WO2015154718A1 - 泊沙康唑药物组合物及其制备方法、应用和药物制剂 - Google Patents

泊沙康唑药物组合物及其制备方法、应用和药物制剂 Download PDF

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WO2015154718A1
WO2015154718A1 PCT/CN2015/076299 CN2015076299W WO2015154718A1 WO 2015154718 A1 WO2015154718 A1 WO 2015154718A1 CN 2015076299 W CN2015076299 W CN 2015076299W WO 2015154718 A1 WO2015154718 A1 WO 2015154718A1
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pharmaceutical composition
posaconazole
composition
weight
carrier material
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PCT/CN2015/076299
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English (en)
French (fr)
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万建胜
李坤
盛小茜
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上海宣泰医药科技有限公司
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Priority to EP15776557.9A priority Critical patent/EP3130354B1/en
Priority to JP2017504231A priority patent/JP6286702B2/ja
Priority to US15/303,389 priority patent/US10022373B2/en
Publication of WO2015154718A1 publication Critical patent/WO2015154718A1/zh

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    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics

Definitions

  • the present invention relates to a pharmaceutical composition, a preparation method, application and pharmaceutical preparation thereof.
  • the present invention relates to a pharmaceutical composition comprising posaconazole as an active ingredient, a method of preparing the pharmaceutical composition, a method of using the pharmaceutical composition for treating and/or preventing a fungal infection and a related disease in a mammal, and A pharmaceutical preparation comprising the pharmaceutical composition.
  • Posaconazole is a derivative of itraconazole and belongs to the second-generation triazole antifungal drug. Its chemical name is 4-[4-[4-[4-[4-[[(3R,5R)- 5-(2,4-difluorophenyl)-5-(1,2,4-triazol-1-ylmethyl)oxalan-3-yl]methoxy]phenyl]piperazine- 1-yl]phenyl]-2-[(2S,3S)-2-hydroxypentan-3-yl]-1,2,4-triazol-3-one, the structural formula is as follows:
  • Posaconazole overcomes the problems of narrow antibacterial spectrum, low bioavailability and drug resistance of the first-generation triazole drugs, and has the characteristics of broad antibacterial spectrum. Compared with fluconazole and itraconazole, posaconazole is more effective in preventing invasive Aspergillus infection and reducing the mortality associated with invasive fungal infections.
  • a suspension containing posaconazole (40 mg/ml) in crystalline form has been used as a suspension Approved for the treatment of invasive fungal infections, such as the treatment of oropharyngeal candidiasis, including infections with other azole antifungal agents, and for prophylactic treatment of patients with these infections due to severe immunodeficiency, Fungal infections in patients with hematopoietic stem cell transplantation (HSCT) with graft versus host disease (GVHD) or in hematological malignancies with long-term neutropenia from chemotherapy.
  • HSCT hematopoietic stem cell transplantation
  • GVHD graft versus host disease
  • posaconazole free base has a solubility of about 0.8 mg/ml.
  • pH is higher than 4
  • posaconazole is almost insoluble (solubility is less than about 1 ⁇ g/ml).
  • US2011123627A discloses a posaconazole comprising an enteric carrier material hydroxypropyl methylcellulose acetate succinate (HPMCAS) polymer which is substantially insoluble when passed through the stomach environment but is readily released upon entry into the intestinal environment.
  • HPMCAS hydroxypropyl methylcellulose acetate succinate
  • the pharmaceutical composition increases the maximum plasma drug concentration and bioavailability of posaconazole in vivo compared to existing marketed posaconazole oral suspensions. However, the pharmaceutical composition limits the release of posaconazole in the stomach, causing the drug to lag behind the plasma drug concentration peak time ( Tmax ) in the body.
  • the posaconazole pharmaceutical composition prepared by the hot melt extrusion process using HPMCAS as a carrier material has a high hardness and is difficult to grind.
  • the pharmaceutical composition is poor in compressibility, which brings difficulties to subsequent processes such as tableting.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising posaconazole and a carrier material, wherein the carrier material comprises: a vinylpyrrolidone-vinyl acetate copolymer or a polymer comprising ethylene glycol units.
  • the pharmaceutical composition can be used to prevent and/or treat fungal infections and related diseases in mammals.
  • the present invention provides the use of a pharmaceutical composition of the first aspect of the invention for the manufacture of a medicament for the prevention and/or treatment of a fungal infection and related diseases in a mammal.
  • the present invention provides a method of preventing and/or treating a fungal infection and a related disease in a mammal comprising administering to the mammal an effective amount of the pharmaceutical composition of the first aspect of the invention.
  • the present invention provides a method of preparing a pharmaceutical composition of the first aspect of the invention, comprising:
  • the resulting extrudate is cooled, comminuted and sieved, optionally mixed with a pharmaceutically acceptable pharmaceutical excipient, thereby obtaining the pharmaceutical composition.
  • the present invention provides a pharmaceutical preparation comprising the pharmaceutical composition of the first aspect of the invention in the form of a powder, granule, pill, capsule or tablet.
  • Figure 1 shows posaconazole - Effect of VA64 content on Tg value in pharmaceutical compositions made with VA64 and/or HPMCAS carrier, where Tg is corresponding to VA64/(VA64+HPMCAS)% at 0%, 25%, 37.5%, 50% and 100% Values are the Tg values for Composition 2-1, Composition 2-2, Composition 2-3, Composition 2-4, and Composition 1-3, or the corresponding blank compositions, respectively.
  • Figure 2 shows posaconazole -
  • Figure 3 shows posaconazole - The dissolution profile of the pharmaceutical composition (Composition 2-3) made of the VA64/HPMCAS mixed carrier and the drug substance in the simulated fasting conditions in the body, wherein the pH was switched from 1.2 to 6.8 at 30 min.
  • Figure 4 shows posaconazole - Dissolution of VA64 content in pharmaceutical compositions made with VA64 and/or HPMCAS carrier (wherein posaconazole and carrier material weight ratio is 1:3) versus dissolution ratio of posaconazole in pH 1.2 and pH 6.8
  • the effect of the dissolution of VA64/(VA64+HPMCAS)% at 0%, 25%, 37.5%, 50% and 100% is Composition 2-1, Composition 2-2, Composition 2, respectively.
  • Dissolution of Compositions 2-4 and Compositions 1-3 Dissolution of Compositions 2-4 and Compositions 1-3.
  • Figure 5 shows posaconazole - An average plasma concentration-time curve of posaconazole after administration of a pharmaceutical composition made of VA64 and/or HPMCAS carrier (Composition 2-1 and Composition 2-2) to a human subject under fasting conditions, wherein VA64/(VA64+HPMCAS)% in Composition 2-1 and Composition 2-2 were 0% and 25%, respectively.
  • metering ratio is the ratio of various substances to a certain weight.
  • the drug posaconazole
  • the carrier material is formulated in a ratio by weight to the carrier material and optionally the pharmaceutically acceptable pharmaceutical excipient.
  • pharmaceutically acceptable means a substance which, within the scope of normal medical judgment, is suitable for contact with the tissue of a patient without undue toxicity, irritation, allergic reaction, etc., having reasonable advantages and disadvantages, and Can be effectively used for its purpose.
  • composition refers to a substance consisting of one or more active ingredients with a carrier material and optionally one or more pharmaceutically acceptable excipients. In the present invention, it may be simply referred to as a composition.
  • pharmaceutical composition 1-1 can be referred to simply as composition 1-1.
  • blank composition means that it does not contain the active ingredient (i.e., posaconazole) relative to the pharmaceutical composition and contains only the carrier material and optionally other pharmaceutically acceptable pharmaceutical excipients.
  • pharmaceutical product refers to a pharmaceutical composition that is administered to a patient in need of treatment, which may generally be in the form of a powder, granules, pills, capsules. , tablets, solutions, suspensions or patches, and the like.
  • dissolved in or dispersed at a molecular level in a carrier material means that the drug is dispersed in the carrier material to form a single phase pharmaceutical composition.
  • the term means that posaconazole is dispersed in the carrier material to form a single phase pharmaceutical composition (also referred to as a solid solution, dispersion or solid dispersion).
  • the obtained posaconazole pharmaceutical composition has a Tg value different from the carrier material and the posaconazole material.
  • the Tg value of the drug are used herein as convenient to describe the invention in various stages of preparation and at various temperatures. Pharmaceutical composition.
  • bioavailability refers to the extent to which a drug or other substance can be utilized by a target tissue after administration.
  • plasma drug concentration peak time ( Tmax ) refers to the time at which the plasma drug concentration peak ( Cmax ) is reached after administration.
  • peak plasma drug concentration ( Cmax ) refers to the maximum plasma drug concentration achieved after administration of the drug.
  • AUC 0- ⁇ refers to the area under the curve of the plasma drug concentration versus time curve from 0 to infinity after administration of the drug; and the term “AUC 0-t” refers to the plasma drug concentration of 0 to t after administration of the drug.
  • the invention provides a posaconazole pharmaceutical composition
  • the pharmaceutical composition of the invention improves the absorption behavior of posaconazole in the human body and increases the absorption and bioavailability of the drug compared with the prior art.
  • the pharmaceutical composition of the present invention is prepared by a simple and easy-to-operate hot melt extrusion method, which improves the process, reduces energy consumption, and improves productivity as compared with the prior art.
  • a certain proportion of vinylpyrrolidone-vinyl acetate copolymer can be prepared as a carrier material and posaconazole can be prepared by the hot melt extrusion process of the present invention. Or a pharmaceutical composition dispersed in the carrier material at a molecular level.
  • a pharmaceutical composition in which posaconazole is dispersed in a vinylpyrrolidone-vinyl acetate copolymer can improve the solubility of posaconazole in the gastrointestinal tract; it can improve dissolution in the stomach environment.
  • the posaconazole has a problem of precipitation precipitation or crystallization caused by a sharp decrease in solubility due to pH change when the stomach is emptied into the intestinal tract, thereby increasing the absorption of posaconazole in the body and improving bioavailability.
  • the pharmaceutical composition can also alter the absorption performance of posaconazole in vivo, increasing Cmax and AUC without delaying its Tmax .
  • the pharmaceutical composition also has better production process characteristics such as easy grinding, good compressibility and the like.
  • the inventors of the present invention have further surprisingly found that the use of a certain ratio of a combination of a vinylpyrrolidone-vinyl acetate copolymer and an enteric polymer such as HPMCAS as a mixed carrier material in the pharmaceutical composition can not only further Improve the solubility of posaconazole in the gastrointestinal tract, and further improve the posaconazole dissolved in the stomach environment with gastric emptying The problem of precipitation precipitation or crystallization caused by a sharp decrease in solubility due to pH change in the intestinal tract, thereby further increasing the absorption and bioavailability of posaconazole.
  • the inventors of the present invention have surprisingly found that the addition of polyethylene glycol 1000 vitamin E succinate (TPGS) to the pharmaceutical composition further improves the solubility of posaconazole in the gastrointestinal tract. Moreover, it is possible to further improve the problem of precipitation precipitation or crystallization caused by a sharp decrease in solubility due to pH change when posaconazole dissolved in the stomach environment enters the intestinal tract with the stomach, thereby further increasing the absorption and biological properties of posaconazole. Utilization.
  • TPGS polyethylene glycol 1000 vitamin E succinate
  • the addition of TPGS reduces the glass transition temperature (Tg) of the pharmaceutical composition, the extruder torque is remarkably lowered, the energy consumption is reduced, and the productivity is improved.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising posaconazole and a carrier material
  • the carrier material comprises: a vinylpyrrolidone-vinyl acetate copolymer or a polymer comprising ethylene glycol units.
  • posaconazole is dissolved or dispersed in the carrier material at a molecular level.
  • the vinylpyrrolidone-vinyl acetate copolymer can be obtained, for example, by radical polymerization of N-vinylpyrrolidone and vinyl acetate in 2-propanol.
  • the vinylpyrrolidone-vinyl acetate copolymer may also be a copolymer having a weight ratio of vinylpyrrolidone to vinyl acetate of from 15:85 to 40:60 as disclosed in, for example, US Pat. No. 5,426,163.
  • the weight ratio of the vinylpyrrolidone unit to the vinyl acetate unit in the vinylpyrrolidone-vinyl acetate copolymer suitable for use as the support material in the present invention is from about 1:9 to about 9:1, preferably from about 4:6 to about 6:4.
  • the copolymer has a K value of from about 25 to about 70.
  • the K value also known as the Fikentscher K value, is a measure of the molecular weight of polymers or mixtures thereof containing vinylpyrrolidone units commonly used in the art and can be as described by H. Fikentscher in Cellulose-Chemie, 1932, 13: 58-64/ The method described in 71-74 was carried out in a 1% by weight aqueous solution.
  • the vinylpyrrolidone-vinyl acetate copolymer used in the present invention may also be a commercially available product such as BASF Corporation.
  • BASF Corporation Commercially available products from VA64 and/or International Specialty Products S630 (both are copolymers of vinylpyrrolidone and vinyl acetate in a weight ratio of 6:4), but is not limited thereto.
  • the carrier material is VA64 (hereinafter referred to as VA64).
  • the ethylene glycol unit-containing polymer suitable for use as a support material in the present invention may be, for example, a polyethylene glycol/vinylcaprolactam/vinyl acetate copolymer, which may be, for example, a commercially available product of BASF Corporation.
  • the carrier material is
  • the carrier material further comprises an enteric polymer, which is cellulose acetate phthalate, cellulose acetate trimellitate, cellulose acetate succinate, Methyl cellulose phthalate, ethyl hydroxymethyl cellulose phthalate, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate (HPMCAS), acetic acid horse Hydroxypropyl methylcellulose, hydroxypropylmethylcellulose trimellitate, carboxymethylethylcellulose, polybutylene phthalate, polyvinyl acetate phthalate Ester, methacrylic acid/ethyl acrylate copolymer (wherein a preferred weight ratio of methacrylic acid to ethyl acrylate is 1:99-99:1) and methacrylic acid/methyl methacrylate copolymer (where methacrylic acid)
  • the preferred weight ratio to methyl methacrylate is one or more of 1:99-99:1),
  • HPMCAS is a cellulose derivative having (1) two types of ether substituents: methyl and 2-hydroxypropyl and (2) two types of ester substituents: acetyl and succinyl. It is referred to in the scientific literature as O-(2-hydroxypropyl)-O-methyl-cellulose acetate succinate.
  • the HPMCAS is preferably at least one or more of the following: (i) having an average acetylation content of 5-9 wt% and an average 14-18 wt% succinyl content based on the weight of HPMCAS.
  • HPMCAS (ii) HPMCAS having an average 7% to 11% by weight acetyl content and an average of 10 to 14% by weight succinyl content, (iii) having an average acetylation content of 10 to 14% by weight and an average of 4 to 8% by weight of succinyl group
  • the HPMCAS may be a commercially available product such as Shin-Etsu Corporation AS-L, AS-M and AS-H, and Ashland commercial product AquaSolve TM L, AquaSolve TM LM, AquaSolve TM LH and AquaSolve AS TM L, AquaSolve AS TM M, AquaSolve AS TM H, but is not limited thereto.
  • the HPMCAS is preferred AS-M.
  • the weight ratio of posaconazole to the support material can range from about 1:1 to about 1:10, preferably from about 1:1 to about 1:5, more preferably about 1:3.
  • the vinylpyrrolidone-vinyl acetate copolymer or the ethylene glycol unit-containing polymer is polymerized with respect to the vinylpyrrolidone-vinyl acetate copolymer or the ethylene glycol-containing unit.
  • the pharmaceutical composition further comprises polyethylene glycol 1000 vitamin E succinate (D- ⁇ -tocopherol polyethylene glycol 1000succinate, TPGS, Vitamin E TPGS, Tocophersolan).
  • polyethylene glycol 1000 vitamin E succinate D- ⁇ -tocopherol polyethylene glycol 1000succinate, TPGS, Vitamin E TPGS, Tocophersolan.
  • the TPGS suitable for use in the present invention is a water-soluble derivative of vitamin E, which is obtained by esterification of a carboxyl group of vitamin E succinate (VES) with polyethylene glycol 1000 (PEG 1000), and has a relative molecular weight of about 1513, which has been loaded.
  • VES vitamin E succinate
  • PEG 1000 polyethylene glycol 1000
  • TPGS acts as a solubilizing agent in the pharmaceutical composition and pharmaceutical preparation of the present invention, and can also reduce the efflux of the drug by affecting the drug transport glycoprotein in the intestinal mucosal cells, thereby contributing to the improvement of oral bioavailability.
  • Exemplary of TPGS in the present invention may be used is a commercially available product of BASF Kolliphor TM TPGS, but is not limited thereto.
  • the TPGS is Kolliphor TM TPGS.
  • the amount of TPGS used in the present invention is not particularly limited and can be adjusted according to actual conditions. Typically, the TPGS is present in an amount of from about 1% to about 12% by weight relative to the total weight of the posaconazole, the support material, and the TPGS.
  • the pharmaceutical composition of the present invention may further comprise a pharmaceutically acceptable pharmaceutical excipient including, but not limited to, a surfactant, a pH adjuster, a diluent, a disintegrant, a binder, and a lubricant.
  • a pharmaceutically acceptable pharmaceutical excipient including, but not limited to, a surfactant, a pH adjuster, a diluent, a disintegrant, a binder, and a lubricant.
  • a pharmaceutically acceptable pharmaceutical excipient including, but not limited to, a surfactant, a pH adjuster, a diluent, a disintegrant, a binder, and a lubricant.
  • the invention also provides a method of making a pharmaceutical composition of the invention, including but not limited to hot melt extrusion and spray drying.
  • a method of making a pharmaceutical composition of the invention including but not limited to hot melt extrusion and spray drying.
  • the specific steps of the hot melt extrusion method are as follows:
  • the resulting extrudate is cooled, comminuted and sieved, optionally mixed with a pharmaceutically acceptable pharmaceutical excipient, thereby obtaining the pharmaceutical composition.
  • the cooling method described in the production method of the present invention is not particularly limited and may include air cooling, water cooling, mechanical cooling, and the like.
  • the extruder used to prepare the pharmaceutical composition of the invention is a twin screw extruder.
  • the type of screw rotation including but not limited to the co-rotating twin screw, the counter-rotating twin screw, and the double-cone screw rotating mode.
  • the extruder used to prepare the pharmaceutical composition of the invention is preferably a co-rotating twin screw extruder.
  • the hot melt extruder is set to a temperature of from about 120 ° C to about 180 ° C and a screw speed of from about 50 to about 500 rpm.
  • the ratio of the length of the screw to the diameter (L/D) can be selected from about 15 to about 40. If the temperature of the hot melt extruder is too low, the L/D is too short, and the screw speed is too slow, the heat and mechanical energy are insufficient during the hot melt process, and then posaconazole, carrier material or polyethylene glycol 1000 vitamin E succinic acid The ester does not reach the molten state, or the posaconazole cannot be dissolved in the molten carrier material.
  • a single-phase solid dispersion (solid solution) in which posaconazole is dissolved or dispersed in the carrier material at a molecular level cannot be obtained. If the temperature of the hot melt extruder is too high, the L/D is too long, and the screw speed is too fast, the thermal energy and mechanical energy are provided in excess during the hot melt process, even if the posaconazole is dissolved or dispersed at the molecular level.
  • a single phase solid dispersion (solid solution) in the support material can also cause unwanted degradation of the posaconazole and/or support material and/or TPGS.
  • the present invention also provides a pharmaceutical preparation comprising the pharmaceutical composition of the present invention. That is, the pharmaceutical composition of the present invention can be further combined with a pharmaceutically acceptable pharmaceutical excipient as needed to prepare various dosage forms.
  • the pharmaceutical preparation may be in the form of a powder, granule, pill, capsule or tablet.
  • the pharmaceutically acceptable pharmaceutical excipients include, but are not limited to, one or more of a surfactant, a pH adjuster, a diluent, a disintegrant, a binder, and a lubricant.
  • the surfactant used in the present invention may be anionic, cationic or zwitterionic. Or a nonionic surfactant, preferably a zwitterionic or nonionic surfactant.
  • the surfactant employed in the present invention may also be a mixture of two or more surfactants. The choice of surfactant may be determined by the particular compound used in the pharmaceutical compositions of the invention. Surfactants suitable for use in the pharmaceutical compositions of the present invention are listed below.
  • Suitable surfactants which may be suitable for use in the present invention are one or more of the following: polyoxyethylene castor oil derivatives such as polyoxyethylene glycerol triricinoleate or polyoxyethylene ether 35 castor oil (Cremophor) EL, BASF) or polyoxyethylene glyceryl hydroxystearate such as polyethylene glycol 40 hydrogenated castor oil (Cremophor RH40) or polyethylene glycol 60 hydrogenated castor oil (Cremophor RH 60); ethylene oxide and propylene oxide Block copolymer, also known as polyoxyethylene polyoxypropylene block copolymer or polyoxyethylene polypropylene glycol, such as Poloxamer 124, Poloxamer 188, Poloxamer 237, Poloxamer 388, Poloxamer 407 (BASF); Polyoxyethylene (20) Single fatty acid esters of sorbitan, such as polyoxyethylene (20) sorbitan monooleate (Tween 80), polyoxyethylene (20) sorbit
  • the surfactant to which the present invention is applicable is preferably a polyoxyethylene castor oil derivative, a block copolymer of ethylene oxide and propylene oxide, and particularly preferably Cremophor RH40 and/or Poloxamer 188.
  • Suitable pH adjusting agents which may be suitable for use in the present invention are citric acid, acetic acid, fumaric acid, maleic acid, tartaric acid, malic acid, succinic acid, fumaric acid, oxalic acid, malonic acid, benzoic acid and One or more of mandelic acid and ascorbic acid, preferably citric acid.
  • Suitable diluents which may be suitable for use in the present invention may be one or more of microcrystalline cellulose, starch, pregelatinized starch, lactose, mannitol and dibasic calcium phosphate.
  • Suitable disintegrants which may be suitable for use in the present invention may be low substituted cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, croscarmellose sodium, carboxymethyl cellulose calcium, carboxymethyl Sodium starch, crosslinked polyvinylpyrrolidone (ie, crospovidone), low substituted hydroxypropylcellulose (L-HPC) having 5-16% by weight of hydroxypropoxy group and methylol starch One or more.
  • Suitable binders which may be suitable for use in the present invention may be sodium carboxymethylcellulose, hydroxypropylcellulose One or more of vitamins, methylcellulose, ethylcellulose, and hypromellose.
  • Suitable lubricants which may be suitable for use in the present invention may be one or more of magnesium stearate, silica, talc, stearic acid and hydrogenated vegetable oil.
  • Glass transition temperature (Tg) accurately weigh about 3 mg of the test substance (posaconazole bulk drug (hereinafter referred to as drug substance), drug-loading composition (ie, the pharmaceutical composition of the present invention) or blank composition Differential scanning calorimetry (mDSC, TA Q2000 Differential Scanning Calorimeter) was performed with a scanning temperature range of 40-180 °C.
  • test substance posaconazole bulk drug (hereinafter referred to as drug substance)
  • drug-loading composition ie, the pharmaceutical composition of the present invention
  • blank composition Differential scanning calorimetry mDSC, TA Q2000 Differential Scanning Calorimeter
  • Powder X-ray diffraction Take an appropriate amount of the analyte (raw drug, drug-loading composition or blank composition), and record the powder X-ray diffraction pattern under the conditions of Cu target, voltage 45 kV, current 45 mA ( D8ADVANCE X-ray diffractometer manufactured by BRUKER).
  • Dissolution sample analysis method the HPLC analysis method described in the above apparent solubility measurement with.
  • Example 1 Posaconazole - VA64 pharmaceutical composition
  • Preparation method posaconazole and carrier material and/or TPGS are mixed directly or in a mixer according to the amount shown in Table 1-1, and then fed to a co-rotating twin-screw extruder (Steer Omicron 12, India)
  • a co-rotating twin-screw extruder Step Omicron 12, India
  • the temperature of the co-rotating twin-screw extruder is controlled between about 120 ° C and about 180 ° C for extrusion, and the screw speed is from about 50 to about 500 rpm.
  • the obtained extrudate was cooled, pulverized, and sieved to obtain a solid powder.
  • other pharmaceutical excipients were uniformly mixed with the solid powder in the amounts shown in Table 1-1 to obtain posaconazole- VA64 pharmaceutical composition.
  • Table 1-1 Posaconazole - Composition of VA64 pharmaceutical composition and amount of each component (% by weight)
  • the posaconazole drug substance (crystal form) has a melting temperature of about 170 ° C, the composition 1-2 has a Tg value of 97.6 ° C, and the composition 1-3 has a Tg value of 71.8 ° C; 2
  • the corresponding blank composition had a Tg value of 106.3 ° C, and the blank composition corresponding to Composition 1-3 had a Tg value of 81.4 ° C.
  • the Tg values of Compositions 1-2 and 1-3 were significantly shifted compared to the Tg values of the two blank compositions, but were significantly different from the Tg value of posaconazole (68 ° C), and Posha The melting peak of Conazole disappeared.
  • the above results clearly show that in each of the pharmaceutical compositions of the present invention, posaconazole is dissolved or dispersed in a carrier material at a molecular level.
  • Table 1-2 Posaconazole - Table of VA64 pharmaceutical composition in pH 6.8 phosphate buffer
  • each of the pharmaceutical compositions of the present invention prepared by the hot melt extrusion method has obvious solubilization effect on posaconazole, indicating VA64 has a better solubilizing effect on posaconazole.
  • the carrier material in the pharmaceutical composition When the weight ratio of VA64) to the drug substance was adjusted from 1:1 to 5:1, the apparent solubility increased from 10.6 ⁇ g/ml to 15.9 ⁇ g/ml, indicating the weight ratio of the carrier material to the drug substance to the solubility of posaconazole. Has little effect. However, a small amount is added based on the composition 1-2.
  • TPGS Composition 1-3
  • compositions 1-2 and Compositions 1-3 had dissolution rates above 93% at each time point after 30 min, indicating that they better enhance the absorption of posaconazole in vivo.
  • Example 2 Posaconazole - VA64/HPMCAS pharmaceutical composition (mixed carrier pharmaceutical composition)
  • posaconazole and carrier material VA64 and / or HPMCAS (specifically AS-M)
  • TPGS / or TPGS
  • the temperature of the co-rotating twin-screw extruder Extrusion is carried out at a temperature between about 120 ° C and about 180 ° C and a screw speed of from about 50 to about 500 rpm.
  • the obtained extrudate was cooled, pulverized, and sieved to obtain a solid powder.
  • other pharmaceutical excipients were uniformly mixed with the solid powder in the amounts shown in Table 2-1 to obtain posaconazole- VA64/HPMCAS pharmaceutical composition.
  • Composition 2-1 is a comparative composition prepared according to US2011123627A, the carrier material of which only contains AS-M is a substance.
  • Table 2-1 Posaconazole - Composition of VA64/HPMCAS pharmaceutical composition and amount of each component (% by weight)
  • FIG. 1 shows posaconazole - Effect of VA64 content on Tg value in pharmaceutical compositions made with VA64 and/or HPMCAS carrier, where Tg is corresponding to VA64/(VA64+HPMCAS)% at 0%, 25%, 37.5%, 50% and 100% Values are the Tg values for Composition 2-1, Composition 2-2, Composition 2-3, Composition 2-4, and Composition 1-3, or the corresponding blank compositions, respectively. It can be seen from Fig. 1 that the Tg value decreases with the increase of the VA64 content in the composition; the Tg value of the drug-containing composition is lower than the Tg value of the blank composition corresponding to each of them by about 10-20 ° C, which is obvious. The offset is significantly different from the Tg value of posaconazole (68 ° C).
  • Figure 2 shows posaconazole -
  • Fig. 2 no diffraction of posaconazole was observed in the X-RD patterns of Composition 1-3 made of a single carrier material and Composition 2-3 and Composition 2-4 made of a mixed carrier material.
  • the peak indicates that in the pharmaceutical composition of the present invention, posaconazole is dissolved or dispersed in a carrier material at a molecular level.
  • Table 2-2 Posaconazole - Apparent solubility of VA64/HPMCAS pharmaceutical composition in pH 6.8 phosphate buffer
  • each of the mixed carrier pharmaceutical compositions of the present invention prepared by the hot melt extrusion method has a significant solubilizing effect on posaconazole.
  • VA64/(VA64+HPMCAS)% was adjusted from 100% (composition 1-3) to 50% (composition 2-4) while maintaining the weight ratio of the drug substance to the carrier material (eg, 1:3).
  • composition 2-3 Increasing the apparent solubility from 44.3 ⁇ g/ml to 68.3 ⁇ g/ml, and continuing to adjust VA64/(VA64+HPMCAS)% from 50% to 37.5% (composition 2-3) to continue the apparent solubility from 68.3 ⁇ g/ml Increased to 93.7 ⁇ g/ml, but will further Reduction of VA64/(VA64+HPMCAS)% to 0% (Composition 2-1) slightly reduced the apparent solubility to 90.1 ⁇ g/ml, indicating that the pharmaceutical composition made of the mixed carrier material was within a certain range to Posacon
  • the solubility of the azole has a beneficial effect. As can be seen from Table 2-2, the solubility of the composition 2-5 to posaconazole was most enhanced.
  • the weight ratio of the drug substance to the carrier material is adjusted from 1:2 (composition 2-5) to 1: 3 (Composition 2-3) and 1:4 (Composition 2-6) increase the apparent solubility of the pharmaceutical composition by at least 119, 93 and 116 times, respectively, than the drug substance, and both are higher than the comparative composition (composition)
  • the apparent solubility of 2-1) indicates that several compositions of VA64/(VA64+HPMCAS)% of 37.5% in the mixed carrier material have the most significant effect on the solubilization of posaconazole.
  • the dissolution profiles of Compositions 2-3 and APIs are shown in Figure 3. It can be seen from Table 2-3 and Figure 3 that the dissolution rate of the drug substance after the conversion from pH 1.2 to 6.8 is greatly reduced, from 98.7% to 5.6%, indicating that posaconazole is in the intestinal tract after gastric emptying in the body. Will precipitate or crystallize from the physiological fluid, thereby reducing its bioavailability in vivo.
  • the dissolution of the pharmaceutical composition of the present invention within 3 hours after the conversion of pH 1.2 to 6.8 was not significant compared to the drug substance, wherein the dissolution of the composition 2-2 to the composition 2-6 at various time points after 30 minutes Both were above 83%, indicating that they can significantly increase the absorption of posaconazole in the body.
  • the dissolution of Composition 2-2 to Composition 2-6 made by mixing the carrier material was significantly improved compared to Composition 2-1 made of a single carrier material, indicating that Composition 2-2
  • the absorption of the composition 2-6 in the stomach is better than that of the composition 2-1; under the condition of pH 6.8, the mixed load
  • the dissolution of Composition 2-2 to Composition 2-6 made of bulk material was similar to Composition 2-1 made of a single carrier material, indicating absorption of Composition 2-2 to Composition 2-6 in the intestine. It would be comparable to Composition 2-1; thus Composition 2-2 to Composition 2-6 made from the mixed carrier material had a better overall absorption in the body than Composition 2-1.
  • Figure 4 shows posaconazole - The dissolution of VA64 content in a pharmaceutical composition made of VA64 and/or HPMCAS carrier (1:3 by weight of posaconazole and carrier material) versus dissolution of posaconazole in a dissolution medium of pH 1.2 and pH 6.8 Effect, wherein the dissolution rates corresponding to VA64/(VA64+HPMCAS)% at 0%, 25%, 37.5%, 50% and 100% are composition 2-1, composition 2-2, composition 2, respectively 3. Dissolution of Compositions 2-4 and Compositions 1-3. It can be seen from Fig.
  • the composition of 0.001% is significantly improved compared to 0%; in the dissolution condition of pH 6.8, when the VA64/(VA64+HPMCAS)% is increased to 50.0% or more, the dissolution rate of each pharmaceutical composition Both fell below 50%.
  • Table 3-1 Posaconazole - Composition of the pharmaceutical composition and amount of each component (% by weight)
  • Preparation method The posaconazole and the carrier material are uniformly mixed in a mixer or in a mixer according to the amounts shown in Table 3-1, and then fed to a hopper of a co-rotating twin-screw extruder (Steer Omicron 12, India). Thereafter, the temperature of the co-rotating screw extruder is controlled between 120 ° C and about 180 ° C, and extrusion is carried out at a screw rotation speed of from about 50 to about 500 rpm. The obtained extrudate was cooled, pulverized, and sieved to obtain a solid powder. Then, other pharmaceutical excipients were uniformly mixed with the solid powder in the amounts shown in Table 3-1 to obtain posaconazole- Pharmaceutical composition.
  • Table 3-2 Posaconazole - Apparent solubility of pharmaceutical compositions in phosphate buffer pH 6.8
  • each posaconazole - The pharmaceutical composition can significantly improve the solubility of posaconazole, and as the weight ratio of the carrier material increases, the solubilization effect becomes more and more obvious.
  • the weight ratio of the carrier material to the drug substance is 5:1 (composition 3-3), the solubility of posaconazole can be increased by at least 159 times.
  • Table 3-3 Posaconazole - Dissolution of pharmaceutical composition in medium conversion of pH 1.2 ⁇ 6.8
  • each posaconazole - compared with the bulk drug -
  • the pharmaceutical composition can significantly improve the dissolution of posaconazole in simulated in vivo conditions.
  • Example 4 Posaconazole - /HPMCAS pharmaceutical composition (mixed carrier pharmaceutical composition)
  • Table 4-1 Posaconazole - /HPMCAS pharmaceutical composition composition and the amount of each component (% by weight)
  • Preparation method posaconazole and mixed carrier materials according to the amounts shown in Table 4-1 ( And HPMCAS (specifically AS-M)) directly or in a mixer, mix and feed to the hopper of the co-rotating twin-screw extruder (Steer Omicron 12, India), and control the temperature of the co-rotating twin-screw extruder at 120 °C. Extrusion is carried out between about 120 ° C and about 180 ° C with a screw speed of from about 50 to about 500 rpm. The obtained extrudate was cooled, pulverized, and sieved to obtain a solid powder. Then, other pharmaceutical excipients and the solid powder were uniformly mixed according to the amounts shown in Table 4-1 to obtain posaconazole- /HPMCAS pharmaceutical composition.
  • Table 4-2 Posaconazole - Apparent solubility of /HPMCAS pharmaceutical composition in pH 6.8 phosphate buffer
  • each posaconazole - The /HPMCAS pharmaceutical composition significantly improved the solubility of posaconazole, with the most significant increase in composition 4-1.
  • Table 4-3 Posaconazole - Dissolution of /HPMCAS pharmaceutical composition in medium conversion of pH 1.2 ⁇ 6.8
  • the /HPMCAS pharmaceutical composition significantly improved the dissolution of posaconazole in simulated in vivo conditions.
  • Example 5 Posaconazole - Evaluation of preparation method of VA64/HPMCAS pharmaceutical composition (mixed carrier pharmaceutical composition)
  • the composition made of the mixed carrier material has a lower energy consumption per kilogram than the compositions 1-3 and 2-1 made of a single carrier material, and the percentage of torque produced is also greater. Low, indicating that the use of a mixed carrier material to prepare a pharmaceutical composition can significantly reduce the energy consumption and instrument torque of the hot melt extrusion process, greatly improving its operability.
  • * refers to the weight percentage of the particles before screening after sieving.
  • the extrudate obtained in the preparation of each of the pharmaceutical compositions was cut into scissors of about 2 cm with scissors, and pulverized for 30 s with a small coffee grinder (Indonesia KG40 type).
  • the pulverized granules were passed through a 60 mesh sieve, and the weight of the obtained powder after drying was weighed to calculate the sieving efficiency.
  • Table 5-2 a pharmaceutical composition comprising a mixed carrier material of VA64 or a VA64 single carrier material was used as compared to the screening efficiency (7.9%) of Composition 2-1 made of a single carrier material HPMCAS. The higher efficiency of sieving indicates that the pulverization process is more operability.
  • Composition 1-3 Composition 2-1 Composition 2-2 Composition 2-3 Composition 2-4 Solid powder* 55.0 55.0 55.0 55.0 Microcrystalline cellulose 29.6 29.6 29.6 29.6 29.6 29.6 Croscone sodium 13.8 13.8 13.8 13.8 13.8 Silica 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0
  • Example 6 Posaconazole - In vivo pharmacokinetic study of VA64/HPMCAS pharmaceutical composition (mixed carrier pharmaceutical composition)
  • the subjects were 9 healthy men aged 20-45 years with a body mass index (BMI) of 19-25. All subjects fully understood the test content and had voluntarily signed the informed consent form.
  • BMI body mass index
  • composition 2-1 concentration of posaconazole (blood concentration) in each plasma sample was determined by LC-MS/MS method, and calculated by pharmacokinetic statistical software DAS 3.2.5 to complete biostatistical analysis to obtain composition 2-1 and combination.
  • the C max , AUC 0-72h , and AUC 0- ⁇ of Composition 2-2 and Composition 2-1 were log-transformed and subjected to analysis of variance, and a two-way one-sided t-test was performed.
  • the test results are shown in Table 6-1 and Figure 5.
  • the 90% confidence interval for C max of composition 2-2 is (106% to 147%)
  • the 90% confidence interval for AUC 0-72h is (115.8% to 147.1%)
  • the 90% confidence interval for AUC 0- ⁇ (117.9% to 146.7%).
  • composition 2-2 Compared to the composition (composition 2-1) using a single carrier material HPMCAS,
  • the posaconazole in the composition of the VA64/HPMCAS mixed carrier material (Composition 2-2) has a faster absorption rate in the body, a higher blood concentration, and a correspondingly higher bioavailability.
  • the arithmetic mean ratio of C max (composition 2-2 / composition 2-1) was 1.23; the arithmetic mean ratio of AUC 0-72h (composition 2-2 / composition 2-1) was 1.29; AUC 0
  • the arithmetic mean ratio of ⁇ ((2-2/composition 2-1) was 1.30.

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Abstract

本发明涉及药物组合物，其包含泊沙康唑和载体材料，其中所述载体材料包含：乙烯基吡咯烷酮-醋酸乙烯酯共聚物或含乙二醇单元的聚合物。本发明还涉及所述药物组合物的制备方法、使用所述药物组合物治疗和/或预防哺乳动物真菌感染和相关疾病的方法以及包含所述药物组合物的药物制剂。

Description

泊沙康唑药物组合物及其制备方法、应用和药物制剂 技术领域
本发明涉及药物组合物及其制备方法、应用和药物制剂。具体而言，本发明涉及包含泊沙康唑作为活性成分的药物组合物、制备所述药物组合物的方法、使用所述药物组合物治疗和/或预防哺乳动物真菌感染和相关疾病的方法以及包含所述药物组合物的药物制剂。
背景技术
泊沙康唑(Posaconazole)是伊曲康唑的衍生物，属于第二代三唑类抗真菌药物，其化学名称为4-[4-[4-[4-[[(3R,5R)-5-(2,4-二氟苯基)-5-(1,2,4-三唑-1-基甲基)氧杂戊环-3-基]甲氧基]苯基]哌嗪-1-基]苯基]-2-[(2S,3S)-2-羟基戊-3-基]-1,2,4-三唑-3-酮，结构式如下：
Figure PCTCN2015076299-appb-000001
美国专利US 5,703,079和US 5,661,151分别公开了泊沙康唑及其合成方法，在此将其全部内容援引加入本文。
泊沙康唑克服了第一代三唑类药物抗菌谱窄、生物利用度低和耐药性等问题，具有抗菌谱广的特性。与氟康唑和伊曲康唑相比，泊沙康唑能更有效地预防侵袭性曲霉菌属感染病，可降低侵袭性真菌感染相关的病死率。
含结晶形式的泊沙康唑(40mg/ml)的混悬剂已作为
Figure PCTCN2015076299-appb-000002
被批准用于治疗侵入性真菌感染，例如治疗口咽念珠菌病，包括耐受其他唑类抗真菌剂治疗的感染，和用作预防性治疗由于严重免疫缺失而非常可能发生这些感染的患者，如具有移植物抗宿主病(GVHD)的造血干细胞移植(HSCT)受体或具有来自化疗的长期嗜中性白血球减少症的血液恶性肿瘤患者中的真菌感染。
然而，适用于制备口服固体剂型的包含泊沙康唑的药物组合物的供给迄今仍受制于泊沙康唑游离碱化合物的弱碱性和低水溶性。泊沙康唑的pKa为3.6(哌嗪)和4.6(三唑)，其在低pH下微溶。例如在胃环境中(pH大约为1.2)，泊沙康唑游离碱具有大约0.8mg/ml的溶解度。但当pH高于4时，泊沙康唑几乎不溶(溶解度小于大约1μg/ml)。因此，当溶解在胃液中的泊沙康唑经胃排空到达肠环境(通常pH不低于大约6.4)时，已溶解的泊沙康唑会结晶析出，从而减少了药物的吸收，影响其生物利用度。
US2011123627A公开了一种使得药物在通过胃环境时基本不可溶但一旦进入小肠环境就容易释放的包含肠溶性载体材料羟丙基甲基纤维素醋酸琥珀酸酯(HPMCAS)聚合物的泊沙康唑药物组合物。与现有的已上市的泊沙康唑口服混悬剂相比，该药物组合物提高了泊沙康唑在体内的最大血浆药物浓度及生物利用度。但该药物组合物限制了泊沙康唑在胃中的释放，使得药物在体内的血浆药物浓度达峰时间(Tmax)滞后。另外，使用HPMCAS作为载体材料经热熔挤出工艺制备的泊沙康唑药物组合物硬度较高，研磨困难。且该药物组合物可压性差，给后续工艺例如压片带来困难。
发明内容
本发明的目的是提供克服现有技术的上述缺陷的泊沙康唑药物组合物。
在第一方面，本发明提供药物组合物，其包含泊沙康唑和载体材料，其中所述载体材料包含：乙烯基吡咯烷酮-醋酸乙烯酯共聚物或含乙二醇单元的聚合物。所述药物组合物可用于预防和/或治疗哺乳动物真菌感染和相关疾病。
在第二方面，本发明提供本发明第一方面的药物组合物在制备用于预防和/或治疗哺乳动物真菌感染和相关疾病的药物中的应用。
在第三方面，本发明提供预防和/或治疗哺乳动物真菌感染和相关疾病的方法，其包括给予所述哺乳动物有效量的本发明第一方面的药物组合物。
在第四方面，本发明提供制备本发明第一方面的药物组合物的方法，其包括：
将热熔挤出机预热至120℃-180℃；
向所述热熔挤出机中进料已混匀的计量比的泊沙康唑、载体材料及任 选存在的药学上可接受的药用辅料的混合物，或者向所述热熔挤出机中直接进料计量比的泊沙康唑、载体材料及任选存在的药学上可接受的药用辅料；
挤出；和
将所得挤出物冷却、粉碎并过筛，任选地与药学上可接受的药用辅料混合，由此得到所述药物组合物。
在第五方面，本发明提供包含本发明第一方面的药物组合物的药物制剂，其是散剂、颗粒剂、丸剂、胶囊剂或片剂的形式。
附图说明
结合以下附图，本发明的目的和特征将变得更为清楚：
图1显示泊沙康唑-
Figure PCTCN2015076299-appb-000003
VA64和/或HPMCAS载体制成的药物组合物中VA64含量对Tg值的影响，其中VA64/(VA64+HPMCAS)％为0％、25％、37.5％、50％和100％时所对应的Tg值分别为组合物2-1、组合物2-2、组合物2-3、组合物2-4和组合物1-3或相应的空白组合物的Tg值。
图2显示泊沙康唑-
Figure PCTCN2015076299-appb-000004
VA64和/或HPMCAS载体制成的药物组合物的X-RD图谱，自下至上依次为原料药、组合物1-3、组合物2-3和组合物2-4的X-RD图谱。
图3显示泊沙康唑-
Figure PCTCN2015076299-appb-000005
VA64/HPMCAS混合载体制成的药物组合物(组合物2-3)及原料药的模拟体内空腹条件的溶出曲线，其中pH在30min时从1.2转换到6.8。
图4显示泊沙康唑-
Figure PCTCN2015076299-appb-000006
VA64和/或HPMCAS载体制成的药物组合物(其中泊沙康唑和载体材料重量比为1:3)中的VA64含量对泊沙康唑在pH 1.2和pH 6.8的溶出介质中的溶出度的影响，其中VA64/(VA64+HPMCAS)％为0％、25％、37.5％、50％和100％时所对应的溶出度分别为组合物2-1、组合物2-2、组合物2-3、组合物2-4和组合物1-3的溶出度。
图5为泊沙康唑-
Figure PCTCN2015076299-appb-000007
VA64和/或HPMCAS载体制成的药物组合物(组合物2-1和组合物2-2)在给予空腹条件下的人体受试者后的泊沙康唑平均血药浓度-时间曲线，其中组合物2-1和组合物2-2中VA64/(VA64+HPMCAS)％分别为0％和25％。
具体实施方式
除非另有定义，本文使用的所有技术和科学术语具有与本发明所属领域技术人员通常理解的相同的含义。若存在矛盾，则以本文提供的定义为准。
当以范围、优选范围或者优选的数值上限以及优选的数值下限的形式表述某个量、浓度或其它值或参数的时候，应当理解相当于具体揭示了通过将任意一对范围上限或优选数值与任意范围下限或优选数值结合起来的任何范围，而不考虑该范围是否具体揭示。除非另外指出，本文所列出的数值范围旨在包括范围的端点，和该范围之内的所有整数和分数。
术语“约”、“大约”当与数值变量并用时，通常指该变量的数值和该变量的所有数值在实验误差内(例如对于平均值95％的置信区间内)或在指定数值的±10％内，或更宽范围内。
术语“计量比”是将各种物质按一定重量进行配比。例如在本发明中，将药物(泊沙康唑)与载体材料及任选存在的药学上可接受的药用辅料按一定重量的比例进行配比。
术语“药学上可接受”的物质指如下物质，其在正常的医学判断范围内适用于与患者的组织接触而不会有不适当毒性、刺激性、过敏反应等，具有合理的利弊比，且能有效用于其目的用途。
术语“药物组合物”指一种或多种活性成分与载体材料和任选存在的一种或多种药学上可接受的药用辅料组成的物质。在本发明中可将其简称为组合物。例如药物组合物1-1可简称为组合物1-1。
术语“空白组合物”是指相对于药物组合物而言，其不含活性成分(即泊沙康唑)而仅含载体材料和任选存在的其它药学上可接受的药用辅料。
术语“药剂产品”、“药物剂型”、“剂型”、“药物制剂”等指被施予需要治疗的患者的药物组合物，其通常可以为下述形式：散剂、颗粒剂、丸剂、胶囊剂、片剂、溶液剂、混悬剂或贴剂等。
术语“溶解在或以分子水平分散在载体材料中”指药物分散在所述载体材料中，形成单相药物组合物。在本发明中，该术语即指泊沙康唑分散在所述载体材料中，形成单相药物组合物(也称为固体溶液、分散体或固体分散体)。所得泊沙康唑药物组合物的Tg值不同于载体材料和泊沙康唑原料 药的Tg值。术语“溶解在”、“以分子水平分散”、“分散体”、“固体溶液”、“固体分散体”在本文中视方便使用，以描述在制备的各阶段中和在各温度下的本发明的药物组合物。
术语“生物利用度”指药物或其他物质在施用后能够为靶组织所利用的程度。
术语“血浆药物浓度达峰时间(Tmax)”指施用后达到血浆药物浓度峰值(Cmax)的时间。
术语“血浆药物浓度峰值(Cmax)”指施用药物后达到的最大血浆药物浓度。
术语“AUC0-∞”指施用药物后时间由0至无穷的血浆药物浓度对时间曲线的曲线下面积；而术语“AUC0-t”指施用药物后时间由0至t的血浆药物浓度对时间曲线的曲线下面积。
除非另有说明，本文中所有的百分比、份数、比值等均是按重量计。
本发明提供了一种泊沙康唑药物组合物，与现有技术相比，本发明的药物组合物改善了泊沙康唑在人体内的吸收行为，增加了该药物的吸收和生物利用度。此外，本发明的药物组合物通过简单且易操作的热熔挤出法制备，与现有技术相比，改善了工艺，降低了能耗，提高了生产能力。
具体地，本发明的发明人发现，一定比例的乙烯基吡咯烷酮-醋酸乙烯酯共聚物作为载体材料和泊沙康唑经过本发明的热熔挤出工艺的处理即可制备成泊沙康唑溶解在或以分子水平分散在所述载体材料中的药物组合物。本发明的发明人更出人意料地发现，泊沙康唑分散在乙烯基吡咯烷酮-醋酸乙烯酯共聚物中的药物组合物可提高泊沙康唑在胃肠道的溶解度；可改善溶解在胃环境中的泊沙康唑随胃排空进入肠道时由于pH变化而溶解度急剧下降导致的析出沉淀或结晶的问题，从而增加泊沙康唑在体内的吸收，提高生物利用度。另一方面，所述药物组合物还能改变泊沙康唑在体内的吸收表现，在不延迟其Tmax的情况下，增加Cmax和AUC。同时，所述药物组合物还具有更好的生产工艺特性，比如容易研磨、较好的可压性等。
另外，本发明的发明人还进一步出人意料地发现，在所述药物组合物中使用一定比例的乙烯基吡咯烷酮-醋酸乙烯酯共聚物和肠溶聚合物例如HPMCAS的组合作为混合载体材料，不仅能进一步提高泊沙康唑在胃肠道的溶解度，而且还能进一步改善溶解在胃环境中的泊沙康唑随胃排空进入 肠道时由于pH变化而溶解度急剧下降导致的析出沉淀或结晶的问题，从而进一步增加泊沙康唑的吸收和生物利用度。
再者，本发明的发明人又出人意料地发现，向所述药物组合物中加入聚乙二醇1000维生素E琥珀酸酯(TPGS)后，可进一步提高泊沙康唑在胃肠道的溶解度，而且还能进一步改善溶解在胃环境中的泊沙康唑随胃排空进入肠道时由于pH变化而溶解度急剧下降导致的析出沉淀或结晶的问题，从而进一步增加泊沙康唑的吸收和生物利用度。此外，采用本发明的热熔挤出工艺制备所述药物组合物时，加入TPGS使药物组合物的玻璃化转换温度(Tg)降低，挤出机扭矩显著降低，能耗减少，生产能力提高。
具体地，本发明提供药物组合物，其包含泊沙康唑和载体材料，其中所述载体材料包含：乙烯基吡咯烷酮-醋酸乙烯酯共聚物或含乙二醇单元的聚合物。
在本发明的一个实施方案中，泊沙康唑溶解在或以分子水平分散在所述载体材料中。
所述乙烯基吡咯烷酮-醋酸乙烯酯共聚物可例如通过在2-丙醇中使N-乙烯基吡咯烷酮与乙酸乙烯酯进行自由基聚合而得到。所述乙烯基吡咯烷酮-醋酸乙烯酯共聚物也可以是例如US5426163A中公开的乙烯基吡咯烷酮与醋酸乙烯酯的重量比为15:85-40:60的共聚物。本发明中适用作载体材料的乙烯基吡咯烷酮-醋酸乙烯酯共聚物中的乙烯基吡咯烷酮单元与醋酸乙烯酯单元的重量比为约1:9-约9:1，优选为约4:6-约6:4。所述共聚物的K值为约25-约70。K值又称为Fikentscher K值，是本领域中常用的对包含乙烯基吡咯烷酮单元的聚合物或其混合物分子量的度量，并且可以如H.Fikentscher在Cellulose-Chemie,1932,13:58-64/71-74中所述的方法以1重量％水溶液进行测定。在一个实施方案中，本发明中使用的乙烯基吡咯烷酮-醋酸乙烯酯共聚物也可为例如BASF公司的市售产品
Figure PCTCN2015076299-appb-000008
VA64和/或International Specialty Products公司的市售产品
Figure PCTCN2015076299-appb-000009
S630(两者都是乙烯基吡咯烷酮与醋酸乙烯酯的重量比为6:4的共聚物)，但不限于此。在本发明的一个优选实施方案中，所述载体材料是
Figure PCTCN2015076299-appb-000010
VA64(以下简称VA64)。
本发明中适用作载体材料的含乙二醇单元的聚合物可以例如是聚乙二醇/乙烯基己内酰胺/醋酸乙烯酯共聚物，其可为例如BASF公司的市售产品
Figure PCTCN2015076299-appb-000011
在本发明的一个优选实施方案中，所述载体材料是
Figure PCTCN2015076299-appb-000012
在本发明的另一个实施方案中，所述载体材料还包含肠溶聚合物，所述肠溶聚合物为乙酸邻苯二甲酸纤维素、乙酸偏苯三酸纤维素、乙酸琥珀酸纤维素、邻苯二甲酸甲基纤维素、邻苯二甲酸乙基羟甲基纤维素、邻苯二甲酸羟丙基甲基纤维素、羟丙基甲基纤维素醋酸琥珀酸酯(HPMCAS)、乙酸马来酸羟丙基甲基纤维素、偏苯三酸羟丙基甲基纤维素、羧甲基乙基纤维素、聚丁酸乙烯邻苯二甲酸酯、聚乙酸乙烯醇邻苯二甲酸酯、甲基丙烯酸/丙烯酸乙酯共聚物(其中甲基丙烯酸与丙烯酸乙酯的优选重量比为1:99-99:1)及甲基丙烯酸/甲基丙烯酸甲酯共聚物(其中甲基丙烯酸与甲基丙烯酸甲酯的优选重量比为1:99-99:1)中的一种或多种，优选选自邻苯二甲酸羟丙基甲基纤维素、HPMCAS、乙酸马来酸羟丙基甲基纤维素以及偏苯三酸羟丙基甲基纤维素，更优选为HPMCAS。
HPMCAS是一种纤维素衍生物，具有(1)两种类型的醚取代基：甲基和2-羟丙基和(2)两种类型的酯取代基：乙酰基和琥珀酰基。在科学文献中称为O-(2-羟丙基)-O-甲基-纤维素醋酸琥珀酸酯。在一些实施方案中，所述HPMCAS优选为下列中的至少一种或多种：基于HPMCAS的重量，(i)具有平均5-9重量％乙酰基含量和平均14-18重量％琥珀酰基含量的HPMCAS，(ii)具有平均7-11重量％乙酰基含量和平均10-14重量％琥珀酰基含量的HPMCAS，(iii)具有平均10-14重量％乙酰基含量和平均4-8重量％琥珀酰基含量的HPMCAS，其中(ii)是更优选的。所述HPMCAS可为例如Shin-Etsu公司的市售产品
Figure PCTCN2015076299-appb-000013
AS-L、
Figure PCTCN2015076299-appb-000014
AS-M和
Figure PCTCN2015076299-appb-000015
AS-H，以及Ashland公司的市售产品AquaSolveTM L、AquaSolveTM LM、AquaSolveTM LH和AquaSolve ASTM L、AquaSolve ASTM M、AquaSolve ASTMH，但不限于此。在本发明的一个优选实施方案中，所述HPMCAS优选
Figure PCTCN2015076299-appb-000016
AS-M。
在本发明的又一个实施方案中，泊沙康唑与载体材料的重量比可以为约1:1-约1:10，优选约1:1-约1:5，更优选约1:3。
在本发明的又一个实施方案中，乙烯基吡咯烷酮-醋酸乙烯酯共聚物或含乙二醇单元的聚合物以相对于所述乙烯基吡咯烷酮-醋酸乙烯酯共聚物或含乙二醇单元的聚合物和肠溶聚合物例如HPMCAS的总重量的10重量％-100重量％的量存在，优选25重量％-100重量％，更优选25重量％-50 重量％，甚至更优选20重量％-40重量％，最优选25重量％-37.5重量％，并且所述范围中各子范围也包括在内，例如由以下数值中的任意两个所组成的范围：25、25.5、26、26.5、27、27.5、28、28.5、29、29.5、30、30.5、31、31.5、32、32.5、33、33.5、34、34.5、35、35.5、36、36.5、37、37.5、38、38.5、39、39.5、40、40.5、41、41.5、42、42.5、43、43.5、44、44.5、45、45.5、46、46.5、47、47.5、48、48.5、49、49.5和50。
在本发明的又一个实施方案中，所述药物组合物还包含聚乙二醇1000维生素E琥珀酸酯(D-α-tocopherol polyethylene glycol 1000succinate,TPGS,Vitamin E TPGS,Tocophersolan)。
本发明中适用的TPGS是维生素E的水溶性衍生物，由维生素E琥珀酸酯(VES)的羧基与聚乙二醇1000(PEG 1000)酯化而成，相对分子量约为1513，已载入美国药典。TPGS在本发明的药物组合物和药物制剂中作为增溶剂起作用，并且还可以通过影响肠道粘膜细胞里的药物转运糖蛋白而减少药物的外排，从而有助于口服生物利用度的提高。本发明中可使用的TPGS的实例为BASF公司的市售产品KolliphorTM TPGS，但不限于此。在本发明的一个优选实施方案中，所述TPGS是KolliphorTM TPGS。
本发明中采用的TPGS的量没有特殊限制，可以根据实际情况进行调整。通常，TPGS以相对于泊沙康唑、所述载体材料和TPGS的总重量的约1-12重量％的量存在。
本发明的药物组合物还可包含药学上可接受的药用辅料，所述药用辅料包括但不限于表面活性剂、pH调节剂、稀释剂、崩解剂、粘合剂和润滑剂中的一种或多种。
另一方面，本发明还提供制备本发明的药物组合物的方法，其包括但不限于热熔挤出法和喷雾干燥法。例如，热熔挤出法的具体步骤如下：
将热熔挤出机预热至约120℃-约180℃；
向所述热熔挤出机中进料已混匀的计量比的泊沙康唑、载体材料及任选存在的药学上可接受的药用辅料的混合物(或进料已混匀的计量比的泊沙康唑、载体材料、TPGS及任选存在的药学上可接受的药用辅料的混合物)，或者向所述热熔挤出机中直接进料计量比的泊沙康唑、载体材料及任选存在的药学上可接受的药用辅料(或直接进料计量比的泊沙康唑、载体材料、TPGS及任选存在的药学上可接受的药用辅料)；
挤出；和
将所得挤出物冷却、粉碎并过筛，任选地与药学上可接受的药用辅料混合，由此得到所述药物组合物。
对于本发明的制备方法中所述的冷却方式没有特别限制，其可包括风冷、水冷、机械冷却等。
对于适用于本发明的挤出机的类型没有特别限制，其包括但不限于单螺杆或双螺杆型热熔挤出机。在本发明的一个实施方案中，用于制备本发明的药物组合物的挤出机是双螺杆型挤出机。在该情况下，对于螺杆转动的类型没有特别限制，其包括但不限于同向双螺杆、异向双螺杆和双锥型螺杆转动模式。在本发明的一个优选实施方案中，用于制备本发明的药物组合物的挤出机优选是同向双螺杆型挤出机。
热熔挤出机设定的温度为约120℃-约180℃，螺杆转速为约50-约500rpm。螺杆长度和直径的比例(L/D)可选取约15-约40。如果热熔挤出机温度过低，L/D过短，螺杆转速过慢，则热熔过程中热能和机械能提供不足，进而泊沙康唑、载体材料或聚乙二醇1000维生素E琥珀酸酯达不到熔融状态，或者泊沙康唑不能溶解在熔融的载体材料中。因此泊沙康唑与载体材料虽然充分混合，但不能得到泊沙康唑溶解在或以分子水平分散在所述载体材料中的单相固体分散体(固体溶液)。如果热熔挤出机温度过高，L/D过长，螺杆转速过快，则热熔过程中热能和机械能提供过量，即使得到的是泊沙康唑溶解在或以分子水平分散在所述载体材料中的单相固体分散体(固体溶液)，也会造成泊沙康唑和/或载体材料和/或TPGS不必要的降解。
另外，本发明还提供包含本发明的药物组合物的药物制剂。即本发明的药物组合物可根据需要进一步与药学上可接受的药用辅料组合以制成各种剂型。在本发明的一个实施方案中，所述药物制剂可以是散剂、颗粒剂、丸剂、胶囊剂或片剂的形式。
所述药学上可接受的药用辅料包括但不限于表面活性剂、pH调节剂、稀释剂、崩解剂、粘合剂和润滑剂中的一种或多种。
应强调的是，该列举的药学上可接受的药用辅料只是阐述性的、代表性的而不是绝无遗漏的。因此，本发明并不限于下文所列举的药学上可接受的辅料。
本发明中采用的表面活性剂可以是阴离子型、阳离子型、两性离子型 或非离子型的表面活性剂，优选为两性离子型或非离子型的表面活性剂。本发明中采用的表面活性剂也可以是两种或更多种表面活性剂的混合物。表面活性剂的选择可以是由本发明的药物组合物中所使用的特定化合物而定。适用于本发明的药物组合物的表面活性剂如下文所列。
可以适用于本发明的合适的表面活性剂为以下中的一种或多种：聚氧乙烯蓖麻油衍生物，例如聚氧乙烯甘油三蓖麻醇酸酯或聚氧乙烯醚35蓖麻油(Cremophor EL，BASF)或聚氧乙烯甘油羟基硬脂酸酯如聚乙二醇40氢化蓖麻油(Cremophor RH40)或聚乙二醇60氢化蓖麻油(Cremophor RH 60)；环氧乙烷和环氧丙烷的嵌段共聚物，又名聚氧乙烯聚氧丙烯嵌段共聚物或聚氧乙烯聚丙二醇，比如Poloxamer 124、Poloxamer 188、Poloxamer 237、Poloxamer 388、Poloxamer 407(BASF)；聚氧乙烯(20)失水山梨醇的单脂肪酸酯，如聚氧乙烯(20)失水山梨醇单油酸酯(Tween 80)、聚氧乙烯(20)失水山梨醇单硬脂酸酯(Tween 60)、聚氧乙烯(20)失水山梨醇单棕榈酸酯(Tween40)、聚氧乙烯(20)失水山梨醇单月桂酸酯(Tween 20)；聚乙二醇脂肪酸酯，例如PEG-200单月桂酸酯、PEG-200双月桂酸酯、PEG-300双月桂酸酯、PEG-400双月桂酸酯、PEG-300双硬脂酸酯、PET-300二油酸酯；亚烷基二醇脂肪酸单酯，例如丙二醇单月桂酸酯(Lauroglycol)；失水山梨醇脂肪酸单酯，例如失水山梨醇单月桂酸酯(Span 20)、失水山梨醇单油酸酯、失水山梨醇单棕榈酸酯(Span 40)或失水山梨醇硬脂酸酯。
本发明适用的表面活性剂优选是聚氧乙烯蓖麻油衍生物、环氧乙烷和环氧丙烷的嵌段共聚物，尤其优选Cremophor RH40和/或Poloxamer 188。
可以适用于本发明的合适的pH调节剂为柠檬酸、乙酸、反丁烯二酸、顺丁烯二酸、酒石酸、苹果酸、琥珀酸、富马酸、草酸、丙二酸、苯甲酸和苦杏仁酸和抗坏血酸中的一种或多种，优选柠檬酸。
可以适用于本发明的合适的稀释剂可以是微晶纤维素、淀粉、预胶化淀粉、乳糖、甘露醇和磷酸氢钙中的一种或多种。
可以适用于本发明的合适的崩解剂可以是低取代纤维素、羧甲基纤维素、羧甲基纤维素钠、交联羧甲基纤维素钠、羧甲基纤维素钙、羧甲基淀粉钠、交联聚乙烯基吡咯烷酮(即交联聚维酮)、具有5-16重量％的羟丙氧基的低取代的羟丙基纤维素(L-HPC)和羟甲基淀粉中的一种或多种。
可以适用于本发明的合适的粘合剂可以是羧甲基纤维素钠、羟丙基纤 维素、甲基纤维素、乙基纤维素和羟丙甲纤维素的一种或多种。
可以适用于本发明的合适的润滑剂可以是硬脂酸镁、二氧化硅、滑石粉、硬脂酸和氢化植物油中的一种或多种。
实施例
各实施例中进行物理化学性质评价所用的测定方法如下：
1.玻璃化转换温度(Tg)：精密称取大约3mg的待测物(泊沙康唑原料药(以下简称原料药)、载药组合物(即本发明的药物组合物)或空白组合物)进行差示扫描量热分析(mDSC，TA Q2000差示扫描量热仪)，扫描温度范围为40-180℃。
2.粉末X-衍射(X-RD)：取待测物(原料药、载药组合物或空白组合物)适量，在Cu靶、电压45kv、电流45mA的条件下记录粉末X-衍射图谱(BRUKER制造的D8ADVANCE型X射线衍射仪)。
3.表观溶解度：称取过量的泊沙康唑药物组合物放入容器中，加入约相当于容器体积2/3的pH 6.8磷酸盐缓冲液后，将容器置于37℃的摇床中震荡3h。将容器内容物用0.45μm滤膜过滤后，收集滤液，用适量的甲醇稀释，经涡旋混合后以HPLC分析方法测定泊沙康唑浓度，HPLC分析方法如下。
Figure PCTCN2015076299-appb-000017
4.溶出度：
Figure PCTCN2015076299-appb-000018
溶出样品分析方法：与上述表观溶解度测定中所述HPLC分析方法相 同。
实施例1泊沙康唑-
Figure PCTCN2015076299-appb-000019
VA64药物组合物
1.制备：泊沙康唑-
Figure PCTCN2015076299-appb-000020
VA64药物组合物的组成及各组分用量如表1-1所示。
制备方法：按表1-1中所示的用量将泊沙康唑和载体材料和/或TPGS直接或者在混合机中混合均匀后进料至同向双螺杆挤出机(印度Steer公司Omicron 12)的加料斗内，将同向双螺杆挤出机的温度控制在约120℃-约180℃之间，进行挤出，螺杆转速为约50-约500rpm。将所得挤出物冷却、粉碎、过筛，得到固体粉末。然后按表1-1中所示的用量将其他药用辅料与该固体粉末混合均匀，即得到泊沙康唑-
Figure PCTCN2015076299-appb-000021
VA64药物组合物。
表1-1泊沙康唑-
Figure PCTCN2015076299-appb-000022
VA64药物组合物的组成及各组分用量(重量％)
Figure PCTCN2015076299-appb-000023
2.物理化学性质评价
2.1.玻璃化转换温度(Tg)测定
经测定，泊沙康唑原料药(晶体型)的熔融温度为约170℃，组合物1-2的Tg值为97.6℃，组合物1-3的Tg值为71.8℃；与组合物1-2对应的空白组合物的Tg值为106.3℃，与组合物1-3对应的空白组合物的Tg值为81.4℃。与这两个空白组合物的Tg值相比，组合物1-2和1-3的Tg值发生明显的偏移，但与泊沙康唑的Tg值(68℃)明显不同，且泊沙康唑的熔融峰消失。上述结果清楚地表明，在本发明的各药物组合物中，泊沙康唑是溶解在或以分子水平分散在载体材料中的。
2.2.表观溶解度测定
表1-2泊沙康唑-
Figure PCTCN2015076299-appb-000024
VA64药物组合物在pH 6.8磷酸盐缓冲液中的表
观溶解度
Figure PCTCN2015076299-appb-000025
由表1-2可知，使用热熔挤出法制备的本发明的各药物组合物对泊沙康唑都具有明显的增溶作用，说明
Figure PCTCN2015076299-appb-000026
VA64对泊沙康唑的增溶效果较好。将药物组合物内的载体材料(
Figure PCTCN2015076299-appb-000027
VA64)和原料药的重量比从1:1调整到5:1时，表观溶解度从10.6μg/ml增加到15.9μg/ml，表明载体材料与原料药的重量比对泊沙康唑溶解度的影响不大。但是，在组合物1-2的基础上少量加入
Figure PCTCN2015076299-appb-000028
TPGS(组合物1-3)就使表观溶解度从14.3μg/ml增加到44.3μg/ml，表明包含TPGS的药物组合物能大幅度提高泊沙康唑的溶解度。
2.3.模拟体内条件的溶出度测定
据报道，人体胃环境的pH值约为1.2，肠环境的pH值约为6.8。对本发明的各药物组合物进行模拟体内条件的溶出度测定，结果如表1-3所示。
表1-3泊沙康唑-
Figure PCTCN2015076299-appb-000029
VA64药物组合物在pH 1.2→6.8的介质转换中的溶出度
Figure PCTCN2015076299-appb-000030
由表1-3可知，原料药在经过pH 1.2到6.8转换后溶出度大幅度降低，从98.7％减小到5.6％，表明泊沙康唑在体内经胃排空到达肠道时会从生理液中沉淀或结晶出来，从而降低其体内生物利用度。和原料药相比，本发明的药物组合物(特别是组合物1-2和组合物1-3)在pH 1.2到6.8转换后3h内的溶出度下降不明显，并且所有本发明的药物组合物在30min之后各个时间点的溶出度均在50％以上，最高达到97.9％，显著高于原料药的溶出度，表明 它们均能够显著提高泊沙康唑在体内的吸收。特别地，组合物1-2和组合物1-3在30min之后各个时间点的溶出度均在93％以上，表明它们可更好地提高泊沙康唑在体内的吸收。
实施例2泊沙康唑-
Figure PCTCN2015076299-appb-000031
VA64/HPMCAS药物组合物(混合载体药物组合物)
1.制备：泊沙康唑-
Figure PCTCN2015076299-appb-000032
VA64/HPMCAS药物组合物的组成及各组分用量如表2-1所示。
制备方法：按表2-1中所示的用量将泊沙康唑和载体材料(VA64和/或HPMCAS(具体为
Figure PCTCN2015076299-appb-000033
AS-M))和/或TPGS直接或者在混合机中混合均匀后进料至同向双螺杆挤出机(印度Steer公司Omicron 12)的加料斗内，将同向双螺杆挤出机的温度控制在约120℃-约180℃之间，进行挤出，螺杆转速为约50-约500rpm。将所得挤出物冷却、粉碎、过筛，得到固体粉末。然后按表2-1中所示的用量将其他药用辅料与该固体粉末混合均匀，即得到泊沙康唑-
Figure PCTCN2015076299-appb-000034
VA64/HPMCAS药物组合物。
组合物2-1为根据US2011123627A制备的对比组合物，其载体材料仅含
Figure PCTCN2015076299-appb-000035
AS-M一种物质。
表2-1泊沙康唑-
Figure PCTCN2015076299-appb-000036
VA64/HPMCAS药物组合物的组成及各组分用量(重量％)
Figure PCTCN2015076299-appb-000037
Figure PCTCN2015076299-appb-000038
2.物理化学性质评价
2.1.玻璃化转换温度(Tg)测定
测定结果如图1所示。图1显示泊沙康唑-
Figure PCTCN2015076299-appb-000039
VA64和/或HPMCAS载体制成的药物组合物中VA64含量对Tg值的影响，其中VA64/(VA64+HPMCAS)％为0％、25％、37.5％、50％和100％时所对应的Tg值分别为组合物2-1、组合物2-2、组合物2-3、组合物2-4和组合物1-3或相应的空白组合物的Tg值。从图1可以看出，随组合物中VA64含量的增加，Tg值呈下降趋势；含药组合物的Tg值比与它们各自对应的空白组合物的Tg值降低约10-20℃，发生明显的偏移，但与泊沙康唑的Tg值(68℃)明显不同。
图2显示泊沙康唑-
Figure PCTCN2015076299-appb-000040
VA64和/或HPMCAS载体制成的药物组合物的X-RD图谱，自下至上依次为原料药、组合物1-3、组合物2-3和组合物2-4的X-RD图谱。从图2可以看出，单一载体材料制成的组合物1-3和混合载体材料制成的组合物2-3和组合物2-4的X-RD图谱中未见泊沙康唑的衍射峰，表明在本发明的药物组合物中，泊沙康唑是溶解在或以分子水平分散在载体材料中的。
2.2.表观溶解度测定
表2-2泊沙康唑-
Figure PCTCN2015076299-appb-000041
VA64/HPMCAS药物组合物在pH 6.8磷酸盐缓冲液中的表观溶解度
Figure PCTCN2015076299-appb-000042
由表2-2可知，使用热熔挤出法制备的本发明的各混合载体药物组合物对泊沙康唑都具有明显的增溶作用。当保持原料药和载体材料的重量比不变(例如1:3)时，将VA64/(VA64+HPMCAS)％从100％(组合物1-3)调整到50％(组合物2-4)使表观溶解度从44.3μg/ml增加到68.3μg/ml，将VA64/(VA64+HPMCAS)％从50％继续调整到37.5％(组合物2-3)使表观溶解度从68.3μg/ml继续增加到93.7μg/ml，但是进一步将 VA64/(VA64+HPMCAS)％降低至0％(组合物2-1)则使表观溶解度稍微降低至90.1μg/ml，表明混合载体材料制成的药物组合物在一定范围内对泊沙康唑的溶解度有有利影响。由表2-2可知，组合物2-5对泊沙康唑的溶解度提高最明显。
另一方面，当保持载体材料中VA64/(VA64+HPMCAS)％不变(例如37.5％)时，将原料药和载体材料的重量比从1:2(组合物2-5)调整到1:3(组合物2-3)和1:4(组合物2-6)使药物组合物的表观溶解度分别比原料药提高至少119、93和116倍，且均高于对比组合物(组合物2-1)的表观溶解度，表明混合载体材料中VA64/(VA64+HPMCAS)％为37.5％的几个组合物对泊沙康唑的增溶效果最为显著。
2.3.模拟体内条件的溶出度测定
表2-3泊沙康唑-
Figure PCTCN2015076299-appb-000043
VA64/HPMCAS药物组合物在pH 1.2→6.8的介质转换中的溶出度
Figure PCTCN2015076299-appb-000044
组合物2-3及原料药的溶出曲线如图3所示。由表2-3和图3可知，原料药在经过pH 1.2到6.8转换后溶出度大幅度降低，从98.7％减小到5.6％，表明泊沙康唑在体内经胃排空到达肠道时会从生理液中沉淀或结晶出来，从而降低其体内生物利用度。和原料药相比，本发明的药物组合物在pH 1.2到6.8转换后的3h内的溶出度下降不明显，其中组合物2-2到组合物2-6在30min之后各个时间点的溶出度均在83％以上，表明它们能够显著提高泊沙康唑在体内的吸收。在pH 1.2的条件下，混合载体材料制成的组合物2-2到组合物2-6的溶出度比单一载体材料制成的组合物2-1均有显著提高，表明组合物2-2到组合物2-6在胃中的吸收会好于组合物2-1；在pH 6.8的条件下，混合载 体材料制成的组合物2-2到组合物2-6的溶出度与单一载体材料制成的组合物2-1接近，表明组合物2-2到组合物2-6在肠道的吸收会与组合物2-1相当；因而混合载体材料制成的组合物2-2到组合物2-6在体内总的吸收要好于组合物2-1。
图4显示泊沙康唑-
Figure PCTCN2015076299-appb-000045
VA64和/或HPMCAS载体制成的药物组合物(泊沙康唑和载体材料重量比为1:3)中的VA64含量对泊沙康唑在pH 1.2和pH 6.8的溶出介质中的溶出度的影响，其中VA64/(VA64+HPMCAS)％为0％、25％、37.5％、50％和100％时所对应的溶出度分别为组合物2-1、组合物2-2、组合物2-3、组合物2-4和组合物1-3的溶出度。从图4可以看出，在pH 1.2的溶出条件下，当VA64/(VA64+HPMCAS)％在25.0％以上时，各药物组合物的溶出度均在75％以上，与VA64/(VA64+HPMCAS)％为0％的组合物2-1相比有着极为显著的提高；在pH 6.8的溶出条件下，当VA64/(VA64+HPMCAS)％提高到50.0％以上时，各药物组合物的溶出度均下降到50％以下。
以上结果表明，VA64/(VA64+HPMCAS)％分别为25.0％和37.5％的混合载体材料制成的组合物2-2和组合物2-3在两种pH溶出介质中的溶出度的综合表现明显优于不含VA64的组合物2-1和仅含VA64的组合物1-3。
实施例3泊沙康唑-
Figure PCTCN2015076299-appb-000046
药物组合物
1.制备：泊沙康唑-
Figure PCTCN2015076299-appb-000047
药物组合物的组成及各组分用量如表3-1所示。
表3-1泊沙康唑-
Figure PCTCN2015076299-appb-000048
药物组合物的组成及各组分用量(重量％)
Figure PCTCN2015076299-appb-000049
制备方法：按表3-1中所示的用量将泊沙康唑和载体材料直接或者在混合机中混合均匀后进料至同向双螺杆挤出机(印度Steer公司Omicron 12)的 加料斗内，将同向螺杆挤出机的温度控制在120℃-约180℃之间，进行挤出，螺杆转速为约50-约500rpm。将所得挤出物冷却、粉碎、过筛，得到固体粉末。然后按表3-1中所示的用量将其他药用辅料与该固体粉末混合均匀，即得到泊沙康唑-
Figure PCTCN2015076299-appb-000050
药物组合物。
2.物理化学性质评价
2.1.表观溶解度测定
表3-2泊沙康唑-
Figure PCTCN2015076299-appb-000051
药物组合物在pH 6.8磷酸盐缓冲液中的表观溶解度
Figure PCTCN2015076299-appb-000052
由表3-2可知，各泊沙康唑-
Figure PCTCN2015076299-appb-000053
药物组合物均能显著提高泊沙康唑的溶解度，而且随着载体材料的重量比增加，增溶效果越来越明显。当载体材料和原料药的重量比为5:1时(组合物3-3)，泊沙康唑的溶解度能提高至少159倍。
2.2.模拟体内条件的溶出度测定
表3-3泊沙康唑-
Figure PCTCN2015076299-appb-000054
药物组合物在pH 1.2→6.8的介质转换中的溶出度
Figure PCTCN2015076299-appb-000055
由表3-3可知，与原料药相比，各泊沙康唑-
Figure PCTCN2015076299-appb-000056
药物组合物均能明显提高泊沙康唑的模拟体内条件的溶出度。
实施例4泊沙康唑-
Figure PCTCN2015076299-appb-000057
/HPMCAS药物组合物(混合载体药物组合物)
1.制备：泊沙康唑-
Figure PCTCN2015076299-appb-000058
/HPMCAS药物组合物的组合及个组分用 量如表4-1所示。
表4-1泊沙康唑-
Figure PCTCN2015076299-appb-000059
/HPMCAS药物组合物的组成及各组分用量(重量％)
Figure PCTCN2015076299-appb-000060
制备方法：按表4-1中所示的用量将泊沙康唑和混合载体材料(
Figure PCTCN2015076299-appb-000061
和HPMCAS(具体为
Figure PCTCN2015076299-appb-000062
AS-M))直接或者在混合机中混合均匀后进料至同向双螺杆挤出机(印度Steer公司Omicron 12)的加料斗内，将同向双螺杆挤出机的温度控制在120℃-约120℃-约180℃之间，进行挤出，螺杆转速为约50-约500rpm。将所得挤出物冷却、粉碎、过筛，得到固体粉末。然后按表4-1中所示的用量将其他药用辅料和该固体粉末混合均匀，即得到泊沙康唑-
Figure PCTCN2015076299-appb-000063
/HPMCAS药物组合物。
2.物理化学性质评价
2.1.表观溶解度测定
表4-2泊沙康唑-
Figure PCTCN2015076299-appb-000064
/HPMCAS药物组合物在pH 6.8磷酸盐缓冲液中的表观溶解度
Figure PCTCN2015076299-appb-000065
由表4-2可知，各泊沙康唑-
Figure PCTCN2015076299-appb-000066
/HPMCAS药物组合物均能显著提高泊沙康唑的溶解度，其中组合物4-1所致的提高最为明显。
2.2.模拟体内条件的溶出度测定
表4-3泊沙康唑-
Figure PCTCN2015076299-appb-000067
/HPMCAS药物组合物在pH 1.2→6.8的介质转换中的溶出度
Figure PCTCN2015076299-appb-000068
Figure PCTCN2015076299-appb-000069
由表4-3可知，与原料药相比，各泊沙康唑-
Figure PCTCN2015076299-appb-000070
/HPMCAS药物组合物均能明显提高泊沙康唑的模拟体内条件的溶出度。
实施例5泊沙康唑-
Figure PCTCN2015076299-appb-000071
VA64/HPMCAS药物组合物(混合载体药物组合物)的制备方法评价
1.热熔挤出工艺
表5-1热熔挤出工艺参数
Figure PCTCN2015076299-appb-000072
具体的工艺见实施例1-4中各药物组合物的制备。如表5-1所示，与单一载体材料制成的组合物1-3和2-1相比，混合载体材料制成的组合物的每千克能耗更低，所产生的扭矩百分比也更低，表明使用混合载体材料制备药物组合物能显著降低热熔挤出工艺的能耗和仪器扭矩，大幅度提升其可操作性。
2.粉碎工艺
表5-2挤出物粉碎工艺参数
Figure PCTCN2015076299-appb-000073
Figure PCTCN2015076299-appb-000074
注：*指过筛后颗粒占过筛前总颗粒的重量百分比。
将各药物组合物的制备中所得的挤出物用剪刀切割成约2cm的条状物，用小型咖啡研磨机(意大利德龙KG40型)粉碎30s。将粉碎后的颗粒过60目筛，称量过晒后所得粉末重量，计算过筛效率。如表5-2所示，与单一载体材料HPMCAS制成的组合物2-1的过筛效率(7.9％)相比，包含VA64的混合载体材料或VA64单一载体材料制成的药物组合物的过筛效率更高，表明其粉碎工艺的可操作性更强。
3.压片工艺
表5-3片剂处方组成(重量％)及压片工艺参数
  组合物1-3 组合物2-1 组合物2-2 组合物2-3 组合物2-4
固体粉末* 55.0 55.0 55.0 55.0 55.0
微晶纤维素 29.6 29.6 29.6 29.6 29.6
交联羧甲基纤维素钠 13.8 13.8 13.8 13.8 13.8
二氧化硅 1.0 1.0 1.0 1.0 1.0
硬脂酸镁 0.6 0.6 0.6 0.6 0.6
压片压力(cm) 13.8 13.8 13.8 13.8 13.8
物料填充量(mg) 800 800 800 800 800
片剂硬度(kg) 38.5 1.9 8.7 15.5 21.0
崩解时间(min) 21.9 0.3 0.6 2.0 3.3
注：*指实施例1-4中在组合物的制备中与药物辅料混合前的固体粉末。
按表5-3中所示的用量将过60目筛的固体粉末和其他辅料混合均匀，用单冲压片机(上海天凡药机制造厂DP-5型)在相同的压力和物料填充量下压片以考察不同处方的可压性(硬度测定仪：天大天发科技有限公司YD-35型)和崩解性能(崩解仪：天大天发科技有限公司ZB-1型)，结果如表5-3所示。由表5-3可见，随着载体材料中VA64含量的降低，片剂硬度降低，崩解时间缩短。
实施例6泊沙康唑-
Figure PCTCN2015076299-appb-000075
VA64/HPMCAS药物组合物(混合载体药物组合物)的体内药代动力学研究
研究采用空腹条件下的开放、随机、二周期、双交叉自身对照的药代动力学对比试验在人体中进行。
1.方法
受试者为9名年龄20-45周岁的健康男性，体重指数(BMI)为19-25。全部受试者均充分理解试验内容并已自愿签署知情同意书。
受试者在第一天18:00入住临床试验病房并在20:00开始禁食。第二天07:00采集血样(给药前的空白血样)，08:00在医生指导下空腹下用240mL水送服含100mg泊沙康唑的组合物2-1或组合物2-2(具体组成见实施例2)。在给药后1、2、3、4、5、6、8、12、24、48、72小时采集血样(共12次，每次3mL)。采集的血样立即移至肝素抗凝管中，摇匀，4000rpm离心5min取血浆，一式两份，-20℃保存供血药浓度测定用。在第九天，采用与第二天相同的方法进行交叉给药，并随后进行相同的血样采集过程。在整个试验期间观察受试者生命体征及不良事件以保证其安全。
采用LC-MS/MS方法测定各血浆样品中的泊沙康唑浓度(血药浓度)，经药代动力学统计软件DAS 3.2.5计算，完成生物统计分析，得到组合物2-1和组合物2-2的药代动力学参数，计算各参数的算数平均值比(组合物2-2/组合物2-1)并考察组合物2-2的AUC和Cmax的90％置信区间分布。将组合物2-2和组合物2-1的Cmax、AUC0-72h、AUC0-∞经对数转换后进行方差分析，并进行双向单侧t检验。
2.结果
试验结果如表6-1和图5所示。结果表明：泊沙康唑的Cmax、AUC0-72h、AUC0-∞在组合物2-1和组合物2-2之间均有显著性差异，以样本量(n＝9)计算得出组合物2-2的Cmax的90％置信区间为(106％～147％)，AUC0-72h的90％置信区间为(115.8％～147.1％)，AUC0-∞的90％置信区间为(117.9％～146.7％)。
表6-1泊沙康唑药代动力学参数
药代动力学参数(算数平均值，n＝9) 组合物2-1 组合物2-2
Cmax(ng·ml-1) 432.8 533.2
AUC0-72h(ng·h·ml-1) 11793 15214
AUC0-∞(ng·h·ml-1) 13251 17276
从图5和表6-1可知，与使用单一载体材料HPMCAS的组合物(组合 物2-1)相比，使用
Figure PCTCN2015076299-appb-000076
VA64/HPMCAS混合载体材料的组合物(组合物2-2)中的泊沙康唑在体内的吸收速度更快，血药浓度更高，相应地生物利用度也更高。Cmax的算数平均值比(组合物2-2/组合物2-1)为1.23；AUC0-72h的算数平均值比(组合物2-2/组合物2-1)为1.29；AUC0-∞的算数平均值比(组合物2-2/组合物2-1)为1.30。这些数据表明：在保证pH 6.8溶出水平与对比组合物2-1一致的前提下，提高泊沙康唑在酸性条件下的溶出度或溶解度会增加药物在体内胃中的吸收，从而提高药物在体内的吸收速率和利用，使得组合物2-2的体内生物利用度整体上得到提高。

Claims (14)

  1. 药物组合物，其包含泊沙康唑和载体材料，其中所述载体材料包含：乙烯基吡咯烷酮-醋酸乙烯酯共聚物或含乙二醇单元的聚合物。
  2. 权利要求1的药物组合物，其中所述乙烯基吡咯烷酮-醋酸乙烯酯共聚物中的乙烯基吡咯烷酮单元与醋酸乙烯酯单元的重量比为1:9-9:1，优选为4:6-6:4。
  3. 权利要求1或2的药物组合物，其中所述含乙二醇单元的聚合物为聚乙二醇/乙烯基己内酰胺/醋酸乙烯酯共聚物。
  4. 权利要求1-3中任一项的药物组合物，其中所述载体材料还包含肠溶聚合物，所述肠溶聚合物为选自乙酸邻苯二甲酸纤维素、乙酸偏苯三酸纤维素、乙酸琥珀酸纤维素、邻苯二甲酸甲基纤维素、邻苯二甲酸乙基羟甲基纤维素、邻苯二甲酸羟丙基甲基纤维素、羟丙基甲基纤维素醋酸琥珀酸酯、乙酸马来酸羟丙基甲基纤维素、偏苯三酸羟丙基甲基纤维素、羧甲基乙基纤维素、聚丁酸乙烯邻苯二甲酸酯、聚乙酸乙烯醇邻苯二甲酸酯、甲基丙烯酸/丙烯酸乙酯共聚物及甲基丙烯酸/甲基丙烯酸甲酯共聚物中的一种或多种。
  5. 权利要求4的药物组合物，其中所述肠溶聚合物为羟丙基甲基纤维素醋酸琥珀酸酯。
  6. 权利要求1-5中任一项的药物组合物，其中泊沙康唑与所述载体材料的重量比为1:1-1:5，优选为1:3。
  7. 权利要求4或5的药物组合物，其中所述乙烯基吡咯烷酮-醋酸乙烯酯共聚物或含乙二醇单元的聚合物以相对于所述乙烯基吡咯烷酮-醋酸乙烯酯共聚物或含乙二醇单元的聚合物和所述肠溶聚合物的总重量的10重量％-100重量％的量存在，优选25重量％-100重量％，更优选25重量％-50重 量％，甚至更优选20重量％-40重量％，并且最优选25重量％-37.5重量％。
  8. 权利要求1-7中任一项的药物组合物，其还包含作为增溶剂的聚乙二醇1000维生素E琥珀酸酯。
  9. 权利要求8的药物组合物，其中所述聚乙二醇1000维生素E琥珀酸酯以相对于泊沙康唑、所述载体材料和聚乙二醇1000维生素E琥珀酸酯的总重量的1-12重量％的量存在。
  10. 权利要求8或9的药物组合物，其还包含药学上可接受的药用辅料，所述药用辅料为选自表面活性剂、pH调节剂、稀释剂、崩解剂、粘合剂、润滑剂中的一种或多种。
  11. 权利要求1-10中任一项的药物组合物，其中泊沙康唑溶解在或以分子水平分散在所述载体材料中。
  12. 预防和/或治疗哺乳动物真菌感染和相关疾病的方法，其包括给予所述哺乳动物有效量的权利要求1-11中任一项的药物组合物。
  13. 制备权利要求1-11中任一项的药物组合物的方法，其包括：
    将热熔挤出机预热至120℃-180℃；
    向所述热熔挤出机中进料已混匀的计量比的泊沙康唑、载体材料及任选存在的药学上可接受的药用辅料的混合物，或者向所述热熔挤出机中直接进料计量比的泊沙康唑、载体材料及任选存在的药学上可接受的药用辅料；
    挤出；和
    将所得挤出物冷却、粉碎并过筛，任选地与药学上可接受的药用辅料混合，由此得到所述药物组合物。
  14. 包含权利要求1-11中任一项的药物组合物的药物制剂，其是散剂、颗粒剂、丸剂、胶囊剂或片剂的形式。
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