WO2011094982A1 - 硫酸氢氯吡格雷固体制剂及其制备工艺 - Google Patents

硫酸氢氯吡格雷固体制剂及其制备工艺 Download PDF

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Publication number
WO2011094982A1
WO2011094982A1 PCT/CN2010/073879 CN2010073879W WO2011094982A1 WO 2011094982 A1 WO2011094982 A1 WO 2011094982A1 CN 2010073879 W CN2010073879 W CN 2010073879W WO 2011094982 A1 WO2011094982 A1 WO 2011094982A1
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Prior art keywords
hydrogen sulfate
clopidogrel hydrogen
silica gel
clopidogrel
tablet
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PCT/CN2010/073879
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English (en)
French (fr)
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雷继峰
沙平
金荣根
施钰文
沈新华
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上海安必生制药技术有限公司
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Publication of WO2011094982A1 publication Critical patent/WO2011094982A1/zh
Priority to US13/567,676 priority Critical patent/US20130011473A1/en
Priority to US14/615,177 priority patent/US9144550B2/en

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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
    • A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
    • 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
    • A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4365—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system having sulfur as a ring hetero atom, e.g. ticlopidine
    • 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
    • A61K9/2009—Inorganic compounds
    • 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

Definitions

  • This invention relates to the field of pharmaceuticals, and more particularly to a process for the preparation of solid preparations of clopidogrel hydrogen sulfate, especially tablets; Background technique
  • the chemical name of clopidogrel hydrogen sulfate is S(+)-2-(2-chlorophenyl)-2-(4, 5, 6, 7, -tetrahydrothiophene [3, 2-c]pyridine-5
  • the hydrogen sulfate salt of methyl acetate has the following structural formula:
  • Clopidogrel selectively inhibits the binding of adenosine diphosphate (ADP) to its platelet receptor and secondary ADP-mediated activation of the glycoprotein GPlllb/llla complex, thereby inhibiting platelet aggregation.
  • ADP adenosine diphosphate
  • clopidogrel inhibits platelet aggregation induced by other agonists by blocking the expansion of platelet activation caused by released ADP.
  • Clopidogrel does not inhibit phosphodiesterase activity. Clopidogrel acts by irreversibly modifying the platelet ADP receptor.
  • the clopidogrel salt has a carboxylate structure and is easily hydrolyzed and degreased to form clopidogrel acid (impurity A;).
  • U.S. Patent No. 4,847, 265 specifically describes the dextrorotatory and pharmaceutically acceptable salts of clopidogrel including hydrochloride, bisulfate, hydrobromide, taurocholate, and clopidogrel at doses ranging from 0.001 g to 0.1 g. .
  • U.S. Patent No. 6,429,210 and U.S. Patent 6,504,030 disclose clopidogrel hydrogen sulfate Form II and a process for its manufacture.
  • U.S. Patent No. 6,679,913 discloses the X-ray powder diffraction pattern peak position of the crystalline form of clopidogrel hydrogen sulfate, and the preparation methods and formulations of Forms III, IV, V, VI and the preparation of Form II.
  • PCT application WO 2006/044548 discloses a solid premix comprising clopidogrel comprising at least one pharmaceutical excipient adsorbed on clopidogrel.
  • PCT application WO2008059298 discloses a formulation of a solid preparation mixed with clopidogrel hydrogen sulfate Form I (as an active ingredient), microcrystalline cellulose and microsilica gel as a filler and binder, and a disintegrant and Other auxiliary materials such as lubricants.
  • the existing clopidogrel hydrogen sulfate tablets contain clopidogrel hydrogen sulfate, a diluent, a binder, a glidant, Disintegrants and lubricants.
  • PLAVIX (Bolivi is equivalent to 75mg clopidogrel which contains mannitol, microcrystalline cellulose, hydroxypropyl cellulose, and uses polyethylene glycol 6000 and hydrogenated castor oil as lubricants. Polyvi is suitable for recent episodes Patients with stroke, myocardial infarction, and diagnosed peripheral arterial disease. This drug reduces the occurrence of atherosclerotic events (such as myocardial infarction, stroke, and vascular death).
  • clopidogrel causes rapid degradation when used in combination with certain excipients such as alkali metal stearate; Therefore, magnesium stearate is usually not used to prevent degradation of clopidogrel.
  • U.S. Patent 6,914,141 discloses a pharmaceutical tablet comprising clopidogrel hydrogen sulfate and a lubricating agent selected from the group consisting of zinc stearate, stearic acid, and sodium stearyl fumarate.
  • U.S. Patent 4,591,592 discloses a method for preventing degradation of clopidogrel hydrogen sulfate comprising the use of ascorbic acid, benzoic acid, tartaric acid, fumaric acid, citric acid and the like.
  • PCT application WO 2005/048992 discloses a formulation of a class of clopidogrel mesylate, hydrobromide and hydrochloride, which discloses the encapsulation of polyvinyl acetate or polyvinyl alcohol with a hydrophobic component such as hydrogenated vegetable oil. Clopidogrel particles, granules or agglomerates.
  • European application EP1970054 considers it important to use a suitable diluent and believes that the combination of certain diluents such as mannitol, mannitol and lactose or MCC enhances the intrinsic adhesion of clopidogrel. It is also believed that the lubricant can help the sheet reduce friction during tableting and ejection, and also prevent the sheet from sticking to the sheet and the mold surface. Thus, it is disclosed to prepare a tablet with a raw material of clopidogrel hydrobromide and hydrochloride, together with lactose, stearic acid and one or more other excipients, and it is recommended to prepare stable chlorine by dry granulation.
  • Pyridine tablets are used to solve the problem of adhesion of clopidogrel hydrobromide and clopidogrel hydrochloride tablets to the punches and dies of conventional tablet presses.
  • clopidogrel salts include hydrogen sulphate
  • it is extremely easy to adsorb on the metal surface, and it is quickly bonded by friction and extrusion. Therefore, the pressing of the upper and lower punches and the pressing of the punch and the die during the tableting make the film quickly adhere to The punches and dies on the tablet press are becoming more and more serious, causing sticking and other irregularities on the surface of the film, resulting in poor quality of the finished product.
  • An object of the present invention is to provide a process for preparing a solid preparation of clopidogrel hydrogen sulfate which is difficult to adhere to a tablet press and a mold when the chloropyrexine sulfate tablet is produced on a large scale. Knot.
  • Another object of the present invention is to provide a clopidogrel hydrogen sulphate tablet which is less prone to sticking during the tableting process and which has an irregular surface.
  • a premixed particle of clopidogrel hydrogen sulfate comprising or consisting of: clopidogrel hydrogen sulfate and a micronized silica gel coated with clopidogrel hydrogen sulfate
  • the weight of the micronized silica gel is 0.5-10% by weight of clopidogrel hydrogen sulfate
  • the average particle size of clopidogrel hydrogen sulfate is 10-100 ⁇ .
  • the weight of the silica gel is 1.0-5% by weight of clopidogrel hydrogen sulfate.
  • clopidogrel hydrogen sulfate is used as an active ingredient, and fine powder silica gel is used as an anti-adhesive/covering agent.
  • the crystalline form of clopidogrel hydrogen sulfate is type I or type II.
  • the clopidogrel hydrogen sulfate has an average particle diameter of 20 to 80 ⁇ m.
  • the fine powder silica gel has the following characteristics: an average particle diameter of about 7 to 16 nm and a specific surface area of 200 to 400 m 2 /g.
  • the clopidogrel hydrogen sulfate and the micropowder silica gel comprise from 90 to 100% by weight of the premixed particles; preferably from 95 to 100%, more preferably from 99 to 100%.
  • the premixed granules are prepared by mixing chloropyridinium hydrogen sulphate powder and micronized silica gel to form the premixed granules.
  • a pharmaceutical composition of clopidogrel hydrogen sulfate comprising the present invention
  • the premixed particles of clopidogrel hydrogen sulfate described in the first aspect and a pharmaceutically acceptable carrier comprising the present invention
  • a pharmaceutically acceptable carrier comprising the present invention
  • the pharmaceutical composition is a solid dosage form.
  • the pharmaceutical composition is a tablet.
  • the tablet is wet granulated (e.g., granulated with a solution of a binder in ethanol;)
  • the composition contains, as an active ingredient, clopidogrel hydrogen sulfate, a micronized silica gel as an anti-adhesive/covering agent, and a carrier selected from the group consisting of a diluent, a binder, and a helper.
  • a carrier selected from the group consisting of a diluent, a binder, and a helper.
  • the pharmaceutical composition contains the following ingredients, based on the total weight of the composition:
  • silica gel as an anti-adhesive/covering agent
  • diluent such as lactose, pregelatinized starch, microcrystalline cellulose;
  • binder such as polyvinylpyrrolidone, hydroxypropylcellulose and hypromellose;
  • 0.2-0.5wt% flow aid such as micro-silica gel
  • disintegrant such as low-substituted hydroxypropyl cellulose, sodium carboxymethyl starch, crospovidone, croscarmellose sodium
  • disintegrant such as low-substituted hydroxypropyl cellulose, sodium carboxymethyl starch, crospovidone, croscarmellose sodium
  • lubricant such as hydrogenated vegetable oil and / or sodium lauryl sulfate;
  • the sum of all components in the pharmaceutical composition is 100% by weight.
  • the pharmaceutical composition is a tablet and contains the following ingredients:
  • microsilica gel as anti-adhesive/covering agent
  • the pharmaceutical composition is prepared by a process comprising the steps of: (a) mixing clopidogrel hydrogen sulfate powder and microsilica gel to form premixed particles of clopidogrel hydrogen sulfate; (b) mixing the premixed granules obtained in the step (a) with a diluent, and then adding an alcohol solution of the binder, and performing wet granulation to obtain wet granules;
  • step (c) drying and granulating the wet granules obtained in step (b) to obtain dry granules;
  • step (d) mixing the dry granules obtained in the step (C) with a glidant, a disintegrant, and a lubricant, followed by tableting to obtain a clopidogrel hydrogen sulfate tablet;
  • step (e) the tablets of step (d) are coated to form a coated tablet.
  • step (b) mixing the premixed granules obtained in the step (a) with a diluent, and then adding an alcohol solution of the binder to carry out wet granulation to obtain wet granules;
  • step (c) drying and granulating the wet granules obtained in step (b) to obtain dry granules;
  • step (d) mixing the dry granules obtained in the step (C) with a glidant, a disintegrant, and a lubricant, followed by tableting to obtain a clopidogrel hydrogen sulfate tablet;
  • step (e) the tablets of step (d) are coated to form a coated tablet.
  • the binder solution is an ethanol solution.
  • premixed granules which help to reduce the bonding of the tablet can be obtained.
  • premixed granules clopidogrel hydrogen sulfate is used as an active ingredient, and the micronized silica gel acts as an anti-adhesive/covering agent, thereby helping to separate the clopidogrel hydrogen sulfate raw material particles from the surrounding environment.
  • the bonding of the sheets on the punch and the die of the tablet press during the tableting process can be overcome, and irregularities on the surface of the tablet can be reduced, thereby improving the quality of the finished product.
  • the present invention has been completed on this basis.
  • the coated tablet of the present invention is tested for stability under the same conditions as the commercially available PLAVIX at 40 ° C / 75% RH, and the detection data of the impurity A - clopidogrel acid shows that the clopidogrel hydrogen sulfate tablet of the present invention is excellent. Yu Fa PLAVIX produced by Sanofi-Aventis Pharmaceutical Co., Ltd. Premixed particles
  • premixed granule of the present invention clopidogrel hydrogen sulfate is used as an active ingredient, and fine powder silica gel is used as an anti-adhesive/covering agent.
  • the weight of the finely divided silica gel is usually from 0.5 to 10%, preferably from 1.0 to 5% by weight based on the weight of clopidogrel hydrogen sulfate.
  • the clopidogrel hydrogen sulfate and the micronized silica gel comprise from 90% to 100%, preferably from 95% to 100%, more preferably from 99% to 100% by weight of the premixed particles.
  • the root cause of the bonding of the film to the punch and die of the tablet press is that clopidogrel hydrogen sulfate is highly adsorbable. Not only is it easy to adsorb on the metal surface, but also the clopidogrel hydrogen sulfate raw material particles are easily adsorbed to each other.
  • the clopidogrel hydrogen sulfate particles adhering to the surface of the punch and the mold are squeezed by the upper and lower punches. And the friction and extrusion between the punch and the die form a bond on the punch and the die of the tablet press, and it becomes more and more serious, resulting in various surface irregularities such as sticking and punching, resulting in poor quality of the finished product. Therefore, it is necessary to prevent the adsorption of clopidogrel hydrogen sulfate and the adhesion due to adsorption.
  • the best way is to let the surface of the particles of clopidogrel hydrogen sulfate cover the excipients that do not dissolve in water, reduce the surface area of clopidogrel hydrogen sulfate contacting the outside, thereby reducing the surface area and contact area of the metal in contact with the metal.
  • the contact area of clopidogrel hydrogen sulfate with moisture in the air can be reduced, thereby reducing the adsorption property, preventing the bonding of the film on the punch and the die of the tablet press during the tableting process, and preventing hydrogen sulfate.
  • Clopidogrel is degraded by contact with moisture in the air to prevent the production of clopidogrel acid (impurity A).
  • the premixed particles use micronized silica gel as an anti-adhesive and/or covering agent to assist the clopidogrel hydrosulfide raw material particles to be separated from the surrounding environment, thereby overcoming the above drawbacks.
  • the clopidogrel hydrogen sulfate which can be used in the present invention is not particularly limited and may be commercially available clopidogrel hydrogen sulfate or clopidogrel hydrogen sulfate prepared by a method known in the art.
  • clopidogrel hydrogen sulfate is in powder form and typically has an average particle size of from 20 to 80 ⁇ .
  • the crystal form of clopidogrel hydrogen sulfate is not particularly limited, and may be type I or type II, and is preferably type I.
  • the content of clopidogrel hydrogen sulfate is usually from 20 to 60% by weight, preferably from 25 to 50% by weight, based on the total weight of the composition.
  • the content of clopidogrel hydrogen sulfate in each tablet is equivalent to a clopidogrel content of 75 to 300 mg, more preferably 75 mg.
  • Microsilica gel as anti-adhesive and / or covering agent is equivalent to a clopidogrel content of 75 to 300 mg, more preferably 75 mg.
  • Micro-silica gel has good fluidity, and its uniform distribution is its advantage.
  • the particle size is extremely small and the specific surface area is large, so that it can be stably and evenly distributed on tens of micron clopidogrel hydrogen sulfate particles.
  • the surface area of the clopidogrel hydrogen sulfate particles in contact with the metal surface is reduced, the probability of adsorption of clopidogrel hydrogen sulfate on the metal surface is reduced, and the adsorption force is lowered, thereby increasing the fluidity.
  • the data of the angle of repose showed that the clopidogrel hydrogen sulfate had an angle of repose greater than 45 ° with increased agitation.
  • the angle of repose of clopidogrel hydrogen sulfate was reduced to 43 ° and the surface of the device was adsorbed.
  • the clopidogrel hydrogen sulfate powder was greatly reduced, so this suggests that the addition of micronized silica gel can reduce the adsorption of clopidogrel hydrogen sulfate and improve the fluidity of clopidogrel hydrogen sulfate.
  • the fine powder silica gel which can be used in the present invention as an anti-adhesive/covering agent is not particularly limited and can be produced by a conventional method.
  • the preferred microsilica gel is a micronized silica gel having an average particle diameter (or particle diameter;) of about 7 to 16 nm and a specific surface area of 200 to 400 m 2 /g.
  • a preferred class of micronized silica gels are fumed silica gels prepared by gas phase processes.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the premixed granules comprising the above-described premixed granules of clopidogrel hydrochloride of the present invention together with a pharmaceutically acceptable carrier.
  • a preferred pharmaceutical composition dosage form is a solid dosage form, especially a tablet.
  • the clopidogrel hydrogen sulfate tablet of the present invention preferably contains the following components: clopidogrel hydrogen sulfate, an anti-adhesive/covering agent, a diluent, a binder, a glidant, a disintegrating agent, and a lubricant.
  • the ingredients are all commercially available.
  • the content of clopidogrel hydrogen sulfate in each tablet is preferably 75 to 300 mg, more preferably 75 mg.
  • the anti-adherent/covering agent/glidant is a micro-powder silica gel. Taking a micro-silica gel prepared by a gas phase method as an example, The particle size is about 7 ⁇ 16nm, the specific surface area is 200 ⁇ 400m 2 /g, and the average particle size of the clopidogrel hydrogen sulfate raw material is about 76 m.
  • the silica content of the micro-powder is At 1 wt% of clopidogrel hydrogen sulfate, the surface area of the microsilica silica gel compared to the surface area of the clopidogrel hydrogen sulfate microparticles is about 27 times sufficient to cover or coat clopidogrel hydrogen sulfate.
  • the silica gel content of the micropowder is preferably from 0.6% to 4.5%, more preferably from 1.3% to 4.3%, based on the weight of the clopidogrel sulfate tablet.
  • the diluent material is lactose, pregelatinized starch, microcrystalline cellulose, more preferably lactose and microcrystalline cellulose.
  • the content of lactose is usually from 15 to 35%, preferably from 20 to 30%, based on the total weight of the tablet; the microcrystalline cellulose content is usually from 5 to 39%, more preferably from 10 to 30%.
  • the binder may be any of various binders conventionally used in the art, such as one or more of polyvinylpyrrolidone, hydroxypropylcellulose and hypromellose, preferably hydroxypropyl.
  • the content of the binder is preferably from 0.5% to 2%, more preferably from 0.6% to 1.5%, based on the weight of the clopidogrel sulfate tablet.
  • the disintegrant may be various disintegrating agents conventionally used in the art, such as low-substituted hydroxypropylcellulose, sodium carboxymethyl starch, crospovidone, and croscarmellose sodium.
  • the content of the crospovidone and/or croscarmellose sodium is from 1.0% to 5.0%, more preferably 1.2% by weight of the clopidogrel sulfate tablet. 4.0%.
  • the lubricant may be a lubricant conventionally used in the art, preferably hydrogenated vegetable oil and sodium lauryl sulfate.
  • the lubricant is present in an amount of 4-8%, preferably 5, by weight of the clopidogrel hydrogen sulfate tablet. %-7%.
  • the production environment of the present invention suggests that the relative humidity is less than 45% RH.
  • the clopidogrel hydrogen sulfate tablet of the present invention needs to be coated with a colored film coating to facilitate the identification, isolation and direct contact with air, and does not affect the moisture.
  • the release of clopidogrel hydrogen sulfate from the formulation because the film coat dissolves rapidly in the stomach.
  • the main advantages of the invention are:
  • the clopidogrel hydrogen sulfate tablet of the invention is directly mixed with the raw material by adding the micro-powder silica gel as an anti-adhesive agent/covering agent, thereby avoiding any surface irregularity caused by adhesion, the sheet surface is smooth, and the lettering is clear.
  • the clopidogrel hydrogen sulfate tablet of the present invention is reduced in the area and probability of contact with water by the addition of the silica gel as an anti-adhesive/covering agent and separately mixed with the raw material, thereby reducing the area and probability of contact with moisture.
  • the production of clopidogrel acid (impurity enthalpy) increases the stability of the formulation.
  • the invention is further disclosed below in conjunction with specific embodiments. It is to be understood that the examples are not intended to limit the scope of the invention.
  • the experimental methods in the following examples which do not specify the specific conditions are usually in accordance with the conditions described in the conventional conditions such as "Pharmaceutics" (People's Health Publishing House, 5th Edition), or in accordance with the conditions recommended by the manufacturer. Unless otherwise stated , otherwise the percentages and parts are by weight.
  • Clopidogrel hydrogen sulfate Form I, with an average particle size of about 76 microns, was purchased from ProLogin Pharmaceutical Co., Ltd. (China, Zhejiang).
  • Micronized silica gel was purchased from Evonik Degussa (China) Investment Co., Ltd. under the trade name AEROSIL® 200 Pharma with a specific surface area of 204 m 2 /g. Comparative example 1:
  • clopidogrel hydrogen sulfate was directly mixed with 60.00 g of lactose and 40.00 g of microcrystalline cellulose, and then granulated by adding a solution of 10% hydroxypropylcellulose in ethanol to obtain wet granules.
  • the wet granules were dried and sized, and the micronized silica gel (1.5 g, equivalent to 0.6% of the tablet weight), microcrystalline cellulose 26.00 g, crospovidone 6.00 g, hydrogenated vegetable oil and sodium lauryl sulfate were added. After mixing with 17.00 g, the tablet was tableted to a weight of 250 mg and a gauge diameter of 9 mm. Comparative example 3
  • the micronized silica gel (5.00g, equivalent to 1.56% of the tablet weight) and the microcrystalline cellulose 50g are firstly mixed, and the uniform material obtained after the sieve having a pore diameter of 0.5 mm is combined with sulfuric acid.
  • Hydrogen clopidogrel 97.9 g, 144.2 g of microcrystalline cellulose, 12 g of L-HPC, and 12 g of hydrogenated castor oil were mixed together at a mixing speed of 20 rpm for a mixing time of 20 minutes. Then, the tablet was pressed to have a tablet weight of 320 mg and a film diameter of 10 mm.
  • Pre-mixed granules were formed by pre-mixing 97.88 g of clopidogrel hydrogen sulfate and silica gel (0.75 g, equivalent to 0.3% of the tablet weight) of the micronized powder. Further, the premixed granules were mixed with 60.00 g of lactose and 40.00 g of microcrystalline cellulose, and granulated by adding a solution of 10% hydroxypropylcellulose in ethanol to obtain wet granules.
  • Example 2 Dry and granule the wet granules, add 26.00 g of microcrystalline cellulose, 6.00 g of crospovidone, 17.00 g of hydrogenated vegetable oil and sodium lauryl sulfate, and mix, tablet, tablet weight 250 mg, tablets The diameter is 9mm.
  • Example 2
  • Pre-mixed granules were formed by pre-mixing 97.88 g of clopidogrel hydrogen sulfate and silica gel (0.75 g, equivalent to 0.3% of the tablet weight) of the micronized powder. Further, the premixed granules were mixed with 60.00 g of lactose and 40.00 g of microcrystalline cellulose, and granulated by adding a solution of 10% hydroxypropylcellulose in ethanol to obtain wet granules.
  • micro-powder silica gel (0.75 g, equivalent to 0.3% of tablet weight), microcrystalline cellulose 26.00 g, crospovidone 6.00 g, hydrogenated vegetable oil and sodium lauryl sulfate were added. After mixing with 17.00 g, the tablet was tableted to a weight of 250 mg and a gauge diameter of 9 mm.
  • Example 3
  • 97.88 g of clopidogrel hydrogen sulfate and fine silica gel (1.50 g, equivalent to 0.6% of the tablet weight) were uniformly mixed in advance to form premixed particles. Then, the premixed granules were added to 60.00 g of lactose and 40.00 g of microcrystalline cellulose, and the mixture was granulated by adding an ethanol solution of 8% hydroxypropylcellulose to obtain wet granules.
  • micro-powder silica gel (0.75 g, equivalent to 0.3% of tablet weight), microcrystalline cellulose 26.00 g, crospovidone 6.00 g, hydrogenated vegetable oil and sodium lauryl sulfate were added. After mixing with 17.00 g, the tablet was tableted to a weight of 250 mg and a gauge diameter of 9 mm.
  • Example 4
  • Pre-mixed granules were formed by pre-mixing 97.88 g of clopidogrel hydrogen sulfate and silica gel (2.50 g, equivalent to 1.0% of the tablet weight) of the micronized powder. Further, the premixed granules were added to 60.00 g of lactose and 40.00 g of microcrystalline cellulose, and granulated by adding a solution of 10% hydroxypropylcellulose in ethanol to obtain wet granules.
  • micro-powder silica gel (0.75 g, equivalent to 0.3% of tablet weight), microcrystalline cellulose 26.00 g, crospovidone 6.00 g, hydrogenated vegetable oil and sodium lauryl sulfate were added. After mixing with 17.00 g, the tablet was pressed, the tablet weight was 250 mg, the film diameter was 9 mm, and the coating was applied.
  • Example 5
  • Pre-mixed granules were formed by pre-mixing 97.88 g of clopidogrel hydrogen sulfate and silica gel (5.00 g, equivalent to 2.0% of the tablet weight) of the micronized powder. Further, the premixed granules were added to 60.00 g of lactose and 40.00 g of microcrystalline cellulose, and granulated by adding a prepared 12% hydroxypropylcellulose in ethanol to obtain wet granules.
  • micro-powder silica gel (0.75 g, equivalent to 0.3% of tablet weight), microcrystalline cellulose 26.00 g, crospovidone 6.00 g, hydrogenated vegetable oil and sodium lauryl sulfate were added. After mixing with 17.00 g, the tablet was tableted to a weight of 250 mg and a gauge diameter of 9 mm.
  • Comparative Example 3 the micronized silica gel and the microcrystalline cellulose were first uniformly mixed and sieved in a ratio of 1:10, and the amount of the micronized silica gel was equivalent to a tablet weight of 1.56%, and then mixed with the clopidogrel hydrogen sulfate raw material and other auxiliary materials, and pressed. There is a sticky rush when the film is taken.
  • Example 1 the clopidogrel hydrogen sulfate raw material was premixed with the micro-silica gel, and the amount of the micro-powder silica gel was equivalent to a tablet weight of 0.3%, and the sticking was found to be improved after tableting.
  • the clopidogrel hydrogen sulfate raw material is pre-mixed with the micro-powder silica gel, and the micro-powder silica gel is added in an amount corresponding to a tablet weight of 0.3%, and the same amount of the micro-powder silica gel is added, and the adhesiveness is improved after tableting, and the effect is better.
  • Example 1 the clopidogrel hydrogen sulphate raw material is premixed with the micro-powder silica gel in an amount of 0.6% to 2.0% equivalent to the tablet weight, and the amount of the micro-silica gel is equivalent to a tablet weight of 0.3%, and no sticking is applied. A phenomenon occurs. The observations were judged according to the criteria shown in Table 1, and are summarized in Table 2.
  • the film appears to have a sticking force (proportion 2);
  • micronized silica gel When used as an anti-adhesive/covering agent, it is pre-mixed with the raw material to form pre-mixed particles.
  • the content in each tablet is only half of the fluxing agent content, and the sticking phenomenon is also improved (Example 1); when the micronized silica gel is used as an anti-adhesive/covering agent and an equal amount of glidant is added at the same time, it is sticky. The rush phenomenon is further improved (Example 2);
  • the micro-powder silica gel is pre-mixed with clopidogrel hydrogen sulfate as an anti-adhesive/covering agent, so that the micro-powder silica gel is uniformly dispersed on the surface of clopidogrel hydrogen sulfate particles, and the pre-mixed particles are formed, even if the amount is only 0.75.
  • the mg/tablet can also reduce the adhesion of the film to a certain extent and improve the sticking phenomenon. When the amount of micro-silica gel is l-5mg/tablet, the sticking phenomenon can be effectively improved.
  • Example 4 and Comparative Example 3 were coated with Opadry type II film coating material (purchased from Shanghai Colorcon Coating Technology Co., Ltd.), and Commercially available PLAVIX is placed under constant temperature and humidity conditions of 40 ° C / 75% relative humidity (RH), open for accelerated stability test for 8 days, taken out, and clopidogrel acid (impurity according to USP32 method) A) Detection. Table 3 force] speed test results
  • Example 3 75 0.01 0.47 As shown in Table 3, the stability of the sheet of the present invention was significantly better than Comparative Example 3 (where WO2008059298) and Plavix (Sanofi).

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Description

硫酸氢氯吡格雷固体制剂及其制备工艺
技术领域
本发明涉及药物领域，更具体地涉及硫酸氢氯吡格雷固体制剂 (尤其是片剂;) 的制备方法。 背景技术
硫酸氢氯吡格雷的化学名称为 S(+)-2-(2-氯苯基 )-2-(4， 5， 6， 7， -四氢噻 吩 [3， 2-c]并吡啶 -5)乙酸甲酯的硫酸氢盐，其结构式如下：
Figure imgf000002_0001
氯吡格雷选择性地抑制二磷酸腺苷 (ADP)与其血小板受体的结合及继发的 ADP介导的糖蛋白 GPlllb/llla复合物的活化， 因此可抑制血小板聚集。 除 ADP 外， 氯吡格雷还能通过阻断由释放的 ADP 所引起的血小板活化的扩增， 抑制 其它激动剂诱导的血小板聚集。 氯吡格雷不能抑制磷酸二酯酶的活性。 氯吡格 雷通过不可逆地修饰血小板 ADP受体起作用。
氯吡格雷盐具有羧酸酯结构， 容易水解脱脂， 形成氯吡格雷酸 (杂质 A；)。 美国专利 US4847265具体描述了氯吡格雷的右旋体及药用盐包括盐酸盐、 硫酸氢盐、 氢溴酸盐、 牛磺胆酸盐， 以及氯吡格雷的使用剂量在 0.001g-0.1g。
美国专利 US6429210和 US6504030公开了硫酸氢氯吡格雷晶型 II及其制造 方法。
美国专利 US6767913公开了硫酸氢氯吡格雷的晶型的 X射线粉末衍射图谱 峰位置， 以及晶型 III、 IV、 V、 VI的制备方法和制剂以及晶型 II的制备方法。
PCT申请 WO 2006/044548公开了包含以氯吡格雷为基础的固体预混合料， 其中包括被吸附在氯吡格雷上的至少一种药用辅料。
PCT申请 WO2008059298公开了一种固体制剂的处方， 它混有硫酸氢氯吡 格雷晶型 I (作为活性成分)， 作为填充剂和粘合剂的微晶纤维素和微粉硅胶， 以及崩解剂和润滑剂等其他辅料。
现有的硫酸氢氯吡格雷片含有硫酸氢氯吡格雷、 稀释剂、 粘合剂、 助流剂、 崩解剂以及润滑剂。
市场上有法国赛诺菲-安万特制药有限公司的硫酸氢氯吡格雷片一
PLAVIX(波利维 相当于 75mg氯吡格雷 它包含甘露醇、 微晶纤维素、 羟丙 纤维素， 并且以聚乙二醇 6000 和氢化蓖麻油作为润滑剂。 波利维适用于有过 近期发作的中风、 心肌梗死和确诊外周动脉疾病的患者。 该药可减少动脉粥样 硬化性事件的发生 (如心肌梗死、 中风和血管性死亡)。
中国市场上还有深圳信立泰药业股份有限公司的硫酸氢氯吡格雷片一泰嘉 (相当于 25mg氯吡格雷；)， 用于预防和治疗因血小板高聚集状态引起的心、脑及 其它动脉的循环障碍疾病。在公开号为 CN100400035的中国专利申请 (；申请人： 深圳信立泰药业有限公司;)中， 公开了一种硫酸氢氯吡格雷片的制备方法： 加入 甘油棕榈酸硬脂酸酯和微粉硅胶， 并通过研磨等量递增法制备， 以增加固体制 剂的稳定性和安全性。
作为噻吩 [3, 2-c]衍生物， 氯吡格雷在与某些辅料 (如碱金属硬脂酸镁等;)共 同使用时会导致快速降解。 因此， 通常不使用硬脂酸镁， 以便防止氯吡格雷的 降解。
美国专利 US6914141公开了一种药用片剂， 它包含硫酸氢氯吡格雷并且润 滑剂选用硬脂酸锌、 硬脂酸、 硬脂酰醇富马酸钠。
美国专利 US4591592公开了一种防止硫酸氢氯吡格雷降解的方法， 它包括 使用抗坏血酸、 安息香酸、 酒石酸、 富马酸、 柠檬酸等。
PCT申请 WO2005/048992公开了一类氯吡格雷甲磺酸盐、氢溴酸盐和盐酸 盐的处方， 其中公开了用聚醋酸乙烯酯或聚乙烯醇和一种疏水性成分如氢化植 物油包住氯吡格雷微粒、 颗粒或附聚物。
欧洲申请 EP1970054认为选用合适的稀释剂很重要， 并认为某些稀释剂如 甘露醇、 甘露醇与乳糖或 MCC 的组合使用， 会增强氯吡格雷盐的内在黏附趋 势。 同时认为润滑剂能够帮助片子在压片和出模过程中降低摩擦力， 也能阻止 片子黏附在片冲和模具表面。 因此公开了用氯吡格雷氢溴酸盐和盐酸盐中的一 种原料， 同乳糖、 硬脂酸和一种或多种其它辅料一起制备片剂， 并建议用干法 造粒制备稳定氯吡格雷片， 以解决制剂生产中氢溴酸氯吡格雷和盐酸氯吡格雷 的片剂粘附在普通压片机的冲头和模具上的难题。 然而， 目前仍缺乏在湿法造 粒工艺中防止硫酸氢氯吡格雷粘附的有效手段。
在制剂技术上制备氯吡格雷片的一大难题是氯吡格雷盐包括硫酸氢盐在 内， 在生产过程中， 极其容易吸附在金属表面， 受到摩擦和挤压则迅速产生粘 结， 因此压片时上下冲头的挤压及冲头与模具的挤压， 使得片子迅速粘结在压 片机的冲头和模具上， 并且越来越严重， 引起粘冲和其它各种片子表面不规则 问题， 导致成品质量较差。
综上所述， 本领域迫切需要开发新的工艺， 从而解决上述的技术问题， 从 而防止或减少在压片过程中在压片机冲头和模具上的粘结现象， 并提高成品质
发明内容
本发明的一个目的就是提供一种硫酸氢氯吡格雷固体制剂的制备工艺， 该 制备工艺使得大规模生产硫酸氢氯吡格雷片 (剂)时， 片子在压片机冲头和模具 上不易粘结。
本发明的另一目的是提供不易在压片过程中产生粘结且表面不规则的硫 酸氢氯吡格雷片剂。 在本发明的第一方面， 提供了一种硫酸氢氯吡格雷的预混合颗粒， 所述的预 混合颗粒包括或由以下成分构成：硫酸氢氯吡格雷以及包裹硫酸氢氯吡格雷的微粉 硅胶， 其中微粉硅胶的重量是硫酸氢氯吡格雷重量的 0.5-10%， 硫酸氢氯吡格雷的 平均粒径为 10-100 μ ηι。
在另一优选例中， 微粉硅胶的重量是硫酸氢氯吡格雷重量的 1.0-5%。
在另一优选例中， 在所述的预混合颗粒中， 硫酸氢氯吡格雷作为活性成分， 而微粉硅胶作为抗粘剂 /覆盖剂。
在另一优选例中， 所述的硫酸氢氯吡格雷的晶型为 I型、 II型。
在另一优选例中， 所述的硫酸氢氯吡格雷的平均粒径为 20-80 μ m。
在另一优选例中，所述的微粉硅胶具有以下特性：平均粒径大约为 7〜16nm， 且比表面积为 200〜400m2/g。
在另一优选例中， 所述的硫酸氢氯吡格雷和微粉硅胶占所述预混合颗粒重量 的 90- 100%; 较佳地 95- 100%， 更佳地 99- 100%。
在另一优选例中， 所述的预混合颗粒是用以下方法制备的： 将硫酸氢氯吡格 雷粉末和微粉硅胶混合， 形成所述的预混合颗粒。
在本发明的第二方面， 提供了一种硫酸氢氯吡格雷药物组合物， 它含有本发 明第一方面中所述的硫酸氢氯吡格雷的预混合颗粒以及药学上可接受的载体。
在另一优选例中， 所述的药物组合物为固体剂型。
在另一优选例中， 所述的药物组合物为片剂。
在另一优选例中， 所述的片剂是湿法造粒 (如用粘合剂的乙醇溶液进行造粒;) 制备 α
在另一优选例中， 所述的组合物含有作为活性成分的硫酸氢氯吡格雷， 作为 抗粘剂 /覆盖剂的微粉硅胶， 以及选自下组的载体： 稀释剂、 粘合剂、 助流剂、 崩 解剂和 /或润滑剂。
在另一优选例中， 在所述的药物组合物中， 按组合物的总重量计算， 含有以 下成分：
20-60wt%硫酸氢氯吡格雷；
0.5-5wt%作为抗粘剂 /覆盖剂的微粉硅胶；
20-50wt%稀释剂 (；如乳糖、 预胶化淀粉、 微晶纤维素；)；
0.5-2wt%粘合剂 (如聚乙烯吡咯烷酮、 羟丙基纤维素和羟丙甲纤维素；)；
0.2-0.5wt%助流剂 (如微粉硅胶)；
1.0-5.0wt%崩解剂 (如低取代羟丙基纤维素、 羧甲基淀粉钠、 交联聚维酮、 交联羧甲基纤维素钠)， 和 /或
4-8wt%润滑剂 (；如氢化植物油和 /或月桂基硫酸钠；)。
更佳地， 药物组合物中所有组分之和为 100wt%。
在另一优选例中， 所述的药物组合物为片剂并且含有以下成分：
25-50wt%硫酸氢氯吡格雷；
l-4wt%作为抗粘剂 /覆盖剂的微粉硅胶；
20-30wt%乳糖和 10-30wt%的微晶纤维素；
0.6-1.5wt%羟丙基纤维素；
0.2-0.5wt%作为助流剂的微粉硅胶；
1.2-4.0wt%交联聚维酮。
在另一优选例中， 所述的药物组合物是用包括以下步骤的方法制备的： (a) 将硫酸氢氯吡格雷粉末和微粉硅胶混合， 形成硫酸氢氯吡格雷的预混 合颗粒； (b) 将步骤 (a)获得的预混合颗粒与稀释剂进行混合， 再加入粘合剂的醇溶液， 进行湿法制粒， 获得湿颗粒；
(c) 对步骤 (b)获得的湿颗粒进行干燥和整粒， 获得干颗粒；
(d) 将步骤 (C)获得的干颗粒与助流剂、崩解剂和润滑剂进行混合， 然后进行压 片， 获得硫酸氢氯吡格雷片剂； 和
(e) 任选地对步骤 (d)的片剂进行包衣， 形成包衣的片剂。
在本发明的第三方面， 提供了一种硫酸氢氯吡格雷药物组合物的制备方法， 包括以下步骤：
(a) 将硫酸氢氯吡格雷粉末和微粉硅胶混合， 形成硫酸氢氯吡格雷的预混 合颗粒；
(b) 将步骤 (a)获得的预混合颗粒与稀释剂进行混合， 再加入粘合剂的醇溶液， 进行湿法制粒， 获得湿颗粒；
(c) 对步骤 (b)获得的湿颗粒进行干燥和整粒， 获得干颗粒；
(d) 将步骤 (C)获得的干颗粒与助流剂、崩解剂和润滑剂进行混合， 然后进行压 片， 获得硫酸氢氯吡格雷片剂； 和
(e) 任选地对步骤 (d)的片剂进行包衣， 形成包衣的片剂。
在另一优选例中， 所述的粘合剂溶液是乙醇溶液。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文 (；如实施例;) 中具体描述的各技术特征可以互相组合， 从而构成新的或优选的技术方案。 限 于篇幅， 在此不再一一累述。 具体实施方式
本发明人经过广泛而深入的研究， 首次发现： 将硫酸氢氯吡格雷与微粉硅 胶进行预混合后， 可以获得有助于减少压片粘结情况的预混合颗粒。 在所述的 预混合颗粒中， 硫酸氢氯吡格雷作为活性成分， 而微粉硅胶作为抗粘剂 /覆盖剂， 从而有助于将硫酸氢氯吡格雷原料微粒同周围环境隔开。用所述预混合颗粒， 即使 采用湿法造粒工艺， 也可克服压片过程中片子在压片机冲头和模具上粘结情况， 减少片剂表面的不规则现象， 从而提高成品质量。 在此基础上完成了本发明。
本发明的包衣片与市售 PLAVIX在 40°C/75%RH 同样条件下进行稳定性考 验，对杂质 A——氯吡格雷酸的检测数据显示，本发明的硫酸氢氯吡格雷片优于法 国赛诺菲-安万特制药有限公司生产的 PLAVIX。 预混合颗粒
本发明的预混合颗粒中， 硫酸氢氯吡格雷作为活性成分， 而微粉硅胶作为抗 粘剂 /覆盖剂。
在本发明的预混合颗粒中， 其中微粉硅胶的重量通常是硫酸氢氯吡格雷重量 的 0.5- 10%， 较佳地 1.0-5%。
通常， 所述的硫酸氢氯吡格雷和微粉硅胶占所述预混合颗粒重量的 90-100%， 较佳地 95- 100%， 更佳地 99- 100%。
为了便于理解本发明， 本发明人提供以下机理。 然而， 应当理解， 本发明 保护范围并不受所述机理的限制：
片子在压片机冲头和模具上的粘结的根本原因在于硫酸氢氯吡格雷具有 极强的吸附性。 不仅容易吸附在金属表面， 而且硫酸氢氯吡格雷原料微粒之间 也很容易相互吸附， 在生产过程中， 粘附在冲头和模具表面的硫酸氢氯吡格雷 微粒受到上下冲头的挤压及冲头与模具间的摩擦和挤压， 在压片机的冲头和模 具上形成粘结， 并且越来越严重， 导致出现粘冲等各种表面不规则现象， 造成 成品质量较差。 因此必须阻止硫酸氢氯吡格雷吸附性以及因吸附而产生的粘 结。
最好的办法是让硫酸氢氯吡格雷的微粒表面覆盖不溶解于水的辅料，减小 硫酸氢氯吡格雷接触外界的表面积， 从而减少了其与金属接触的表面积和相互 之间的接触面积， 同时可以减小硫酸氢氯吡格雷与空气中水分的接触面积， 这 样既可以降低其吸附性， 防止压片过程中片子在压片机冲头和模具上的粘结， 又可以防止硫酸氢氯吡格雷因与空气中的水分接触而产生降解， 防止氯吡格雷 酸 (；杂质 A)的产生。
本发明的新工艺， 预混合颗粒以微粉硅胶为抗粘剂和 /或覆盖剂， 协助硫 酸氢氯吡格雷原料微粒同周围环境隔开， 从而克服了上述缺陷。 活性成分硫酸氢氯吡格雷
可用于本发明的硫酸氢氯吡格雷没有特别限制，可以是市售的硫酸氢氯吡 格雷或用本领域已知方法制备的硫酸氢氯吡格雷。
通常， 硫酸氢氯吡格雷是粉末形式， 其平均粒径通常为 20-80 μ ηι。 在本发明中， 硫酸氢氯吡格雷的晶型没有特别限制， 可以是 I型、 II型， 优选 I型。
在本发明的药物组合物中， 硫酸氢氯吡格雷的含量通常为 20-60wt%， 较佳 地 25-50wt%， 按组合物总重量计。
当药物组合物为片剂时，硫酸氢氯吡格雷在每片中的含量相当于氯吡格雷 的含量为 75〜300mg， 更佳的为 75mg。 作为抗粘剂和 /或覆盖剂的微粉硅胶
微粉硅胶有良好的流动性， 能很好地均匀分布是它的优势， 粒径极小， 比 表面积很大， 使它可以稳定地均匀分布在几十微米的硫酸氢氯吡格雷微粒上， 从而减小了硫酸氢氯吡格雷微粒与金属表面接触的表面积， 降低了硫酸氢氯吡 格雷吸附在金属表面的几率， 降低吸附力， 从而增加了流动性。
休止角检测的数据显示， 硫酸氢氯吡格雷在增加搅拌的情况下， 其休止角 大于 45 ° ， 加入微粉硅胶后， 能够使硫酸氢氯吡格雷的休止角降至 43 ° ， 同时 设备表面吸附的硫酸氢氯吡格雷粉大幅减少， 因此这提示： 微粉硅胶的加入能 降低硫酸氢氯吡格雷的吸附性， 并改善了硫酸氢氯吡格雷的流动性。
可用于本发明的、 作为抗粘剂 /覆盖剂的微粉硅胶， 没有特别限制， 可以用 常规方法制备。 优选的微粉硅胶是平均粒径 (或粒径;)大约为 7〜16nm， 其比表 面积为 200〜400m2/g的微粉硅胶。一类优选的微粉硅胶是气相法制备的微粉硅 胶。 药物组合物
本发明还提供含有所述预混合颗粒的药物组合物，它含有本发明上述的硫酸 氢氯吡格雷的预混合颗粒以及药学上可接受的载体。
一种优选的药物组合物剂型是固体剂型， 尤其是片剂。
本发明的硫酸氢氯吡格雷片， 优选含有下述组分： 硫酸氢氯吡格雷、 抗粘 剂 /覆盖剂、 稀释剂、 粘合剂、 助流剂、 崩解剂以及润滑剂。 所述成分均市售可 得。
所述的硫酸氢氯吡格雷在每片中的相当于氯吡格雷的含量较佳的为 75〜 300mg， 更佳的为 75mg。
所述的抗粘剂 /覆盖剂 /助流剂为微粉硅胶。 以气相法制备的微粉硅胶为例， 其 粒径大约为 7〜16nm， 其比表面积为 200〜400m2/g， 硫酸氢氯吡格雷德原料平均 粒径约为 76 m，根据微粉硅胶的粒径和原料粒径， 当微粉硅胶含量为硫酸氢氯吡 格雷的 lwt%时， 微粉硅胶表面积与硫酸氢氯吡格雷微粒表面积相比较的倍数约为 27倍， 足以覆盖或包裹硫酸氢氯吡格雷。
通常， 微粉硅胶含量较佳的为硫酸氢氯吡格雷片重量的 0.6%-4.5%， 更佳的为 1.3%-4.3%。
所述的稀释剂材料的为乳糖、 预胶化淀粉、 微晶纤维素， 更佳的为乳糖和 微晶纤维素。 其中， 按片剂总重量计， 乳糖的含量通常为 15-35%， 较佳地为 20-30%； 微晶纤维素含量通常为 5-39%， 更佳的为 10-30%。
所述的粘合剂可采用本领域常规使用的各种粘合剂，如聚乙烯吡咯烷酮、羟丙 基纤维素和羟丙甲纤维素中的一种或多种，较佳的为羟丙基纤维素；粘合剂的含量 较佳的为硫酸氢氯吡格雷片重量的 0.5%-2%， 更佳的为 0.6%-1.5%。
所述的崩解剂可采用本领域常规使用的各种崩解剂， 如低取代羟丙基纤维素、 羧甲基淀粉钠、 交联聚维酮、 交联羧甲基纤维素钠， 较佳的为交联聚维酮和 /或交 联羧甲基纤维素钠， 崩解剂的含量较佳的为硫酸氢氯吡格雷片重量的 1.0%-5.0%， 更佳的为 1.2%-4.0%。
所述的润滑剂可采用本领域常规使用的润滑剂，较佳的为氢化植物油和月桂基 硫酸钠， 润滑剂的含量为硫酸氢氯吡格雷片重量的 4-8%， 较佳地为 5%-7%。
制法
在本发明中， 优选的硫酸氢氯吡格雷片的制备工艺为：
1、 将硫酸氢氯吡格雷、 微粉硅胶单独混合， 直至微粉硅胶均匀分布在原料 微粒表面。
2、 加入稀释剂混匀后， 用配制好的粘合剂的醇溶液 (乙醇溶液)制湿颗粒；
3、 干燥湿颗粒， 整粒后， 加入崩解剂、 润滑剂和助流剂， 混匀后， 压片即 得。
本发明的生产环境建议相对湿度低于 45%RH，本发明的硫酸氢氯吡格雷片 需包有色的薄膜衣， 起到易于识别、 隔绝与空气的直接接触、 防潮的作用， 但 并不影响硫酸氢氯吡格雷从制剂中的释放， 因为该薄膜衣在胃中能迅速溶解。 本发明的主要优点在于： 本发明的硫酸氢氯吡格雷片由于加入了作为抗粘剂 /覆盖剂的微粉硅胶 直接与原料混合， 避免了任何因粘附引起的片表面不规则现象， 片面光滑， 刻 字清晰。
(2)本发明的硫酸氢氯吡格雷片， 由于加入了作为抗粘剂 /覆盖剂的微粉硅 胶并单独与原料混合， 减少了硫酸氢氯吡格雷与水分接触的面积和几率， 从而 减少了氯吡格雷酸 (杂质 Α)的产生， 增加了制剂的稳定性。 下面结合具体实施例， 进一步公开本发明。 应理解， 这些实施例仅用于说 明本发明而不用于限制本发明的范围。 下列实施例中未注明具体条件的实验方 法， 通常按照常规条件如《药剂学》（人民卫生出版社， 第 5版》中所述的条件， 或按照制造厂商所建议的条件。 除非另外说明， 否则百分比和份数按重量计。 实施例
材料：
硫酸氢氯吡格雷： I晶型， 平均粒径约 76微米， 购自普洛家园药业有限公司 (中国， 浙江)。
微粉硅胶购自赢创德固赛 (；中国;)投资有限公司， 商品名为 AEROSIL® 200 Pharma, 比表面积 204m2/g。 对比例 1 :
将硫酸氢氯吡格雷 97.88g直接与乳糖 60.00g、微晶纤维素 40.00g混合均匀 后， 加入配制好的 10%羟丙纤维素的乙醇溶液制粒， 获得湿颗粒。 对湿颗粒进 行干燥、 整粒， 加入微晶纤维素 26.00g、 交联聚维酮 6.00g、 氢化植物油和十 二烷基硫酸钠共 17.00g混匀后， 压片， 片重为 250mg， 片径为 9mm。 对比例 2 :
将硫酸氢氯吡格雷 97.88g直接与乳糖 60.00g、微晶纤维素 40.00g混合均匀 后， 加入配制好的 10%羟丙纤维素的乙醇溶液制粒， 获得湿颗粒。 对湿颗粒进 行干燥、 整粒， 加入微粉硅胶 (1.5g， 相当于片重的 0.6%)、 微晶纤维素 26.00g、 交联聚维酮 6.00g、 氢化植物油和十二烷基硫酸钠共 17.00g混匀后， 压片， 片 重为 250mg， 片径为 9mm。 对比例 3
按照 PCT申请 WO2008059298的处方和工艺， 将微粉硅胶 (5.00g， 相当于 片重的 1.56%)与微晶纤维素 50g先混匀，过孔径为 0.5mm的筛后所得到的均匀 物料， 与硫酸氢氯吡格雷 97.9g、 144.2g微晶纤维素、 12gL-HPC、 12g氢化蓖 麻油一起混合， 混合速度为 20rpm， 混合时间为 20 分钟。 然后压片， 片重为 320mg， 片径为 10mm。 实施例 1 :
硫酸氢氯吡格雷片剂
将硫酸氢氯吡格雷 97.88g和微粉硅胶 (0.75g，相当于片重的 0.3%)预先混合 均匀后， 形成预混合颗粒。 再将预混合颗粒与乳糖 60.00g、 微晶纤维素 40.00g 混匀， 加入配制好的 10%羟丙纤维素的乙醇溶液制粒， 获得湿颗粒。 对湿颗粒 进行干燥、 整粒， 加入微晶纤维素 26.00g、 交联聚维酮 6.00g、 氢化植物油和 十二烷基硫酸钠共 17.00g混匀后， 压片， 片重为 250mg， 片径为 9mm。 实施例 2 :
将硫酸氢氯吡格雷 97.88g和微粉硅胶 (0.75g，相当于片重的 0.3%)预先混合 均匀后， 形成预混合颗粒。 再将预混合颗粒与乳糖 60.00g、 微晶纤维素 40.00g 混匀， 加入配制好的 10%羟丙纤维素的乙醇溶液制粒， 获得湿颗粒。 对湿颗粒 进行干燥、整粒，加入微粉硅胶 (0.75g，相当于片重的 0.3%)、微晶纤维素 26.00g、 交联聚维酮 6.00g、 氢化植物油和十二烷基硫酸钠共 17.00g混匀后， 压片， 片 重为 250mg， 片径为 9mm。 实施例 3 :
将硫酸氢氯吡格雷 97.88g和微粉硅胶 (1.50g，相当于片重的 0.6%)预先混合 均匀后，形成预混合颗粒。再将预混合颗粒加入乳糖 60.00g、微晶纤维素 40.00g 混匀， 加入配制好的 8%羟丙纤维素的乙醇溶液制粒， 获得湿颗粒。 对湿颗粒 进行干燥、整粒，加入微粉硅胶 (0.75g，相当于片重的 0.3%)、微晶纤维素 26.00g、 交联聚维酮 6.00g、 氢化植物油和十二烷基硫酸钠共 17.00g混匀后， 压片， 片 重为 250mg， 片径为 9mm。 实施例 4 :
将硫酸氢氯吡格雷 97.88g和微粉硅胶 (2.50g，相当于片重的 1.0%)预先混合 均匀后，形成预混合颗粒。再将预混合颗粒加入乳糖 60.00g、微晶纤维素 40.00g 混匀， 加入配制好的 10%羟丙纤维素的乙醇溶液制粒， 获得湿颗粒。 对湿颗粒 进行干燥、整粒，加入微粉硅胶 (0.75g，相当于片重的 0.3%)、微晶纤维素 26.00g、 交联聚维酮 6.00g、 氢化植物油和十二烷基硫酸钠共 17.00g混匀后， 压片， 片 重为 250mg， 片径为 9mm， 并包衣。 实施例 5 :
将硫酸氢氯吡格雷 97.88g和微粉硅胶 (5.00g，相当于片重的 2.0%)预先混合 均匀后，形成预混合颗粒。再将预混合颗粒加入乳糖 60.00g、微晶纤维素 40.00g 混匀， 加入配制好的 12%羟丙纤维素的乙醇溶液制粒， 获得湿颗粒。 对湿颗粒 进行干燥、整粒，加入微粉硅胶 (0.75g，相当于片重的 0.3%)、微晶纤维素 26.00g、 交联聚维酮 6.00g、 氢化植物油和十二烷基硫酸钠共 17.00g混匀后， 压片， 片 重为 250mg， 片径为 9mm。 实施例 6
冲压过程中粘结性能的比较
对上述各实施例中， 观察片剂制备过程中的粘冲现象， 结果如下： 对比例 1中， 压片不久即出现粘冲现象。
对比例 2 中， 即使将微粉硅胶外加并且加入比例相当于片重 0.6%， 压片 10分钟后略有粘冲。
对比例 3中， 先将微粉硅胶和微晶纤维素以 1 : 10的比例混合均匀过筛， 微 粉硅胶加入量相当于片重 1.56%， 再与硫酸氢氯吡格雷原料及其它辅料混合， 压片时有粘冲。
实施例 1中， 将硫酸氢氯吡格雷原料先与微粉硅胶预混， 微粉硅胶加入量 相当于片重 0.3%， 压片后发现粘冲得到改善。
实施例 2中， 将硫酸氢氯吡格雷原料先与微粉硅胶预混， 微粉硅胶加入量 相当于片重 0.3%， 并且外加相同量的微粉硅胶， 压片后发现粘冲得到改善， 效 果优于实施例 1。 实施例 3-5 中， 先将硫酸氢氯吡格雷原料与微粉硅胶预混， 加入量为相当 于片重的 0.6%〜2.0%， 外加微粉硅胶量相当于片重 0.3%， 均没有粘冲现象发 生。 按表 1所示的标准对观察结果进行评判， 汇总于表 2。
表 1 判定粘冲的标准
Figure imgf000013_0001
Figure imgf000013_0002
从表 2中可以看到：
当处方中没有微粉硅胶时， 片子出现粘冲 (对比例 1) ;
当微粉硅胶仅作为助流剂，而没有作为抗粘剂 /覆盖剂时，片子出现粘冲 (对 比例 2)；
当微晶纤维素和微粉硅胶预先混合， 然后再与硫酸氢氯吡格雷及其他辅料 混合时 (WO2008/059298)， 压片过程中并没有改善粘冲情况 (；对比例 3)。
当微粉硅胶作为抗粘剂 /覆盖剂先与原料充分预混， 形成预混合颗粒， 则即 使在每片中的含量仅为作助流剂含量的一半， 粘冲现象也有改善 (实施例 1); 当微粉硅胶作为抗粘剂 /覆盖剂且同时加入等量的助流剂时， 粘冲现象进一 步得到改善 (；实施例 2);
当固定助流剂的量， 而加入的作为抗粘剂 /覆盖剂的微粉硅胶随着每片中含 量的逐步增加， 片子的粘冲现象得到解决 (实施例 3-5)。
由此可知， 微粉硅胶作为抗粘剂 /覆盖剂先与硫酸氢氯吡格雷充分预混， 使 微粉硅胶均匀地分散在硫酸氢氯吡格雷微粒表面， 形成预混合颗粒后， 即使使 用量仅 0.75mg/片， 也能够在一定程度上降低片子的粘附力， 改善粘冲现象。 当微粉硅胶用量为 l-5mg/片时， 可有效改善粘冲现象。 从上述两个表中可以获得： PCT申请 WO2008059298将微粉硅胶同微晶纤 维素先预混在一起作为稀释剂和粘合剂， 制成的片子虽然在稳定性方面情况与 本发明制成的片子相似， 但不能改善压片时的粘冲情况。 本发明的处方工艺制 成片子无论在解决粘冲问题上还是在稳定性问题上都优于上述片子， 因此质量 更好。 原因在于在同样使用微粉硅胶的情况下， 不同的制造工艺， 微粉硅胶所 起到的作用完全不同， 对片子质量的保证情况也不同。 实施例 7
在本实施例中， 在相同环境下、 相同时间内对各种片剂进行加速稳定性测 试：
将实施例 4和对比例 3制得的硫酸氢氯吡格雷片用欧巴代 II型薄膜包衣材 料 (；购自上海卡乐康 (Colorcon)包衣技术有限公司）进行包衣， 并与市售 PLAVIX 同时放入 40°C/75%相对湿度 (； RH)的恒温恒湿条件下，敞开进行加速稳定性考验 8天， 取出， 按照美国药典 USP32的方法， 进行氯吡格雷酸 (杂质 A)检测。 表 3力 ]速试验结果
存放条件 产品批号或实施例 规格 (mg) RC A (%)， 0天 RC A (%)， 8天
40°C/75%RH Plavix(Sanofi) 9F48964 75 0.00 0.76
40°C/75%RH 对比例 3 75 0.01 0.62
40°C/75%RH 实施例 3 75 0.01 0.47 如表 3所示， 本发明的片子的稳定性明显优于对比例 3(WO2008059298处 方)和 Plavix(Sanofi)。
根据实施例 7的检验数据， 发现在同样的加速稳定性考验条件下， 本发明 所制的硫酸氢氯吡格雷片生成的杂质 A 氯吡格雷酸少于 Plavix和对比例 3 制得的硫酸氢氯吡格雷片， 可以判定本发明所提供的处方和工艺优于 Plavix和 PCT申请 WO2008059298的处方和工艺。 在本发明提及的所有文献都在本申请中引用作为参考， 就如同每一篇文献 被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后， 本领域技术人员可以对本发明作各种改动或修改， 这些等价形式同样落于本申 请所附权利要求书所限定的范围。

Claims

权 利 要 求
1. 一种硫酸氢氯吡格雷的预混合颗粒， 其特征在于， 所述的预混合颗粒包括 或由以下成分构成：硫酸氢氯吡格雷以及包裹硫酸氢氯吡格雷的微粉硅胶，其中微 粉硅胶的重量是硫酸氢氯吡格雷重量的 0.5-10%， 硫酸氢氯吡格雷的平均粒径为 10-100 μ m。
2. 如权利要求 1所述的硫酸氢氯吡格雷的预混合颗粒， 其特征在于， 微粉硅胶 的重量是硫酸氢氯吡格雷重量的 1.0-5%; 或者
所述的硫酸氢氯吡格雷和微粉硅胶占所述预混合颗粒重量的 90-100%。
3. 如权利要求 1所述的硫酸氢氯吡格雷的预混合颗粒， 其特征在于， 所述的预 混合颗粒是用以下方法制备的： 将硫酸氢氯吡格雷粉末和微粉硅胶混合， 形成所 述的预混合颗粒。
4. 一种硫酸氢氯吡格雷药物组合物， 其特征在于， 它含有权利要求 1所述的硫 酸氢氯吡格雷的预混合颗粒以及药学上可接受的载体。
5. 如权利要求 4所述的药物组合物， 其特征在于， 所述的药物组合物为固体剂 型。
6. 如权利要求 4所述的药物组合物， 其特征在于， 所述的药物组合物为片剂。
7. 如权利要求 4所述的药物组合物， 其特征在于， 所述的组合物含有作为活性 成分的硫酸氢氯吡格雷， 作为抗粘剂 /覆盖剂的微粉硅胶， 以及选自下组的载体： 稀释剂、 粘合剂、 助流剂、 崩解剂和 /或润滑剂。
8. 如权利要求 4所述的药物组合物， 其特征在于， 所述的药物组合物为片剂并 且含有以下成分：
25-50wt%硫酸氢氯吡格雷；
l-4wt%作为抗粘剂 /覆盖剂的微粉硅胶；
20-30wt%乳糖和 10-30wt%的微晶纤维素；
0.6-1.5wt%羟丙基纤维素；
0.2-0.5wt%作为助流剂的微粉硅胶；
1.2-4.0wt%交联聚维酮。
9. 如权利要求 4所述的药物组合物， 其特征在于， 所述的药物组合物是用包括 以下步骤的方法制备的： (a) 将硫酸氢氯吡格雷粉末和微粉硅胶混合， 形成硫酸氢氯吡格雷的预混 合颗粒；
(b) 将步骤 (a)获得的预混合颗粒与稀释剂进行混合， 再加入粘合剂的醇溶液， 进行湿法制粒， 获得湿颗粒；
(c) 对步骤 (b)获得的湿颗粒进行干燥和整粒， 获得干颗粒；
(d) 将步骤 (C)获得的干颗粒与助流剂、崩解剂和润滑剂进行混合， 然后进行压 片， 获得硫酸氢氯吡格雷片剂； 和
(e) 任选地对步骤 (d)的片剂进行包衣， 形成包衣的片剂。
10. 一种硫酸氢氯吡格雷药物组合物的制备方法，其特征在于，包括以下步骤:
(a) 将硫酸氢氯吡格雷粉末和微粉硅胶混合， 形成硫酸氢氯吡格雷的预混 合颗粒；
(b) 将步骤 (a)获得的预混合颗粒与稀释剂进行混合， 再加入粘合剂的醇溶液， 进行湿法制粒， 获得湿颗粒；
(c) 对步骤 (b)获得的湿颗粒进行干燥和整粒， 获得干颗粒；
(d) 将步骤 (C)获得的干颗粒与助流剂、崩解剂和润滑剂进行混合， 然后进行压 片， 获得硫酸氢氯吡格雷片剂； 和
(e) 任选地对步骤 (d)的片剂进行包衣， 形成包衣的片剂。
PCT/CN2010/073879 2010-02-05 2010-06-12 硫酸氢氯吡格雷固体制剂及其制备工艺 WO2011094982A1 (zh)

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