as follows: (g)
Sulfur hydracid clopidogrel 24.46
1,2-propylene glycol 75
Sucrose monooleate acid esters 10
944.46g processes 1000 soft capsules altogether.
Preparation technology: take by weighing the PEG400,1 of recipe quantity, 2-propylene glycol, glycerol, sucrose monooleate acid esters, polysorbate60 add in the dissolving tank, under 45-70 ℃ condition, stir and make it mix homogeneously; Medicine is crossed 60 mesh sieves, take by weighing the sulfur hydracid clopidogrel (crystal formation is not limit) of recipe quantity, add in the blending agent; After treating medicine dissolution, filter and change medicine liquid tank, 30-38 ℃ of insulation over to; Connect encapsulating machine, be pressed into soft capsule, drying; The qualified back packing of quality testing, labeling, packing promptly get sulfur hydracid clopidogrel soft capsule.
Embodiment 11 sulfur hydracid clopidogrel preparation of soft capsule
Prescription is formed as follows: (g)
Sulfur hydracid clopidogrel 97.875
PEG400 880
1,2-propylene glycol 100
Tween 80 15
1102.875g processes 1000 soft capsules altogether.
Preparation technology: take by weighing the PEG400,1 of recipe quantity, 2-propylene glycol, ethanol, tween add in the dissolving tank, under 45-70 ℃ condition, stir and make it mix homogeneously; Medicine is crossed 60 mesh sieves, take by weighing the sulfur hydracid clopidogrel (crystal formation is not limit) of recipe quantity, add in the blending agent; After treating medicine dissolution, filter and change medicine liquid tank, 30-38 ℃ of insulation over to; Connect encapsulating machine, be pressed into soft capsule, drying; The qualified back packing of quality testing, labeling, packing promptly get sulfur hydracid clopidogrel soft capsule.
Embodiment 12 malic acid clopidogrel preparation of soft capsule
Prescription is formed as follows: (g)
Malic acid clopidogrel 108
PEG200 864
1,2-propylene glycol 91
Hydrogenation polyoxyethylene castor oil 15
HS-15 15
1108g processes 1000 soft capsules altogether.
Preparation technology: take by weighing the PEG200,1 of recipe quantity, 2-propylene glycol, ethanol, polyoxyethylene castor oil, HS-15 add in the dissolving tank, under 45-70 ℃ condition, stir and make it mix homogeneously; Medicine is crossed 60 mesh sieves, take by weighing the malic acid clopidogrel (crystal formation is not limit) of recipe quantity, add in the blending agent; After treating medicine dissolution, filter and change medicine liquid tank, 30-38 ℃ of insulation over to; Connect the capsule filling and sealing machine, filling, sealing, letter sorting, check, packing promptly get liquid hard capsule.
Embodiment 13 sulfur hydracid clopidogrel preparation of soft capsule
Prescription is formed as follows: (g)
Sulfur hydracid clopidogrel 48.938
PEG400 930
1,2-propylene glycol 50
HS-15 20
Brij
35 10
1058.938g processes 1000 soft capsules altogether.
Preparation technology: the PEG400,1 that takes by weighing recipe quantity; 2-propylene glycol, Brij
35, HS-15; Add in the dissolving tank, under 45-70 ℃ condition, stir and make it mix homogeneously; Medicine is crossed 60 mesh sieves, take by weighing the sulfur hydracid clopidogrel (crystal formation is not limit) of recipe quantity, add in the blending agent; After treating medicine dissolution, filter and change medicine liquid tank, 30-38 ℃ of insulation over to; Connect the capsule filling and sealing machine, filling, sealing, letter sorting, check, packing promptly get liquid hard capsule.
Embodiment 14 sulfur hydracid clopidogrel preparation of soft capsule
Prescription is formed as follows: (g)
Sulfur hydracid clopidogrel 48.938
PEG400 730
1,2-propylene glycol 50
HS-15 20
Brij
35 10
1058.938g processes 1000 soft capsules altogether.
Preparation technology: the PEG400, the PEG600,1 that take by weighing recipe quantity; 2-propylene glycol, Brij
35, HS-15; Add in the dissolving tank, under 45-70 ℃ condition, stir and make it mix homogeneously; Medicine is crossed 60 mesh sieves, takes by weighing the sulfur hydracid clopidogrel of recipe quantity, add in the blending agent, treat medicine dissolution after, filter and change medicine liquid tank over to, 30-38 ℃ of insulation connects the capsule filling and sealing machine, fills, sealing, letter sorting, check, packing promptly get liquid hard capsule.
Prescription is formed as follows: (g)
Sulfur hydracid clopidogrel 12.24
PEG200 616
PEG800 100
1,2-propylene glycol 80
Ethanol 7
820.24g processes 1000 soft capsules altogether.
Preparation technology: take by weighing PEG200, the PEG800,1 of recipe quantity, 2-propylene glycol, ethanol, polyoxyethylene castor oil add in the dissolving tank, under 45-70 ℃ condition, stir and make it mix homogeneously; Medicine is crossed 60 mesh sieves, take by weighing the sulfur hydracid clopidogrel (crystal formation is not limit) of recipe quantity, add in the blending agent; After treating medicine dissolution, filter and change medicine liquid tank, 30-38 ℃ of insulation over to; Connect encapsulating machine, be pressed into soft capsule, drying; The qualified back packing of quality testing, labeling, packing promptly get sulfur hydracid clopidogrel soft capsule.
Embodiment 16 sulfur hydracid clopidogrel preparation of soft capsule
Prescription is formed as follows: (g)
Sulfur hydracid clopidogrel 12.24
PEG200 230
1,2-propylene glycol 6
Ethanol 11
Poloxamer 188 15
874.24g processes 1000 soft capsules altogether.
Preparation technology: take by weighing PEG200, the PEG400,1 of recipe quantity, 2-propylene glycol, ethanol, poloxamer 188 add in the dissolving tank, under 45-70 ℃ condition, stir and make it mix homogeneously; Medicine is crossed 60 mesh sieves, take by weighing the sulfur hydracid clopidogrel of recipe quantity, add in the blending agent; After treating medicine dissolution, filter and change medicine liquid tank, 30-38 ℃ of insulation over to; Connect encapsulating machine, be pressed into soft capsule, drying; The qualified back packing of quality testing, labeling, packing promptly get sulfur hydracid clopidogrel soft capsule.
Claims (9)
1. one kind with (+)-(s)-α-(2-chlorphenyl)-6; The 7-dihydro-thiophene also-[3; 2-c] pyridine-5 (4H) methyl acetate pharmaceutically acceptable salt is the pharmaceutical composition of active component, it is characterized in that containing (+)-(s)-α-(2-chlorphenyl)-6 of 1.4%-10%, the 7-dihydro-thiophene is also-[3; 2-c] pyridine-5 (4H) methyl acetate pharmaceutically acceptable salt, 90%-98.6% is pharmaceutically acceptable medium.
2. according to the described pharmaceutically acceptable medium of claim 1, it is characterized in that containing solvent, cosolvent and surfactant, wherein the mass ratio of the salt of solvent and clopidogrel is 8-68:1; The mass percent of cosolvent in medium is 2-15%; The mass percent of surfactant in medium is 0.1-5%.
3. according to the described solvent of claim 2, it is characterized in that it being that molecular weight is 200 ~ 800 daltonian Polyethylene Glycol, optional a kind of or combination in any wherein.
4. according to the described cosolvent of claim 2, it is characterized in that being selected from ethanol, propylene glycol, a kind of or combination in any in the glycerol.
5. according to the described surfactant of claim 2, it is characterized in that but be not limited to a kind of or combination in any of (a)-(h):
(a) reactant of natural or castor oil hydrogenated and oxirane;
(b) tween;
(c) polyoxyethylene fatty acid;
(d) polyoxyethylene-polyoxypropylene copolymer and block copolymer (poloxamer), preferred poloxamer 188;
(e) saturated C
10-C
22Substituted (such as hydroxyl) the polyoxyethylene monoesters of fatty acid, like Solutol
HS-15 etc.;
(f) polyoxyethylene alkyl ether is like Brij
35 etc.;
(g) polyethylene glycol glycerol base fatty acid ester is like TGMS-15 etc.;
(h) C of sucrose
12-C
18Fatty acid ester, like monoleate of sucrose etc.
6. according to claim 1 described (+)-(s)-α-(2-chlorphenyl)-6; The 7-dihydro-thiophene also-[3; 2-c] pyridine-5 (4H) methyl acetate pharmaceutically acceptable salt, it is characterized in that being selected from but be not limited to: (+)-(s)-sulfur hydracid clopidogrel, (+)-(s)-hydrobromic acid clopidogrel, (+)-(s)-LOMAR PWA EINECS 246-676-2 clopidogrel, (+)-(s)-benzenesulfonic acid clopidogrel, (+)-(s)-p-methyl benzenesulfonic acid clopidogrel, (+)-(s)-oxalic acid clopidogrel, (+)-(s)-hydrochloric acid clopidogrel, (+)-(s)-citric acid clopidogrel, (+)-(s)-malic acid clopidogrel etc.
7. according to the described propylene glycol of claim 4, refer to 1, ammediol, 1, a kind of in the 2-propylene glycol or the combination in any of the two.
8. refer to Tween20 according to the described tween of claim 5 (Tween), Tween40, Tween60, a kind of or combination in any between four among the Tween80.
9. according to claim 1 described (+)-(s)-α-(2-chlorphenyl)-6, the 7-dihydro-thiophene also-[3,2-c] pyridines-5 (4H) methyl acetate pharmaceutically acceptable salt is the pharmaceutical composition of active component, can be made into soft capsule or liquid hard capsule.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2023012479A1 (en) * | 2021-08-03 | 2023-02-09 | Liqmeds Worldwide Limited | An oral pharmaceutical solution of clopidogrel |
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2012
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2023012479A1 (en) * | 2021-08-03 | 2023-02-09 | Liqmeds Worldwide Limited | An oral pharmaceutical solution of clopidogrel |
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