WO2017041680A1 - 一种沃替西汀或其盐的药用组合物及其制备方法 - Google Patents

一种沃替西汀或其盐的药用组合物及其制备方法 Download PDF

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WO2017041680A1
WO2017041680A1 PCT/CN2016/098095 CN2016098095W WO2017041680A1 WO 2017041680 A1 WO2017041680 A1 WO 2017041680A1 CN 2016098095 W CN2016098095 W CN 2016098095W WO 2017041680 A1 WO2017041680 A1 WO 2017041680A1
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Prior art keywords
vortioxetine
pharmaceutically acceptable
salt
hydrobromide
composition
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PCT/CN2016/098095
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English (en)
French (fr)
Inventor
张席妮
熊志刚
王颖奇
资春鹏
熊理查
Original Assignee
常州方楠医药技术有限公司
常州爱诺新睿医药技术有限公司
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Priority claimed from CN201510562105.0A external-priority patent/CN106491604A/zh
Priority claimed from CN201610474113.4A external-priority patent/CN107536834A/zh
Priority claimed from CN201610581662.1A external-priority patent/CN107638425A/zh
Application filed by 常州方楠医药技术有限公司, 常州爱诺新睿医药技术有限公司 filed Critical 常州方楠医药技术有限公司
Publication of WO2017041680A1 publication Critical patent/WO2017041680A1/zh
Priority to US15/914,587 priority Critical patent/US20180193334A1/en

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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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

  • the invention belongs to the field of pharmaceutical preparations, and in particular relates to a composition of vortioxetine or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable adjuvant, a preparation method thereof, and a use of the above composition for preparing a medicament for treating affective disorders.
  • Vortioxetine chemical name 1-[2-(2,4-methylphenylthio)phenyl]piperazine hydrobromide, trade name Brintellix, is Lingbei, Denmark A serotonin reuptake inhibitor developed by the company (Lundbeck) and Takeda, Japan. Votilizine hydrobromide was approved by the US Food and Drug Administration on September 30, 2013 for the treatment of major depression. Decision Resources, the world's leading pharmaceutical and healthcare research and consulting firm, has released a report predicting that by 2022, vortixetine will be in the five major markets of the United States, Japan, and the European Union (France, Germany, Italy, Spain). , the United Kingdom)pion will become a heavy drug. Based on data obtained to date, vortixetine is expected to be the most successful new drug in the unipolar depression market, given its positive impact on cognition and its tolerable side effects.
  • Vortioxetine or a pharmaceutically acceptable salt thereof.
  • Chinese patent CN 101472906 discloses crystalline forms of vortioxetine free base and various pharmaceutically acceptable salts, including the alpha-crystalline, beta-crystalline and gamma-crystalline forms of vortioxetine hydrobromide.
  • the marketed crystalline form of this drug is the ⁇ -crystal form of vortioxetine hydrobromide, which is also the thermodynamically most stable crystalline form of hydrobromide.
  • the solid form of the drug directly affects the dissolution rate of the drug substance, the dissolution rate of the drug, and the bioavailability.
  • a new solid form of the drug is usually developed. Solid forms with better drug solubility and higher bioavailability are necessary.
  • the solid form of the drug has an amorphous state.
  • the amorphous state of the drug as a special form of solid matter, has an important use in drug preparation.
  • Amorphous drugs can be widely used not only in pharmaceutical preparations, but also in a variety of technical means and methods to improve the stability of amorphous drugs, making them a good quality drug.
  • Patent WO 2014/177491 reports a composition for adsorbing amorphous vortioxetine hydrobromide to an inorganic carrier.
  • the vortioxetine hydrobromide salt in the composition is in an amorphous form and has a certain increase in dissolution relative to the crystalline form of vortioxetine hydrobromide.
  • the adsorption capacity of the inorganic adsorbent for the active ingredient, vortioxetine hydrobromide is not very high, so it is necessary to add a large amount of inorganic adsorbent to make the vortioxetine hydrobromide into an amorphous form.
  • Patent WO 2016/062860 also provides a composition comprising an amorphous form of vortioxetine hydrobromide, which first adsorbs vortioxetine hydrobromide on the adsorbent and forms a new combination in the other component.
  • the vortioxetine hydrobromide salt is in an amorphous form.
  • a large amount of adsorbent is also added.
  • the adsorbent has strong adsorption capacity for the active ingredient, and has a great influence on the release of the drug, and the improvement of the dissolution rate is not obvious; at the same time, the inorganic adsorbent needs other organic auxiliary materials to be bonded together for granulation and tableting. A large amount of adsorbent will require a larger amount of organic excipients, which will cause certain difficulties in the formulation of tablets. In turn, it affects the bioavailability and efficacy of the drug.
  • An object of the present invention is to provide a composition of vortioxetine or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable adjuvant, and a process for the preparation thereof, which provide an amorphous form of vortioxetine with good stability and dispersibility.
  • the composition of the pharmaceutically acceptable salt thereof and the pharmaceutically acceptable adjuvant increases the dissolution rate of vortioxetine or a pharmaceutically acceptable salt thereof, and the preparation method is not limited by the drying process, and is not affected by the solvent type and solvent. The quantity is limited, the operation is simple, the cost is low, the implementation is easy, and the industrial production can be realized.
  • a pharmaceutical composition of vortioxetine or a salt thereof comprising vortioxetine or a pharmaceutically acceptable salt thereof and two or more pharmaceutically acceptable excipients
  • the weight ratio of the statin or a pharmaceutically acceptable salt thereof to all the pharmaceutically acceptable excipients is from 1:0.1 to 100, wherein the vortioxetine or a pharmaceutically acceptable salt thereof in the composition is an amorphous state.
  • the vortioxetine or a pharmaceutically acceptable salt thereof in the composition is an amorphous state.
  • the medicinal adjuvant is selected from the group consisting of an excipient, a propellant, a solubilizer, a cosolvent, an emulsifier, a colorant, a binder, a disintegrant, a filler, a lubricant, a wetting agent, an osmotic pressure regulator, Stabilizers, glidants, flavoring agents, preservatives, suspending agents, coating materials, fragrances, anti-adhesives, integrators, penetration enhancers, pH adjusters, buffers, plasticizers, surface active agents Agent, foaming agent, antifoaming agent, thickener, inclusion agent, moisturizer, absorbent, diluent, flocculant and deflocculant, antioxidant, adsorbent, filter aid, release retardant At least one.
  • At least one of the pharmaceutical excipients is selected from the group consisting of hydroxypropylmethylcellulose, hydroxypropylcellulose, povidone, polyethylene glycol, ethylcellulose, liposome, methacrylic acid copolymerization , polyvinyl acetate, carboxymethyl ethyl cellulose, carboxymethyl cellulose phthalate, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate , polyacrylic resin, carboxyvinyl, alginate, carrageenan, carboxyacetolactone, gum, polyvinyl alcohol, pregelatinized starch, crosslinked starch, sodium carboxymethyl starch, dextrin, polyethylene oxide Chitosan, Chitosan, collagen, cyclodextrin, lactose, galactose, D-mannitol, sorbitol, xylitol, urea, citric acid, tartaric acid, fumaric
  • the vortioxetine is in the form of its hydrobromide salt
  • the medicinal adjuvant contains an organic carrier and an adsorbent
  • the vortioxetine forms a solid dispersion with the organic carrier, the solid dispersion and the adsorbent Forming a composition, wherein the weight ratio of vortioxetine hydrobromide to the organic carrier is 1:0.1 to 10, and the weight ratio of vortioxetine hydrobromide to the adsorbent is 1:0.1 to 10, wherein
  • the fluoxetine hydrobromide salt in the composition is in an amorphous state, and the X-ray powder diffraction spectrum of the composition is free of crystals of vortioxetine hydrobromide after subtracting the background peak of the pharmaceutically acceptable adjuvant Characteristic peaks.
  • the pharmaceutical excipient comprises an organic vehicle, an adsorbent and a pharmaceutical preparation auxiliary, and the vortioxet forms a solid dispersion with the organic carrier, and the solid dispersion forms a composition with the adsorbent and the pharmaceutical preparation auxiliary.
  • the weight of the vortioxetine hydrobromide salt is 20% to 80% of the total weight of the solid dispersion
  • the weight of the adsorbent is 0.1 to 100% by weight of the solid dispersion
  • the weight of the auxiliary material is the weight of the solid dispersion.
  • organic vehicle is selected from pharmaceutically acceptable small molecule organic compounds, polymers or copolymers.
  • the organic carrier is selected from the group consisting of hydroxypropylmethylcellulose, hydroxypropylcellulose, povidone, polyethylene glycol, ethylcellulose, liposome, methacrylic acid copolymer, polyvinyl acetate.
  • carboxymethyl ethyl cellulose carboxymethyl cellulose phthalate, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate, polyacrylic resin, Carbopol, alginate, carrageenan, carboxyacetolactone, gum, polyvinyl alcohol, pregelatinized starch, crosslinked starch, sodium carboxymethyl starch, dextrin, polyethylene oxide, chitosan, At least one of chitosan, collagen, cyclodextrin, lactose, galactose, D-mannitol, sorbitol, xylitol, urea, citric acid, tartaric acid, fumaric acid, maleic acid, and succinic acid One.
  • the adsorbent is at least one selected from the group consisting of silica, alumina, titania, magnesia, calcium carbonate, and zinc oxide.
  • the pharmaceutical preparation auxiliary is selected from the group consisting of an excipient, a propellant, a solubilizer, a solubilizer, an emulsifier, a colorant, a binder, a disintegrator, a filler, a lubricant, a wetting agent, and an osmotic pressure adjusting agent.
  • stabilizers flow aids, flavoring agents, preservatives, suspending agents, coating materials, fragrances, anti-adhesives, integrators, penetration enhancers, pH adjusters, buffers, plasticizers, surfaces Active agent, foaming agent, defoaming agent, thickener, inclusion agent, moisturizer, absorbent, diluent, flocculant and deflocculant, antioxidant, adsorbent, filter aid, release retardant At least one of them.
  • a method for preparing a pharmaceutical composition of the vortioxetine or a salt thereof of the present invention comprises the following steps:
  • the present invention provides a method of preparing a composition of another vortioxetine or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable adjuvant, comprising the steps of:
  • At least one of the pharmaceutical excipients is selected from the group consisting of an excipient, a propellant, a solubilizer, a cosolvent, an emulsifier, a colorant, a binder, a disintegrant, a filler, Lubricants, wetting agents, osmotic pressure regulators, stabilizers, glidants, flavoring agents, preservatives, suspending agents, coating materials, fragrances, anti-adhesives, integrators, penetration enhancers, pH values Conditioner, buffer, plasticizer, surfactant, foaming agent, antifoaming agent, thickener, inclusion agent, moisturizer, absorbent, diluent, flocculant and deflocculant, antioxidant, adsorption Agent, filter aid or release retarder.
  • At least one of the pharmaceutical excipients is selected from the group consisting of hydroxypropylmethylcellulose, hydroxypropylcellulose, povidone, polyethylene glycol, ethylcellulose, liposome, methacrylic acid copolymerization , polyvinyl acetate, carboxymethyl ethyl cellulose, carboxymethyl cellulose phthalate, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate , polyacrylic resin, carboxyvinyl, alginate, carrageenan, carboxyacetolactone, gum, polyvinyl alcohol, pregelatinized starch, crosslinked starch, sodium carboxymethyl starch, dextrin, polyethylene oxide , chitosan, chitosan, collagen, cyclodextrin, lactose, galactose, D-mannitol, sorbitol, xylitol, urea, citric acid, tartaric acid
  • the solvent in the step 1) is selected from the group consisting of alcohols having 12 or less carbon atoms, phenols, ethers, halogenated hydrocarbons, ketones, aldehydes, nitriles, amides, sulfones, sulfoxides, carboxylic acids, and At least one of the water; step 2) the method of removing the solvent includes: evaporation, vacuum evaporation, spray drying, freeze drying, hot melt extrusion, filtration, centrifugation or stirring film drying.
  • a method for preparing a composition of an amorphous form of vortioxetine hydrobromide and a pharmaceutically acceptable adjuvant comprising the steps of:
  • organic vehicle is selected from pharmaceutically acceptable small molecule organic compounds, polymers or copolymers.
  • the organic vehicle is selected from the group consisting of hydroxypropylmethylcellulose, hydroxypropylcellulose, povidone, polyethylene glycol, ethylcellulose, liposomes, methacrylic acid copolymers, polyvinyl acetate, Carboxymethylethylcellulose, carboxymethylcellulose phthalate, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, polyacrylic resin, poly Carboxyethylene, alginate, carrageenan, carboxyacetolactone, gum, polyvinyl alcohol, pregelatinized starch, crosslinked starch, sodium carboxymethyl starch, dextrin, polyethylene oxide, chitosan, several At least one of butan, collagen, cyclodextrin, lactose, galactose, D-mannitol, sorbitol, xylitol, urea, citric acid, tartaric acid, fumaric acid, maleic acid, and succinic
  • the adsorbent is at least one selected from the group consisting of silica, alumina, titania, magnesia, calcium carbonate, and zinc oxide.
  • the solvent of the step 1) is selected from the group consisting of alcohols having 12 or less carbon atoms, phenols, ethers, halogenated hydrocarbons, ketones, aldehydes, nitriles, amides, sulfones, sulfoxides, carboxylic acids, and At least one of the water; step 2) the method of removing the solvent includes: evaporation, vacuum evaporation, spray drying, freeze drying, hot melt extrusion, filtration, centrifugation or stirring film drying.
  • a method for preparing a pharmaceutical composition of amorphous vortioxetine hydrobromide comprises the following steps:
  • the invention also provides a preparation method of another pharmaceutical composition containing the amorphous vortioxetine hydrobromide, comprising the following steps:
  • the pharmaceutical adjuvant is selected from the group consisting of organic carriers selected from pharmaceutically acceptable small molecule organics, polymers or copolymers.
  • the organic carrier is selected from the group consisting of hydroxypropylmethylcellulose, hydroxypropylcellulose, povidone, polyethylene Alcohol, ethyl cellulose, liposome, methacrylic acid copolymer, polyvinyl acetate, carboxymethyl ethyl cellulose, carboxymethyl cellulose phthalate, hydroxypropyl methyl cellulose phthalate Formate, hydroxypropylmethylcellulose acetate succinate, polyacrylic resin, carboxyvinyl, alginate, carrageenan, carboxyacetolactone, gum, polyvinyl alcohol, pregelatinized starch, crosslinked starch At least one of sodium carboxymethyl starch, dextrin, polyethylene oxide, chitosan, chitosan, and collagen.
  • the solvent in the step 1) is selected from the group consisting of alcohols having 12 or less carbon atoms, phenols, ethers, halogenated hydrocarbons, ketones, aldehydes, nitriles, amides, sulfones, sulfoxides, carboxylic acids, and At least one of the water; step 2) the method of removing the solvent includes: evaporation, vacuum evaporation, spray drying, freeze drying, hot melt extrusion, filtration, centrifugation or stirring film drying.
  • the present invention also provides a use of a pharmaceutical composition comprising an amorphous form of vortioxetine hydrobromide for the preparation of a medicament for treating a psychiatric disorder, including: mood disorders, depression, anxiety, Post-traumatic stress disorder, depression with cognitive impairment, Alzheimer's disease, depression with residual symptoms, habitual pain, and eating disorders.
  • a psychiatric disorder including: mood disorders, depression, anxiety, Post-traumatic stress disorder, depression with cognitive impairment, Alzheimer's disease, depression with residual symptoms, habitual pain, and eating disorders.
  • composition in the present invention means a mixture, a composite, a copolymer, a coprecipitate, a eutectic, a solid dispersion, a solvate, and a hydrate.
  • the pharmaceutical excipients in the present invention are excipients and additives used in the production of pharmaceuticals and formulation, including excipients, propellants, solubilizers, solubilizers, emulsifiers, colorants, binders, disintegrators, fillers , lubricants, wetting agents, osmotic pressure regulators, stabilizers, glidants, flavoring agents, preservatives, suspending agents, coating materials, fragrances, anti-adhesives, integrators, penetration enhancers, pH Value modifier, buffer, plasticizer, surfactant, foaming agent, antifoaming agent, thickener, inclusion agent, moisturizer, absorbent, diluent, flocculant and deflocculant, antioxidant, Adsorbents, filter aids, release retarders, etc.
  • composition of the vortioxetine of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable adjuvant, using Cu-K ⁇ radiation the background peak of the pharmaceutically acceptable excipient is deducted from the X-ray powder diffraction spectrum expressed by degree 2 ⁇
  • a characteristic peak of the crystalline form of ticetine or a pharmaceutically acceptable salt thereof indicating that vortioxetine or a pharmaceutically acceptable salt thereof is in an amorphous state.
  • the crystalline state of vortioxetine or a pharmaceutically acceptable salt thereof is generally used in the prior art, and no report of its amorphous state has been reported.
  • the vortioxetine of the present invention or a pharmaceutically acceptable salt thereof is an amorphous state
  • the molecule In a highly disordered state the surface free energy of the substance is larger, the molecules in the solid matter have higher energy than the molecules in the crystalline solid matter, are more easily dispersed, increase the dissolution rate, and improve the vortioxetine or its pharmacy.
  • the bioavailability of the acceptable salt is particularly important.
  • the "solid dispersant" method is used to block the drug molecule by the polymer network structure of the medicinal adjuvant, thereby inhibiting crystallization. Occurs to keep it dispersed and amorphous.
  • the pharmaceutical excipients of the present invention are selected from two or more kinds of pharmaceutical excipients. Compared with single excipients, a variety of excipients are compatible with each other, which can better exert the functions of dispersing, blocking drug molecules and inhibiting crystallization.
  • this structural feature of having multiple amine groups for vortioxetine or a pharmaceutically acceptable salt thereof can introduce polyhydric alcohols into the medicinal excipients, and hydrogen bonds are easily formed between the drug molecules and the hydroxyl groups of the alcohols, thereby generating strong interactions, enhancing the dispersion of the drugs in the auxiliary materials, and being better.
  • the inhibition of crystallization of drug molecules can also play different roles in pharmaceutical preparations, which is beneficial to the development of pharmaceutical preparations.
  • the invention adopts medicinal excipients which are widely used, low in cost and good in solubility, and these medicinal excipients are mixed with vortioxetine or a pharmaceutically acceptable salt thereof, are not limited by the drying process, and are not affected by the solvent type and solvent.
  • the composition has the stability of the amorphous state, is easy to operate, low in cost, easy to realize, and can realize industrial production.
  • composition of the amorphous vortioxetine or a pharmaceutically acceptable salt thereof prepared by the present invention and two or more kinds of pharmaceutically acceptable excipients has high dispersibility and stability, and various medicinal excipients can be used in medicine.
  • the formulation plays a different role and is beneficial to the development of the formulation. After being prepared into a solid preparation, the disintegration can make the dispersion of the drug particles better, the dispersion and dissolution rate are faster, and the absorption of the drug is facilitated. Therefore, the dissolution rate of the drug in the amorphous state is significantly increased, which is more conducive to the absorption of the drug by the body, and the bioavailability of the drug is improved, so that the drug can better exert the therapeutic effect of the clinical disease.
  • the preparation method of the composition of the morphine or the pharmaceutically acceptable salt thereof and the pharmaceutically acceptable adjuvant in the amorphous state of the present invention is not limited by the drying process, and is not limited by the kind of the solvent and the amount of the solvent, and is easy to handle. The cost is low, easy to implement, and industrial production can be realized.
  • composition of the morphine or the pharmaceutically acceptable salt thereof and the pharmaceutically acceptable adjuvant in the amorphous state prepared by the present invention has no significant change in the substance under high temperature and high humidity conditions, and no wortidine or its The pharmaceutically acceptable salt crystallized; under accelerated test conditions (40 ⁇ 2 ° C, humidity 75% ⁇ 5%), there was no significant change in the relevant substance, and no vortioxetine or a pharmaceutically acceptable salt thereof crystallized,
  • the composition of the amorphous form of vortioxetine or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable adjuvant of the present invention can maintain good physical stability and chemical stability, and has broad application prospects.
  • Example 1 is an X-ray powder diffraction pattern of a composition of amorphous vortioxetine hydrobromide and D-mannitol and povidone K30 of Example 1 of the present invention.
  • Example 2 is an X-ray powder diffraction pattern of a composition of amorphous vortioxetine hydrobromide and sorbitol and polyacrylic resin L100 according to Example 12 of the present invention.
  • Example 3 is an X-ray powder diffraction pattern of a composition of amorphous vortioxetine hydrobromide, povidone K30, and colloidal silica (Aerosil 200) according to Example 38 of the present invention.
  • Figure 4 is an amorphous form of vortioxetine hydrobromide, hydroxypropylmethylcellulose (HPMC E3) according to Example 39 of the present invention.
  • Figure 5 is an X-ray powder diffraction pattern of a composition of a composition of amorphous vortioxetine hydrobromide, povidone K30, microcrystalline cellulose and colloidal silica Aerosil 200 according to Example 57 of the present invention. .
  • Figure 6 is an X-ray powder diffraction pattern of microcrystalline cellulose used in Example 57 of the present invention.
  • Example 7 is an X-ray powder diffraction pattern of a composition of amorphous vortioxetine, hydroxypropylmethylcellulose HPMC E3, mannitol, and colloidal silica Aerosil 200 according to Example 58 of the present invention.
  • Figure 8 is an X-ray powder diffraction pattern of a composition of a composition of amorphous vortioxetine hydrobromide, povidone K30, microcrystalline cellulose and colloidal silica Aerosil 200 according to Example 73 of the present invention. .
  • the X-ray powder diffraction pattern of the present invention was collected on a Ultima IV X-ray diffractometer.
  • the method parameters of the X-ray powder diffraction according to the present invention are as follows:
  • Scanning range: from 2.0 to 60.0 degrees;
  • Scan rate 60 degrees / minute.
  • vortioxetine hydrobromide Any solid form of vortioxetine hydrobromide can be used in the preparation of the pharmaceutical compositions of the present invention.
  • the loading rate of vortioxetine hydrobromide in the pharmaceutical composition is calculated as follows:
  • Loading ratio content of vortioxetine hydrobromide in the pharmaceutical composition / total weight of the pharmaceutical composition.
  • Votilizine hydrobromide (50 mg), D-mannitol (50 mg) and povidone K30 (50 mg) were dissolved in methanol (800 ⁇ l) and heated to 60 ° C to dissolve. The solution was rapidly cooled to -10 ° C, a white solid precipitated, filtered, and dried to obtain a composition of amorphous vortioxetine hydrobromide and D-mannitol and povidone K30, the X-ray of the composition
  • the powder diffraction pattern is shown in Fig. 1. As can be seen from Fig. 1, there is no characteristic peak of the wortite statin hydrobromide crystal form after subtracting the background peak of the medicinal adjuvant in the X-ray powder diffraction pattern.
  • Dissolve vortioxetine 50 mg
  • polyacrylic resin Eudragit L100 50 mg
  • polyethylene glycol 4000 200 mg
  • the above solution was slowly concentrated to dryness in a rotary evaporator to give a white solid to give a mixture of amorphous vorticoxin and polyacrylic resin Eudragit L100 and polyethylene glycol 4000, the X-ray powder diffraction pattern of the composition.
  • Votilizine hydrochloride (2 g), lactose (2 g) and polyethylene glycol 8000 (10 g) were added to water (300 ml) and heated to 60 ° C to dissolve.
  • the above solution was dried with JISL micro spray dryer LSD-48, the inlet temperature was maintained at 60 ° C, the outlet temperature was 50 ° C, and the outlet material was collected to obtain a white solid, which was further dried under vacuum to obtain amorphous vortioxetine hydrochloride and lactose and poly
  • a composition of ethylene glycol 8000 having an X-ray powder diffraction pattern of the composition, after subtracting the background peak of the pharmaceutical excipient, has no characteristic peak of the wortite statin hydrochloride crystal form.
  • the fluoxetine hydrobromide salt (1 g), galactose (1 g) and hydroxypropylmethylcellulose E50 (0.2 g) were added to water (10 ml), and the mixture was heated to 40 ° C and stirred to dissolve.
  • the above solution was freeze-dried to obtain a white solid, that is, a composition of amorphous vortioxetine hydrobromide and galactose and hydroxypropylmethylcellulose E50, the X-ray powder diffraction pattern of the composition was deducted There is no characteristic peak of the vortioxetine hydrobromide crystal form after the background peak of the adjuvant.
  • the vortioxetine (5 g), urea (10 g) and polyethylene glycol 8000 (50 g) were heated to melt and rapidly cooled to room temperature with stirring to give a white solid.
  • the solid is pulverized to obtain a white powdery solid, that is, a composition of amorphous vortioxetine and urea and polyethylene glycol 8000.
  • the X-ray powder diffraction pattern of the composition is deducted from the background peak of the medicinal adjuvant. No characteristic peak of the wortidine crystal form.
  • the vortioxetine (1 g), ethanol (0.1 g), sorbitol (1 g) and polyethylene glycol 10000 (20 g) were heated to 240 ° C, mixed well and rapidly cooled to room temperature to give a white solid.
  • the solid is pulverized to obtain a white powdery solid, that is, a composition of amorphous vortioxetine and sorbitol and polyethylene glycol 10000.
  • the X-ray powder diffraction pattern of the composition is subtracted from the background peak of the medicinal adjuvant. There is no characteristic peak of the wortite surface form.
  • a mixture of vortioxetine hydrobromide (1 g), methanol (20 g), polyacrylic resin Eudragit L100 (2 g) and methacrylic acid copolymer type A (4 g) was heated to 50 ° C and stirred. Dissolve, remove the solvent by evaporation in vacuo, and cool to room temperature to obtain a white solid, that is, a combination of amorphous vortioxetine hydrobromide and polyacrylic resin Eudragit L100 and methacrylic acid copolymer type A, X- of the composition In the ray powder diffraction pattern, there is no characteristic peak of the vortioxetine hydrobromide crystal form after subtracting the background peak of the medicinal adjuvant.
  • Votilizine hydrobromide 50 mg
  • sorbitol 100 mg
  • polyacrylic resin Eudragit L100 100 mg
  • the solution was slowly concentrated to dryness in a rotary evaporator to give a white solid, i.e., a combination of amorphous vortioxetine hydrobromide and sorbitol and polyacrylic resin Eudragit L100, X-ray powder diffraction of the composition.
  • Fig. 2 it can be seen from Fig. 2 that there is no characteristic peak of the wortite statin hydrobromide crystal form after subtracting the background peak of the medicinal adjuvant in the X-ray powder diffraction pattern.
  • Vootioxetine 50 mg
  • dextrin 50 mg
  • carbopol Carbomer 940 50 mg
  • methanol 4 ml
  • tetrahydrofuran 1 ml
  • the solution was slowly concentrated to dryness in a rotary evaporator to give a white solid which crystallised as a white solid, i.e., a combination of amorphous vorticoxin with dextrin and carbomer Carbomer 940, X-ray of the composition
  • a white solid which crystallised as a white solid, i.e., a combination of amorphous vorticoxin with dextrin and carbomer Carbomer 940, X-ray of the composition
  • a white solid which crystallised as a white solid, i.e., a combination of amorphous vorticoxin with dextrin and carbomer Carbomer 940
  • Votiloxime nitrate 50 mg
  • maleic acid 100 mg
  • sodium carboxymethylcellulose SCMC 500 mg
  • dimethyl sulfoxide 5 ml
  • the solution was slowly concentrated to dryness to give a white solid, i.e., a combination of amorphous vortioxetine nitrate and maleic acid and sodium carboxymethylcellulose SCMC, which was subtracted from the X-ray powder diffraction pattern of the composition.
  • Vootioxetine hydrochloride 50 mg
  • povidone K90 100 mg
  • alginate E401 100 mg
  • the solution was slowly concentrated to dryness in a rotary evaporator to give a white solid, i.e., a combination of amorphous vorticoxine hydrochloride and povidone K90 and alginate E401, X-ray powder diffraction of the composition.
  • a white solid i.e., a combination of amorphous vorticoxine hydrochloride and povidone K90 and alginate E401, X-ray powder diffraction of the composition.
  • Votitin 50 mg
  • gum Galactosol 100 mg
  • carrageenan E407 100 mg
  • methanol 30 ml
  • Most of the solvent is removed, filtered, and dried to give a white solid, a combination of amorphous vortioxetine and gum Galactosol and carrageenan E407.
  • the X-ray powder diffraction pattern of the composition is subtracted from the background peak of the medicinal excipient. There is no characteristic peak of the wortite surface form.
  • the fluoxetine hydrobromide (50 mg), galactose (100 mg) and chitosan (200 mg) were suspended in methanol (50 ml), heated to 50 ° C and stirred and mixed.
  • the above solution was slowly concentrated in a rotary evaporator to remove most of the solvent, filtered, and dried to give a white solid, that is, a combination of amorphous vortioxetine hydrobromide and galactose and chitosan, X of the composition
  • a white solid that is, a combination of amorphous vortioxetine hydrobromide and galactose and chitosan, X of the composition
  • Votilizine (300 mg), liposome (300 mg) and polyacrylic resin Eudragit E100 (300 mg) were dissolved in ethanol (600 ⁇ l), tetrahydrofuran (900 ⁇ l) and N,N-dimethyl In formamide (600 ⁇ l), heat to 50 ° C to stir and dissolve, the solution was cooled to -30 ° C, a white solid precipitated, filtered and dried to obtain amorphous vortixetine and liposome and polyacrylic resin Eudragit
  • the X-ray powder diffraction pattern of the composition has no characteristic peak of the wortidine crystal form after subtracting the background peak of the pharmaceutically acceptable adjuvant.
  • Votilizine (30 mg), xylitol (30 mg) and collagen Peptan (200 mg) were dissolved in ethanol (600 ⁇ l) and acetonitrile (600 ⁇ L) and heated to 50 ° C to dissolve.
  • the above solution was slowly concentrated in a rotary evaporator to remove most of the solvent, and a white solid was precipitated, filtered, and dried to obtain a composition of amorphous vortioxetine and xylitol and collagen Peptan, the X-ray powder of the composition.
  • amorphous vortioxetine and xylitol and collagen Peptan the X-ray powder of the composition.
  • Votilizine (30 mg), D-mannitol (30 mg) and gum Galactosol (150 mg) were dissolved in methanol (900 ⁇ l) and heated to 50 ° C to dissolve.
  • the above solution was slowly concentrated in a rotary evaporator to remove most of the solvent, and a white solid was precipitated, which was filtered and dried to give an amorphous form of fluoxetine and D-mannitol and gum.
  • Votilizine hydrobromide (30 mg), succinic acid (3 mg) and sodium carboxymethylcellulose SCMS (3 mg) were added to water (30 ml), heated to 100 ° C and stirred and mixed. The solution was slowly concentrated in a rotary evaporator to remove the solvent to give a white solid, i.e., a combination of amorphous fluoxetine hydrobromide and succinic acid and sodium carboxymethylcellulose SCMC. X-rays of the composition. In the powder diffraction pattern, there is no characteristic peak of the vortioxetine hydrobromide crystal form after subtracting the background peak of the medicinal adjuvant.
  • Example 35 Influential factors test of a combination of amorphous vortioxetine hydrobromide and D-mannitol and povidone K30
  • Table 1 illustrates: amorphous vortioxetine hydrobromide and D-mannitol and povidone K30 compositions were placed under high temperature and high humidity conditions for 10 days without significant changes in related substances, without wortidine or Its pharmaceutically acceptable salt crystallizes out.
  • Example 36 Accelerated test of amorphous vortioxetine hydrobromide and D-mannitol and povidone K30 compositions
  • Table 2 illustrates that the amorphous vortioxetine hydrobromide salt of the present invention and the D-mannitol and povidone K30 compositions were placed under accelerated test conditions for 6 months without significant change in related substances, without Wortisi The hydrazine hydrobromide crystallizes out.
  • composition of the amorphous vortioxetine of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable adjuvant has a markedly increased dissolution, and is more advantageous for improving the bioavailability of the drug, so that the drug can better exert clinical diseases.
  • therapeutic effect the amorphous substance can maintain good physicality under accelerated test conditions (40 ⁇ 2°C, humidity 75% ⁇ 5%) Stability and chemical stability.
  • the measurement objects were respectively: the composition obtained in Example 1 of the present invention; the mixture of vortioxetine crystal form (the morphisine crystal form ( ⁇ crystal form) and the D-mannitol and povidone K30 were physically mixed The weight ratio was 1:1:1, and the vortioxetine crystal form ( ⁇ crystal form) was prepared according to the method of Example 4c of the patent CN101472906.
  • Example 1 of the present invention A sufficient amount of the composition obtained in Example 1 of the present invention and a mixture of vortioxetine crystal form were weighed and placed in two stoppered Erlenmeyer flasks, and a dilution solution of a specified pH was added. Formulated as a supersaturated solution with a tight seal. Three samples were prepared in parallel for each pH dilution. It was shaken in a constant temperature water bath shaker at 37 ° C ⁇ 0.5 ° C for 12 h to fully dissolve to achieve saturation. The supernatant was filtered with a 0.45 ⁇ m microporous membrane, diluted appropriately, shaken, and injected into the liquid chromatograph. The apparent solubility of the three parallel samples in this pH buffer was calculated by external standard method and averaged.
  • Table 3 shows that at each pH value, the apparent solubility of the composition of the amorphous wortite and the D-mannitol and povidone K30 of the present invention is significantly higher than that of the wortite crystal form ( ⁇ crystal form) The apparent solubility of the mixture.
  • Example 54 Influencing factors test for compositions of amorphous vortioxetine hydrobromide, povidone K30 and colloidal silica (Aerosil 200)
  • Table 4 illustrates that the composition of amorphous vortioxetine hydrobromide, povidone K30 and colloidal silica (Aerosil 200) was left under high temperature and high humidity conditions for 10 days without significant change in related substances. No woticiltin hydrobromide crystals precipitated.
  • Example 55 Accelerated test of a composition of amorphous vortioxetine hydrobromide, povidone K30 and colloidal silica (Aerosil 200)
  • Table 5 illustrates that the composition of the amorphous form of vortioxetine hydrobromide, povidone K30 and colloidal silica (Aerosil 200) of the present invention was placed under accelerated test conditions for 6 months, and the related substances were not significant. Changed, no wortoxicillin hydrobromide crystals precipitated.
  • the measurement objects were respectively: the composition obtained in Example 38 of the present invention; the mixture of the vortioxetine crystal form (the vortioxetine crystal form ( ⁇ crystal form) and the povidone K30, colloidal silica (Aerosil) 200) After physical mixing at a weight ratio of 1:1:1, the vortioxetine crystal form ( ⁇ crystal form) was prepared according to the method of Example 4c of the patent CN101472906.
  • Example 1 of the present invention A sufficient amount of the composition obtained in Example 1 of the present invention and a mixture of vortioxetine crystal form were weighed and placed in two stoppered Erlenmeyer flasks, and a dilution solution of a specified pH was added. Formulated as a supersaturated solution with a tight seal. Three samples were prepared in parallel for each pH dilution. It was shaken in a constant temperature water bath shaker at 37 ° C ⁇ 0.5 ° C for 12 h to fully dissolve to achieve saturation. The supernatant was filtered with a 0.45 ⁇ m microporous membrane, diluted appropriately, shaken, and injected into the liquid chromatograph. The apparent solubility of the three parallel samples in this pH buffer was calculated by external standard method and averaged.
  • Table 6 shows that the apparent solubility of the composition of the amorphous wortite and the D-mannitol and povidone K30 of the present invention is significantly higher than that of the wortite crystal form ( ⁇ crystal form) at each pH value.
  • the apparent solubility of the mixture is significantly higher than that of the wortite crystal form ( ⁇ crystal form) at each pH value.
  • the background peak of the medicinal excipient is subtracted from the X-ray powder diffraction pattern without the crystal form of wortite statin hydrobromide.
  • the characteristic peak, X-ray powder diffraction pattern of microcrystalline cellulose is shown in Fig. 6.
  • Example 75 Influential factors test of compositions of amorphous vortioxetine hydrobromide, povidone K30, microcrystalline cellulose and colloidal silica (Aerosil 200)
  • Table 7 illustrates that the composition of amorphous vortioxetine hydrobromide, povidone K30, microcrystalline cellulose and colloidal silica (Aerosil 200) is placed under high temperature and high humidity conditions for 10 days. There was no significant change in the material, and no vortixetine hydrobromide crystallized.
  • Example 76 Accelerated test of a composition of amorphous vortioxetine hydrobromide, povidone K30, microcrystalline cellulose and colloidal silica (Aerosil 200)
  • Table 8 illustrates that the composition of amorphous vortioxetine hydrobromide, povidone K30, microcrystalline cellulose and colloidal silica (Aerosil 200) was placed under accelerated test conditions for 6 months, related substances. There was no significant change, and no vortioxetine hydrobromide crystallized.
  • the measurement objects were respectively: the composition obtained in Example 57 of the present invention; the mixture of the vortioxetine crystal form (the morphisine crystal form ( ⁇ crystal form) and the povidone K30, the microcrystalline cellulose and the colloidal state Silica (Aerosil 200) was physically mixed at a weight ratio of 1:0.6:0.6:0.4, and the vortioxetine crystal form ( ⁇ crystal form) was prepared according to the method of Example 4c of the patent CN101472906.
  • Example 57 of the present invention A sufficient amount of the composition obtained in Example 57 of the present invention and a mixture of vortioxetine crystal form were weighed and placed in two stoppered Erlenmeyer flasks, and a dilution of the specified pH was added. Formulated as a supersaturated solution with a tight seal. Three samples were prepared in parallel for each pH dilution. It was shaken in a constant temperature water bath shaker at 37 ° C ⁇ 0.5 ° C for 12 h to fully dissolve to achieve saturation. The supernatant was filtered with a 0.45 ⁇ m microporous membrane, diluted appropriately, shaken, and injected into the liquid chromatograph. The apparent solubility of the three parallel samples in this pH buffer was calculated by external standard method and averaged.
  • Table 9 shows that the apparent solubility of the composition of the amorphous wortite and the D-mannitol and povidone K30 of the present invention is significantly higher than that of the wortite crystal form ( ⁇ crystal form) at various pH values.
  • the apparent solubility of the mixture is significantly higher than that of the wortite crystal form ( ⁇ crystal form) at various pH values.
  • the pharmaceutical composition of the amorphous vortioxetine hydrobromide salt of the invention has a significantly increased dissolution rate, is more favorable for improving the bioavailability of the drug, and enables the drug to better exert the therapeutic effect of the clinical disease, the amorphous type
  • the material maintains good physical and chemical stability under accelerated test conditions (40 ⁇ 2 ° C, humidity 75% ⁇ 5%).

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Abstract

本发明提供一种无定型沃替西汀或其盐的药用组合物及其制备方法。该药用组合物包含无定型沃替西汀或其药学上可接受的盐与两种或两种以上的药用辅料。所述药用组合物的稳定性及分散性良好，增加了沃替西汀或其药学上可接受的盐的溶出度，更有利于提高药物制剂的生物利用度和机体对药物的吸收。

Description

一种沃替西汀或其盐的药用组合物及其制备方法 技术领域
本发明属于药物制剂领域，具体涉及沃替西汀或其药学上可接受的盐与药用辅料的组合物及其制备方法，以及上述组合物制备治疗情感障碍的药物的用途。
背景技术
沃替西汀氢溴酸盐(Vortioxetine)，化学名为1-[2-(2,4-甲基苯硫基)苯基]哌嗪氢溴酸盐，商品名为Brintellix，是丹麦灵北公司(Lundbeck)和日本武田公司(Takeda)开发的5-羟色胺再摄取抑制剂。沃替西汀氢溴酸盐于2013年9月30日被美国食品和药品监管局批准上市，用于重度抑郁症的治疗。全球领先的制药与医疗保健问题研究和咨询公司——决策资源公司(Decision Resources)发布报告预测，到2022年，沃替西汀在美国、日本、欧盟五大主要市场(法国、德国、意大利、西班牙、英国)中将成为重磅药物。根据迄今取得的数据，鉴于其对认知的积极影响及可耐受的副作用属性，沃替西汀预计将成为单相抑郁症市场中最成功的新药。
但沃替西汀或其药学上可接受的盐存在多种晶型。中国专利CN 101472906公开了沃替西汀游离碱和多种药学上可接受的盐的晶型，包括沃替西汀氢溴酸盐的α-晶型、β-晶型和γ-晶型。该药物的上市晶型为沃替西汀氢溴酸盐的β-晶型，也是氢溴酸盐中热力学最稳定的晶型。
沃替西汀游离碱在水中的溶解度非常低，仅为0.1毫克/毫升。将沃替西汀游离碱与氢溴酸成盐，可以明显改善其在水中的溶解度，但也仅为1.2毫克/毫升。
药物的固体形态直接影响原料药的溶解速率、制剂的溶出度和生物利用度，为了提高药物的生物利用度，降低用量、降低毒副作用，通常会开发药物的新的固体形态，因此，开发该药物溶解性更好、生物利用度更高的固体形式就显得很有必要。
药物的固体形态除晶态外，还有无定型状态，药物的无定型状态作为固体物质的一种特殊形态，在药物制备中有着重要的用途。无定型态药物不仅可以广泛应用于药物制剂中，而且可以通过多种技术手段和方法提高无定型态药物的稳定性，使之成为具有优良品质的药物。
专利WO2014/177491报道了一种将无定型沃替西汀氢溴酸盐吸附到无机载体上的组合物。该组合物中的沃替西汀氢溴酸盐为无定形态，且溶出度相对于晶型沃替西汀氢溴酸盐有一定提高。但无机吸附剂对活性成分--沃替西汀氢溴酸盐的吸附能力并不是很高，因此需要加入大量的无机吸附剂才能使沃替西汀氢溴酸盐成为无定形态。 专利WO2016/062860也提供了一种含有无定型沃替西汀氢溴酸盐的组合物，先将沃替西汀氢溴酸盐吸附在吸附剂上，在于另一种组分形成新的组合物，该组合物中沃替西汀氢溴酸盐为无定形态。该技术方案为使活性成分完成形成无定形态，同样加入了大量的吸附剂。吸附剂对活性成分的吸附能力很强，对药物的释放会造成较大影响，溶出度的提高并不明显；同时，无机吸附剂需要其他有机辅料粘合在一起才能进行造粒和压片，大量的吸附剂会需要更大量的有机辅料，这将给片剂的处方开发造成一定困难。进而影响药物的生物利用度和疗效。
由于沃替西汀氢溴酸盐在生物利用度方面的不足和无定型药物活性成分在药物制剂方面的良好的应用前景，寻找新的无定型沃替西汀氢溴酸盐及其制备方法就显得十分必要。
发明内容
本发明的目的是提供一种沃替西汀或其药学上可接受的盐与药用辅料的组合物及其制备方法，得到稳定性及分散性良好的无定型态的沃替西汀或其药学上可接受的盐与药用辅料的组合物，增加了沃替西汀或其药学上可接受的盐的溶出度，该制备方法不受干燥过程的限制，也不受溶剂种类和溶剂量的限制，操作简便，成本低廉，易于实现，可实现工业化生产。
为了达到上述目的，本发明的技术方案如下：
一种沃替西汀或其盐的药用组合物，其特征在于，所述组合物包含沃替西汀或其药学上可接受的盐与两种或两种以上的药用辅料，沃替西汀或其药学上可接受的盐与全部药用辅料的重量比为1:0.1～100，其中，所述组合物中的沃替西汀或其药学上可接受的盐为无定型态，所述组合物的X-射线粉末衍射光谱中，扣除药用辅料的背景峰后无沃替西汀或其药学上可接受的盐晶体的特征峰。
进一步，所述药用辅料选自赋形剂、抛射剂、增溶剂、助溶剂、乳化剂、着色剂、黏合剂、崩解剂、填充剂、润滑剂、润湿剂、渗透压调节剂、稳定剂、助流剂、矫味剂、防腐剂、助悬剂、包衣材料、芳香剂、抗黏合剂、整合剂、渗透促进剂、pH值调节剂、缓冲剂、增塑剂、表面活性剂、发泡剂、消泡剂、增稠剂、包合剂、保湿剂、吸收剂、稀释剂、絮凝剂与反絮凝剂、抗氧剂、吸附剂、助滤剂、释放阻滞剂中的至少一种。
优选地，所述药用辅料中的至少一种选自羟丙甲基纤维素、羟丙基纤维素、聚维酮、聚乙二醇、乙基纤维素、脂质体、甲基丙烯酸共聚物、聚醋酸乙烯、羧甲基乙基纤维素、羧甲基纤维素邻苯二甲酸酯、羟丙甲基纤维素邻苯二甲酸酯、羟丙甲基纤维素醋酸酯琥珀酸酯、聚丙烯酸树脂、聚羧乙烯、藻酸盐、卡拉胶、羧基乙酸内酯、树胶、聚乙烯醇、预胶化淀粉、交联淀粉、羧甲基淀粉钠、糊精、聚环氧乙烷、壳聚糖、 几丁聚糖、胶原蛋白、环糊精、乳糖、半乳糖、D-甘露醇、山梨醇、木糖醇、尿素、枸橼酸、酒石酸、富马酸、马来酸或琥珀酸。
进一步，所述沃替西汀为其氢溴酸盐形式，所述药用辅料中包含有机载体和吸附剂，沃替西汀与有机载体形成固体分散体，所述的固体分散体与吸附剂形成组合物，其中，沃替西汀氢溴酸盐与有机载体的重量比为1:0.1～10，沃替西汀氢溴酸盐与吸附剂的重量比为1:0.1～10，其中，组合物中的沃替西汀氢溴酸盐为无定型态，所述组合物的X-射线粉末衍射光谱中扣除药用辅料的背景峰后无沃替西汀氢溴酸盐的晶体的特征峰。
更进一步，所述药用辅料中包含有机载体、吸附剂和药用制剂辅料，沃替西汀与有机载体形成固体分散体，所述的固体分散体与吸附剂和药用制剂辅料形成组合物，沃替西汀氢溴酸盐的重量为固体分散体的总重量的20％～80％，吸附剂的重量为固体分散体的重量的0.1～100％，辅料的重量为固体分散体的重量的0.1％～200％，其中，所述的沃替西汀氢溴酸盐为无定型态，所述组合物的X-射线粉末衍射光谱中，扣除有机载体、吸附剂和药用辅料的背景峰后无沃替西汀氢溴酸盐晶体的特征峰。
进一步，所述的有机载体选自药学上可接受的小分子有机化合物、聚合物或共聚物。
优选地，所述的有机载体选自羟丙甲基纤维素、羟丙基纤维素、聚维酮、聚乙二醇、乙基纤维素、脂质体、甲基丙烯酸共聚物、聚醋酸乙烯、羧甲基乙基纤维素、羧甲基纤维素邻苯二甲酸酯、羟丙甲基纤维素邻苯二甲酸酯、羟丙甲基纤维素醋酸酯琥珀酸酯、聚丙烯酸树脂、聚羧乙烯、藻酸盐、卡拉胶、羧基乙酸内酯、树胶、聚乙烯醇、预胶化淀粉、交联淀粉、羧甲基淀粉钠、糊精、聚环氧乙烷、壳聚糖、几丁聚糖、胶原蛋白、环糊精、乳糖、半乳糖、D-甘露醇、山梨醇、木糖醇、尿素、枸橼酸、酒石酸、富马酸、马来酸和琥珀酸中的至少一种。
又，所述吸附剂选自二氧化硅、氧化铝、二氧化钛、氧化镁、碳酸钙和氧化锌中的至少一种。
再，所述药用制剂辅料选自赋形剂、抛射剂、增溶剂、助溶剂、乳化剂、着色剂、黏合剂、崩解剂、填充剂、润滑剂、润湿剂、渗透压调节剂、稳定剂、助流剂、矫味剂、防腐剂、助悬剂、包衣材料、芳香剂、抗黏合剂、整合剂、渗透促进剂、pH值调节剂、缓冲剂、增塑剂、表面活性剂、发泡剂、消泡剂、增稠剂、包合剂、保湿剂、吸收剂、稀释剂、絮凝剂与反絮凝剂、抗氧剂、吸附剂、助滤剂、释放阻滞剂中的至少一种。
本发明的沃替西汀或其盐的药用组合物的制备方法，包括如下步骤：
1)将沃替西汀或其药学上可接受的盐与药用辅料混合，加热至药用辅料熔融；其中，沃替西汀或其药学上可接受的盐与全部药用辅料的重量比为1:0.1～100；
2)混合均匀后冷却，将得到的混合物粉碎，得到无定型态的沃替西汀或其药学上可接受的盐与药用辅料的组合物。
本发明提供给了另一种的沃替西汀或其药学上可接受的盐与药用辅料的组合物的制备方法，包括如下步骤：
1)将沃替西汀或其药学上可接受的盐和药用辅料在溶剂中混合，混合温度为-50～150℃，形成含沃替西汀或其药学上可接受的盐和药用辅料的溶液或悬浮液，其中，沃替西汀或其药学上可接受的盐与溶剂的重量比为0.001～100:1，沃替西汀或其药学上可接受的盐与药用辅料的重量比为1:0.1～100；
2)除去步骤1)得到的溶液或悬浮液中的溶剂，得到无定型态的沃替西汀或其药学上可接受的盐与药用辅料的组合物。
进一步，上述两种制备方法中，所述药用辅料中的至少一种选自赋形剂、抛射剂、增溶剂、助溶剂、乳化剂、着色剂、黏合剂、崩解剂、填充剂、润滑剂、润湿剂、渗透压调节剂、稳定剂、助流剂、矫味剂、防腐剂、助悬剂、包衣材料、芳香剂、抗黏合剂、整合剂、渗透促进剂、pH值调节剂、缓冲剂、增塑剂、表面活性剂、发泡剂、消泡剂、增稠剂、包合剂、保湿剂、吸收剂、稀释剂、絮凝剂与反絮凝剂、抗氧剂、吸附剂、助滤剂或释放阻滞剂。
优选地，所述药用辅料中的至少一种选自羟丙甲基纤维素、羟丙基纤维素、聚维酮、聚乙二醇、乙基纤维素、脂质体、甲基丙烯酸共聚物、聚醋酸乙烯、羧甲基乙基纤维素、羧甲基纤维素邻苯二甲酸酯、羟丙甲基纤维素邻苯二甲酸酯、羟丙甲基纤维素醋酸酯琥珀酸酯、聚丙烯酸树脂、聚羧乙烯、藻酸盐、卡拉胶、羧基乙酸内酯、树胶、聚乙烯醇、预胶化淀粉、交联淀粉、羧甲基淀粉钠、糊精、聚环氧乙烷、壳聚糖、几丁聚糖、胶原蛋白、环糊精、乳糖、半乳糖、D-甘露醇、山梨醇、木糖醇、尿素、枸橼酸、酒石酸、富马酸、马来酸或琥珀酸。
又，步骤1)所述溶剂选自碳原子数载12个以下的醇类、酚类、醚类、卤代烃、酮类、醛类、腈类、酰胺、砜、亚砜、羧酸和水中的至少一种；步骤2)除去溶剂的方法包括：蒸发、真空蒸发、喷雾干燥、冷冻干燥、热熔挤出、过滤、离心或搅拌薄膜干燥。
一种无定型沃替西汀氢溴酸盐与药用辅料的组合物的制备方法，包括如下步骤：
1)将沃替西汀氢溴酸盐、有机载体和吸附剂在溶剂中混合，混合温度为-50～150℃，形成含沃替西汀氢溴酸盐、有机载体和吸附剂的溶液或悬浮液，其中，沃替西汀氢溴酸盐与溶剂的重量比为0.001～100:1，沃替西汀氢溴酸盐与有机载体的重量比为1:0.1～10，沃替西汀氢溴酸盐与吸附剂的重量比为1:0.1～10；
2)除去步骤1)得到的溶液或悬浮液中的溶剂，得到无定型态的沃替西汀氢溴酸盐的药用组合物。
进一步，所述有机载体选自药学上可接受的小分子有机化合物、聚合物或共聚物。
优选地，所述有机载体选自羟丙甲基纤维素、羟丙基纤维素、聚维酮、聚乙二醇、乙基纤维素、脂质体、甲基丙烯酸共聚物、聚醋酸乙烯、羧甲基乙基纤维素、羧甲基纤维素邻苯二甲酸酯、羟丙甲基纤维素邻苯二甲酸酯、羟丙甲基纤维素醋酸酯琥珀酸酯、聚丙烯酸树脂、聚羧乙烯、藻酸盐、卡拉胶、羧基乙酸内酯、树胶、聚乙烯醇、预胶化淀粉、交联淀粉、羧甲基淀粉钠、糊精、聚环氧乙烷、壳聚糖、几丁聚糖、胶原蛋白、环糊精、乳糖、半乳糖、D-甘露醇、山梨醇、木糖醇、尿素、枸橼酸、酒石酸、富马酸、马来酸和琥珀酸中的至少一种。
又，所述吸附剂选自二氧化硅、氧化铝、二氧化钛、氧化镁、碳酸钙和氧化锌中的至少一种。
再，步骤1)所述溶剂选自碳原子数为12个以下的醇类、酚类、醚类、卤代烃、酮类、醛类、腈类、酰胺、砜、亚砜、羧酸和水中的至少一种；步骤2)除去溶剂的方法包括：蒸发、真空蒸发、喷雾干燥、冷冻干燥、热熔挤出、过滤、离心或搅拌薄膜干燥。
一种无定型沃替西汀氢溴酸盐的药用组合物的制备方法，包括如下步骤：
1)将沃替西汀氢溴酸盐、至少一种有机载体、至少一种吸附剂和至少一种药用制剂辅料在溶剂中混合，混合温度为-50～150℃，形成含沃替西汀氢溴酸盐、有机载体、吸附剂和药用制剂辅料的溶液或悬浮液，其中，沃替西汀氢溴酸盐与溶剂的重量比为0.001～100:1，沃替西汀氢溴酸盐的重量为固体分散体的总重量的20％-80％，药用制剂辅料的重量为固体分散体的重量的0.1％～80％；
2)除去步骤1)得到的溶液或悬浮液中的溶剂，得到无定型态的沃替西汀氢溴酸盐的药用组合物。
本发明还提供了另一种含有无定型沃替西汀氢溴酸盐的药用组合物的制备方法，包括如下步骤：
1)将沃替西汀氢溴酸盐、至少一种有机载体、至少一种吸附剂和至少一种药用制剂辅料以及溶剂在流化床中混合，混合温度为0～150℃，形成含沃替西汀氢溴酸盐、有机载体、吸附剂和药用辅料的溶液或悬浮液，其中，沃替西汀氢溴酸盐与溶剂的重量比为0.001～100:1，沃替西汀氢溴酸盐的重量为固体分散体的总重量的20％-80％，药用制剂辅料的重量为固体分散体的重量的0.1％～80％；
2)除去步骤1)得到混合物中的溶剂，得到无定型态的沃替西汀氢溴酸盐的药用组合物。
进一步，所述药用辅料选自所述的有机载体选自药学上可接受的小分子有机物、聚合物或共聚物。
优选地，所述的有机载体选自羟丙甲基纤维素、羟丙基纤维素、聚维酮，聚乙二 醇、乙基纤维素、脂质体、甲基丙烯酸共聚物、聚醋酸乙烯、羧甲基乙基纤维素、羧甲基纤维素邻苯二甲酸酯、羟丙甲基纤维素邻苯二甲酸酯、羟丙甲基纤维素醋酸酯琥珀酸酯、聚丙烯酸树脂、聚羧乙烯、藻酸盐、卡拉胶、羧基乙酸内酯、树胶、聚乙烯醇、预胶化淀粉、交联淀粉、羧甲基淀粉钠、糊精、聚环氧乙烷、壳聚糖、几丁聚糖和胶原蛋白中的至少一种。
又，步骤1)所述溶剂选自碳原子数为12个以下的醇类、酚类、醚类、卤代烃、酮类、醛类、腈类、酰胺、砜、亚砜、羧酸和水中的至少一种；步骤2)除去溶剂的方法包括：蒸发、真空蒸发、喷雾干燥、冷冻干燥、热熔挤出、过滤、离心或搅拌薄膜干燥。
本发明还提供了一种含有无定型沃替西汀氢溴酸盐的药用组合物在用于制备治疗精神疾病的药物的用途，所述精神疾病包括：情绪失调、抑郁症、焦虑症、创伤后应激障碍、伴有认知缺损的抑郁症、阿尔兹海默症、有残留症状的抑郁症、习惯性疼痛和进食障碍。
本发明中的组合物是指混合物、复合物、共聚物、共沉淀物、共晶、固体分散体、溶剂合物和水合物。
本发明中药用辅料为生产药品和调配处方时使用的赋形剂和附加剂，包括赋形剂、抛射剂、增溶剂、助溶剂、乳化剂、着色剂、黏合剂、崩解剂、填充剂、润滑剂、润湿剂、渗透压调节剂、稳定剂、助流剂、矫味剂、防腐剂、助悬剂、包衣材料、芳香剂、抗黏合剂、整合剂、渗透促进剂、pH值调节剂、缓冲剂、增塑剂、表面活性剂、发泡剂、消泡剂、增稠剂、包合剂、保湿剂、吸收剂、稀释剂、絮凝剂与反絮凝剂、抗氧剂、吸附剂、助滤剂、释放阻滞剂等。
本发明的沃替西汀或其药学上可接受的盐与药用辅料的组合物，使用Cu-Kα辐射，以度2θ表示的X-射线粉末衍射光谱中扣除药用辅料的背景峰无沃替西汀或其药学上可接受的盐结晶态的特征峰，表明沃替西汀或其药学上可接受的盐为无定型状态。现有技术中一般使用沃替西汀或其药学上可接受的盐的结晶态，未见其无定型态的报道。一般由于晶态物质分子的有序和周期性排列，降低了分子间相互作用的能量，能量较低，而本发明的沃替西汀或其药学上可接受的盐为无定型态，分子处于高度无序状态，物质的表面自由能更大，固体物质中的分子较晶态固体物质中的分子有更高的能量，更容易分散，增加其溶出度，提高沃替西汀或其药学上可接受的盐的生物利用度。
本发明将沃替西汀或其药学上可接受的盐和药用辅料混合均匀后，使用“固体分散剂”法，通过药用辅料的多聚体网状结构将药物分子阻隔，抑制结晶的发生，使其保持分散和无定型状态。本发明中的药用辅料选用两种或两种以上的药用辅料。与单一辅料相比，多种药用辅料相互配伍，可以更好地发挥分散、阻隔药物分子和抑制结晶的作用。例如，针对沃替西汀或其药学上可接受的盐具有多个胺基的这一结构特点， 本发明在药用辅料中可引入多羟基的醇类，药物分子和醇类的羟基之间易形成氢键，产生较强的相互作用，可增强药物在辅料中的分散度，并能更好地抑制药物分子的结晶。此外，多种药用辅料也可以在药物制剂中发挥不同的作用，有利于药物制剂的开发。
本发明采用应用广泛、价格低廉、溶解性好的药用辅料，这些药用辅料与沃替西汀或其药学上可接受的盐混合，不受干燥过程的限制，也不受溶剂种类和溶剂量的限制，配合蒸发、喷雾干燥、冷冻干燥和热熔挤出等技术，可以得到沃替西汀或其药学上可接受的盐的无定型形式，增加沃替西汀或其盐的药用组合物无定型态的稳定性，操作简便，成本低廉，易于实现，可实现工业化生产。
与现有技术相比，本发明的有益效果是：
1)本发明制备的无定型沃替西汀或其药学上可接受的盐与两种或两种以上的药用辅料的组合物具有高度分散性及稳定性，各种药用辅料可在药物制剂中发挥不同的作用，有利于制剂配方的开发。在制成固体制剂后，经过崩解可使药物粒子的分散程度更好，分散及溶出速度更快，有利于药物的吸收。因此，无定型状态药物的溶出度明显增加，更有利于机体对药物的吸收，提高药物的生物利用度，使药物能够更好地发挥临床疾病治疗作用。
2)本发明无定型状态的沃替西汀或其药学上可接受的盐与药用辅料的组合物的制备方法不受干燥过程的限制，也不受溶剂种类和溶剂量的限制，操作简便，成本低廉，易于实现，可实现工业化生产。
3)本发明制备的无定型状态的沃替西汀或其药学上可接受的盐与药用辅料的组合物在高温、高湿条件下，有关物质无显著改变，无沃替西汀或其药学上可接受的盐结晶析出；在加速试验条件下(40±2℃，湿度75％±5％)，有关物质无显著改变，无沃替西汀或其药学上可接受的盐结晶析出，本发明的无定型状态的沃替西汀或其药学上可接受的盐与药用辅料的组合物能保持良好的物理稳定性和化学稳定性，将会有广阔的应用前景。
附图说明
图1为本发明实施例1的无定型沃替西汀氢溴酸盐和D-甘露醇及聚维酮K30的组合物的X-射线粉末衍射图。
图2为本发明实施例12的无定型沃替西汀氢溴酸盐和山梨醇及聚丙烯酸树脂L100的组合物的X-射线粉末衍射图。
图3为本发明实施例38的无定型沃替西汀氢溴酸盐、聚维酮K30和胶态二氧化硅(Aerosil 200)的组合物的X-射线粉末衍射图。
图4为本发明实施例39的无定型沃替西汀氢溴酸盐、羟丙甲基纤维素(HPMC E3) 和胶态二氧化硅(Aerosil 200)的组合物的X-射线粉末衍射图。
图5为本发明实施例57的无定型沃替西汀氢溴酸盐、聚维酮K30、微晶纤维素及胶态二氧化硅Aerosil 200的组合物的组合物的X-射线粉末衍射图。
图6为本发明实施例57中使用的微晶纤维素的X-射线粉末衍射图。
图7为本发明实施例58的无定型沃替西汀、羟丙甲基纤维素HPMC E3、甘露醇及胶态二氧化硅Aerosil 200的组合物的X-射线粉末衍射图。
图8为本发明实施例73的无定型沃替西汀氢溴酸盐、聚维酮K30、微晶纤维素及胶态二氧化硅Aerosil 200的组合物的组合物的X-射线粉末衍射图。
具体实施方式
以下结合具体实施例对本发明作进一步说明，但本发明的保护范围不受以下实施例的限制。
本发明所述的X-射线粉末衍射图在Ultima IV X-射线衍射仪上采集。本发明所述的X-射线粉末衍射的方法参数如下：
X-射线粉末参数：Cu-Kα
Kα
Figure PCTCN2016098095-appb-000001
：1.5418；
电压：40千伏；
电流：40毫安；
发散狭缝：自动；
扫描模式：连续；
扫描范围：自2.0至60.0度；
取样步长：0.0200度；
扫描速率：60度/分钟。
任何沃替西汀氢溴酸盐的固体形式，都可以用于本发明中的药用组合物的制备。
沃替西汀氢溴酸盐在所述药用组合物中的负载率的计算方式如下：
负载率＝药用组合物中沃替西汀氢溴酸盐的含量/药用组合物的总重量。
实施例1
将沃替西汀氢溴酸盐(50毫克)、D-甘露醇(50毫克)和聚维酮K30(50毫克)溶于甲醇(800微升)中，加热到60℃搅拌溶清。将上述溶液迅速降温到-10℃，析出白色固体，过滤，干燥，得到无定型沃替西汀氢溴酸盐与D-甘露醇及聚维酮K30的组合物，该组合物的X-射线粉末衍射图如图1所示，由图1可以看出，X-射线粉末衍射图中扣除药用辅料的背景峰后无沃替西汀氢溴酸盐晶型的特征峰。
实施例2
将沃替西汀(50毫克)、聚丙烯酸树脂Eudragit L100(50毫克)和聚乙二醇4000(200毫克)溶于乙醇(600微升)和水(600微升)中，在-40℃下搅拌混合均匀。将上述溶液在旋转蒸发器中缓慢浓缩至干，得到白色固体，得到无定型沃替西汀与聚丙烯酸树脂Eudragit L100及聚乙二醇4000的组合物，该组合物的X-射线粉末衍射图中，扣除药用辅料的背景峰后无沃替西汀晶型的特征峰。
实施例3
将沃替西汀盐酸盐(2克)、乳糖(2克)和聚乙二醇8000(10克)加入水(300毫升)中，加热到60℃搅拌溶清。将上述溶液用JISL微型喷雾干燥机LSD-48干燥，维持进口温度60℃、出口温度50℃，收集出口物料，得到白色固体，进一步真空干燥得到无定型沃替西汀盐酸盐与乳糖及聚乙二醇8000的组合物，该组合物的X-射线粉末衍射图中，扣除药用辅料的背景峰后无沃替西汀盐酸盐晶型的特征峰。
实施例4
将沃替西汀其氢溴酸盐(1克)、半乳糖(1克)和羟丙甲基纤维素E50(0.2克)加到水(10毫升)中，加热到40℃搅拌溶清。将上述溶液冷冻干燥，得到白色固体，即无定型沃替西汀氢溴酸盐与半乳糖及羟丙甲基纤维素E50的组合物，该组合物的X-射线粉末衍射图中，扣除药用辅料的背景峰后无沃替西汀氢溴酸盐晶型的特征峰。
实施例5
将沃替西汀(5克)、尿素(10克)和聚乙二醇8000(50克)加热到熔融，搅拌下迅速冷却到室温，得到白色固体。将上述固体粉碎，得到白色粉末状固体，即无定型沃替西汀与尿素及聚乙二醇8000的组合物，该组合物的X-射线粉末衍射图中，扣除药用辅料的背景峰后无沃替西汀晶型的特征峰。
实施例6
将沃替西汀(1克)、乙醇(0.1克)、山梨醇(1克)和聚乙二醇10000(20克)加热到240℃，混合均匀，迅速冷却到室温，得到白色固体。将上述固体粉碎，得到白色粉末状固体，即无定型沃替西汀与山梨醇及聚乙二醇10000的组合物，该组合物的X-射线粉末衍射图中，扣除药用辅料的背景峰后无沃替西汀晶型的特征峰。
实施例7
将沃替西汀富马酸盐(1克)、富马酸(2克)、四氢呋喃(10克)、乙醇(20 克)和脂质体(4克)的混合物加热到60℃，搅拌，混合均匀，真空蒸发除去溶剂，冷却到室温得到白色固体，即无定型沃替西汀富马酸与富马酸及脂质体的组合物，该组合物的X-射线粉末衍射图中，扣除药用辅料的背景峰后无沃替西汀富马酸盐晶型的特征峰。
实施例8
将沃替西汀氢溴酸盐(1克)、甲醇(20克)、聚丙烯酸树脂Eudragit L100(2克)和甲基丙烯酸共聚物A型(4克)的混合物加热到50℃，搅拌，溶清，真空蒸发除去溶剂，冷却到室温得到白色固体，即无定型沃替西汀氢溴酸盐与聚丙烯酸树脂Eudragit L100及甲基丙烯酸共聚物A型的组合物，该组合物的X-射线粉末衍射图中，扣除药用辅料的背景峰后无沃替西汀氢溴酸盐晶型的特征峰。
实施例9
将沃替西汀(1克)、甲醇(20克)、预胶化淀粉(1克)和乙基纤维素(2克)的混合物加热到30℃，搅拌，混合均匀，真空蒸发除去溶剂，冷却到室温得到白色固体，即无定型沃替西汀与预胶化及乙基纤维素的组合物，该组合物的X-射线粉末衍射图中，扣除药用辅料的背景峰后无沃替西汀晶型的特征峰。
实施例10
将沃替西汀氢溴酸盐(1克)、甲醇(20克)、木糖醇(2克)和羟丙基纤维素SSL(4克)的混合物加热到30℃，搅拌溶清，真空蒸发除去溶剂，冷却到室温得到白色固体，即无定型沃替西汀氢溴酸盐与木糖醇及羟丙基纤维素SSL的组合物，该组合物的X-射线粉末衍射图中，扣除药用辅料的背景峰后无沃替西汀氢溴酸盐晶型的特征峰。
实施例11
将沃替西汀氢溴酸盐(1克)、甲醇(20克)、水(10克)、枸橼酸(1克)和聚醋酸乙烯(4克)的混合物加热到30℃，搅拌溶清，真空蒸发除去溶剂，冷却到室温得到白色固体，即无定型沃替西汀氢溴酸与枸橼酸及聚醋酸乙烯的组合物，该组合物的X-射线粉末衍射图中，扣除药用辅料的背景峰后无沃替西汀氢溴酸盐晶型的特征峰。
实施例12
将沃替西汀氢溴酸盐(50毫克)、山梨醇(100毫克)和聚丙烯酸树脂Eudragit L100 (100毫克)加入到甲醇(750微升)，室温下搅拌溶清。将上述溶液在旋转蒸发器中缓慢浓缩至干，得到白色固体，即无定型沃替西汀氢溴酸盐与山梨醇及聚丙烯酸树脂Eudragit L100的组合物，该组合物的X-射线粉末衍射图如图2所示，由图2可以看出，X-射线粉末衍射图中扣除药用辅料的背景峰后无沃替西汀氢溴酸盐晶型的特征峰。
实施例13
将沃替西汀(50毫克)羧甲基纤维素邻苯二甲酸酯Agucoat CPD(2毫克)和聚丙烯酸树脂Eudragit S100(3毫克)加入到甲醇(4毫升)和乙酸乙酯(1毫升)，-30℃下搅拌溶清。将上述溶液在旋转蒸发器中缓慢浓缩至干，得到白色固体，搅拌下析出白色固体，即无定型沃替西汀与羧甲基纤维素邻苯二甲酸酯Agucoat CPD及聚丙烯酸树脂Eudragit S100的组合物，该组合物的X-射线粉末衍射图中，扣除药用辅料的背景峰后无沃替西汀晶型的特征峰。
实施例14
将沃替西汀(50毫克)、糊精(50毫克)和聚羧乙烯Carbomer 940(50毫克)加入到甲醇(4毫升)和四氢呋喃(1毫升)，-30℃下搅拌混合均匀。将上述溶液在旋转蒸发器中缓慢浓缩至干，得到白色固体，搅拌下析出白色固体，即无定型沃替西汀与糊精及聚羧乙烯Carbomer 940的组合物，该组合物的X-射线粉末衍射图中，扣除药用辅料的背景峰后无沃替西汀或其药学上可接受的盐晶型的特征峰。
实施例15
将沃替西汀氢溴酸盐(50毫克)、β-环糊精(100毫克)和预胶化淀粉Pharma-Gel(100毫克)加入到甲醇(4毫升)和水(1毫升)，室温下混合均匀。将上述溶液在旋转蒸发器中缓慢浓缩至干，得到白色固体，搅拌下析出白色固体，即无定型沃替西汀氢溴酸盐与β-环糊精及预胶化淀粉Pharma-Gel的组合物，该组合物的X-射线粉末衍射图中，扣除药用辅料的背景峰后无沃替西汀氢溴酸盐晶型的特征峰。
实施例16
将沃替西汀(50毫克)、β-环糊精(100毫克)和高支链交联淀粉(50毫克)加入到甲醇(4毫升)和水(1毫升)，室温下搅拌溶清，将上述溶液在旋转蒸发器中缓慢浓缩至干，得到白色固体，搅拌下析出白色固体，即无定型沃替西汀与β-环糊精(100毫克)及高支链交联淀粉的组合物，该组合物的X-射线粉末衍射图中，扣除药用辅料的背景峰后无沃替西汀晶型的特征峰。
实施例17
将沃替西汀硝酸盐(50毫克)、马来酸(100毫克)和羧甲基纤维素钠SCMC(500毫克)加入到二甲基亚砜(5毫升)，室温下搅拌溶清。将上述溶液缓慢浓缩至干，得到白色固体，即无定型沃替西汀硝酸盐与马来酸及羧甲基纤维素钠SCMC的组合物，该组合物的X-射线粉末衍射图中，扣除药用辅料的背景峰后无沃替西汀硝酸盐晶型的特征峰。
实施例18
将沃替西汀(50毫克)、聚乙二醇4000(100毫克)和几丁聚糖(400毫克)加入到乙醇(5毫升)，室温下搅拌溶清，将上述溶液在旋转蒸发器中缓慢浓缩至干，得到白色固体，即无定型沃替西汀与聚乙二醇4000及几丁聚糖的组合物，该组合物的X-射线粉末衍射图中，扣除药用辅料的背景峰后无沃替西汀晶型的特征峰。
实施例19
将沃替西汀氢溴酸盐(50毫克)、D-甘露醇(50毫克)和羧甲基淀粉钠Explotab(500毫克)加入到乙醇(5毫升)，室温下搅拌混合均匀，将上述溶液在旋转蒸发器中缓慢浓缩至干，得到白色固体，即无定型沃替西汀氢溴酸盐与D-甘露醇及羧甲基淀粉钠Explotab的组合物，该组合物的X-射线粉末衍射图中，扣除药用辅料的背景峰后无沃替西汀氢溴酸盐晶型的特征峰。
实施例20
将沃替西汀盐酸盐(50毫克)、聚维酮K90(100毫克)和藻酸盐E401(100毫克)加入到乙醇(5毫升)，室温下搅拌混合均匀。将上述溶液在旋转蒸发器中缓慢浓缩至干，得到白色固体，即无定型沃替西汀盐酸盐与聚维酮K90及藻酸盐E401的组合物，该组合物的X-射线粉末衍射图中，扣除药用辅料的背景峰后无沃替西汀盐酸盐晶型的特征峰。
实施例21
将沃替西汀氢溴酸盐(50毫克)、L-酒石酸(100毫克)和羧甲基纤维素邻苯二甲酸酯Agucoat CPD(1克)悬浮于甲醇(30毫升)，加热到50℃搅拌混合均匀。将上述溶液在旋转蒸发器中缓慢浓缩除去大部分溶剂，过滤，干燥，得到白色固体，即无定型沃替西汀氢溴酸盐与L-酒石酸及及羧甲基纤维素邻苯二甲酸酯Agucoat CPD的组合物，该组合物的X-射线粉末衍射图中，扣除药用辅料的背景峰后无沃替西汀氢溴 酸盐晶型的特征峰。
实施例22
将沃替西汀(50毫克)、树胶Galactosol(100毫克)和卡拉胶E407(100毫克)悬浮于甲醇(30毫升)，加热到50℃搅拌混合均匀，将上述溶液在旋转蒸发器中缓慢浓缩除去大部分溶剂，过滤，干燥，得到白色固体，即无定型沃替西汀与树胶Galactosol及卡拉胶E407的组合物，该组合物的X-射线粉末衍射图中，扣除药用辅料的背景峰后无沃替西汀晶型的特征峰。
实施例23
将沃替西汀氢溴酸盐(50毫克)、半乳糖(100毫克)和壳聚糖(200毫克)悬浮于甲醇(50毫升)，加热到50℃搅拌混合均匀。将上述溶液在旋转蒸发器中缓慢浓缩除去大部分溶剂，过滤，干燥，得到白色固体，即无定型沃替西汀氢溴酸盐与半乳糖及壳聚糖的组合物，该组合物的X-射线粉末衍射图中，扣除药用辅料的背景峰后无沃替西汀氢溴酸盐晶型的特征峰。
实施例24
将沃替西汀(300毫克)、脂质体(300毫克)和聚丙烯酸树脂Eudragit E100(300毫克)溶于乙醇(600微升)、四氢呋喃(900微升)和N,N-二甲基甲酰胺(600微升)中，加热到50℃搅拌溶清，将上述溶液降温到-30℃，析出白色固体，过滤，干燥，得到无定型沃替西汀与脂质体及聚丙烯酸树脂Eudragit E100的组合物，该组合物的X-射线粉末衍射图中，扣除药用辅料的背景峰后无沃替西汀晶型的特征峰。
实施例25
将沃替西汀(30毫克)、木糖醇(30毫克)和胶原蛋白Peptan(200毫克)溶于乙醇(600微升)和乙腈(600微升)中，加热到50℃搅拌溶清。将上述溶液在旋转蒸发器中缓慢浓缩除去大部分溶剂，析出白色固体，过滤，干燥，得到无定型沃替西汀与木糖醇及胶原蛋白Peptan的组合物，该组合物的X-射线粉末衍射图中，扣除药用辅料的背景峰后无沃替西汀晶型的特征峰。
实施例26
将沃替西汀(30毫克)、D-甘露醇(30毫克)和树胶Galactosol(150毫克)溶于甲醇(900微升)加热到50℃搅拌溶清。将上述溶液在旋转蒸发器中缓慢浓缩除去大部分溶剂，析出白色固体，过滤，干燥，得到无定型沃替西汀与D-甘露醇及树胶 Galactosol的组合物，该组合物的X-射线粉末衍射图中，扣除药用辅料的背景峰后无沃替西汀晶型的特征峰。
实施例27
将沃替西汀(30毫克)、几丁聚糖(30毫克)和羟丙甲基纤维素邻苯二甲酸酯HPMCP(30毫克)加入到乙醇(750微升)和水(750微升)，加热到80℃搅拌混合均匀。将上述溶液在旋转蒸发器中缓慢浓缩除去溶剂，得到白色固体，即无定型沃替西汀与几丁聚糖及羟丙甲基纤维素邻苯二甲酸酯HPMCP的组合物，该组合物的X-射线粉末衍射图中，扣除药用辅料的背景峰后无沃替西汀晶型的特征峰。
实施例28
将沃替西汀氢溴酸盐(30毫克)、D-甘露醇(30毫克)和羧基乙酸内酯(300毫克)加入到乙醇(750微升)和水(750微升)，加热到80℃搅拌混合均匀。将上述溶液在旋转蒸发器中缓慢浓缩除去溶剂，得到白色固体，即无定型沃替西汀氢溴酸盐与D-甘露醇及羧基乙酸内酯的组合物，该组合物的X-射线粉末衍射图中，扣除药用辅料的背景峰后无沃替西汀氢溴酸盐晶型的特征峰。
实施例29
将沃替西汀(30毫克)、β-环糊精(60毫克)和糊精Maltrin M100(60毫克)加入到乙醇(750微升)和水(750微升)，加热到80℃搅拌混合均匀。将上述溶液在旋转蒸发器中缓慢浓缩除去溶剂，得到白色固体，即无定型沃替西汀与β-环糊精及糊精Maltrin M100的组合物，该组合物的X-射线粉末衍射图中，扣除药用辅料的背景峰后无沃替西汀晶型的特征峰。
实施例30
将沃替西汀氢溴酸盐(30毫克)、琥珀酸(3毫克)和羧甲基纤维素钠SCMS(3毫克)加入到水(30毫升)，加热到100℃搅拌混合均匀。将上述溶液在旋转蒸发器中缓慢浓缩除去溶剂，得到白色固体，即无定型沃替西汀氢溴酸盐与琥珀酸及羧甲基纤维素钠SCMC的组合物，该组合物的X-射线粉末衍射图中，扣除药用辅料的背景峰后无沃替西汀氢溴酸盐晶型的特征峰。
实施例31
将沃替西汀(5毫克)、山梨醇(5毫克)和聚环氧乙烷Polyox WSR301(30毫克)加入到甲醇(300微升)和水(60微升)，60℃下搅拌混合均匀。将上述溶液在 旋转蒸发器中缓慢浓缩除去溶剂，得到白色固体，即无定型沃替西汀与山梨醇及聚环氧乙烷Polyox WSR301的组合物，该组合物的X-射线粉末衍射图中，扣除药用辅料的背景峰后无沃替西汀晶型的特征峰。
实施例32
将沃替西汀氢溴酸盐(30毫克)、山梨醇(20毫克、)聚乙二醇8000(20毫克)和聚乙烯醇EG-40(20毫克)加入到甲醇(300微升)和水(60微升)，60℃下搅拌溶清，将上述溶液在旋转蒸发器中缓慢浓缩除去溶剂，得到白色固体，即无定型沃替西汀氢溴酸盐与山梨醇、聚乙二醇8000及聚乙烯醇EG-40的组合物，该组合物的X-射线粉末衍射图中，扣除药用辅料的背景峰后无沃替西汀氢溴酸盐晶型的特征峰。
实施例33
将沃替西汀(50毫克)、木糖醇(50毫克)和羟丙甲基纤维素醋酸酯琥珀酸酯Agoat MG(1克)加入到乙醇(10毫升)和水(2毫升)，80℃下搅拌混合均匀，将上述溶液在旋转蒸发器中缓慢浓缩至干，得到白色固体，即无定型沃替西汀与木糖醇及羟丙甲基纤维素醋酸酯琥珀酸酯Agoat MG的组合物，该组合物的X-射线粉末衍射图中，扣除药用辅料的背景峰后无沃替西汀晶型的特征峰。
实施例34
将沃替西汀(50毫克)、山梨醇(100毫克)和羧甲基乙基纤维素(1克)加入到乙醇(10毫升)和水(1毫升)，80℃下搅拌混合均匀，将上述溶液在旋转蒸发器中缓慢浓缩至干，得到白色固体，即无定型沃替西汀与山梨醇及羧甲基乙基纤维素的组合物，该组合物的X-射线粉末衍射图中，扣除药用辅料的背景峰后无沃替西汀晶型的特征峰。
实施例35：无定型沃替西汀氢溴酸盐与D-甘露醇及聚维酮K30的组合物的影响因素试验
材料：实施例1所得无定型沃替西汀氢溴酸盐与D-甘露醇及聚维酮K30的组合物
表1：
Figure PCTCN2016098095-appb-000002
Figure PCTCN2016098095-appb-000003
表1说明：无定型沃替西汀氢溴酸盐与D-甘露醇及聚维酮K30组合物在高温、高湿条件下，放置10天，有关物质无显著改变，无沃替西汀或其药学上可接受的盐结晶析出。
实施例36：无定型沃替西汀氢溴酸盐与D-甘露醇及聚维酮K30组合物的加速试验
材料：实施例1所得无定型沃替西汀氢溴酸盐与D-甘露醇及聚维酮K30的组合物。
实验条件：温度40℃±2℃，湿度75％±5％，结果参见表2。
表2：
Figure PCTCN2016098095-appb-000004
表2说明：本发明的无定型沃替西汀氢溴酸盐与D-甘露醇及聚维酮K30组合物在加速试验条件下，放置6个月，有关物质无显著改变，无沃替西汀氢溴酸盐结晶析出。
本发明的无定型沃替西汀或其药学上可接受的盐与药用辅料的组合物，其溶出度明显增加，更有利于提高药物的生物利用度，使药物能够更好地发挥临床疾病治疗作用，该无定型物在加速试验条件下(40±2℃，湿度75％±5％)，能保持良好的物理 稳定性和化学稳定性。
实施例37：测定表观溶解度
比较本发明组合物与沃替西汀晶型物混合物的表观溶解度。
测定对象分别为：本发明实施例1得到的组合物；沃替西汀晶型物的混合物(沃替西汀晶型物(β晶型)与D-甘露醇、聚维酮K30经过物理混合，重量比为1:1：1，沃替西汀晶型物(β晶型)根据专利CN101472906实施例4c的方法制备得到。
表观溶解度的测定：分别称取足量本发明实施例1获得的组合物及沃替西汀晶型物的混合物，置于两个具塞锥形瓶中，加入指定pH值的稀释液，配制成过饱和溶液，密封盖紧。每个pH稀释液中平行制备三份样品。置于37℃±0.5℃的恒温水浴摇床中振荡12h，使其充分溶解以达到饱和。取上清液用0.45微米的微孔滤膜趁热过滤，并适当稀释，摇匀，分别注入液相色谱仪。以外标法计算三份平行样品在此pH缓冲液中的表观溶解度，取平均值。
各种pH值稀释液的配制：
(1)pH＝1.0的稀释液：9毫升浓盐酸加水稀释至1000毫升。
(2)pH＝4.5的稀释液：取醋酸铵7.7克，加水50毫升溶解后，加冰醋酸6毫升与适量的水使成100毫升，即得。
(3)pH＝6.8的稀释液：取0.2摩尔/升的磷酸二氢钾溶液250毫升,加0.2摩尔/升的氢氧化钠溶液118毫升，用水稀释至1000毫升，摇匀，即得。
(4)pH＝7.4的稀释液：取磷酸二氢钾1.36克,加0.l摩尔/升的氢氧化钠溶液79毫升，用水稀释至200毫升，即得。
实验结果如表3所示：
Figure PCTCN2016098095-appb-000005
表3表明：在各个pH值下，本发明的无定型沃替西汀与D-甘露醇、聚维酮K30的组合物的表观溶解度明显高于沃替西汀晶型物(β晶型)的混合物的表观溶解度。
实施例38
将沃替西汀氢溴酸盐(50毫克)和聚维酮K30(30毫克)加入到甲醇(900微升)中，加热到60℃搅拌溶清，再加入胶态二氧化硅Aerosil 200(30毫克)。将上述混 合物迅速降温到-10℃，析出白色固体，过滤，干燥，得到无定型沃替西汀氢溴酸盐与聚维酮K30及胶态二氧化硅Aerosil 200的组合物102毫克，活性成分的负载率为47.2％。该组合物的X-射线粉末衍射图如图3所示，由图3可知，X-射线粉末衍射图中扣除药用辅料的背景峰后无沃替西汀氢溴酸盐晶型的特征峰。
实施例39
将沃替西汀(50毫克)和羟丙甲基纤维素HPMC E3(30毫克)加入到甲醇(800微升)和二氯甲烷(800微升)中，在40℃下搅拌溶解，再加入胶态二氧化硅Aerosil 200(30毫克)。将上述混合物在旋转蒸发器中缓慢浓缩至干，进一步真空干燥，得到白色固体，即无定型沃替西汀与羟丙甲基纤维素HPMC E3及胶态二氧化硅Aerosil 200的组合物110毫克，活性成分的负载率为45.4％。该组合物的X-射线粉末衍射图如图4所示，X-射线粉末衍射图中扣除药用辅料的背景峰后无沃替西汀氢溴酸盐晶型的特征峰。
实施例40
将沃替西汀氢溴酸盐(2克)和聚乙二醇8000(1.2克)加入到甲醇(50毫升)中，加热到60℃搅拌溶清，再加入硅酸铝镁Neusilin UFL2(0.6克)。将上述混合物在旋转蒸发器中缓慢浓缩至干，进一步真空干燥，得到白色固体，进一步真空干燥，得到无定型沃替西汀氢溴酸盐与聚乙二醇8000及硅酸铝镁Neusilin UFL2的组合物3.8克，活性成分的负载率为52.6％。该组合物的X-射线粉末衍射图中，扣除药用辅料的背景峰后无沃替西汀氢溴酸盐晶型的特征峰。
实施例41
将沃替西汀氢溴酸盐(1克)和羟丙甲基纤维素E50(0.8克)加入到水(10毫升)和甲醇(10毫升)中，加热到60℃搅拌溶清，再加入二氧化硅Syloid 244 FP(0.3克)。将上述混合物在旋转蒸发器中缓慢浓缩至干，进一步真空干燥，得到白色固体，即无定型沃替西汀氢溴酸盐与羟丙甲基纤维素E50及二氧化硅Syloid 244 FP的组合物2.1克，活性成分的负载率为47.1％。该组合物的X-射线粉末衍射图中，扣除药用辅料的背景峰后无沃替西汀氢溴酸盐晶型的特征峰。
实施例42
将沃替西汀氢溴酸盐(5克)、尿素(0.5克)和聚维酮K30(2.5克)加入到甲醇(200毫升)中，加热到60℃搅拌溶清，再加入硅酸铝镁Neusilin UFL2(0.6克)。将上述混合物在旋转蒸发器中缓慢浓缩至干，进一步真空干燥，得到白色固体，得到 无定型沃替西汀氢溴酸盐与尿素、聚维酮K30及硅酸铝镁Neusilin UFL2的组合物8克，活性成分的负载率为62.5％。该组合物的X-射线粉末衍射图中，扣除药用辅料的背景峰后无沃替西汀晶型的特征峰。
实施例43
将沃替西汀氢溴酸盐(1克)和聚丙烯酸树脂Eudragit L100(0.8克)加入到甲醇(30毫升)中，加热到60℃搅拌溶清，再加入硅酸铝镁Neusilin UFL2(0.6克)。将上述混合物迅速降温到10℃，析出白色固体，过滤，干燥，得到无定型沃替西汀氢溴酸盐与聚丙烯酸树脂Eudragit L100及硅酸铝镁Neusilin UFL2的组合物2.3克，活性成分的负载率为42.1％。该组合物的X-射线粉末衍射图中，扣除药用辅料的背景峰后无沃替西汀氢溴酸盐晶型的特征峰。
实施例44
将沃替西汀氢溴酸盐(1克)和聚丙烯酸树脂Eudragit L100(0.6克)加入到甲醇(30毫升)中，加热到60℃搅拌溶清，再加入二氧化硅Syloid 72FP(0.4克)。将上述混合物迅速降温到10℃，析出白色固体，过滤，干燥，得到无定型沃替西汀氢溴酸盐与聚丙烯酸树脂Eudragit L100及二氧化硅Syloid 72FP的组合物1.9克，活性成分的负载率为50.4％。该组合物的X-射线粉末衍射图中，扣除药用辅料的背景峰后无沃替西汀氢溴酸盐晶型的特征峰。
实施例45
将沃替西汀氢溴酸盐(1克)和聚维酮K30(0.5克)加入到二氯甲烷(20毫升)中，加热到40℃搅拌溶清，再加入硅酸铝镁Neusilin UFL2(0.6克)。将上述混合物迅速加入到正庚烷(200毫升)，析出白色固体，过滤，干燥，得到无定型沃替西汀氢溴酸盐与聚维酮K30及硅酸铝镁Neusilin UFL2的组合物2.0克，活性成分的负载率为48.5％。该组合物的X-射线粉末衍射图中，扣除药用辅料的背景峰后无沃替西汀氢溴酸盐晶型的特征峰。
实施例46
将沃替西汀氢溴酸盐(1克)和聚维酮K30(0.6克)加入到二氯甲烷(20毫升)中，加热到40℃搅拌溶清，再加入胶态二氧化硅Aerosil 380(0.3克)。将上述混合物迅速加入到正庚烷(200毫升)，析出白色固体，过滤，干燥，得到无定型沃替西汀氢溴酸盐与聚维酮K30及胶态二氧化硅Aerosil 380的组合物1.84克，活性成分的负载率为53.1％。该组合物的X-射线粉末衍射图中，扣除药用辅料的背景峰后无沃替 西汀氢溴酸盐晶型的特征峰。
实施例47
将沃替西汀氢溴酸盐(1克)和聚维酮K30(0.7克)加入到二氯甲烷(20毫升)中，加热到40℃搅拌溶清，再加入二氧化硅Syloid 244 FP(0.3克)。将上述混合物迅速加入到正庚烷(200毫升)，析出白色固体，过滤，干燥，得到无定型沃替西汀氢溴酸盐与聚维酮K30及二氧化硅Syloid 244 FP的组合物1.92克，活性成分的负载率为50.8％。该组合物的X-射线粉末衍射图中，扣除药用辅料的背景峰后无沃替西汀氢溴酸盐晶型的特征峰。
实施例48
将沃替西汀氢溴酸盐(1克)和聚维酮K30(2克)加入到二氯甲烷(20毫升)中，加热到40℃搅拌溶清，再加入二氧化硅Syloid 244 FP(1克)。将上述混合物迅速加入到正庚烷(200毫升)，析出白色固体，过滤，干燥，得到无定型沃替西汀氢溴酸盐与聚维酮K30及二氧化硅Syloid 244 FP的组合物3.8克，活性成分的负载率为25.1％。该组合物的X-射线粉末衍射图中，扣除药用辅料的背景峰后无沃替西汀氢溴酸盐晶型的特征峰。
实施例49
将沃替西汀氢溴酸盐(1克)和聚维酮K30(0.7克)加入到二氯甲烷(20毫升)中，加热到40℃搅拌溶清，再加入氧化镁(0.5克)。将上述混合物迅速加入到正庚烷(200毫升)，析出白色固体，过滤，干燥，得到无定型沃替西汀氢溴酸盐与聚维酮K30及氧化镁的组合物2.08克，活性成分的负载率为47.1％。该组合物的X-射线粉末衍射图中，扣除药用辅料的背景峰后无沃替西汀氢溴酸盐晶型的特征峰。
实施例50
将沃替西汀氢溴酸盐(1克)和羟丙甲基纤维素HPMC E3(0.8克)加入到二氯甲烷(20毫升)中，加热到40℃搅拌溶清，再加入氧化锌(0.7克)。将上述混合物在旋转蒸发器上浓缩至干，进一步干燥，得到无定型沃替西汀氢溴酸盐与羟丙甲基纤维素HPMC E3及氧化锌的组合物2.5克，活性成分的负载率为40％。该组合物的X-射线粉末衍射图中，扣除药用辅料的背景峰后无沃替西汀氢溴酸盐晶型的特征峰。
实施例51
将沃替西汀氢溴酸盐(1克)和羟丙甲基纤维素HPMC E3(2克)加入到二氯甲 烷(20毫升)中，加热到40℃搅拌溶清，再加入二氧化钛(5克)。将上述混合物在旋转蒸发器上浓缩至干，进一步干燥，得到无定型沃替西汀氢溴酸盐与羟丙甲基纤维素HPMC E3及二氧化钛的组合物8克，活性成分的负载率为12.5％。该组合物的X-射线粉末衍射图中，扣除药用辅料的背景峰后无沃替西汀氢溴酸盐晶型的特征峰。
实施例52
将沃替西汀氢溴酸盐(1克)和羟丙甲基纤维素HPMC E3(3克)加入到二氯甲烷(20毫升)中，加热到40℃搅拌溶清，再加入胶态二氧化硅Aerosil 380(5克)。将上述混合物在旋转蒸发器上浓缩至干，进一步干燥，得到无定型沃替西汀氢溴酸盐与羟丙甲基纤维素HPMC E3及Aerosil 380的组合物9克，活性成分的负载率为11.1％。该组合物的X-射线粉末衍射图中，扣除药用辅料的背景峰后无沃替西汀氢溴酸盐晶型的特征峰。
实施例53
将沃替西汀氢溴酸盐(1克)和聚维酮K30(3克)加入到四氢呋喃(60毫升)中，加热到60℃搅拌溶清，再加入胶态二氧化硅Aerosil 380(5克)。将上述混合物在旋转蒸发器上浓缩至干，进一步干燥，得到无定型沃替西汀氢溴酸盐与聚维酮K30及Aerosil 380的组合物9克，活性成分的负载率为11.1％。该组合物的X-射线粉末衍射图中，扣除药用辅料的背景峰后无沃替西汀氢溴酸盐晶型的特征峰。
实施例54：无定型沃替西汀氢溴酸盐、聚维酮K30和胶态二氧化硅(Aerosil 200)的组合物的影响因素试验
材料：实施例38所得无定型沃替西汀氢溴酸盐、聚维酮K30和胶态二氧化硅(Aerosil 200)的组合物，实验结果参见表4。
表4：
Figure PCTCN2016098095-appb-000006
表4说明：无定型沃替西汀氢溴酸盐、聚维酮K30和胶态二氧化硅(Aerosil 200)的组合物在高温、高湿条件下，放置10天，有关物质无显著改变，无沃替西汀氢溴酸盐结晶析出。
实施例55：无定型沃替西汀氢溴酸盐、聚维酮K30和胶态二氧化硅(Aerosil 200)的组合物的加速试验
材料：实施例38所得无定型沃替西汀氢溴酸盐、聚维酮K30和胶态二氧化硅(Aerosil 200)的组合物。
实验条件：温度40℃±2℃，湿度75％±5％，结果参见表5。
表5：
Figure PCTCN2016098095-appb-000007
表5说明：本发明的无定型沃替西汀氢溴酸盐、聚维酮K30和胶态二氧化硅(Aerosil 200)的组合物在加速试验条件下，放置6个月，有关物质无显著改变，无沃替西汀氢溴酸盐结晶析出。
实施例56：测定表观溶解度
比较本发明组合物与沃替西汀晶型物混合物的表观溶解度。
测定对象分别为：本发明实施例38得到的组合物；沃替西汀晶型物的混合物(沃替西汀晶型物(β晶型)与聚维酮K30、胶态二氧化硅(Aerosil 200)经过物理混合，重量比为1:1:1，沃替西汀晶型物(β晶型)根据专利CN101472906实施例4c的方法制备得到。
表观溶解度的测定：分别称取足量本发明实施例1获得的组合物及沃替西汀晶型物的混合物，置于两个具塞锥形瓶中，加入指定pH值的稀释液，配制成过饱和溶液，密封盖紧。每个pH稀释液中平行制备三份样品。置于37℃±0.5℃的恒温水浴摇床中振荡12h，使其充分溶解以达到饱和。取上清液用0.45微米的微孔滤膜趁热过滤，并适当稀释，摇匀，分别注入液相色谱仪。以外标法计算三份平行样品在此pH缓冲液中的表观溶解度，取平均值。
各种pH值稀释液的配制：
(1)pH＝1.0的稀释液：9毫升浓盐酸加水稀释至1000毫升。
(2)pH＝4.5的稀释液：取醋酸铵7.7克，加水50毫升溶解后，加冰醋酸6毫升与适量的水使成100毫升，即得。
(3)pH＝6.8的稀释液：取0.2摩尔/升的磷酸二氢钾溶液250毫升,加0.2摩尔/升的氢氧化钠溶液118毫升，用水稀释至1000毫升，摇匀，即得。
(4)pH＝7.4的稀释液：取磷酸二氢钾1.36克,加0.l摩尔/升的氢氧化钠溶液79毫升，用水稀释至200毫升，即得。
实验结果如表6所示：
表6：
Figure PCTCN2016098095-appb-000008
表6表明：在各个pH值下，本发明的无定型沃替西汀与D-甘露醇、聚维酮K30的组合物的表观溶解度明显高于沃替西汀晶型物(β晶型)的混合物的表观溶解度。
实施例57
将沃替西汀氢溴酸盐(50毫克)和聚维酮K30(30毫克)加入到甲醇(900微升)中，加热到60℃搅拌溶清，再加入胶态二氧化硅Aerosil 200(30毫克)和微晶纤维素(20毫克)。将上述混合物迅速降温到-10℃，析出白色固体，过滤，干燥，得到无定型沃替西汀氢溴酸盐、聚维酮K30、微晶纤维素及胶态二氧化硅Aerosil 200的组合物121毫克，活性成分的负载率为38.2％。该组合物的X-射线粉末衍射图如图5所示，由图5可以看出，X-射线粉末衍射图中扣除药用辅料的背景峰后无沃替西汀氢溴酸盐晶型的特征峰，微晶纤维素的X-射线粉末衍射图如图6所示。
实施例58
将沃替西汀(50毫克)和羟丙甲基纤维素HPMC E3(30毫克)加入到甲醇(800微升)和二氯甲烷(800微升)中，在40℃下搅拌溶解，再加入胶态二氧化硅Aerosil 200(30毫克)和甘露醇(50毫克)。将上述混合物在旋转蒸发器中缓慢浓缩至干，进一步真空干燥，得到白色固体，即无定型沃替西汀、羟丙甲基纤维素HPMC E3、甘露醇及胶态二氧化硅Aerosil 200的组合物160毫克，活性成分的负载率为31.2％。该组合物的X-射线粉末衍射图如图7所示，由图7可以看出，X-射线粉末衍射图中扣除药用辅料的背景峰后无沃替西汀氢溴酸盐晶型的特征峰。
实施例59
将沃替西汀氢溴酸盐(2克)和聚乙二醇8000(1.2克)加入到甲醇(50毫升)中，加热到60℃搅拌溶清，再加入硅酸铝镁Neusilin UFL2(0.6克)和乳糖(2克)。将上述混合物在旋转蒸发器中缓慢浓缩至干，进一步真空干燥，得到白色固体，进一步真空干燥，得到无定型沃替西汀氢溴酸盐、聚乙二醇8000、乳糖及硅酸铝镁Neusilin UFL2的组合物5.8克，活性成分的负载率为34.4％。该组合物的X-射线粉末衍射图中，扣除药用辅料的背景峰后无沃替西汀氢溴酸盐晶型的特征峰。
实施例60
将沃替西汀氢溴酸盐(1克)和羟丙甲基纤维素E50(0.8克)加入到水(10毫升)和甲醇(20毫升)中，加热到60℃搅拌溶清，再加入二氧化硅Syloid 244 FP(0.3克)和微晶纤维素(0.5克)。将上述混合物在旋转蒸发器中缓慢浓缩至干，进一步真空干燥，得到白色固体，即无定型沃替西汀氢溴酸盐与羟丙甲基纤维素E50及二氧化硅Syloid 244 FP的组合物2.8克，活性成分的负载率为35.7％。该组合物的X-射线粉末衍射图中，扣除药用辅料的背景峰后无沃替西汀氢溴酸盐晶型的特征峰。
实施例61
将沃替西汀氢溴酸盐(5克)、尿素(0.5克)和聚维酮K30(2.5克)加入到甲醇(200毫升)中，加热到60℃搅拌溶清，再加入硅酸铝镁Neusilin UFL2(0.6克)和甘露醇(5克)。将上述混合物在旋转蒸发器中缓慢浓缩至干，进一步真空干燥，得到白色固体，得到无定型沃替西汀氢溴酸盐与尿素、聚维酮K30、甘露醇和硅酸铝镁Neusilin UFL2的组合物14.1克，活性成分的负载率为35.4％。该组合物的X-射线粉末衍射图中，扣除药用辅料的背景峰后无沃替西汀晶型的特征峰。
实施例62
将沃替西汀氢溴酸盐(1克)和聚丙烯酸树脂Eudragit L100(0.8克)加入到甲醇(30毫升)中，加热到60℃搅拌溶清，再加入硅酸铝镁Neusilin UFL2(0.6克)和羧甲基淀粉钠(1克)。将上述混合物迅速降温到10℃，析出白色固体，过滤，干燥，得到无定型沃替西汀氢溴酸盐与聚丙烯酸树脂Eudragit L100、羧甲基淀粉钠和硅酸铝镁Neusilin UFL2的组合物3.2克，活性成分的负载率为30.1％。该组合物的X-射线粉末衍射图中，扣除药用辅料的背景峰后无沃替西汀氢溴酸盐晶型的特征峰。
实施例63
将沃替西汀氢溴酸盐(1克)和聚丙烯酸树脂Eudragit L100(0.6克)加入到甲醇(30毫升)中，加热到60℃搅拌溶清，再加入二氧化硅Syloid 72FP(0.4克)和甘露醇(0.1克)。将上述混合物迅速降温到10℃，析出白色固体，过滤，干燥，得到无定型沃替西汀氢溴酸盐与聚丙烯酸树脂Eudragit L100及二氧化硅Syloid 72FP的组合物2.0克，活性成分的负载率为50.8％。该组合物的X-射线粉末衍射图中，扣除药用辅料的背景峰后无沃替西汀氢溴酸盐晶型的特征峰。
实施例64
将沃替西汀氢溴酸盐(1克)和聚维酮K30(0.5克)加入到二氯甲烷(25毫升)中，加热到40℃搅拌溶清，再加入硅酸铝镁Neusilin UFL2(0.6克)。将上述混合物迅速加入到正庚烷(200毫升)与微晶纤维素(2克)的混合物中，析出白色固体，过滤，干燥，得到无定型沃替西汀氢溴酸盐、聚维酮K30、微晶纤维素及硅酸铝镁Neusilin UFL2的组合物4.0克，活性成分的负载率为24.5％。该组合物的X-射线粉末衍射图中，扣除药用辅料的背景峰后无沃替西汀氢溴酸盐晶型的特征峰。
实施例65
将沃替西汀氢溴酸盐(1克)和聚维酮K30(0.6克)加入到二氯甲烷(20毫升)中，加热到40℃搅拌溶清，再加入胶态二氧化硅Aerosil 380(0.3克)。将上述混合物迅速加入到正庚烷(200毫升)与微晶纤维素(2克)的混合物中，析出白色固体，过滤，干燥，得到无定型沃替西汀氢溴酸盐与聚维酮K30及胶态二氧化硅Aerosil 380的组合物3.9克，活性成分的负载率为24.3％。该组合物的X-射线粉末衍射图中，扣除药用辅料的背景峰后无沃替西汀氢溴酸盐晶型的特征峰。
实施例66
将沃替西汀氢溴酸盐(1克)和聚维酮K30(0.7克)加入到二氯甲烷(20毫升)中，加热到40℃搅拌溶清，再加入二氧化硅Syloid 244 FP(0.3克)。将上述混合物 迅速加入到正庚烷(200毫升)与交联羧甲基纤维素钠(2克)的混合物中，析出白色固体，过滤，干燥，得到无定型沃替西汀氢溴酸盐、聚维酮K30、交联羧甲基纤维素钠及二氧化硅Syloid 244 FP的组合物3.9克，活性成分的负载率为24.6％。该组合物的X-射线粉末衍射图中，扣除药用辅料的背景峰后无沃替西汀氢溴酸盐晶型的特征峰。
实施例67
将沃替西汀氢溴酸盐(1克)和聚维酮K30(2克)加入到二氯甲烷(20毫升)中，加热到40℃搅拌溶清，再加入二氧化硅Syloid 244 FP(1克)和交联羧甲基纤维素钠(0.5克)。将上述混合物在旋转蒸发器中缓慢浓缩至干，进一步真空干燥，得到白色固体，即无定型沃替西汀氢溴酸盐、聚维酮K30、交联羧甲基纤维素钠及二氧化硅Syloid 244 FP的组合物4.5克，活性成分的负载率为22.2％。该组合物的X-射线粉末衍射图中，扣除药用辅料的背景峰后无沃替西汀氢溴酸盐晶型的特征峰。
实施例68
将沃替西汀氢溴酸盐(1克)和聚维酮K30(0.7克)加入到二氯甲烷(20毫升)中，加热到40℃搅拌溶清，再加入氧化镁(0.5克)和甘露醇(0.5克)。将上述混合物在旋转蒸发器中缓慢浓缩至干，进一步真空干燥，得到白色固体，即无定型沃替西汀氢溴酸盐、聚维酮K30、甘露醇及氧化镁的组合物2.7克，活性成分的负载率为37.0％。该组合物的X-射线粉末衍射图中，扣除药用辅料的背景峰后无沃替西汀氢溴酸盐晶型的特征峰。
实施例69
将沃替西汀氢溴酸盐(1克)和羟丙甲基纤维素HPMC E3(0.8克)加入到二氯甲烷(25毫升)中，加热到40℃搅拌溶清，再加入氧化锌(0.7克)和微晶纤维素(1克)。将上述混合物在旋转蒸发器上浓缩至干，进一步干燥，得到无定型沃替西汀氢溴酸盐、羟丙甲基纤维素HPMC E3、微晶纤维素及氧化锌的组合物3.5克，活性成分的负载率为28.5％。该组合物的X-射线粉末衍射图中，扣除药用辅料的背景峰后无沃替西汀氢溴酸盐晶型的特征峰。
实施例70
将沃替西汀氢溴酸盐(1克)和羟丙甲基纤维素HPMC E3(2克)加入到二氯甲烷(30毫升)中，加热到40℃搅拌溶清，再加入二氧化钛(5克)和微晶纤维素(2克)。将上述混合物在旋转蒸发器上浓缩至干，进一步干燥，得到无定型沃替西汀氢 溴酸盐、羟丙甲基纤维素HPMC E3、微晶纤维素及二氧化钛的组合物10克，活性成分的负载率为10.0％。该组合物的X-射线粉末衍射图中，扣除药用辅料的背景峰后无沃替西汀氢溴酸盐晶型的特征峰。
实施例71
将沃替西汀氢溴酸盐(1克)和羟丙甲基纤维素HPMC E3(3克)加入到二氯甲烷(20毫升)中，加热到40℃搅拌溶清，再加入胶态二氧化硅Aerosil 380(5克)和乳糖(1克)。将上述混合物在旋转蒸发器上浓缩至干，进一步干燥，得到无定型沃替西汀氢溴酸盐、羟丙甲基纤维素HPMC E3、乳糖及Aerosil 380的组合物10克，活性成分的负载率为10.0％。该组合物的X-射线粉末衍射图中，扣除药用辅料的背景峰后无沃替西汀氢溴酸盐晶型的特征峰。
实施例72
将沃替西汀氢溴酸盐(1克)和聚维酮K30(3克)加入到四氢呋喃(60毫升)中，加热到60℃搅拌溶清，再加入胶态二氧化硅Aerosil 380(5克)和微晶纤维素(1克)。将上述混合物在旋转蒸发器上浓缩至干，进一步干燥，得到无定型沃替西汀氢溴酸盐、聚维酮K30、微晶纤维素及Aerosil 380的组合物10克，活性成分的负载率为10.0％。该组合物的X-射线粉末衍射图中，扣除药用辅料的背景峰后无沃替西汀氢溴酸盐晶型的特征峰。
实施例73
将沃替西汀氢溴酸盐(1克)和聚维酮K30(0.8克)加入到甲醇(30毫升)中，加热到60℃搅拌溶清，再加入胶态二氧化硅Aerosil 200(0.3克)。将上述混合物在流化床中喷雾干燥，负载到微晶纤维素(2g)上，得到无定型沃替西汀氢溴酸盐、聚维酮K30、微晶纤维素及Aerosil 200的组合物3.8克，活性成分的负载率为25.3％。该组合物的X-射线粉末衍射图如图8所示，由图8可以看出，X-射线粉末衍射图扣除药用辅料的背景峰后无沃替西汀氢溴酸盐晶型的特征峰。
实施例74
将沃替西汀氢溴酸盐(1克)和羟丙甲基纤维素HPMC E3(0.8克)加入到甲醇(30毫升)中，加热到60℃搅拌溶清，再加入胶态二氧化硅Aerosil 200(0.5克)。将上述混合物在流化床中喷雾干燥，负载到乳糖(3克)上，得到无定型沃替西汀氢溴酸盐、聚维酮K30、乳糖及Aerosil 200的组合物4.7克，活性成分的负载率为20.5％。该组合物的X-射线粉末衍射图中，扣除药用辅料的背景峰后无沃替西汀氢溴酸盐晶型 的特征峰。
实施例75：无定型沃替西汀氢溴酸盐、聚维酮K30、微晶纤维素和胶态二氧化硅(Aerosil 200)的组合物的影响因素试验
材料：实施例57所得无定型沃替西汀氢溴酸盐、聚维酮K30、微晶纤维素和胶态二氧化硅(Aerosil 200)的组合物，结果参见表7。
表7：
Figure PCTCN2016098095-appb-000009
表7说明：无定型沃替西汀氢溴酸盐、聚维酮K30、微晶纤维素和胶态二氧化硅(Aerosil 200)的组合物在高温、高湿条件下，放置10天，有关物质无显著改变，无沃替西汀氢溴酸盐结晶析出。
实施例76：无定型沃替西汀氢溴酸盐、聚维酮K30、微晶纤维素和胶态二氧化硅(Aerosil 200)的组合物的加速试验
材料：实施例57所得无定型沃替西汀氢溴酸盐、聚维酮K30、微晶纤维素和胶态二氧化硅(Aerosil 200)的组合物实验条件：温度40℃±2℃，湿度75％±5％。
表8：
Figure PCTCN2016098095-appb-000010
Figure PCTCN2016098095-appb-000011
表8说明：无定型沃替西汀氢溴酸盐、聚维酮K30、微晶纤维素和胶态二氧化硅(Aerosil 200)的组合物在加速试验条件下，放置6个月，有关物质无显著改变，无沃替西汀氢溴酸盐结晶析出。
实施例77：测定表观溶解度
比较本发明组合物与沃替西汀晶型物混合物的表观溶解度。
测定对象分别为：本发明实施例57得到的组合物；沃替西汀晶型物的混合物(沃替西汀晶型物(β晶型)与聚维酮K30、微晶纤维素和胶态二氧化硅(Aerosil 200)经过物理混合，重量比为1:0.6:0.6:0.4，沃替西汀晶型物(β晶型)根据专利CN101472906实施例4c的方法制备得到。
表观溶解度的测定：分别称取足量本发明实施例57获得的组合物及沃替西汀晶型物的混合物，置于两个具塞锥形瓶中，加入指定pH值的稀释液，配制成过饱和溶液，密封盖紧。每个pH稀释液中平行制备三份样品。置于37℃±0.5℃的恒温水浴摇床中振荡12h，使其充分溶解以达到饱和。取上清液用0.45微米的微孔滤膜趁热过滤，并适当稀释，摇匀，分别注入液相色谱仪。以外标法计算三份平行样品在此pH缓冲液中的表观溶解度，取平均值。
各种pH值稀释液的配制：
(1)pH＝1.0的稀释液：9毫升浓盐酸加水稀释至1000毫升。
(2)pH＝2.0的稀释液：甲液：取磷酸16.6毫升，加水至100毫升摇匀。乙液：取磷酸氢二钠71.63克,加水使溶解成1000毫升。取上述甲液72.5毫升与乙液27.5毫升混合，摇匀，即得。
(3)pH＝3.0的稀释液：取冰醋酸50毫升，加水800毫升混合后，用氢氧化锂调节p H值至3.0，再加水稀释至1000毫升，即得。
(4)pH＝4.5的稀释液：取醋酸铵7.7克，加水50毫升溶解后，加冰醋酸6毫升与适量的水使成100毫升，即得。
(5)pH＝5.6的稀释液：取邻苯二甲酸氢钾10克，加水900毫升，搅拌使溶解，用氢氧化钠试液(必要时用稀盐酸)调节pH值至5.6,加水稀释至1000毫升，混匀，即得。
(6)pH＝6.8的稀释液：取0.2摩尔/升的磷酸二氢钾溶液250毫升,加0.2摩尔/升的氢氧化钠溶液118毫升，用水稀释至1000毫升，摇匀，即得。
(7)pH＝7.4的稀释液：取磷酸二氢钾1.36克,加0.l摩尔/升的氢氧化钠溶液79毫升，用水稀释至200毫升，即得。
实验结果如表9所示：
表9：
Figure PCTCN2016098095-appb-000012
表9表明：在各个pH值下，本发明的无定型沃替西汀与D-甘露醇、聚维酮K30的组合物的表观溶解度明显高于沃替西汀晶型物(β晶型)的混合物的表观溶解度。
本发明的无定型沃替西汀氢溴酸盐的药用组合物，其溶出度明显增加，更有利于提高药物的生物利用度，使药物能够更好地发挥临床疾病治疗作用，该无定型物在加速试验条件下(40±2℃，湿度75％±5％)，能保持良好的物理稳定性和化学稳定性。

Claims (27)

  1. 一种沃替西汀或其盐的药用组合物，其特征在于，所述组合物包含沃替西汀或其药学上可接受的盐，以及两种或两种以上的药用辅料，沃替西汀或其药学上可接受的盐与药用辅料总量的重量比为1:0.1～100，其中，所述组合物中的沃替西汀或其药学上可接受的盐为无定型态，所述组合物的X-射线粉末衍射光谱中，扣除药用辅料的背景峰后无沃替西汀或其药学上可接受的盐晶体的特征峰。
  2. 根据权利要求1所述的沃替西汀或其盐的药用组合物，其特征在于，所述药用辅料选自赋形剂、抛射剂、增溶剂、助溶剂、乳化剂、着色剂、黏合剂、崩解剂、填充剂、润滑剂、润湿剂、渗透压调节剂、稳定剂、助流剂、矫味剂、防腐剂、助悬剂、包衣材料、芳香剂、抗黏合剂、整合剂、渗透促进剂、pH值调节剂、缓冲剂、增塑剂、表面活性剂、发泡剂、消泡剂、增稠剂、包合剂、保湿剂、吸收剂、稀释剂、絮凝剂与反絮凝剂、抗氧剂、吸附剂、助滤剂、释放阻滞剂中的至少一种。
  3. 根据权利要求1所述的沃替西汀或其盐的药用组合物，其特征在于，所述药用辅料中的至少一种选自羟丙甲基纤维素、羟丙基纤维素、聚维酮、聚乙二醇、乙基纤维素、脂质体、甲基丙烯酸共聚物、聚醋酸乙烯、羧甲基乙基纤维素、羧甲基纤维素邻苯二甲酸酯、羟丙甲基纤维素邻苯二甲酸酯、羟丙甲基纤维素醋酸酯琥珀酸酯、聚丙烯酸树脂、聚羧乙烯、藻酸盐、卡拉胶、羧基乙酸内酯、树胶、聚乙烯醇、预胶化淀粉、交联淀粉、羧甲基淀粉钠、糊精、聚环氧乙烷、壳聚糖、几丁聚糖、胶原蛋白、环糊精、乳糖、半乳糖、D-甘露醇、山梨醇、木糖醇、尿素、枸橼酸、酒石酸、富马酸、马来酸或琥珀酸。
  4. 根据权利要求1所述的沃替西汀或其盐的药用组合物，其特征在于，所述沃替西汀为其氢溴酸盐形式，所述药用辅料中包含有机载体和吸附剂，沃替西汀氢溴酸盐与有机载体形成固体分散体，所述的固体分散体与吸附剂形成组合物，其中，沃替西汀氢溴酸盐与有机载体的重量比为1:0.1～10，沃替西汀氢溴酸盐与吸附剂的重量比为1:0.1～10，其中，组合物中的沃替西汀氢溴酸盐为无定型态，所述组合物的X-射线粉末衍射光谱中扣除药用辅料的背景峰后无沃替西汀氢溴酸盐的晶体的特征峰。
  5. 根据权利要求1所述的沃替西汀或其盐的药用组合物，其特征在于，所述沃替西汀为其氢溴酸盐形式，所述药用辅料中包含有机载体、吸附剂和药用制剂辅料，沃替西汀与有机载体形成固体分散体，所述的固体分散体与吸附剂和药用制剂辅料形成组合物，沃替西汀氢溴酸盐的重量为固体分散体的总重量的20％～80％，吸附剂的重量为固体分散体的重量的0.1％～100％，药用制剂辅料的重量为固体分散体的重量的0.1％～200％，其中，所述的沃替西汀氢溴酸盐为无定型态，所述组合物的 X-射线粉末衍射光谱中，扣除有机载体、吸附剂和药用辅料的背景峰后无沃替西汀氢溴酸盐晶体的特征峰。
  6. 根据权利要求5所述的沃替西汀或其药学上可接受的盐与药用辅料的组合物，其特征在于，所述吸附剂选自二氧化硅、氧化铝、二氧化钛、氧化镁、碳酸钙和氧化锌中的至少一种。
  7. 根据权利要求4或5所述的沃替西汀或其盐的药用组合物，其特征在于，所述的有机载体选自药学上可接受的小分子有机化合物、聚合物或共聚物。
  8. 根据权利要求4或5或7所述的沃替西汀或其盐的药用组合物，其特征在于，所述的有机载体选自羟丙甲基纤维素、羟丙基纤维素、聚维酮、聚乙二醇、乙基纤维素、脂质体、甲基丙烯酸共聚物、聚醋酸乙烯、羧甲基乙基纤维素、羧甲基纤维素邻苯二甲酸酯、羟丙甲基纤维素邻苯二甲酸酯、羟丙甲基纤维素醋酸酯琥珀酸酯、聚丙烯酸树脂、聚羧乙烯、藻酸盐、卡拉胶、羧基乙酸内酯、树胶、聚乙烯醇、预胶化淀粉、交联淀粉、羧甲基淀粉钠、糊精、聚环氧乙烷、壳聚糖、几丁聚糖、胶原蛋白、环糊精、乳糖、半乳糖、D-甘露醇、山梨醇、木糖醇、尿素、枸橼酸、酒石酸、富马酸、马来酸和琥珀酸中的至少一种。
  9. 根据权利要求4或5所述的沃替西汀或其盐的药用组合物，其特征在于，所述药用辅料选自赋形剂、抛射剂、增溶剂、助溶剂、乳化剂、着色剂、黏合剂、崩解剂、填充剂、润滑剂、润湿剂、渗透压调节剂、稳定剂、助流剂、矫味剂、防腐剂、助悬剂、包衣材料、芳香剂、抗黏合剂、整合剂、渗透促进剂、pH值调节剂、缓冲剂、增塑剂、表面活性剂、发泡剂、消泡剂、增稠剂、包合剂、保湿剂、吸收剂、稀释剂、絮凝剂与反絮凝剂、抗氧剂、吸附剂、助滤剂、释放阻滞剂中的至少一种。
  10. 根据权利要求1所述的沃替西汀或其盐的药用组合物的制备方法，包括如下步骤：
    1)将沃替西汀或其药学上可接受的盐与药用辅料混合，加热至药用辅料熔融；其中，沃替西汀或其药学上可接受的盐与全部药用辅料的重量比为1:0.1～100；
    2)混合均匀后冷却，将得到的混合物粉碎，得到无定型态的沃替西汀或其药学上可接受的盐与药用辅料的组合物。
  11. 根据权利要求10所述的沃替西汀或其盐的药用组合物的制备方法，其特征在于，所述药用辅料中的至少一种选自自赋形剂、抛射剂、增溶剂、助溶剂、乳化剂、着色剂、黏合剂、崩解剂、填充剂、润滑剂、润湿剂、渗透压调节剂、稳定剂、助流剂、矫味剂、防腐剂、助悬剂、包衣材料、芳香剂、抗黏合剂、整合剂、渗透促进剂、pH值调节剂、缓冲剂、增塑剂、表面活性剂、发泡剂、消泡剂、增稠剂、包合剂、保湿剂、吸收剂、稀释剂、絮凝剂与反絮凝剂、抗氧剂、吸附剂、助滤剂或释放阻滞剂。
  12. 根据权利要求10所述的沃替西汀或其盐的药用组合物的制备方法，其特征在于，所述药用辅料中的至少一种选自羟丙甲基纤维素、羟丙基纤维素、聚维酮、聚乙二醇、乙基纤维素、脂质体、甲基丙烯酸共聚物、聚醋酸乙烯、羧甲基乙基纤维素、羧甲基纤维素邻苯二甲酸酯、羟丙甲基纤维素邻苯二甲酸酯、羟丙甲基纤维素醋酸酯琥珀酸酯、聚丙烯酸树脂、聚羧乙烯、藻酸盐、卡拉胶、羧基乙酸内酯、树胶、聚乙烯醇、预胶化淀粉、交联淀粉、羧甲基淀粉钠、糊精、聚环氧乙烷、壳聚糖、几丁聚糖、胶原蛋白、环糊精、乳糖、半乳糖、D-甘露醇、山梨醇、木糖醇、尿素、枸橼酸、酒石酸、富马酸、马来酸或琥珀酸。
  13. 根据权利要求1所述的沃替西汀或其盐的药用组合物的制备方法，包括如下步骤：
    1)将沃替西汀或其药学上可接受的盐和药用辅料在溶剂中混合，混合温度为-50～150℃，形成含沃替西汀或其药学上可接受的盐和药用辅料的溶液或悬浮液，其中，沃替西汀或其药学上可接受的盐与溶剂的重量比为0.001～100:1，沃替西汀或其药学上可接受的盐与全部药用辅料的重量比为1:0.1～100；
    2)除去步骤1)得到的溶液或悬浮液中的溶剂，得到无定型态的沃替西汀或其药学上可接受的盐与药用辅料的组合物。
  14. 根据权利要求13所述的沃替西汀或其盐的药用组合物的制备方法，其特征在于，所述药用辅料中的至少一种选自自赋形剂、抛射剂、增溶剂、助溶剂、乳化剂、着色剂、黏合剂、崩解剂、填充剂、润滑剂、润湿剂、渗透压调节剂、稳定剂、助流剂、矫味剂、防腐剂、助悬剂、包衣材料、芳香剂、抗黏合剂、整合剂、渗透促进剂、pH值调节剂、缓冲剂、增塑剂、表面活性剂、发泡剂、消泡剂、增稠剂、包合剂、保湿剂、吸收剂、稀释剂、絮凝剂与反絮凝剂、抗氧剂、吸附剂、助滤剂或释放阻滞剂。
  15. 根据权利要求13所述的沃替西汀或其盐的药用组合物的制备方法，其特征在于，所述药用辅料中的至少一种选自羟丙甲基纤维素、羟丙基纤维素、聚维酮、聚乙二醇、乙基纤维素、脂质体、甲基丙烯酸共聚物、聚醋酸乙烯、羧甲基乙基纤维素、羧甲基纤维素邻苯二甲酸酯、羟丙甲基纤维素邻苯二甲酸酯、羟丙甲基纤维素醋酸酯琥珀酸酯、聚丙烯酸树脂、聚羧乙烯、藻酸盐、卡拉胶、羧基乙酸内酯、树胶、聚乙烯醇、预胶化淀粉、交联淀粉、羧甲基淀粉钠、糊精、聚环氧乙烷、壳聚糖、几丁聚糖、胶原蛋白、环糊精、乳糖、半乳糖、D-甘露醇、山梨醇、木糖醇、尿素、枸橼酸、酒石酸、富马酸、马来酸或琥珀酸。
  16. 根据权利要求13所述的沃替西汀或其盐的药用组合物的制备方法，其特征在于，步骤1)所述溶剂选自碳原子数在12个以下的醇类、酚类、醚类、卤代烃、酮类、醛类、腈类、酰胺、砜、亚砜、羧酸和水中的至少一种；步骤2)除去溶剂的方法包括：蒸发、真空蒸发、喷雾干燥、冷冻干燥、热熔挤出、过滤、离心或搅拌薄 膜干燥。
  17. 根据权利要求4所述的沃替西汀或其盐的药用组合物的制备方法，包括如下步骤：
    1)将沃替西汀氢溴酸盐、有机载体和吸附剂在溶剂中混合，混合温度为-50～150℃，形成含沃替西汀氢溴酸盐、有机载体和吸附剂的溶液或悬浮液，其中，沃替西汀氢溴酸盐与溶剂的重量比为0.001～100:1，沃替西汀氢溴酸盐与有机载体的重量比为1:0.1～10，沃替西汀氢溴酸盐与吸附剂的重量比为1:0.1～10；
    2)除去步骤1)得到的溶液或悬浮液中的溶剂，得到无定型态的沃替西汀氢溴酸盐的药用组合物。
  18. 根据权利要求17所述的沃替西汀或其盐的药用组合物的制备方法，其特征在于，所述有机载体选自药学上可接受的小分子有机化合物、聚合物或共聚物。
  19. 根据权利要求17所述的沃替西汀或其盐的药用组合物的制备方法，其特征在于，所述所述有机载体选自羟丙甲基纤维素、羟丙基纤维素、聚维酮、聚乙二醇、乙基纤维素、脂质体、甲基丙烯酸共聚物、聚醋酸乙烯、羧甲基乙基纤维素、羧甲基纤维素邻苯二甲酸酯、羟丙甲基纤维素邻苯二甲酸酯、羟丙甲基纤维素醋酸酯琥珀酸酯、聚丙烯酸树脂、聚羧乙烯、藻酸盐、卡拉胶、羧基乙酸内酯、树胶、聚乙烯醇、预胶化淀粉、交联淀粉、羧甲基淀粉钠、糊精、聚环氧乙烷、壳聚糖、几丁聚糖、胶原蛋白、环糊精、乳糖、半乳糖、D-甘露醇、山梨醇、木糖醇、尿素、枸橼酸、酒石酸、富马酸、马来酸和琥珀酸中的至少一种。
  20. 根据权利要求17所述的沃替西汀或其盐的药用组合物的制备方法，其特征在于，所述吸附剂选自二氧化硅、氧化铝、二氧化钛、氧化镁、碳酸钙和氧化锌中的至少一种。
  21. 根据权利要求17所述的沃替西汀或其盐的药用组合物的制备方法，其特征在于，步骤1)所述溶剂选自碳原子数在12个以下的醇类、酚类、醚类、卤代烃、酮类、醛类、腈类、酰胺、砜、亚砜、羧酸和水中的至少一种；步骤2)除去溶剂的方法包括：蒸发、真空蒸发、喷雾干燥、冷冻干燥、热熔挤出、过滤、离心或搅拌薄膜干燥。
  22. 根据权利要求5所述的沃替西汀或其盐的药用组合物的制备方法，包括如下步骤：
    1)将沃替西汀氢溴酸盐、至少一种有机载体、至少一种吸附剂和至少一种药用制剂辅料在溶剂中混合，混合温度为-50～150℃，形成溶液或悬浮液，其中，沃替西汀氢溴酸盐与溶剂的重量比为0.001～100:1，沃替西汀氢溴酸盐的重量为固体分散体的总重量的20％-80％，辅料的重量为固体分散体的重量的0.1％～80％；
    2)除去步骤1)得到的溶液或悬浮液中的溶剂，得到无定型态的沃替西汀氢溴酸盐的药用组合物。
  23. 一种权利要求5所述的沃替西汀或其盐的药用组合物的制备方法，包括如下步骤：
    1)将沃替西汀氢溴酸盐、至少一种有机载体、至少一种吸附剂和至少一种药用制剂辅料以及溶剂在流化床中混合，混合温度为0～150℃，形成含沃替西汀氢溴酸盐、有机载体、吸附剂和药用制剂辅料的溶液或悬浮液，其中，沃替西汀氢溴酸盐与溶剂的重量比为0.001～100:1，沃替西汀氢溴酸盐的重量为固体分散体的总重量的20％-80％，药用制剂辅料的重量为固体分散体的重量的0.1％～80％；
    2)除去步骤1)得到混合物中的溶剂，得到无定型态的沃替西汀氢溴酸盐的药用组合物。
  24. 根据权利要求22或23所述的沃替西汀或其盐的药用组合物的制备方法，其特征在于，所述药用制剂辅料选自所述的有机载体选自药学上可接受的小分子有机物、聚合物或共聚物。
  25. 根据权利要求22或23所述的沃替西汀或其盐的药用组合物的制备方法，其特征在于，所述的有机载体选自羟丙甲基纤维素、羟丙基纤维素、聚维酮，聚乙二醇、乙基纤维素、脂质体、甲基丙烯酸共聚物、聚醋酸乙烯、羧甲基乙基纤维素、羧甲基纤维素邻苯二甲酸酯、羟丙甲基纤维素邻苯二甲酸酯、羟丙甲基纤维素醋酸酯琥珀酸酯、聚丙烯酸树脂、聚羧乙烯、藻酸盐、卡拉胶、羧基乙酸内酯、树胶、聚乙烯醇、预胶化淀粉、交联淀粉、羧甲基淀粉钠、糊精、聚环氧乙烷、壳聚糖、几丁聚糖和胶原蛋白中的至少一种。
  26. 根据权利要求22所述的含有无定型沃替西汀氢溴酸盐的药用组合物的制备方法，其特征在于，步骤1)所述溶剂选自碳原子数在12个以下的醇类、酚类、醚类、卤代烃、酮类、醛类、腈类、酰胺、砜、亚砜、羧酸和水中的至少一种；步骤2)除去溶剂的方法为蒸发、真空蒸发、喷雾干燥、冷冻干燥、热熔挤出、过滤、离心或搅拌薄膜干燥。
  27. 如权利要求1或4或5的沃替西汀或其盐的药用组合物在制备治疗精神疾病的药物中的用途，所述精神疾病包括：情绪失调、抑郁症、焦虑症、创伤后应激障碍、伴有认知缺损的抑郁症、阿尔兹海默症、有残留症状的抑郁症、习惯性疼痛和进食障碍。
PCT/CN2016/098095 2015-09-07 2016-09-05 一种沃替西汀或其盐的药用组合物及其制备方法 WO2017041680A1 (zh)

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