WO2017036389A1 - 卡格列净与药用辅料的组合物及其制备方法 - Google Patents

卡格列净与药用辅料的组合物及其制备方法 Download PDF

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WO2017036389A1
WO2017036389A1 PCT/CN2016/097411 CN2016097411W WO2017036389A1 WO 2017036389 A1 WO2017036389 A1 WO 2017036389A1 CN 2016097411 W CN2016097411 W CN 2016097411W WO 2017036389 A1 WO2017036389 A1 WO 2017036389A1
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composition
cardinol
agent
pharmaceutical
pharmaceutical excipient
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PCT/CN2016/097411
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English (en)
French (fr)
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张席妮
熊志刚
胡涛
资春鹏
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常州方楠医药技术有限公司
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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
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings

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  • the invention belongs to the field of pharmaceutical preparations, and particularly relates to a composition of a cardinol and a medicinal adjuvant and a preparation method thereof, and to a pharmaceutical composition containing an amorphous form of a complex dispersion of caviar and a preparation method thereof And the use of the composition for treating a disease associated with diabetes.
  • Canagliflozin chemical name (1S)-1,5-dehydro-1-C-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]- 4-methylphenyl]-D-glucitol.
  • the product name is INVOKANA, which is a therapeutic drug for type II diabetes developed by Johnson & Johnson. Cangliet was approved by the US FDA on March 29, 2013. Canglietine is the first listed net-based drug in the United States and has performed well after the market. As a new mechanism of action, the market for type 2 diabetes will continue to expand.
  • 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. Generally, due to the ordered and periodic arrangement of crystalline material molecules, the energy of the interaction between molecules is reduced, the energy is lower, and the molecules of the amorphous state are in a highly disordered state, and the surface free energy of the substance is larger, and the solid matter is The molecules in the crystal have higher energy than the molecules in the crystalline solid matter, are more easily dispersed, increase their dissolution, and improve the bioavailability of the drug.
  • 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.
  • the Chinese patent CN101573368 discloses the amorphous state of cavigliflozin
  • the Chinese patent CN101573368 indicates in the specification that the preparation method provided by the patent WO2005/012326 obtains an amorphous form of capretat, and also indicates an amorphous state.
  • Cagliflozin is not easy to filter and dry, and it is unstable and needs to be stored under special conditions.
  • the above-mentioned single-component amorphous cardinol is difficult to meet the medicinal requirements due to the above deficiencies.
  • Patent WO2014195966 discloses a solid dispersion of cardinide and a single polymeric material.
  • the solid dispersion contains only one polymeric pharmaceutical excipient. Since the dispersion of a single polymeric pharmaceutical excipient is not very satisfactory, it is often necessary to obtain a relatively large amount of pharmaceutical excipients in order to obtain an amorphous drug molecule and stabilize it in an amorphous state.
  • Pharmaceutical preparations must use a variety of pharmaceutical excipients, and the total amount of excipients is also limited. If a single excipient is used in a large amount, it will also bring certain difficulties to the development of pharmaceutical preparations.
  • the object of the present invention is to provide a composition of carbendazim and a medicinal auxiliary material and a preparation method thereof, and obtain a composition of an amorphous form of kalepside and a medicinal auxiliary material which has good stability and dispersibility, and increases
  • the dissolution rate of the cardinol is not limited by the drying process, nor is it limited by the type of the solvent and the amount of the solvent, and the operation is simple, the cost is low, the implementation is easy, and industrial production can be realized.
  • a composition of carbendazole and a medicinal excipient comprising a cardinol and a pharmaceutically acceptable excipient, wherein the weight ratio of the two is 1:0.1 to 100, wherein the cardage is net In the stereotyped state, in the X-ray powder diffraction spectrum of the composition, the characteristic peak of the crystal of the cardinol-free crystal is absent after subtracting the background peak of the medicinal adjuvant.
  • 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.
  • the medicinal adjuvant is selected from the group consisting of hydroxypropylmethylcellulose, hydroxypropylcellulose, povidone, polyethylene glycol, ethylcellulose, liposome, methacrylic acid copolymer, polyacetic acid Ethylene, carboxymethylethylcellulose, carboxymethylcellulose phthalate, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, polyacrylic resin , carboxyvinyl, alginate, carrageenan, carboxyacetolactone, gum, polyvinyl alcohol, pregelatinized starch, crosslinked starch, sodium carboxymethyl starch, dextrin, polyethylene oxide, chitosan At least one of chitosan, ion exchange resin and collagen.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a degreggin solid dispersion, which forms a solid dispersion with an organic vehicle and forms a composition with a pharmaceutical preparation excipient. 20% to 80% by weight of the total weight of the solid dispersion, and the weight of the auxiliary material is 0.1% to 80% by weight of the solid dispersion, wherein the cardage is in an amorphous state, and the X of the composition In the ray powder diffraction spectrum, the characteristic peak of the cardinol-free crystal is absent after subtracting the background peak of the carrier and the medicinal adjuvant.
  • the organic vehicle is selected from a pharmaceutically acceptable small molecule organic compound, a polymer or a copolymer Things.
  • the organic vehicle 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, ion exchange resin, and collagen.
  • 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 adjustment.
  • Agents stabilizers, glidants, flavoring agents, preservatives, suspending agents, coating materials, fragrances, anti-adhesives, integrators, penetration enhancers, pH adjusters, buffers, plasticizers, Surfactant, foaming agent, antifoaming agent, thickener, inclusion agent, moisturizer, absorbent, diluent, flocculant and deflocculant, antioxidant, adsorbent, filter aid, release retarder At least one of them.
  • composition of the cardinol and the pharmaceutical excipient of the invention comprises the following steps:
  • the invention provides a preparation method of another composition of cardage and a pharmaceutical excipient, comprising the following steps:
  • 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.
  • the pharmaceutical excipient described in step 1) is selected from the group consisting of hydroxypropylmethylcellulose, hydroxypropylcellulose, povidone, polyethylene glycol, ethylcellulose, liposome, methacrylic acid copolymerization.
  • polyvinyl acetate 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, At least one of 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, the step 2) removing the solvent includes evaporation, vacuum evaporation, spray drying, freeze drying, hot melt extrusion, filtration, centrifugation or stirring film drying.
  • the preparation method of the pharmaceutical composition containing the cardiglipide solid dispersion of the invention comprises the following steps:
  • the present invention provides a process for the preparation of a pharmaceutical composition comprising a cardinide solid dispersion comprising the following steps:
  • the organic vehicle described in the step 1) is selected from a small molecule organic compound, a polymer or a copolymer.
  • the organic carrier described in the step 1) is selected from the group consisting of hydroxypropylmethylcellulose, hydroxypropylcellulose, povidone, polyethylene glycol, ethylcellulose, liposomes, Methacrylic acid copolymer, polyvinyl acetate, carboxymethylethyl cellulose, carboxymethyl cellulose phthalate, hydroxypropylmethyl cellulose phthalate, hydroxypropyl methyl cellulose acetate Ester succinate, polyacrylic resin, carboxyvinyl, alginate, carrageenan, carboxyacetolactone, gum, polyvinyl alcohol, pregelatinized starch, crosslinked starch, sodium carboxymethyl starch, dextrin, poly At least one of ethylene oxide, chitosan, chitosan, and collagen.
  • the pharmaceutical preparation auxiliary agent described in the step 1) is selected from the group consisting of an excipient, a propellant, a solubilizer, a solubilizer, an emulsifier, a colorant, a binder, a disintegrant, a filler, and a lubricant.
  • Agent wetting agent, osmotic pressure regulator, stabilizer, glidant, flavoring agent, preservative, suspending agent, coating material, fragrance, anti-adhesive agent, integrator, penetration enhancer, pH adjustment Agent, buffer, plasticizer, surfactant, foaming agent, antifoaming agent, thickener, inclusion agent, moisturizer, absorbent, diluent, flocculant and deflocculant, antioxidant, adsorbent At least one of a filter aid and a release retarder.
  • 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, and substances. At least one of a sulfone, a carboxylic acid, and water, the steps 2)
  • the method of removing the solvent includes evaporation, vacuum evaporation, spray drying, freeze drying, hot melt extrusion, filtration, centrifugation or stirring film drying.
  • 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 pharmaceutically acceptable pharmaceutical excipients and pharmaceutical preparation excipients in the present invention refer to excipients and additives used in the production of pharmaceuticals and formulation formulations, including excipients, propellants, solubilizers, solubilizers, emulsifiers, Colorants, binders, disintegrants, fillers, lubricants, wetting agents, osmotic pressure regulators, stabilizers, glidants, flavoring agents, preservatives, suspending agents, coating materials, fragrances, Anti-adhesive, integrator, penetration enhancer, pH adjuster, buffer, plasticizer, surfactant, foaming agent, antifoaming agent, thickener, inclusion agent, moisturizer, absorbent, thinner , flocculants and deflocculants, antioxidants, adsorbents, filter aids, release retarders, etc.
  • the present invention also provides a pharmaceutical composition comprising amorphous cl —, for use in the manufacture of a medicament for treating a disease associated with diabetes, the diabetes comprising: diabetes, diabetic retinopathy, diabetic nephropathy, diabetic neuropathy, Delayed wound healing, insulin resistance, hyperglycemia, hyperinsulinemia, elevated blood levels of fatty acids, elevated blood levels of glycerol, hyperlipidemia, obesity, hypertriglyceridemia, X syndrome, Progression or onset of diabetic complications, atherosclerosis or hypertension.
  • diabetes comprising: diabetes, diabetic retinopathy, diabetic nephropathy, diabetic neuropathy, Delayed wound healing, insulin resistance, hyperglycemia, hyperinsulinemia, elevated blood levels of fatty acids, elevated blood levels of glycerol, hyperlipidemia, obesity, hypertriglyceridemia, X syndrome, Progression or onset of diabetic complications, atherosclerosis or hypertension.
  • composition of the cardinol and the medicinal excipient of the present invention using Cu-K ⁇ radiation, deducting the characteristic peak of the background peak of the medicinal excipient from the X-ray powder diffraction spectrum of the drug-free excipient , indicating that the cardinal is in an amorphous state.
  • the crystalline state of cavigliflozin is generally used, and no report of its amorphous state has been reported.
  • the energy of the interaction between molecules is reduced, and the energy is low, while the cardage of the present invention is an amorphous state, and the molecules are in a highly disordered state.
  • the surface free energy is larger, the molecules in the solid matter have higher energy than the molecules in the crystalline solid matter, are more likely to disperse, increase the dissolution rate, and improve the bioavailability of the calichelip.
  • the "solid dispersant” method is used to block the drug molecules through the polymer network structure of the medicinal auxiliary materials, thereby suppressing the occurrence of crystallization and keeping them dispersed and absent.
  • Stereotype adopts the medicinal excipients which are widely used, low in price and good in solubility, and the medicinal excipients are mixed with the cardionet, and can be obtained by the techniques of evaporation, spray drying, freeze drying and hot melt extrusion.
  • the amorphous form increases the stability of the amorphous form of the cardinol in the composition of the cardinol of the present invention.
  • the invention selects a pharmaceutically widely used and low-cost auxiliary material, and obtains a composition of kaglipide and a medicinal auxiliary material, and is easy to develop a formulation formula, and the preparation method of the invention is not limited by the drying process, and is not affected by the solvent type. And the amount of solvent is limited, the operation is simple, the cost is low, and it is easy to realize, and industrial production can be realized.
  • composition of the amorphous form of capsamine and the medicinal excipient prepared by the invention has high dispersibility and stability, and after disintegration after being prepared into a solid preparation, the dispersing of the drug particles can be better, dispersing and dissolving. Faster, which is good for drug absorption. 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.
  • composition of the cardinol and the pharmaceutical excipient in the amorphous state of the invention is not limited by the drying process, nor is it limited by the type of the solvent and the amount of the solvent, and is easy to operate, low in cost, and easy to implement. Realize industrial production.
  • composition of the cardiostat and the pharmaceutical excipient in the amorphous state prepared by the invention can maintain good physical stability and chemical stability under accelerated test conditions (40 ⁇ 2° C., humidity: 75% ⁇ 5%). Sex. Therefore, the present invention will have broad application prospects.
  • Fig. 1 is an X-ray powder diffraction pattern of a composition of amorphous form of cardinol and D-mannitol and povidone K30 according to Example 1 of the present invention.
  • Figure 2 is an X-ray powder diffraction pattern of a composition of amorphous kaglibine and sorbitol and polyacrylic resin L100 according to Example 12 of the present invention.
  • Figure 3 is an X-ray powder diffraction pattern of a composition of amorphous form of capsate and hydroxypropylcellulose and microcrystalline cellulose according to Example 47 of the present invention.
  • Figure 4 is an X-ray powder diffraction pattern of microcrystalline cellulose used in Example 47 of the present invention.
  • Figure 5 is an X-ray powder diffraction pattern of a composition of an amorphous form of paclocillin solid dispersion and silica Syloid 244 FP of Example 76 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.
  • the loading rate of cavigliflozin in the pharmaceutical composition is calculated as follows:
  • Loading ratio the content of calpaquinol in the pharmaceutical composition / the weight of the calichel.
  • Cagliflozin (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 above solution was rapidly cooled to -10 ° C, a white solid was precipitated, filtered, and dried to obtain a composition of amorphous calglipide with D-mannitol and povidone K30, and the X-ray powder diffraction pattern of the composition was as follows. As shown in Fig. 1, it can be seen from Fig. 1 that the X-ray powder diffraction pattern has no characteristic peak of the cardiglian crystal form after subtracting the background peak of the medicinal adjuvant.
  • Cagliflozin (2 g), lactose (2 g) and polyethylene glycol 8000 (10 g) were added to water (300 ml), and heated to 60 ° C to stir and 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 caldamine and lactose and polyethylene glycol.
  • Cagliflozin (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 combination of amorphous calpaparin and galactose and hydroxypropylmethylcellulose E50.
  • the X-ray powder diffraction pattern of the composition was subtracted from the background of the medicinal adjuvant. There is no characteristic peak of the cardinal crystal form after the peak.
  • Carbopol (5 g), urea (10 g) and polyethylene glycol 8000 (50 g) were heated to melt, and rapidly cooled to room temperature with stirring to obtain a white solid.
  • the solid is pulverized to obtain a white powdery solid, that is, a composition of amorphous cl —, and urea and polyethylene glycol 8000.
  • the X-ray powder diffraction pattern of the composition is subtracted from the background peak of the medicinal adjuvant. No characteristic peak of the card Glycine crystal form.
  • Carbopol (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 combination of amorphous cligeride 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 cardinal crystal form.
  • Cagegliflozin 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 clappazone and gum Galactosol and carrageenan E407.
  • the X-ray powder diffraction pattern of the composition is subtracted from the background peak of the pharmaceutical excipient. There is no characteristic peak of the cardinal crystal form.
  • Cagegliflozin (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), the mixture was heated to 50 ° C, stirred and dissolved, and the solution was cooled to -30 ° C to precipitate a white solid, which was filtered and dried to obtain amorphous Cagliar and liposomes and polyacrylic resin Eudragit
  • the X-ray powder diffraction pattern of the composition has no characteristic peak of the cardiglian crystal form after subtracting the background peak of the medicinal adjuvant.
  • Example 35 Influential factors test of a combination of amorphous capretitive and D-mannitol and povidone K30
  • Table 1 shows that: amorphous clathlon and D-mannitol and povidone K30 compositions were placed under high temperature and high humidity conditions for 10 days, and there was no significant change in related substances, and no cardinol crystals were precipitated.
  • Example 36 Accelerated Test of Amorphous Cagnelide and D-Mannitol and Povidone K30 Compositions
  • Table 2 shows that the composition of amorphous clegalid and D-mannitol and povidone K30 was allowed to stand for 6 months under accelerated test conditions, and there was no significant change in related substances, and no cardinol crystals were precipitated.
  • the amorphous form of the cardiostat of the present invention is the composition of the amorphous cardinol and the D-mannitol and povidone K30 obtained in Example 1 of the present invention; the mixture of the cardighepsine hemihydrate a mixture obtained by physically mixing cardighepsine hemihydrate, D-mannitol and povidone K30 in a weight ratio of 1:1:1, wherein the cardighepsine hemihydrate is according to Example 2 of the patent CN101573368 The method is prepared.
  • amorphous capsate hydrochloride composition of the present invention Sufficiently weigh a sufficient amount of the amorphous capsate hydrochloride composition of the present invention, a mixture of cagliflozin hemihydrate in two stoppered conical flasks, and add a dilution of the specified pH. Formulated as a supersaturated solution with a tight seal. Three samples were prepared in parallel for each pH dilution. The mixture was shaken for 12 hours in a constant temperature water bath shaker at 37 ° C ⁇ 0.5 ° C to dissolve it sufficiently to reach saturation. The supernatant was filtered hot with a 0.45 micron microporous membrane. Dilute appropriately, shake well, and inject into the liquid chromatograph separately. 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 amorphous form of the present invention and the combination of D-mannitol and povidone K30 is significantly higher than that of Cagliflozin hemihydrate and D-mannose Apparent solubility of a mixture of alcohol and povidone K30.
  • the amorphous composition of the cardinol and the medicinal excipient of the invention has a significantly increased dissolution rate, and is more beneficial to improving the bioavailability of the drug, so that the drug can better exert the therapeutic effect of the clinical disease, and the amorphous substance is Accelerated test strip Under the condition (40 ⁇ 2°C, humidity 75% ⁇ 5%), it can maintain good physical stability and chemical stability.
  • Any physical form of carbendazim can be used to prepare a solid dispersion of amorphous cl —.
  • the cardinol (50 mg) and povidone K30 (50 mg) were dissolved in methanol (600 ⁇ l), heated to 60 ° C and stirred to dissolve, and then microcrystalline cellulose (50 mg) was added.
  • the solution was rapidly cooled to -10 ° C, and a white solid was precipitated, filtered, and dried in vacuo to give a composition of amorphous clathron solid dispersion and microcrystalline cellulose, which was deducted from the X-ray powder diffraction pattern.
  • the background peaks of the carrier and the medicinal excipients have no characteristic peaks of the cardinal crystal form.
  • the cardinol (50 mg) and polyethylene glycol 4000 (200 mg) were dissolved in ethanol (600 ⁇ l) and water (600 ⁇ l), stirred and mixed at -40 ° C, and then added with microcrystalline fibers. Vegetarian (50 mg).
  • the above solution was slowly concentrated to dryness in a rotary evaporator to obtain a white solid, that is, a combination of amorphous calcilide and microcrystalline cellulose.
  • the X-ray powder diffraction pattern of the composition was deducted from the carrier and medicinal. There is no characteristic peak of the cardinal crystal form after the background peak of the excipient.
  • Cicleley (5 g) and polyethylene glycol 8000 (10 g) were added to methanol (300 ml), heated to 60 ° C, and dissolved, and then croscarmellose sodium (0.1 g) was added.
  • 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 an amorphous caldamine solid dispersion and a crosslinked carboxy group.
  • a composition of sodium methylcellulose having an X-ray powder diffraction pattern of the composition having no characteristic peaks of the cardiglian crystal form after subtracting the background peak of the carrier and the pharmaceutically acceptable adjuvant.
  • Carbopol (1 g) and hydroxypropylmethylcellulose E50 (0.2 g) were added to water (10 ml), heated to 40 ° C, stirred and mixed, and crospovidone (0.2 g) was added.
  • the above solution is freeze-dried to obtain a white solid, that is, a composition of an amorphous form of the complex and the cross-linked povidone, in which the background of the carrier and the medicinal excipient is subtracted in the X-ray powder diffraction pattern of the composition. There is no characteristic peak of the cardinal crystal form after the peak.
  • a white powdery solid that is, a composition of an amorphous form of cardiglian solid dispersion and mannitol, in which the background peak of the carrier and the pharmaceutically acceptable excipient is subtracted in the X-ray powder diffraction pattern of the composition No characteristic peak of the card Glycine crystal form.
  • Carbopol (1 g), mannitol (0.1 g) and polyethylene glycol 10000 (10 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 combination of an amorphous form of the complex and the mannitol, in which the background peak of the carrier and the pharmaceutically acceptable excipient is subtracted in the X-ray powder diffraction pattern of the composition. No characteristic peak of the card Glycine crystal form.
  • the cardinol (50 mg) and carrageenan E407 (500 mg) were suspended in methanol (30 ml), heated to 50 ° C, stirred and mixed, and then microcrystalline cellulose (50 mg) was added.
  • 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 clathlon solid dispersion and microcrystalline cellulose, X-ray powder of the composition.
  • a white solid that is, a combination of amorphous clathlon solid dispersion and microcrystalline cellulose, X-ray powder of the composition.
  • the background peak of the carrier and the medicinal excipient was subtracted, there was no characteristic peak of the cardinal crystal form.
  • the cardinol (30 mg) and the polyacrylic resin Eudragit E100 (30 mg) were dissolved in methanol (600 ⁇ l), heated to 50 ° C, and dissolved by stirring, followed by the addition of lactose (30 mg).
  • the solution was cooled to 10 ° C, a white solid was precipitated, filtered, and dried to obtain a composition of an amorphous form of the complex and the lactose.
  • the X-ray powder diffraction pattern of the composition was deducted from the carrier and the medicinal auxiliary. After the background peak, there is no characteristic peak of the cardinal crystal form.
  • the cardinol (30 mg) and the collagen Peptan (300 mg) were dissolved in methanol (600 ⁇ l) and acetonitrile (600 ⁇ l), heated to 50 ° C, stirred and dissolved, and then microcrystalline cellulose was added (30 Mg). The solution was cooled to 10 ° C, a white solid was precipitated, filtered, and dried to obtain a composition of amorphous calpaparin and collagen Peptan. The X-ray powder diffraction pattern of the composition was deducted from the carrier and the medicinal excipient. There is no characteristic peak of the Cappellin crystal form after the background peak.
  • the cardinol (30 mg) and the gelatin Galactosol (300 mg) were dissolved in tetrahydrofuran (300 ⁇ l) and methanol (600 ⁇ l), heated to 50 ° C, stirred and dissolved, and then added with microcrystalline cellulose (30 mg). ). The solution was cooled to 10 ° C, a white solid was precipitated, filtered, and dried to obtain an amorphous form of the complex.
  • Cicleley (10 g) and hydroxypropylmethylcellulose E50 (10 g) were added to methanol (100 ml), and the mixture was stirred and stirred at room temperature, followed by the addition of colloidal silica Aerosil 200 (5 g).
  • the above mixture was spray-dried in a fluidized bed and loaded onto microcrystalline cellulose (10 g) to obtain 33.8 g of a white solid, i.e., amorphous caldamine, hydroxypropylmethylcellulose E50, colloidal silica.
  • the composition of Aerosil 200 and microcrystalline cellulose had a loading ratio of active ingredient of 28.6%.
  • the X-ray powder diffraction pattern of the composition showed no characteristic peak of the cardinal crystal form after subtracting the background peak of the medicinal adjuvant.
  • Cicleley (10 g) and polyacrylic resin Eudragit S100 (20 g) were added to methanol (100 ml), and the mixture was stirred at room temperature.
  • the above mixture was spray-dried in a fluidized bed and loaded onto microcrystalline cellulose (20 g) to obtain 46.3 g of a white solid, that is, a composition of amorphous caldamine, polyacrylic resin Eudragit S100 and microcrystalline cellulose.
  • the loading ratio of the active ingredient was 21.7%.
  • the X-ray powder diffraction pattern of the composition deducted the characteristic peak of the cardinal crystal form after subtracting the background peak of the pharmaceutical excipient.
  • Example 77 Influential factors test of a combination of amorphous kalbergem, povidone K30, silica Syloid 244 FP and microcrystalline cellulose
  • Table 4 shows that the combination of amorphous calglipide, povidone K30, silica Syloid 244 FP and microcrystalline cellulose was placed under high temperature and high humidity conditions for 10 days without significant change in related substances. Glycine crystallization is precipitated.
  • Example 78 Accelerated Stability Experiment of Composition of Amorphous Kageglifloxacin Solid Dispersion and Microcrystalline Cellulose
  • Table 5 shows that the combination of amorphous calglipide, povidone K30, silica Syloid 244 FP and microcrystalline cellulose was placed under accelerated test conditions for 6 months without significant change in related substances. The net crystals precipitated.
  • the object to be measured is: a composition of the amorphous form of the cardiostat of the present invention, which is obtained by the method of the present invention, wherein the amorphous form of kalepside, povidone K30, silica Syloid 244 FP and microcrystalline cellulose; Cagliflozin
  • the mixture of the mixture is a mixture of calpaquine hemihydrate, povidone K30, silica Syloid 244 FP and microcrystalline cellulose, and the weight ratio is 1:1:0.5:1, wherein the card Glyceride hemihydrate was prepared according to the method of Example 2 of Patent CN101573368.
  • Table 6 shows that at each pH value, the apparent solubility of the amorphous clathrene, povidone K30, silica Syloid 244 FP and microcrystalline cellulose compositions of the present invention is significantly higher than that of the cardiolide semi-hydrate. Apparent solubility of a mixture of povidone K30, silica Syloid 244 FP and microcrystalline cellulose.
  • composition of the present invention comprising the amorphous form of the complex and the medicinal excipients has a significantly increased dissolution rate, which is more beneficial to improving the bioavailability of the drug, so that the drug can better exert the therapeutic effect of the clinical disease.
  • the amorphous material maintains good physical and chemical stability under accelerated test conditions (40 ⁇ 2 ° C, humidity 75% ⁇ 5%).

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Abstract

一种卡格列净与药用辅料的组合物及其制备方法，该组合物中，卡格列净为无定型态。本发明还涉及一种含有卡格列净固体分散体的药用组合物，包含卡格列净与有机载体形成的固体分散体，以及至少一种药学上可接受的辅料，其中卡格列净为无定型态。本发明药物组合物增加了卡格列净的溶出度，有利于提高药物的生物利用度。

Description

[根据细则26改正09.09.2016]　卡格列净与药用辅料的组合物及其制备方法 技术领域
本发明属于药物制剂领域，具体涉及一种卡格列净与药用辅料的组合物及其制备方法，还涉及一种含有无定型卡格列净固体分散体的药用组合物及其制备方法，以及该组合物治疗与糖尿病相关疾病的用途。
背景技术
卡格列净(Canagliflozin)，化学名为(1S)-1,5-脱氢-1-C-[3-[[5-(4-氟苯基)-2-噻吩基]甲基]-4-甲基苯基]-D-葡萄糖醇。商品名为INVOKANA，是美国强生公司开发的II型糖尿病治疗用药。坎格列净于2013年3月29日被美国FDA批准上市。坎格列净是第1个在美国上市的列净类药物，上市后市场表现良好。作为一种新作用机制的II型糖尿病用药，其市场还会不断扩大。
卡格列净存在多种晶型。该药物的上市晶型为卡格列净半水合物晶型。中国专利CN101573368公开了卡格列净半水合物晶型和卡格列净无水物的非晶形态。专利WO2013/064909也公开了无定型卡格列净。中国专利CN103641822公开了新的卡格列净半水合物晶型。CN103980261、CN103980262和CN103936725分别报道了卡格列净无水晶型A、B和C。
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。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，而无定型态的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，提高药物的生物利用度。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。
虽然中国专利CN101573368公开了卡格列净的无定型态，但中国专利CN101573368在说明书中指出由专利WO2005/012326提供的制备方法得到非晶态的卡格列净，同时也指出非晶态的卡格列净不易过滤和干燥，而且不稳定、还需要特殊条件下保存。显然，上述单一成分的无定型卡格列净由于以上这些不足，难以满足药用的要求。
专利WO2014195966公开了一种卡格列净和一种单一高分子材料的固体分散体。该固体分散体中只含有一种高分子药用辅料。由于单一的高分子药用辅料对药物的分散作用并不是非常理想，所以要得到无定型药物分子并使之稳定在无定型状态往往需要比较大的药用辅料的量。药物制剂须用到多种药用辅料，且辅料总量也有一定限制，如某种单一辅料的用量较大时，也会对药物制剂配方的开发带来一定困难。
由于现有的无定形态卡格列净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，寻找新的无定型卡格列净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卡格列净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卡格列净与药用辅料的组合物，增加了卡格列净的溶出度，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：
一种卡格列净与药用辅料的组合物，该组合物包含卡格列净与药用辅料，两者的重量比为1:0.1～100，其中，所述的卡格列净为无定型态，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卡格列净的晶体的特征峰。
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，所述的药用辅料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、离子交换树脂和胶原蛋白中的至少一种。
本发明还提供了一种含有卡格列净固体分散体的药用组合物，卡格列净与有机载体形成固体分散体，再与药用制剂辅料形成组合物，卡格列净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％，其中，所述的卡格列净为无定型态，所述组合物的X-射线粉末衍射光谱中，扣除载体和药用辅料的背景峰后无卡格列净晶体的特征峰。
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、离子交换树脂和胶原蛋白中的至少一种。
又，所述的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。
本发明的卡格列净与药用辅料的组合物的制备方法，包括如下步骤：
1)将卡格列净和药用辅料混合，加热至药用辅料熔融；其中，卡格列净与药用辅料的重量比为1:0.1～100；
2)混合均匀后冷却，将混合物粉碎，得到无定型态的卡格列净与药用辅料的组合物。
本发明提供另一种卡格列净与药用辅料的组合物的制备方法，包括如下步骤：
1)将卡格列净和药用辅料在溶剂中混合，混合温度为-50～150℃，形成含卡格列净和药用辅料的溶液或悬浮液，其中，卡格列净与溶剂的重量比为0.001～100:1，卡格列净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，得到无定型态的卡格列净与药用辅料的组合物。
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，步骤1)中所述的药用辅料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。
本发明的含有卡格列净固体分散体的药用组合物的制备方法，包括如下步骤：
1)将卡格列净、至少一种有机载体和至少一种药用制剂辅料混物，加热至熔融，其中，卡格列净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)混合均匀后冷却，将得到的混合物粉碎，得到含无定型态的卡格列净固体分散体的药用组合物。
本发明提供另一种含有卡格列净固体分散体的药用组合物的制备方法，包括如下步骤：
1)将卡格列净、至少一种有机载体和至少一种药用制剂辅料在溶剂中混合，混合温度为-50～150℃，形成含卡格列净、有机载体和药用制剂辅料的溶液或悬浮液，其中，卡格列净与溶剂的重量比为0.001～100:1，卡格列净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，得到含无定型态的卡格列净固体分散体的药用组合物。
进一步，上述制备方法中，步骤1)中所述的有机载体选自小分子有机化合物、聚合物或共聚物。
优选地，上述制备方法中，步骤1)中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，上述制备方法中，步骤1)中所述的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。
再，上述制备方法中，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。
本发明中药学上可接受的药用辅料和药用制剂辅料是指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。
本发明还提供一种含有无定型卡格列净的药用组合物在制备治疗与糖尿病相关疾病的药物中的用途，所述疾病包括：糖尿病、糖尿病视网膜病变、糖尿病肾病变、糖尿病神经病变、延迟性伤口愈合、胰岛素阻抗性、高血糖症、高胰岛素血症、脂肪酸的血中浓度升高、甘油的血中浓度升高、高血脂症、肥胖、高甘油三酯血症、X症候群、糖尿病并发症、动脉粥样硬化正或高血压的进展或发病。
本发明的卡格列净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卡格列净结晶态的特征峰，表明卡格列净为无定型状态。现有技术中一般使用卡格列净的结晶态，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，而本发明的卡格列净为无定型态，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，提高卡格列净的生物利用度。
本发明将卡格列净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，这些药用辅料与卡格列净混合，配合蒸发、喷雾干燥、冷冻干燥和热熔挤出等技术可以得到卡格列净的无定型形式，增加本发明卡格列净的组合物中的卡格列净的无定型态的稳定性。
本发明选用在药学上应用广泛的、价格低廉的辅料，得到卡格列净与药用辅料的组合物，易于开发制剂配方，本发明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。
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卡格列净与药用辅料的组合物具有高度分散性及稳定性，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卡格列净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卡格列净与药用辅料的组合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。因此，本发明将会有广阔的应用前景。
附图说明
图1为本发明实施例1的无定型卡格列净和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的无定型卡格列净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47的无定型卡格列净和羟丙基纤维素及微晶纤维素的组合物的X-射线粉末衍射图。
图4为本发明实施例47中使用的微晶纤维素的X-射线粉末衍射图。
图5为本发明实施例76的无定型帕博西林固体分散体与二氧化硅Syloid 244 FP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 PCTCN2016097411-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。
任何物理形式的卡格列净都可以用于制备本发明中无定型卡格列净的组合物。
卡格列净在所述药用组合物中的负载率的计算方式如下：
负载率＝药用组合物中卡格列净的含量/卡格列净的投料重量。
实施例1
将卡格列净(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，得到无定型卡格列净与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可见，X-射线粉末衍射图中扣除药用辅料的背景峰后无卡格列净晶型的特征峰。
实施例2
将卡格列净(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，得到无定型卡格列净与聚丙烯酸树脂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卡格列净晶型的特征峰。
实施例3
将卡格列净(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卡格列净与乳糖及聚乙二醇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卡格列净晶型的特征峰。
实施例4
将卡格列净(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，即无定型卡格列净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卡格列净晶型的特征峰。
实施例5
将卡格列净(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，即无定型卡格列净与尿素及聚乙二醇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卡格列净晶型的特征峰。
实施例6
将卡格列净(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，即无定型卡格列净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卡格列净晶型的特征峰。
实施例7
将卡格列净(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，即无定型卡格列净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卡格列净晶型的特征峰。
实施例8
将卡格列净(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，即无定型卡格列净与聚丙烯酸树脂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卡格列净晶型的特征峰。
实施例9
将卡格列净(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，即无定型卡格列净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卡格列净晶型的特征峰。
实施例10
将卡格列净(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，即无定型卡格列净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卡格列净晶型的特征峰。
实施例11
将卡格列净(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，即无定型卡格列净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卡格列净晶型的特征峰。
实施例12
将卡格列净(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，即无定型卡格列净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可见，X-射线粉末衍射图中扣除药用辅料的背景峰后无卡格列净晶型的特征峰。
实施例13
将卡格列净(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，即无定型卡格列净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卡格列净晶型的特征峰。
实施例14
将卡格列净(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，即无定型卡格列净与糊精及聚羧乙烯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卡格列净晶型的特征峰。
实施例15
将卡格列净(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，即无定型卡格列净与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卡格列净晶型的特征峰。
实施例16
将达格列净(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，即无定型达格列净与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 的背景峰后无卡格列净晶型的特征峰。
实施例17
将卡格列净(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。将上述溶液在旋转蒸发器中缓慢浓缩至干，得到白色固体，即无定型卡格列净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卡格列净晶型的特征峰。
实施例18
将卡格列净(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，即无定型卡格列净与聚乙二醇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卡格列净晶型的特征峰。
实施例19
将卡格列净(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，即无定型卡格列净与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卡格列净晶型的特征峰。
实施例20
将卡格列净(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，即无定型卡格列净与聚维酮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卡格列净晶型的特征峰。
实施例21
将卡格列净(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，即无定型卡格列净与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卡格列净晶型的特征峰。
实施例22
将卡格列净(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，即无定型卡格列净与树胶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卡格列净晶型的特征峰。
实施例23
将卡格列净(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，即无定型卡格列净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卡格列净晶型的特征峰。
实施例24
将卡格列净(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，得到无定型卡格列净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卡格列净晶型的特征峰。
实施例25
将卡格列净(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，得到无定型卡格列净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卡格列净晶型的特征峰。
实施例26
将卡格列净(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，得到无定型卡格列净与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卡格列净晶型的特征峰。
实施例27
将卡格列净(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，即无定型卡格列净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卡格列净晶型的特征峰。
实施例28
将卡格列净(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，即无定型卡格列净与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卡格列净晶型的特征峰。
实施例29
将卡格列净(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，得到棕色固体，即无定型卡格列净与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卡格列净晶型的特征峰。
实施例30
将卡格列净(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，即无定型卡格列净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卡格列净晶型的特征峰。
实施例31
将卡格列净(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，即无定型卡格列净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卡格列净晶型的特征峰。
实施例32
将卡格列净(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，即无定型卡格列净与山梨醇、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卡格列净晶型的特征峰。
实施例33
将卡格列净(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，即无定型卡格列净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卡格列净晶型的特征峰。
实施例34
将卡格列净(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，即无定型卡格列净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卡格列净晶型的特征峰。
实施例35：无定型卡格列净与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所得无定型卡格列净与D-甘露醇及聚维酮K30的组合物
实验条件及结果参见表1。
表1：
Figure PCTCN2016097411-appb-000002
表1说明：无定型卡格列净与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，无卡格列净结晶析出。
实施例36：无定型卡格列净与D-甘露醇及聚维酮K30组合物的加速试验
材料：实施例1所得无定型卡格列净与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％。
实验过程及结果参见表2。
表2：
Figure PCTCN2016097411-appb-000003
表2说明：无定型卡格列净与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，无卡格列净结晶析出。
实施例37：测定表观溶解度
比较本发明无定型态的卡格列净组合物与卡格列净半水合物混合物的表观溶解性。
测定对象：本发明无定型卡格列净组合物为本发明实施例1得到的无定型卡格列净与D-甘露醇及聚维酮K30的组合物；卡格列净半水合物的混合物为卡格列净半水合物、D-甘露醇及聚维酮K30经物理混合得到的混合物，重量比为1:1:1，其中，卡格列净半水合物根据专利CN101573368的实施例2的方法制备得到。
表观溶解度的测定：分别称取足量本发明的无定型卡格列净组合物、卡格列净半水合物的混合物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12小时，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pH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3所示：
表3：
Figure PCTCN2016097411-appb-000004
表3表明：在各个pH值下，本发明的无定型卡格列净与D-甘露醇及聚维酮K30的组合物的表观溶解度明显高于卡格列净半水合物与D-甘露醇及聚维酮K30的混合物的表观溶解度。
本发明的卡格列净与药用辅料的无定型组合物，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38
任何物理形式的卡格列净都可以用于制备无定型卡格列净的固体分散体。
将卡格列净(50毫克)和聚维酮K30(50毫克)溶于甲醇(600微升)中，加热到60℃搅拌溶清，再加入微晶纤维素(50毫克)。将上述溶液迅速降温到-10℃，析出白色固体，过滤，真空干燥，得到无定型卡格列净固体分散体与微晶纤维素的组合物，该组合物的X-射线粉末衍射图中扣除载体和药用辅料的背景峰后无卡格列净晶型的特征峰。
实施例39
将卡格列净(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，再加入微晶纤维素(50毫克)。将上述溶液在旋转蒸发器中缓慢浓缩至干，得到白色固体，即无定型卡格列净与微晶纤维素的组合物，该组合物的X-射线粉末衍射图中，扣除载体和药用辅料的背景峰后无卡格列净晶型的特征峰。
实施例40
将卡格列净(5克)和聚乙二醇8000(10克)加入甲醇(300毫升)中，加热到60℃搅拌溶清，再加入交联羧甲基纤维素钠(0.1克)。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卡格列净固体分散体与交联羧甲基纤维素钠的组合物，该组合物的X-射线粉末衍射图中，扣除载体和药用辅料的背景峰后无卡格列净晶型的特征峰。
实施例41
将卡格列净(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℃搅拌混合均匀，再加入交联聚维酮(0.2克)。将上述溶液冷冻干燥，得到白色固体，即无定型卡格列净固体分散体与交联聚维酮的组合物，该组合物的X-射线粉末衍射图中，扣除载体和药用辅料的背景峰后无卡格列净晶型的特征峰。
实施例42
将卡格列净(1克)、甘露醇(5克)和聚乙二醇8000(5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，即无定型卡格列净固体分散体和甘露醇的组合物，该组合物的X-射线粉末衍射图中，扣除载体和药用辅料的背景峰后无卡格列净晶型的特征峰。
实施例43
将卡格列净(1克)、甘露醇(0.1克)和聚乙二醇10000(10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，即无定型卡格列净固体分散体与甘露醇的组合物，该组合物的X-射线粉末衍射图中，扣除载体和药用辅料的背景峰后无卡格列净晶型的特征峰。
实施例44
将卡格列净(1克)、四氢呋喃(10克)、乙醇(20克)和脂质体(4克)的混合物加热到90℃，搅拌下混合均匀。再加入微晶纤维素(2克)，搅拌均匀，真空蒸发除去溶剂，得到白色固体，即无定型卡格列净固体分散体与微晶纤维素的组合物，该组合物的X-射线粉末衍射图中，扣除载体和药用辅料的背景峰后无卡格列净晶型的特征峰。
实施例45
将卡格列净(1克)、甲醇(20克)和甲基丙烯酸共聚物A型(4克)的混合物加热到50℃，搅拌下溶清，再加入交联聚维酮(1克)，真空蒸发除去溶剂，冷却到室温得到白色固体，即无定型卡格列净固体分散体与交联聚维酮的组合物，该组合物的X-射线粉末衍射图中，扣除载体和药用辅料的背景峰后无卡格列净晶型的特征峰。
实施例46
将卡格列净(1克)、乙醇(20克)、四氢呋喃(10克)和乙基纤维素(2克)的混合物加热到30℃，搅拌，混合均匀，再加入硬脂酸镁(0.1克)，真空蒸发除去溶剂，冷却到室温得到白色固体，即无定型卡格列净固体分散体与硬脂酸镁的组合物，该组合物的X-射线粉末衍射图中，扣除载体和药用辅料的背景峰后无卡格列净晶型的特征峰。
实施例47
将卡格列净(1克)、甲醇(10克)和羟丙基纤维素SSL(1克)的混合物加热到30℃，搅拌溶清，再加入微晶纤维素(0.5克)，真空蒸发除去溶剂，冷却到室温得到白色固体，即无定型卡格列净固体分散体与微晶纤维素的组合物，该组合物的X-射线粉末衍射图如图3所示，X-射线粉末衍射图中扣除药用辅料的背景峰后无卡格列净晶型的特征峰，所述微晶纤维素的X-射线粉末衍射图如图4所示。
实施例48
将卡格列净(1克)、甲醇(20克)、二氯甲烷(10克)和聚醋酸乙烯(4克)的混合物加热到30℃，搅拌溶清，再加入微晶纤维素(0.5克)真空蒸发除去溶剂，冷却到室温得到白色固体，即无定型卡格列净固体分散体与微晶纤维素的组合物，该组合物的X-射线粉末衍射图中，扣除载体和药用辅料的背景峰后无卡格列净晶型的特征峰。
实施例49
将卡格列净(50毫克)和聚丙烯酸树脂Eudragit L100(100毫克)加入到甲醇(750微升)，60℃下搅拌溶清，再加入微晶纤维素(100毫克)。将上述悬浮液迅速冷却至20℃，析出白色固体。过滤、真空干燥，得到白色固体，即无定型卡格列净固体分散体与微晶纤维素的组合物，该组合物的X-射线粉末衍射图中扣除载体和药用辅料的背景峰后无卡格列净晶型的特征峰。
实施例50
将卡格列净(50毫克)和聚丙烯酸树脂Eudragit S100(5毫克)加入到甲醇(4毫升)和乙酸乙酯(1毫升)，-30℃下搅拌溶清。在加入羧甲基淀粉钠(100毫克)。将上述溶液在旋转蒸发器中缓慢浓缩至干，得到白色固体，即无定型卡格列净固体分散体与羧甲基淀粉钠的组合物，该组合物的X-射线粉末衍射图中，扣除载体和药用辅料的背景峰后无卡格列净晶型的特征峰。
实施例51
将卡格列净(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，再加入微晶纤维素(50毫克)。将上述溶液在旋转蒸发器中缓慢浓缩至干，得到白色固体，即无定型卡格列净固体分散体与微晶纤维素的组合物，该组合物的X-射线粉末衍射图中，扣除载体和药用辅料的背景峰后无卡格列净晶型的特征峰。
实施例52
将卡格列净(50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，再加入交联羧甲基纤维素钠(100毫克)。将上述溶液在旋转蒸发器中缓慢浓缩至干，得到白色固体，即无定型卡格列净固体分散体与交联羧甲基纤维素钠的组合物，该组合物的X-射线粉末衍射图中，扣除载体和药用辅料的背景峰后无卡格列净晶型的特征峰。
实施例53
将卡格列净(50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，再加入交联羧甲基纤维素钠(100毫克)。将上述溶液在旋转蒸发器中缓慢浓缩至干，得到白色固体，即无无定型卡格列净固体分散体与交联羧甲基纤维素钠的组合物，该组合物的X-射线粉末衍射图中，扣除载体和药用辅料的背景峰后无卡格列净晶型的特征峰。
实施例54
将卡格列净(50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，再加入交联羧甲基纤维素钠(100毫克)。将上述溶液在旋转蒸发器中缓慢浓缩至干，得到白色固体，即无定型卡格列净固体分散体与交联羧甲基纤维素钠的组合物，该组合物的X-射线粉末衍射图中，扣除载体和药用辅料的背景峰后无卡格列净晶型的特征峰。
实施例55
将卡格列净(50毫克)和几丁聚糖(500毫克)加入到乙醇(5毫升)，室温下搅拌溶清，再加入微晶纤维素(50毫克)。将上述溶液在旋转蒸发器中缓慢浓缩至干，得到白色固体，即无定型卡格列净固体分散体与微晶纤维素的组合物，该组合物的X-射线粉末衍射图中，扣除载体和药用辅料的背景峰后无卡格列净晶型的特征峰。
实施例56
将卡格列净(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，再加入乳糖(100毫克)。将上述溶液在旋转蒸发器中缓慢浓缩至干，得到白色固体，即无定型卡格列净固体分散体与乳糖的组合物，该组合物的X-射线粉末衍射图中，扣除载体和药用辅料的背景峰后无卡格列净晶型的特征峰。
实施例57
将卡格列净(50毫克)和藻酸盐E401(500毫克)加入到乙醇(5毫升)，室温下搅拌混合均匀，在加入乳糖(10毫克)。将上述溶液在旋转蒸发器中缓慢浓缩至干，得到白色固体，即无定型卡格列净固体分散体与乳糖的组合物，该组合物的X-射线粉末衍射图中，扣除载体和药用辅料的背景峰后无卡格列净晶型的特征峰。
实施例58
将卡格列净(50毫克)和羧甲基纤维素邻苯二甲酸酯Agucoat CPD(0.5克)悬浮于甲醇(30毫升)，加热到50℃搅拌混合均匀，再加入乳糖(50毫克)。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，即无定型卡 格列净固体分散体与乳糖的组合物，该组合物的X-射线粉末衍射图中，扣除载体和药用辅料的背景峰后无卡格列净晶型的特征峰。
实施例59
将卡格列净(50毫克)和卡拉胶E407(500毫克)悬浮于甲醇(30毫升)，加热到50℃搅拌混合均匀，再加入微晶纤维素(50毫克)。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，即无定型卡格列净固体分散体与微晶纤维素的组合物，该组合物的X-射线粉末衍射图中，扣除载体和药用辅料的背景峰后无卡格列净晶型的特征峰。
实施例60
将卡格列净(50毫克)和壳聚糖(5克)溶于甲醇(50毫升)，加热到50℃搅拌混合均匀，再加入乳糖(100毫克)。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，即无定型卡格列净固体分散体与乳糖的组合物，该组合物的X-射线粉末衍射图中，扣除载体和药用辅料的背景峰后无卡格列净晶型的特征峰。
实施例61
将卡格列净(30毫克)和聚丙烯酸树脂Eudragit E100(30毫克)溶于甲醇(600微升)中，加热到50℃搅拌溶清，再加入乳糖(30毫克)。将上述溶液降温到10℃，析出白色固体，过滤，干燥，得到无定型卡格列净固体分散体与乳糖的组合物，该组合物的X-射线粉末衍射图中，扣除载体和药用辅料的背景峰后无卡格列净晶型的特征峰。
实施例62
将卡格列净(30毫克)和胶原蛋白Peptan(300毫克)溶于甲醇(600微升)和乙腈(600微升)中，加热到50℃搅拌溶清，再加入微晶纤维素(30毫克)。将上述溶液降温到10℃，析出白色固体，过滤，干燥，得到无定型卡格列净与胶原蛋白Peptan的组合物，该组合物的X-射线粉末衍射图中，扣除载体和药用辅料的背景峰后无卡格列净晶型的特征峰。
实施例63
将卡格列净(30毫克)和树胶Galactosol(300毫克)溶于四氢呋喃(300微升)和甲醇(600微升)中，加热到50℃搅拌溶清，再加入微晶纤维素(30毫克)。将上述溶液降温到10℃，析出白色固体，过滤，干燥，得到无定型卡格列净固体分散体与 微晶纤维素的组合物，该组合物的X-射线粉末衍射图中，扣除载体和药用辅料的背景峰后无卡格列净晶型的特征峰。
实施例64
将卡格列净(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，加入羧甲基纤维素钠(30毫克)。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，即无定型卡格列净与羧甲基纤维素钠的组合物，该组合物的X-射线粉末衍射图中，扣除载体和药用辅料的背景峰后无卡格列净晶型的特征峰。
实施例65
将卡格列净(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，再加入乳糖(200毫克)。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，即无定型卡格列净固体分散体与乳糖的组合物，该组合物的X-射线粉末衍射图中，扣除载体和药用辅料的背景峰后无卡格列净晶型的特征峰。
实施例66
将卡格列净(30毫克)和糊精Maltrin M100(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，再加入乳糖(200毫克)。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，即无定型卡格列净固体分散体与乳糖的组合物，该组合物的X-射线粉末衍射图中，扣除载体和药用辅料的背景峰后无卡格列净晶型的特征峰。
实施例67
将卡格列净(30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，再加入微晶纤维素(30毫克)。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，即无定型卡格列净固体分散体与微晶纤维素的组合物，该组合物的X-射线粉末衍射图中，扣除载体和药用辅料的背景峰后无卡格列净晶型的特征峰。
实施例68
将卡格列净(30毫克)和羧甲基纤维素钠SCMC(30毫克)加入到甲醇(300微升)和水(60微升)，60℃下搅拌混合均匀，再加入微晶纤维素(60毫克)。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，即无定型卡格列净固体分散 体与微晶纤维素的组合物，该组合物的X-射线粉末衍射图中，扣除载体和药用辅料的背景峰后无卡格列净晶型的特征峰。
实施例69
将卡格列净(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，加入胶态二氧化硅Aerosil 200(20毫克)。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，即无定型卡格列净固体分散体与胶态二氧化硅Aerosil 200的组合物，该组合物的X-射线粉末衍射图中扣除载体和药用辅料的背景峰后无卡格列净晶型的特征峰。
实施例70
将卡格列净(30毫克)和聚乙烯醇EG-40(60毫克)加入到甲醇(300微升)和水(60微升)，60℃下搅拌溶清，再加入乳糖(30毫克)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，即无定型卡格列净固体分散体与乳糖的组合物，该组合物的X-射线粉末衍射图中，扣除载体和药用辅料的背景峰后无卡格列净晶型的特征峰。
实施例71
将卡格列净(50毫克)和羟丙甲基纤维素醋酸酯琥珀酸酯Agoat MG(2克)加入到乙醇(10毫升)和水(2毫升)，80℃下搅拌混合均匀，再加入微晶纤维素(50毫克)。将上述溶液在旋转蒸发器中缓慢浓缩至干，得到白色固体，即无定型卡格列净固体分散体与微晶纤维素的组合物，该组合物的X-射线粉末衍射图中，扣除载体和药用辅料的背景峰后无卡格列净晶型的特征峰。
实施例72
将卡格列净(50毫克)和羧甲基乙基纤维素(2克)加入到乙醇(10毫升)和水(1毫升)，80℃下搅拌混合均匀，再加入交联羧甲基纤维素钠(50毫克)。将上述溶液在旋转蒸发器中缓慢浓缩至干，得到白色固体，即无定型卡格列净固体分散体与交联羧甲基纤维素钠的组合物，该组合物的X-射线粉末衍射图中，扣除载体和药用辅料的背景峰后无卡格列净晶型的特征峰。
实施例73
将卡格列净(10克)和聚维酮K30(20克)加入到甲醇(100毫升)和二氯甲烷(20毫升)，室温下搅拌溶清。将上述混合物在流化床中喷雾干燥，负载到微晶纤维素(20克)上，得到白色固体47.5克，即无定型卡格列净、聚维酮K30与微晶纤维素 的组合物，活性成分的负载率为20.3％。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卡格列净晶型的特征峰。
实施例74
将卡格列净(10克)和羟丙甲基纤维素E50(10克)加入到甲醇(100毫升)，室温下搅拌溶清，再加入胶态二氧化硅Aerosil 200(5克)。将上述混合物在流化床中喷雾干燥，负载到微晶纤维素(10克)上，得到白色固体33.8克，即无定型卡格列净、羟丙甲基纤维素E50、胶态二氧化硅Aerosil 200与微晶纤维素的组合物，活性成分的负载率为28.6％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卡格列净晶型的特征峰。
实施例75
将卡格列净(10克)和聚丙烯酸树脂Eudragit S100(20克)加入到甲醇(100毫升)，室温下搅拌溶清。将上述混合物在流化床中喷雾干燥，负载到微晶纤维素(20克)上，得到白色固体46.3克，即无定型卡格列净、聚丙烯酸树脂Eudragit S100与微晶纤维素的组合物，活性成分的负载率为21.7％。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卡格列净晶型的特征峰。
实施例76
将卡格列净(10克)和聚维酮K30(10克)加入到甲醇(80毫升)和丙酮(20毫升)，室温下搅拌溶清，再加入二氧化硅Syloid 244 FP(5克)。将上述混合物在流化床中喷雾干燥，负载到微晶纤维素(10克)上，得到白色固体32.9克，即无定型卡格列净、聚维酮K30、二氧化硅Syloid 244 FP与微晶纤维素的组合物，活性成分的负载率为29.7％。该组合物的X-射线粉末衍射图如图5所示，由图5可知，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卡格列净晶型的特征峰。
实施例77：无定型卡格列净、聚维酮K30、二氧化硅Syloid 244 FP与微晶纤维素的组合物的影响因素试验
材料：实施例76所得无定型卡格列净、聚维酮K30、二氧化硅Syloid 244 FP与微晶纤维素的组合物。
表4：
Figure PCTCN2016097411-appb-000005
Figure PCTCN2016097411-appb-000006
表4说明：无定型卡格列净、聚维酮K30、二氧化硅Syloid 244 FP与微晶纤维素的组合物在高温、高湿条件下，放置10天，有关物质无显著改变，无卡格列净结晶析出。
实施例78：无定型卡格列净固体分散体与微晶纤维素的组合物的加速稳定性实验
材料：实施例76所得无定型卡格列净、聚维酮K30、二氧化硅Syloid 244 FP与微晶纤维素的组合物。
实验条件：温度40℃±2℃，湿度75％±5％。
表5：
Figure PCTCN2016097411-appb-000007
表5说明：无定型卡格列净、聚维酮K30、二氧化硅Syloid 244 FP与微晶纤维素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，无卡格列净结晶析出。
实施例79：测定表观溶解度
比较本发明无定型态的卡格列净组合物与卡格列净半水合物混合物的表观溶解性。
测定对象：本发明无定型卡格列净组合物为本发明实施例76得到的无定型卡格列净、聚维酮K30、二氧化硅Syloid 244 FP与微晶纤维素的组合物；所述卡格列净半水 合物的混合物为卡格列净半水合物、聚维酮K30、二氧化硅Syloid 244 FP与微晶纤维素经物理混合得到的混合物，重量比为1:1:0.5:1，其中，卡格列净半水合物根据专利CN101573368的实施例2的方法制备得到。
表观溶解度的测定：分别称取足量本发明的无定型卡格列净组合物、所述卡格列净半水合物的混合物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12小时，使其充分溶解以达到饱和。取上清液用0.45um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pH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6所示：
表6：
Figure PCTCN2016097411-appb-000008
Figure PCTCN2016097411-appb-000009
表6表明：在各个pH值下，本发明无定型卡格列净、聚维酮K30、二氧化硅Syloid244 FP与微晶纤维素的组合物的表观溶解度明显高于卡格列净半水合物、聚维酮K30、二氧化硅Syloid 244 FP与微晶纤维素的混合物的表观溶解度。
本发明的含无定型卡格列净固体分散体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。

Claims (24)

  1. 一种卡格列净与药用辅料的组合物，其特征在于，所述组合物中，卡格列净与药用辅料的重量比为1:0.1～100，其中，所述的卡格列净为无定型态，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卡格列净晶体的特征峰。
  2. 根据权利要求1所述的卡格列净与药用辅料的组合物，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所述的卡格列净与药用辅料的组合物，其特征在于，所述药用辅料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、离子交换树脂和胶原蛋白中的至少一种。
  4. 根据权利要求1所述的卡格列净与药用辅料的组合物，其特征在于，所述药用辅料中包含有机载体和药用制剂辅料，卡格列净先与有机载体形成固体分散体，所述的固体分散体再与药用制剂辅料形成组合物，其中，卡格列净的重量为固体分散体的总重量的20％～80％，所述药用制剂辅料的重量为固体分散体的重量的0.1％～80％。
  5. 根据权利要求4所述的卡格列净与药用辅料的组合物，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。
  6. 根据权利要求4所述的卡格列净与药用辅料的组合物，其特征在于，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、离子交换树脂和胶原蛋白中的至少一种。
  7. 根据权利要求4所述的卡格列净与药用辅料的组合物，其特征在于，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。
  8. 如权利要求1所述的卡格列净与药用辅料的组合物的制备方法，包括如下步骤：
    1)将卡格列净与药用辅料混合，加热至药用辅料熔融；其中，卡格列净与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，得到无定型态的卡格列净与药用辅料的组合物。
  9. 根据权利要求8所述的卡格列净与药用辅料的组合物的制备方法，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8所述的卡格列净与药用辅料的组合物的制备方法，其特征在于，所述的药用辅料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。
  11. 如权利要求1所述的卡格列净与药用辅料的组合物的制备方法，包括如下步骤：
    1)将卡格列净和药用辅料在溶剂中混合，混合温度为-50～150℃，形成含卡格列净和药用辅料的溶液或悬浮液，其中，卡格列净与溶剂的重量比为0.001～100:1，卡格列净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，得到无定型态的卡格列净与药用辅料的组合物。
  12. 根据权利要求11所述的卡格列净与药用辅料的组合物的制备方法，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。
  13. 根据权利要求11所述的卡格列净与药用辅料的组合物的制备方法，其特征在于，所述的药用辅料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、离子交换树脂和胶原蛋白中的至少一种。
  14. 根据权利要求11所述的卡格列净与药用辅料的组合物的制备方法，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。
  15. 如权利要求4所述的卡格列净与药用辅料的组合物的制备方法，包括如下步骤：
    1)将卡格列净、至少一种有机载体和至少一种药用制剂辅料混合，加热至熔融，其中，卡格列净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)混合均匀后冷却，将得到的混合物粉碎，得到含无定型态的卡格列净固体分散体的药用组合物。
  16. 根据权利要求15所述的卡格列净与药用辅料的组合物的制备方法，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、聚合物和共聚物。
  17. 根据权利要求15或16所述的卡格列净与药用辅料的组合物的制备方法，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。
  18. 根据权利要求15所述的卡格列净与药用辅料的组合物的制备方法，其特征在于，所述的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。
  19. 如权利要求4所述卡格列净与药用辅料的组合物的制备方法，包括如下步骤：
    1)将卡格列净、至少一种有机载体和至少一种药用制剂辅料在溶剂中混合，混合温度为-50～150℃，形成含卡格列净、有机载体和药用制剂辅料的溶液或悬浮液，其中，卡格列净与溶剂的重量比为0.001～100:1，卡格列净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，即得。
  20. 根据权利要求19所述的卡格列净与药用辅料的组合物的制备方法，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。
  21. 根据权利要求19或20所述的卡格列净与药用辅料的组合物的制备方法，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、离子交换树脂和胶原蛋白中的至少一种。
  22. 根据权利要求19所述的卡格列净与药用辅料的组合物的制备方法，其特征在于，所述的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。
  23. 根据权利要求19所述的卡格列净与药用辅料的组合物的制备方法，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。
  24. 如权利要求1或4的卡格列净与药用辅料的组合物在制备治疗与糖尿病相关疾病的药物中的用途，所述疾病包括：糖尿病、糖尿病视网膜病变、糖尿病肾病变、糖尿病神经病变、延迟性伤口愈合、胰岛素阻抗性、高血糖症、高胰岛素血症、脂肪酸的血中浓度升高、甘油的血中浓度升高、高血脂症、肥胖、高甘油三酯血症、X症候群、糖尿病并发症、动脉粥样硬化正或高血压的进展或发病。
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