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WO2008065674A1 - Préparation d'une dispersion moléculaire à écoulement libre comprenant une base de clopidrogel - Google Patents

Préparation d'une dispersion moléculaire à écoulement libre comprenant une base de clopidrogel Download PDF

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Publication number
WO2008065674A1
WO2008065674A1 PCT/IN2007/000173 IN2007000173W WO2008065674A1 WO 2008065674 A1 WO2008065674 A1 WO 2008065674A1 IN 2007000173 W IN2007000173 W IN 2007000173W WO 2008065674 A1 WO2008065674 A1 WO 2008065674A1
Authority
WO
WIPO (PCT)
Prior art keywords
clopidogrel
solid dispersion
pharmaceutically acceptable
polymer
solid
Prior art date
Application number
PCT/IN2007/000173
Other languages
English (en)
Other versions
WO2008065674A8 (fr
Inventor
Venkateswarlu Guntuka
Bhumireddy Chennakesava Reddy
Harish Chandra Pandey
Original Assignee
Venkateswarlu Guntuka
Bhumireddy Chennakesava Reddy
Harish Chandra Pandey
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Venkateswarlu Guntuka, Bhumireddy Chennakesava Reddy, Harish Chandra Pandey filed Critical Venkateswarlu Guntuka
Priority to EP07827489A priority Critical patent/EP2086510A1/fr
Publication of WO2008065674A1 publication Critical patent/WO2008065674A1/fr
Publication of WO2008065674A8 publication Critical patent/WO2008065674A8/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/167—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface
    • A61K9/1676—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface having a drug-free core with discrete complete coating layer containing drug

Definitions

  • the present invention relates to a free flowing molecular dispersion of clopidogrel base comprising clopidogrel base, a polymer, such as, hydroxypropylmethylcellulose or a mixture of polymers, such as, hydroxypropylmethylcellulose and ethyl cellulose, pharmaceutically acceptable excipients and optionally surfactant and a process for preparing the same.
  • a polymer such as, hydroxypropylmethylcellulose or a mixture of polymers, such as, hydroxypropylmethylcellulose and ethyl cellulose
  • pharmaceutically acceptable excipients and optionally surfactant and a process for preparing the same.
  • Clopidogrel is an inhibitor of induced platelet aggregation and acts by inhibiting the binding of adenosine diphosphate to its receptor. Clopidogrel is metabolized by the liver into active form. Its antiplatelet activity is extended in that it stops any platelet activity even up to ten days after administration. Chemically clopidogrel is methyl (+)- ([pound])-[deg.]c-(o-chlorophenyl)-6,7- dihydrothieno[3,2-c]pyridine-5(4H)-acetate.
  • U.S. Pat. No. 4,529,596 disclose clopidogrel. Clopidogrel's ability to inhibit platelet aggregation makes it an effective drug for reducing the incidence of ischemic strokes, heart attacks or claudication due to vascular diseases such as atherosclerosis. Clopidogrel reduces the chance of arterial blockage, thus preventing strokes and heart attacks.
  • Clopidogrel is presently used as its bisulphate or hydrogensulphate salt.
  • the hydrogensulphate salt has the disadvantage that concentrated sulfuric acid is required to prepare it, and that corresponding products have a very strong acidic reaction because of the acidic proton. These acidic properties have an adverse effect on compatibility with many pharmaceutical excipients and thus the stability of dosage forms made from it.
  • EP1310245 describes that there is an interaction between platelet aggregation inhibitor clopidogrel and magnesium stearate where magnesium stearate causes degradation of clopidogrel.
  • This invention purports to overcome this problem by using zinc stearate, stearic acid, sodium stearyl fumarate as lubricant instead of magnesium stearate.
  • US5520928 relates to use of stearic acid
  • WO0001364 relates to use of PEG and talc instead of magnesium stearate.
  • US4591592 relates to use of a chelating agent such as stearic acid, benzoic acid, tartaric acid or fumaric acid and an antioxidant together with magnesium stearate.
  • WO/2005/070464 decribes a stable pharmaceutical formulation of clopidogrel bisulphate wherein hydrogenated vegetable oil is used as lubricant.
  • Clopidogrel base has not been used for formulation because it exists as an oil that is contaminated with solvents and clopidogrel acid. There is, therefore, an urgent need to make clopidogrel base that can be of use in pharmaceutical formulations.
  • WO 2006031847 provides processes for preparing clopidogrel base substantially free of solvents and suitable for use in pharmaceutical formulations.
  • clopidogrel due to its physical nature, there is still a problem of formulating the base in a stable and bioavailable formulation.
  • the reports in the literature about clopidogrel are focussed on the development of either novel polymorphs of clopidogrel bisulphate or the development of amorphous clopidogrel bisulphate.
  • the use of clopidogrel base as an active pharmaceutical ingredient for developing a pharmaceutical dosage form has not been explored. This is due to the fact that clopidogrel base occurs as an amorphous semisolid paste-like mass and, therefore, is not conducive to being converted into an acceptable solid oral formulation.
  • clopidogrel base as an active pharmaceutical ingredient in pharmaceutical dosage forms thus requires that the clopidogrel base be processed so as to render it suitable for further processing to develop a dosage form.
  • WO 2006/044548 relates to premixes comprising clopidogrel and a pharmaceutically acceptable excipient, and processes for the preparation of these compositions.
  • a composition containing clopidogrel is prepared by adsorbing a solution containing clopidogrel base onto a pharmaceutical excipient or a mixture of pharmaceutical excipients and then removing solvent.
  • this invention can have the problems of poor flowability and stability.
  • This approach also has limitation of the maximum content of clopidogrel possible in these compositions. The flowability of the material is a limiting factor and it is generally difficult to make a composition with a clopidogrel content of more than 30 percent.
  • clopidogrel base when processed to form a molecular dispersion or a solid solution in certain pharmaceutically acceptable polymers allows the formation of a free flowing granular powder containing clopidogrel base, with enhanced flowability,dissolution and stability.
  • an object of the invention is to provide clopidogrel base in powder form which is free flowing and has enhanced stability and adequate dissolution.
  • Another object is to provide clopidogrel base which is easily and conveniently processed into pharmaceutical compositions.
  • a further object is to provide a process of preparation of clopidogrel base in powder form which is free flowing and has enhanced stability.
  • a molecular dispersion comprising clopidogrel base and a pharmaceutically acceptable polymer, pharmaceutically acceptable excipients and optionally a surfactant.
  • a molecular dispersion comprising clopidogrel base, a pharmaceutically acceptable polymer, pharmaceutically, acceptable excipients, substrate of inert component and optionally a surfactant.
  • a formulation of clopidogrel needs to have sufficient flowability and compressibility to be converted into a tablet or to be filled into capsules.
  • clopidogrel being an oily liquid, can not be processed either in a tablet or a capsule. Its conversion into a molecular dispersion affords a granular solid material that can be conveniently subjected to unit operations like size reduction and granulation that may be required to impart flowability and compressibility. If a dispersion does not form ciopidogrel will remain a liquid mixed with excipients and will not acquire properties needed for formulation into a tablet or a capsule.
  • the blend of present invention is easily isolated in the form of stable, free-flowing granules, which exhibit good processing characteristics and can be easily and conveniently processed into pharmaceutical compositions (such as, for example, tablets, capsules, and the like).
  • Blend refers to a solid composition, comprising generally of powders or granules, of clopidogrel base coated as a molecular dispersion in a water-soluble or insoluble polymer and a surfactant, onto at least one pharmaceutically acceptable excipient that is compatible with clopidogrel base to form a tertiary "molecular dispersion” or a “solid solution or dispersion”.
  • solid dispersion refers to the dispersion of one or more active ingredient in an inert carrier or matrix at solid state prepared by melting (fusion), solvent, or the melting solvent method.
  • Such drug-carrier combinations can also be prepared through coprecipitation of the two or more compounds from a common solvent.
  • the present invention is about a similar process using a fluid bed processor to accomplish coprecipitation of the drug- polymer- surfactant coprecipitate from a common solvent on to a pharmaceutically acceptable excipient or excipient mixture.
  • the approach involves a fluidized bed coating system, wherein a drug-carrier solution is sprayed onto the granular surface of excipients to produce either granules ready for tableting or drug-coated granules for encapsulation in one step.
  • the method has been applied for both controlled- and immediate-release solid dispersions.
  • the invention describes a molecular dispersion containing clopidogrel prepared by spraying a solution comprising clopidogrel base and a pharmaceutically acceptable polymer, either alone or in combination with another polymer, onto a pharmaceutical excipient or a mixture of pharmaceutical excipients and then removing solvent in a fluid-bed processor.
  • the molecular dispersion of clopidogrel thus prepared can be used directly, or used in combination with additional excipients to prepare desired pharmaceutical dosage forms.
  • the process can be carried out in a fluid bed processor using a bottom spray, a top spray or a tangential spray attachment.
  • the flowability, processability and other characteristics of the clopidogrel base dispersion of the invention can be readily controlled through the choice of appropriate pharmaceutically acceptable excipients onto which the clopidogrel-polymer solution is coated; and by varying the process variables like the spray rate and the degree of fluidization. Further control on the particle size distribution can be exercised by subjecting the molecular dispersion obtained from the process to a size-reduction step.
  • the flowability of the clopidogrel base is significantly enhanced by its conversion into the molecular dispersion blend according to this application. Such a significant improvement in the flow properties of a material indicates superior handling capabilities during processing into pharmaceutical dosage forms.
  • Another important solid-state property of a pharmaceutical compound is its rate of dissolution in an aqueous fluid.
  • the rate of dissolution of an active ingredient in a patient's stomach or in intestinal fluids can have therapeutic consequences because it affects the rate at which an orally-administered active ingredient reaches the bloodstream.
  • the development of solid dispersions as a practically viable method to enhance bioavailability of poorly water-soluble drugs overcame the limitations of previous approaches such as salt formation, solubilization by cosolvents, and particle size reduction. Once the solid dispersion is exposed to aqueous media & the carrier dissolved, the dispersed drug is released as very fine, colloidal particles. Because of greatly enhanced surface area obtained in this way, the dissolution rate and the bioavailability of poorly water-soluble drugs are generally expected to be high.
  • the commercial use of such systems has been limited primarily because of manufacturing problems with solid dispersion systems.
  • the components are required to be in a finely divided form.
  • the clopidogrel molecular dispersion blend of the present invention can be subject to operations such as size reduction, particle size classification, such as, by sieving, blending with other components, and the like, without substantial alteration of the flow properties and other important features of the blend.
  • Clopidogrel base occurs as a semisolid mass which is difficult to handle and to process into a pharmaceutical formulation.
  • the flowability of the clopidogrel base is significantly enhanced by its conversion into the dispersion according to this invention.
  • the clopidogrel formulation of the invention is preferably based on compositions having a substrate forming inert component which may comprise of microcrystalline cellulose, a cyclodextrine or an ion-exchange resin.
  • the substrate forming inert component is coated with a formulation which comprises clopidogrel, a water soluble polymer (either alone or in combination with another polymer) and a surface active agent, dissolved in a suitable solvent or a solvent mixture.
  • the substrate forming inert component is typically in a concentration of 20- 50% of the final product weight.
  • the substrate forming component is granulated with a pharmaceutically acceptable binder to provide uniformly sized granules to facilitate coating in a fluid bed processor.
  • Clopidogrel may comprise from 10 to 40 weight % and preferably 30 to 40 wt % of the final formulation.
  • Polymers to form the molecular dispersion, are selected from water soluble polymers like hydroxypropylmethylcellulose, hydroxypropylcellulose and methylcellulose; either alone or in combination with ethylcellulose. These polymers are used at a level of 10 to 100% of the clopidogrel weight.
  • the surface active agent is any pharmaceutically acceptable, non-toxic surfactant. Suitable surface active agents include sodium lauryl sulfate, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80 and the like. The surface active agent are present at a level of from 0.1 to 5 wt % and preferably 0.25 to 2.5 wt % based on the total weight of the drug-polymer composition.
  • the drug-polymer solution is prepared in a solvent mixture which consists of one or more solvents from isopropanol, ethanol, dichloromethane, acetone and water.
  • the molecular dispersion is formed by spraying the substrate granules with an aqueous or non-aqueous solution which contains the clopidogrel, the polymer(s) and the surface active agent.
  • the material is dried in the same coater till the moisture content is reduced to a level below 2%.
  • the dried material is powdered using a suitable size-reduction equipment to get a material of the desired size distribution. This is further combined with commonly used excipients to make the desired pharmaceutical dosage form.
  • the clopidogrel molecular dispersion blend of the invention can be further processed, either alone or with other active agents into various pharmaceutical dosage forms as is, or by combining with pharmaceutically acceptable excipients.
  • the different pharmaceutical dosage forms where the clopidogrel molecular dispersion blend of the invention finds utility include, for example, tablets, capsules (hard and soft gelatin), granules, lozenges, sachets, pills, oral solutions, suspensions, and the like.
  • Other pharmaceutically acceptable additives may be used as required for conversion of the blend into the final pharmaceutical dosage form and may include diluents, lubricants, glidants, disintegrating agents, wetting agents, and the like.
  • the clopidogrel molecular dispersion blend renders clopidogrel base amenable for processing into a pharmaceutical dosage forms.
  • This blend offers numerous advantages to the formulator. It occurs as free flowing granules and thereby allows itself to be directly compressed. Consequently, various unit operations as granulation, drying, milling, sieving and the like can be avoided.
  • the enhanced flow property and density enables compression of clopidogrel molecular dispersion blend into tablets, with or without granulation, and filling into capsules or sachets.
  • a clopidogrel base molecular dispersion blend was prepared, using the following:
  • Microcrystalline cellulose is granulated by mixing with a 12 percent solution of polyvinylpyrrolidone in isopropanol. This mixture is dried in a draught of air.
  • the dried material is powdered and the 18 to 40 mesh size fraction is collected for coating with the clopidogrel molecular dispersion.
  • 360 g of clopidogrel base is dissolved in a solution of 272.5g of hydroxypropylmethylcellulose and 7g of Polysorbate 80 in 5054g of isopropanol and 720 g of water, with stirring.
  • Granulated microcrystalline cellulose is loaded in to a bottom spray attachment of a fluid bed processor.
  • Microcrystalline cellulose granules are coated with the clopidogrel:HPMC:Polysorbate 80 solution.
  • the coated material is dried at 40-45° until a loss on drying at 105° of 1-2 percent by weight is achieved. 6.
  • the dried granules are sifted through a 40 ASTM mesh sieve.
  • the tablets made above are coated with a 5 percent solution of hydroxypropylmethylcellulose (6 cps) in a mixture of isopropanol and water, further comprising of titanium dioxide and red ferric oxide as pigments, triethylcitrate as the plasticizer and talc and lactose as the antitack.
  • 6 cps hydroxypropylmethylcellulose
  • the dissolution of clopidogrel from the tablets made from the molecular dispersion blend as described above and the pure clopidogrel was determined in various dissolution medium in a paddle type dissolution tester.
  • the amount of clopidogrel dissolved at regular intervals till one hour was estimated by using a UV specrophotometric method.
  • Dissolution of the pure clopidogrel base and its dissolution from tablets made from 5 its molecular dispersion in hydroxypropylmethylcellulose is given below.
  • the enhancement in dissolution is obvious.

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  • Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical & Material Sciences (AREA)
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Abstract

La présente invention concerne une dispersion moléculaire solide à écoulement libre comprenant une base de clopidogrel, au moins un polymère pharmaceutiquement acceptable, au moins un excipient pharmaceutiquement acceptable et éventuellement un surfactant. La présente invention concerne également un procédé de préparation d'une dispersion solide comprenant les étapes suivantes : dissolution d'une base de clopidogrel dans un polymère solide pharmaceutiquement acceptable, ou d'un mélange de polymères ou d'un mélange d'un polymère et d'un surfactant; et retrait du solvant par vaporisation de ladite solution sur un substrat comprenant un excipient pharmaceutiquement acceptable, dans un processeur à lit fluidisé.
PCT/IN2007/000173 2006-11-27 2007-04-30 Préparation d'une dispersion moléculaire à écoulement libre comprenant une base de clopidrogel WO2008065674A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP07827489A EP2086510A1 (fr) 2006-11-27 2007-04-30 Préparation d'une dispersion moléculaire à écoulement libre comprenant une base de clopidrogel

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN2191/CHE/2006 2006-11-27
IN2191CH2006 2006-11-27

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WO2008065674A1 true WO2008065674A1 (fr) 2008-06-05
WO2008065674A8 WO2008065674A8 (fr) 2008-10-09

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114732788A (zh) * 2022-04-14 2022-07-12 浙江高跖医药科技股份有限公司 一种硫酸氢氯吡格雷固体制剂及其制备工艺
CN115212180A (zh) * 2022-09-03 2022-10-21 深圳市信宜特科技有限公司 一种阿司匹林和硫酸氢氯吡格雷的复方制剂及其制备方法

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006074066A1 (fr) * 2004-12-30 2006-07-13 Nektar Therapeutics Formulation non cristalline comprenant du clopidogrel

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006074066A1 (fr) * 2004-12-30 2006-07-13 Nektar Therapeutics Formulation non cristalline comprenant du clopidogrel

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
ANAND V ET AL: "ION-EXCHANGE RESINS: CARRYING DRUG DELIVERY FORWARD", DDT - DRUG DISCOVERY TODAY, ELSEVIER SCIENCE LTD, GB, vol. 6, no. 17, 17 September 2001 (2001-09-17), pages 905 - 914, XP001127363, ISSN: 1359-6446 *
HO H-O ET AL: "The preparation and characterization of solid dispersions on pellets using a fluidized-bed system", INTERNATIONAL JOURNAL OF PHARMACEUTICS 09 AUG 1996 NETHERLANDS, vol. 139, no. 1-2, 9 August 1996 (1996-08-09), pages 223 - 229, XP002455273, ISSN: 0378-5173 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114732788A (zh) * 2022-04-14 2022-07-12 浙江高跖医药科技股份有限公司 一种硫酸氢氯吡格雷固体制剂及其制备工艺
CN115212180A (zh) * 2022-09-03 2022-10-21 深圳市信宜特科技有限公司 一种阿司匹林和硫酸氢氯吡格雷的复方制剂及其制备方法
CN115212180B (zh) * 2022-09-03 2024-05-10 深圳市信宜特科技有限公司 一种阿司匹林和硫酸氢氯吡格雷的复方制剂及其制备方法

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WO2008065674A8 (fr) 2008-10-09
EP2086510A1 (fr) 2009-08-12

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