WO2017084597A1 - 一种阿普斯特的无定型物、其制备方法及应用 - Google Patents

一种阿普斯特的无定型物、其制备方法及应用 Download PDF

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WO2017084597A1
WO2017084597A1 PCT/CN2016/106201 CN2016106201W WO2017084597A1 WO 2017084597 A1 WO2017084597 A1 WO 2017084597A1 CN 2016106201 W CN2016106201 W CN 2016106201W WO 2017084597 A1 WO2017084597 A1 WO 2017084597A1
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apster
amorphous
solid dispersion
solvent
pharmaceutical
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PCT/CN2016/106201
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English (en)
French (fr)
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张席妮
熊志刚
资春鹏
张三丰
杨庆昆
周涛
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常州爱诺新睿医药技术有限公司
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Priority claimed from CN201510798142.1A external-priority patent/CN106727344A/zh
Priority claimed from CN201510997064.8A external-priority patent/CN106916096A/zh
Application filed by 常州爱诺新睿医药技术有限公司 filed Critical 常州爱诺新睿医药技术有限公司
Priority to EP16865774.0A priority Critical patent/EP3378852A1/en
Publication of WO2017084597A1 publication Critical patent/WO2017084597A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/4035—Isoindoles, e.g. phthalimide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1611—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide

Definitions

  • the invention belongs to the field of pharmaceutical preparations, relates to an amorphous substance of Apster and a preparation method thereof, and to a solid dispersion of amorphous Apster and a preparation method thereof, and provides a medicinal use.
  • Apples is a small molecule phosphodiesterase 4 (PDE4) inhibitor developed by Celgene, which was approved by the US Food and Drug Administration (FDA) on March 21, 2014. Treatment for adult patients with active psoriatic arthritis.
  • the drug is the first and only PDE4 inhibitor approved by the FDA for the treatment of plaque psoriasis. Since the high drug market, the market has responded well. At the same time, the drug is also being applied for indications for the treatment of moderate to severe plaque psoriasis.
  • Apster there are many crystal forms in Apster.
  • the marketed crystalline form of the drug is the Apster anhydrate crystalline form Form B.
  • U.S. Patent No. 7,893,101 discloses Forms, Top B, Form C, Form D, Form E, Form F, and Form G of Appart's crystal form and Apster's crystal form.
  • U.S. Patent No. 15,283,249 discloses amorphous Apster and provides a spectrum and preparation of XRPD.
  • 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 order and periodicity of crystalline material molecules Arrangement, reducing the energy of the interaction between molecules, the energy is lower, while the molecules of the amorphous state are in a highly disordered state, the surface free energy of the substance is larger, and the molecules in the solid matter are more than the molecules in the crystalline solid matter. Higher energy, easier to disperse, increase its 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.
  • An amorphous type of Apster that uses Cu-K ⁇ to irradiate the amorphous substance, and has no sharp diffraction peak in the X-ray powder diffraction spectrum expressed by degree 2 ⁇ .
  • the X-ray powder diffraction spectrum has three broad peaks between 2.0 and 50.0, as shown in FIG.
  • the invention provides a preparation method of an apast amorphous substance, comprising the following steps:
  • step 2) The solution of the step 1) is added to the solvent II at a temperature of -80 to 100 ° C to form a suspension in which the solvent I and the solvent II are different, and the volume ratio of the solution to the solvent II is 1:1 to 200. ;
  • the solvent I is selected from at least one of an alcohol, a ketone, an ether, a halogenated hydrocarbon, an amide, a sulfone or a sulfoxide having 8 or less carbon atoms
  • the solvent II is selected from the group consisting of 8 or less carbons.
  • the invention provides a preparation method of another aprost amorphous substance, comprising:
  • the organic solvent is at least one selected from the group consisting of alcohols having 8 or less carbon atoms, ethers, ketones, and nitriles.
  • the method of removing the solvent is a solvent evaporation method.
  • the amorphous substance of the Apster of the present invention is a new solid form of Apost, due to the presence of crystalline molecules
  • the order and periodic arrangement reduce the energy of the interaction between molecules, and the energy is lower, while the molecules in the solid matter in the amorphous state have higher energy than the molecules in the crystalline solid matter, and are easy to disperse, which is beneficial to increase. Solubility.
  • the substance in the amorphous state of the present invention has a high degree of dispersibility.
  • the amorphous form can disperse the drug particles more, disperse faster, and facilitate drug absorption.
  • the molecules of the amorphous drug are highly disordered, and the surface free energy of the substance is larger. Therefore, the solubility of the amorphous drug is significantly increased, which is more conducive to the absorption of the drug by the body. To enable drugs to better play the role of clinical disease treatment.
  • the invention provides a solid dispersion of a Pust and a medicinal auxiliary material and a preparation method thereof, and obtains a solid dispersion of an amorphous form and a medicinal auxiliary material with good stability and dispersibility, and an increase
  • the dissolution rate of the apster, the preparation method is not limited by the drying process, nor is it limited by the type of solvent and the amount of solvent, the operation is simple, the cost is low, the implementation is easy, and industrial production can be realized.
  • the present invention provides a solid dispersion of apster and a pharmaceutically acceptable excipient, the solid dispersion comprising a Pust and two or more pharmaceutically acceptable excipients, the weight of the apster and all medicinal excipients
  • the ratio is 1:0.1-100, wherein the Apster in the solid dispersion is in an amorphous state, and the X-ray powder diffraction spectrum of the solid dispersion is not deducted from the background peak of the medicinal auxiliary material.
  • the characteristic peak of the crystal of Apster is 1:0.1-100, wherein the Apster in the solid dispersion is in an amorphous state, and the X-ray powder diffraction spectrum of the solid dispersion is not deducted from the background peak of the medicinal auxiliary material. The characteristic peak of the crystal of Apster.
  • At least one of the pharmaceutical excipients is at least one selected from the group consisting of a diluent, a lubricant, a binder, a disintegrant, a surfactant, a film-forming material, a coating material, and a capsule material.
  • At least one of the pharmaceutical excipients is selected from the group consisting of hydroxypropylmethylcellulose, hydroxypropylcellulose, povidone, polyethylene glycol, ethylcellulose, microcrystalline cellulose, liposomes , methacrylic acid copolymer, 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, citric acid, tartaric acid,
  • the preparation method of the solid dispersion of the apster and the medicinal adjuvant of the invention comprises the following steps:
  • At least one of the pharmaceutical excipients is at least one selected from the group consisting of a diluent, a lubricant, a binder, a disintegrant, a surfactant, a film-forming material, a coating material, and a capsule material.
  • At least one of the pharmaceutical excipients described in step 1) is selected from the group consisting of hydroxypropylmethylcellulose, hydroxypropylcellulose, povidone, polyethylene glycol, ethylcellulose, and microcrystalline fibers. , liposome, methacrylic acid copolymer, polyvinyl acetate, carboxymethylethylcellulose, carboxymethylcellulose phthalate, hydroxypropylmethylcellulose ortho-benzene Diformate, hydroxypropylmethylcellulose acetate succinate, polyacrylic resin, carboxyvinyl, alginate, carrageenan, carboxyacetolactone, gum, polyvinyl alcohol, pregelatinized starch, cross-linking Starch, sodium carboxymethyl starch, dextrin, polyethylene oxide, chitosan, chitosan, collagen, cyclodextrin, lactose, galactose, D-mannitol, sorbitol, xylitol, At least one of
  • the invention provides a preparation method of another solid dispersion of apster and a medicinal adjuvant, comprising the following steps:
  • At least one of the pharmaceutical excipients is at least one selected from the group consisting of a diluent, a lubricant, a binder, a disintegrant, a surfactant, a film-forming material, a coating material, and a capsule material.
  • At least one of the pharmaceutical excipients described in step 1) is selected from the group consisting of hydroxypropylmethylcellulose, hydroxypropylcellulose, povidone, polyethylene glycol, ethylcellulose, liposomes , methacrylic acid copolymer, 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, tart
  • 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 water.
  • At least one of the steps 2) 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 pharmaceutical composition
  • a pharmaceutical composition comprising amorphous aptist and two or more pharmaceutically acceptable excipients, at least one selected from the group consisting of diluted At least one of a agent, a lubricant, a binder, a disintegrant, a surfactant, a film-forming material, a coating material, and a capsule material.
  • At least one of the pharmaceutical excipients in the above pharmaceutical composition is selected from the group consisting of hydroxypropylmethylcellulose, hydroxypropylcellulose, povidone, polyethylene glycol, ethylcellulose, and microcrystalline cellulose. , liposome, methacrylic acid copolymer, polyvinyl acetate, carboxymethyl ethyl cellulose, carboxymethyl cellulose phthalate, hydroxypropyl methyl cellulose phthalate, hydroxypropyl Methylcellulose 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
  • composition of any of the above uses for the preparation of a medicament for treating psoriatic arthritis.
  • composition of any of the above uses for the manufacture of a medicament for the treatment of moderate to severe plaque psoriasis.
  • the amorphous substance of the Apster of the present invention has a markedly increased solubility, and the apparent solubility increases by more than 60% under most pH conditions, which is more conducive to improving the bioavailability of the drug and making the drug better.
  • the amorphous substance can maintain good physical stability and chemical stability under accelerated test conditions (40 ⁇ 2° C., humidity 75% ⁇ 5%), and therefore, the present invention will have a broad Application prospects.
  • the preparation method of the Apster amorphous substance of the invention is simple in operation, easy to realize, and can realize industrial production.
  • the amorphous dispersion prepared by the present invention has high dispersibility and stability with a solid dispersion of two or more kinds of medicinal adjuvants, and various pharmaceutical excipients may have different effects in the pharmaceutical preparation. Conducive to the development of formulation formulations. 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 solid dispersion of the Aptast and the medicinal auxiliary material in the amorphous state of the invention is not limited by the drying process, and is not limited by the type of the solvent and the amount of the solvent, and is easy to operate, low in cost, and easy to realize. Industrial production can be achieved.
  • the solid dispersion of the amorphous state of the Aptast and the medicinal auxiliary material prepared by the invention has no significant change under the high temperature and high humidity conditions, and no apex crystal precipitates; under the accelerated test condition ( 40 ⁇ 2°C, humidity: 75% ⁇ 5%), there is no significant change in the related substances, no Apester crystals are precipitated, and the solid dispersion of the amorphous state of the present invention and the pharmaceutical excipient can maintain good physicality. Stability and chemical stability will have broad application prospects.
  • Figure 1 is an X-ray powder diffraction pattern of an Apster amorphous material according to Example 1 of the present invention.
  • Example 2 is a graph showing the thermal weight loss and differential scanning calorimetry (TGA/DSC) analysis of the Apster amorphous material of Example 1 of the present invention.
  • Figure 3 is an X-ray powder diffraction pattern of a solid dispersion of amorphous Apster and hydroxypropylcellulose SSL and povidone K30 of Example 12 of the present invention.
  • Example 4 is an X-ray powder diffraction pattern of a solid dispersion of amorphous Apster and sorbitol and polyacrylic resin L100 according to Example 23 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:
  • Scan range: from 2.0 to 60.0 degrees
  • thermogravimetric and differential scanning calorimetry The parameters of the differential scanning calorimetry described in the present invention are as follows:
  • Fig. 1 The X-ray powder diffraction pattern of the amorphous material is as shown in Fig. 1. There is no sharp diffraction peak in the X-ray powder diffraction spectrum expressed by degree 2 ⁇ , and there are three broad peaks at a degree 2 ⁇ of 2.0 to 50.0.
  • the thermogravimetric and differential scanning calorimetry (TGA/DSC) analysis of the amorphous material is shown in Fig. 2. It can be seen from Fig. 2 that the differential scanning calorimetry chart contains an endothermic event with an initial temperature of 339 °C. The thermogravimetric diagram shows complete weight loss after heating to 378 °C.
  • Apost 50 mg was suspended in tetrahydrofuran (750 ⁇ l) and dissolved by stirring at room temperature. The solution was quickly concentrated to dryness on a rotary evaporator to give a pale yellow solid, i.
  • Apost 50 mg was suspended in ethanol (5000 ⁇ l) and dissolved by stirring at room temperature. The solution was quickly concentrated to dryness on a rotary evaporator to give a pale yellow solid, i.
  • Apost 50 mg was suspended in acetonitrile (200 ⁇ l) and stirred and heated to dissolve. The solution was quickly concentrated to dryness over 5 minutes on a rotary evaporator to give a pale yellow solid, i.
  • Apost 50 mg was added to acetonitrile (750 ⁇ l) and stirred to dissolve at room temperature.
  • the above solution was added to n-heptane (10 ml) cooled to -80 ° C, and a pale-yellow solid was precipitated with stirring, filtered, and dried to give a solid of 45 mg, that is, an amorphous form of Apost.
  • Apost (30 mg) was added to N,N-dimethylformamide (60 ⁇ L) and stirred to dissolve at room temperature. The above solution was quickly added to water (450 ⁇ l) heated to 80 ° C, and a pale yellow solid was precipitated with stirring, filtered, and dried to give a solid 27 mg, that is, an amorphous form of Apost.
  • Apost (30 mg) was added to acetone (300 ⁇ l) and stirred to dissolve at room temperature. The above solution was added to water (1500 ⁇ l), and a pale yellow solid was precipitated with stirring, filtered, and dried to give a solid 25 mg, that is, an amorphous form of Apost.
  • Example 9 Influential factors test of amorphous Apster
  • Table 1 shows that amorphous APS is placed under high temperature and high humidity conditions for 10 days, and there is no significant change in related substances, and no Apast crystals are precipitated.
  • Table 2 shows that the amorphous Aptast was placed under accelerated test conditions for 6 months, and there was no significant change in the relevant substances, and no Apast crystals were precipitated.
  • the objects to be measured were respectively: the amorphous substance of Apster obtained in Example 8 of the present invention; and the Form B was prepared according to the method of Example 12 of Patent CN102702070).
  • Table 3 shows the apparent solubility of the Apster amorphous form (Form B) at various pH values.
  • the amorphous substance of the Apster of the invention has a significantly increased solubility, which is more favorable for 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 under accelerated test conditions (40) ⁇ 2 °C, humidity 75% ⁇ 5%), can maintain good physical stability and chemical stability.
  • APS 50 mg
  • polyacrylic resin Eudragit L100 50 mg
  • polyethylene glycol 4000 200 mg
  • ethanol 600 ⁇ l
  • water 600 ⁇ L
  • the solvent was evaporated in vacuo to give a white solid, that is, a solid dispersion of amorphous APS and polyacrylic resin Eudragit L100 and polyethylene glycol 4000.
  • X-ray powder diffraction pattern of the solid dispersion there is no characteristic peak of the Apster crystal form after subtracting the background peak of the pharmaceutical excipient.
  • Apost (1 g), galactose (1 g) and hydroxypropylmethylcellulose E50 (0.2 g) were added to water (10 ml) and heated to 40 ° C to stir and dissolve.
  • the above solution was lyophilized to give a white solid, a solid dispersion of amorphous aptist and galactose and hydroxypropylmethylcellulose E50.
  • the solid dispersion In the X-ray powder diffraction pattern of the solid dispersion, there is no characteristic peak of the Apster crystal form after subtracting the background peak of the pharmaceutical excipient.
  • a mixture of Apost (1 g), methanol (20 g), water (10 g), citric acid (1 g) and polyvinyl acetate (4 g) was heated to 30 ° C, stirred and evaporated, and evaporated in vacuo. The solvent was removed and cooled to room temperature to give a white solid, a solid dispersion of amorphous APS and EtOAc and EtOAc. In the X-ray powder diffraction pattern of the solid dispersion, there is no characteristic peak of the Apster crystal form after subtracting the background peak of the pharmaceutical excipient.
  • the X-ray powder diffraction pattern of the solid dispersion is shown in Fig. 4. The X-ray powder diffraction pattern has no characteristic peak of the Apst crystal form after subtracting the background peak of the medicinal adjuvant.
  • Apost (50 mg), dextrin (50 mg) and carbopol Carbomer 940 (50 mg) were added to methanol (4 ml) and tetrahydrofuran (1 ml), and the mixture was stirred and mixed at -30 °C.
  • the solution was concentrated by rotary evaporation to remove the solvent, which was cooled to room temperature to afford a white solid, a solid dispersion of amorphous apster and dextrin and carbomer carbomer 940.
  • the X-ray powder diffraction pattern of the solid dispersion there is no characteristic peak of the Apster crystal form after subtracting the background peak of the pharmaceutical excipient.
  • Apost (50 mg), ⁇ -cyclodextrin (100 mg) and pregelatinized starch Pharma-Gel (100 mg) were added to methanol (4 ml) and water (1 ml) and mixed at room temperature.
  • the solution was slowly concentrated in a rotary evaporator to remove the solvent to give a white solid, that is, a solid dispersion of amorphous APS and ⁇ -cyclodextrin and pregelatinized starch Pharma-Gel.
  • a white solid that is, a solid dispersion of amorphous APS and ⁇ -cyclodextrin and pregelatinized starch Pharma-Gel.
  • the X-ray powder diffraction pattern of the solid dispersion there is no characteristic peak of the Apster crystal form after subtracting the background peak of the pharmaceutical excipient.
  • Apost (50 mg), galactose (100 mg) and chitosan (200 mg) were suspended in methanol (50 ml), heated to 50 ° C and stirred well.
  • 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 solid dispersion of amorphous APS and galactose and chitosan.
  • a white solid that is, a solid dispersion of amorphous APS and galactose and chitosan.
  • the X-ray powder diffraction pattern of the solid dispersion there is no characteristic peak of the Apster crystal form after subtracting the background peak of the pharmaceutical excipient.
  • APS 300 mg
  • liposomes 300 mg
  • polyacrylic resin Eudragit E100 300 mg
  • APS 300 mg
  • tetrahydrofuran 900 ⁇ l
  • N,N-dimethyl In formamide 600 ⁇ l
  • heat to 50 ° C to stir and dissolve, and cool the solution to -30 ° C, precipitate a white solid, filter, and dry to obtain amorphous Apost and liposome and polyacrylic resin Eudragit A solid dispersion of E100.
  • X-ray powder diffraction pattern of the solid dispersion there is no characteristic peak of the Apster crystal form after subtracting the background peak of the pharmaceutical excipient.
  • Apost (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. Rotating the above solution The solvent was slowly concentrated in an evaporator to remove most of the solvent, and a white solid was precipitated, which was filtered and dried to give a solid dispersion of amorphous apster and xylitol and collagen Peptan. In the X-ray powder diffraction pattern of the solid dispersion, there is no characteristic peak of the Apster crystal form after subtracting the background peak of the pharmaceutical excipient.
  • Apost (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 solution was slowly concentrated in a rotary evaporator to remove the solvent to give a white solid, which afforded a solid dispersion of amorphous A.p. In the X-ray powder diffraction pattern of the solid dispersion, there is no characteristic peak of the Apster crystal form after subtracting the background peak of the pharmaceutical excipient.
  • Example 46 Solid dispersion of amorphous Apster and hydroxypropyl cellulose SSL and povidone K30 Influencing factor test
  • Table 4 shows that amorphous APS and hydroxypropyl cellulose SSL and povidone K30 solid dispersions were placed under high temperature and high humidity conditions for 10 days without significant changes in related substances, and no Apast crystals were precipitated. .
  • MATERIALS Solid dispersion of amorphous Apster and hydroxypropyl cellulose SSL and povidone K30 obtained in Example 12.
  • Table 5 illustrates that the amorphous Apster and hydroxypropyl cellulose SSL and povidone K30 solid dispersions of the present invention were placed under accelerated test conditions for 6 months without significant changes in related substances, and no Apster Crystallization precipitated.
  • the measurement objects were respectively: the solid dispersion obtained in Example 12 of the present invention; the mixture of the Apster crystal form (Form B, hydroxypropylcellulose SSL, and povidone K30) Physically mixed, the weight ratio was 1:1:1, and the Form B was prepared according to the method of Example 12 of Patent CN102702070.
  • Example 12 of the present invention Sufficiently weigh a sufficient amount of the solid dispersion obtained in Example 12 of the present invention and the above-mentioned mixture of Apster crystal forms, placed in two stoppered Erlenmeyer flasks, and diluted at a specified pH. The liquid is formulated into a supersaturated solution and the seal is tightly closed. 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 taken, 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 at each pH value, the apparent solubility of the amorphous Arposter solid dispersion and microcrystalline cellulose composition of the present invention is significantly higher than that of the crystalline form (Form B) and hydroxyl Apparent solubility of a mixture of propyl cellulose SSL and povidone K30.
  • Example 49 Solid dispersion of amorphous Apster with sorbitol and polyacrylic resin Eudragit L100 Influential factor test
  • Table 7 shows that the solid dispersion of amorphous Apost and sorbitol and polyacrylic resin Eudragit L100 was allowed to stand under high temperature and high humidity conditions for 10 days, and there was no significant change in related substances, and no Apast crystals were precipitated.
  • Example 50 Accelerated Test of Solid Dispersion of Amorphous Apster with Sorbitol and Polyacrylic Acid Eudragit L100
  • Table 8 illustrates that the solid dispersion of the amorphous Apster of the present invention and the sorbitol and polyacrylic resin Eudragit L100 was allowed to stand for 6 months under accelerated test conditions, and the related substances were not significantly changed, and no Apast crystals were precipitated. .
  • the measurement objects were respectively: the solid dispersion obtained in Example 23 of the present invention; the mixture of the Apster crystal form (Form B), sorbitol and polyacrylic resin Eudragit L100 were physically mixed, and the weight was The ratio is 1:2:2, and the Form B is prepared according to the method of Example 12 of Patent CN102702070.
  • Table 9 shows that the apparent solubility of the solid dispersion of the amorphous apster sorbitol and the polyacrylic resin Eudragit L100 of the present invention at each pH value is significantly higher than that of the crystalline form (Form B) and Apparent solubility of a mixture of sorbitol and polyacrylic resin Eudragit L100.
  • the amorphous solid dispersion of the apster and the medicinal excipient of the invention has a significantly increased dissolution rate and is more advantageous
  • the drug can better exert the therapeutic effect of the clinical disease, and the amorphous substance can maintain good physical stability under accelerated test conditions (40 ⁇ 2° C., humidity: 75% ⁇ 5%). And chemical stability.

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Abstract

一种阿普斯特的无定型物、其制备方法及应用，该无定型物的X-射线粉末衍射光谱中，无尖锐的衍射峰，在度2θ为2.0～50.0之间有三个宽峰。一种无定型阿普斯特的固体分散体及其制造方法，其包含无定型阿普斯特与两种或两种以上的药用辅料，阿普斯特与全部药用辅料的重量比为1:0.1～100。该阿普斯特无定型物以及无定型固体分散体增加了阿普斯特的溶解性，更有利于提高药物制剂的生物利用度，与现有晶型阿普斯特相比，其溶解度明显增加，更有利于机体对药物的吸收，使药物能够更好地发挥临床疾病治疗作用，该无定型物及无定型固体分散体在加速试验条件下，能保持良好的物理稳定性和化学稳定性，且制备方法操作简单，易于实现工业化生产。

Description

一种阿普斯特的无定型物、其制备方法及应用 技术领域
本发明属于药物制剂领域，涉及一种阿普斯特的无定型物及其制备方法，本发明还涉及一种无定型阿普斯特的固体分散体及其制备方法，提供了一种药用组合物，用于治疗有活动性的银屑病关节炎和中度至重度斑块银屑病。
背景技术
阿普斯特(英文名：Apremilast)，化学名为N-[2-[(1S)-1-(3-乙氧基-4-甲氧苯基)-2-(甲磺酰基)乙基]-2,3-二氢-1,3-二氧代-1H-异吲哚-4-基]乙酰胺，商品名为OTEZLA。其结构如式(I)所示：
Figure PCTCN2016106201-appb-000001
阿普斯特是美国新基公司(Celgene)开发的一种小分子磷酸二酯酶4(PDE4)抑制剂，该产品于2014年3月21日被美国食品药品监管局(FDA)批准上市，用于活动型银屑病关节炎的成人患者的治疗。该药是FDA批准的首个也是唯一一个用于斑块型银屑病治疗的PDE4抑制剂。高药物上市以来，市场反应良好。同时该药物也正在申请适应症范围，用于治疗中度至重度斑块银屑病。
阿普斯特存在多种晶型。该药物的上市晶型为阿普斯特无水物晶型Form B。美国专利US7893101公开了阿普斯特晶型和阿普斯特的晶型Form A、From B、Form C、Form D、Form E、Form F和Form G。美国专利US15283249公开了无定型阿普斯特，并提供了XRPD的谱图和制备方法。
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。
虽然美国专利US15283249公开了阿普斯特的无定型态，但该无定型阿普斯特是通过研磨和喷雾干燥制备得到。研磨需要用到球磨机，喷雾干燥需要用到喷雾干燥仪。这两种方法对生产设备都有较高要求，生产成本较高。
由于现有的无定形态阿普斯特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，寻找新的无定型阿普斯特及其制备方法就显得十分必要。
发明内容
本发明的目的在于提供一种阿普斯特的无定型物、其制备方法及应用，该无定型物为阿普斯特的新的固体形式，增加了阿普斯特的溶解性，更有利于提高药物制剂的生物利用度。
为了达到上述目的，本发明提供的技术方案如下：
一种阿普斯特的无定型物，使用Cu-Kα辐射该无定型物，以度2θ表示的X-射线粉末衍射光谱中无尖锐的衍射峰。
优选地，所述的X-射线粉末衍射光谱在2.0～50.0之间有三个宽峰，如图1所示。
本发明提供一种阿普斯特的无定型物的制备方法，包括如下步骤：
1)将阿普斯特溶于溶剂I中，形成浓度为0.01～1克/毫升的溶液；
2)将步骤1)的溶液加入溶剂II中，温度为-80～100℃，形成悬浊液，其中，溶剂I和溶剂II不同，所述溶液和溶剂II的体积比为1:1～200；
3)将步骤2)中形成的悬浊液过滤，干燥滤饼，得到阿普斯特的无定型物。
优选地，所述溶剂I选自含8个以下碳原子的醇类、酮类、醚类、卤代烃、酰胺、砜或亚砜中的至少一种，溶剂II选自含8个以下碳原子的烃类、芳烃类或水中的至少一种。
本发明提供另一种阿普斯特的无定型物的制备方法，包括：
1)将阿普斯特溶于有机溶剂中，形成浓度为0.01～1克/毫升的溶液；
2)将步骤1)所得的溶液的溶剂除去，得到阿普斯特的无定型物。
进一步，所述的有机溶剂选自含8个及以下碳原子的醇类、醚类、酮类或腈类溶剂中的至少一种。
优选地，除去溶剂的方法为溶剂蒸发法。
本发明的阿普斯特的无定型物为阿普斯特的新固体形式，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，而无定型态下的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，容易分散，利于增加溶解度。
本发明的无定型状态的物质具有高度分散性，这种无定型态在制成固体制剂后，经过崩解可使药物粒子的分散程度更好，分散速度更快，有利于药物的吸收。同时，与晶态物质相比，无定型态药物的分子处于高度无序状态，物质的表面自由能更大，因此，无定型态药物的溶解度明显增加，更有利于机体对药物的吸收，使药物能够更好地发挥临床疾病治疗作用。
本发明提供一种阿普斯特与药用辅料的固体分散体及其制备方法，得到稳定性及分散性良好的无定型态的阿普斯特与药用辅料的固体分散体，增加了阿普斯特的溶出度，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。
本发明提供一种阿普斯特与药用辅料的固体分散体，该固体分散体包含阿普斯特与两种或两种以上的药用辅料，阿普斯特与全部药用辅料的重量比为1:0.1～100，其中，所述固体分散体中的阿普斯特为无定型态，所述固体分散体的X-射线粉末衍射光谱中，扣除药用辅料的背景峰后无阿普斯特的晶体的特征峰。
进一步，所述药用辅料中的至少一种选自稀释剂、润滑剂、粘合剂、崩解剂、表面活性剂、成膜材料、包衣材料和胶囊材料中的至少一种。
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、微晶纤维素、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、枸橼酸、酒石酸、尿素、马来酸和琥珀酸中的至少一种。
本发明的阿普斯特与药用辅料的固体分散体的制备方法，包括如下步骤：
1)将阿普斯特和两种或两种以上的药用辅料混合，加热至药用辅料熔融；其中，阿普斯特与全部药用辅料的重量比为1:0.1～100；
2)混合均匀后冷却，将混合物粉碎，得到无定型态的阿普斯特与药用辅料的固体分散体。
进一步，所述药用辅料中的至少一种选自稀释剂、润滑剂、粘合剂、崩解剂、表面活性剂、成膜材料、包衣材料和胶囊材料中的至少一种。
优选地，步骤1)中所述的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、微晶纤维素、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。
本发明提供另一种阿普斯特与药用辅料的固体分散体的制备方法，包括如下步骤：
1)将阿普斯特和两种或两种以上的药用辅料在溶剂中混合，混合温度为-50～150℃，形成含阿普斯特和药用辅料的溶液或悬浮液，其中，阿普斯特与溶剂的重量比为0.001～100:1，阿普斯特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，得到无定型态的阿普斯特与药用辅料的固体分散体。
进一步，所述药用辅料中的至少一种选自稀释剂、润滑剂、粘合剂、崩解剂、表面活性剂、成膜材料、包衣材料和胶囊材料中的至少一种。
优选地，步骤1)中所述的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、马来酸和琥珀酸中的至少一种。
又，步骤1)所述溶剂选自含12个以下碳原子的醇类、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药用组合物，所述药用组合物含有无定型阿普斯特和两种或两种以上的药用辅料，所述药用辅料中的至少一种选自稀释剂、润滑剂、粘合剂、崩解剂、表面活性剂、成膜材料、包衣材料和胶囊材料中的至少一种。
进一步，上述药用组合物中的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、微晶纤维素、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，以上任一所述的组合物用于制备治疗银屑病关节炎药物的用途。
再，以上任一所述的组合物用于制备治疗中度至重度斑块银屑病药物的用途。
与现有技术相比，本发明的有益效果是：
1)本发明的阿普斯特的无定型物，其溶解度明显增加，在大多数pH值条件下，表观溶解度增加60％以上，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，因此，本发明将会有广阔的应用前景。本发明阿普斯特无定型物的制备方法操作简单，容易实现，可实现工业化生产。
2)本发明制备的无定型阿普斯特与两种或两种以上的药用辅料的固体分散体具有高度分散性及稳定性，各种药用辅料可在药物制剂中附会不同的作用，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。
3)本发明无定型状态的阿普斯特与药用辅料的固体分散体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。
4)本发明制备的无定型状态的阿普斯特与药用辅料的固体分散体在高温、高湿条件下，有关物质无显著改变，无阿普斯特结晶析出；在加速试验条件下(40±2℃，湿度75％±5％)，有关物质无显著改变，无阿普斯特结晶析出，本发明的无定型状态的阿普斯特与药用辅料的固体分散体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的阿普斯特无定型物的X-射线粉末衍射图。
图2为本发明实施例1的阿普斯特无定型物的热失重分及差示扫描量热(TGA/DSC)分析图。
图3为本发明实施例12的无定型阿普斯特和羟丙基纤维素SSL及聚维酮K30的固体分散体的X-射线粉末衍射图。
图4为本发明实施例23的无定型阿普斯特和山梨醇及聚丙烯酸树脂L100的固体分散体的X-射线粉末衍射图。
具体实施方式
以下以具体实施例是为了更详尽地说明本发明的效果，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 PCTCN2016106201-appb-000002
：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
本发明所述的美国热电Q600型热失重及差示扫描量热(TGA/DSC)分析图在热失重及差示扫描量热同步测定仪上采集。本发明所述的差示扫描量热分析的参数如下：
保护气体：氮气
温度范围：20-800℃
扫描速率：10℃/分钟。
实施例1：
将阿普斯特(50毫克)悬浮于二氯甲烷(750微升)，室温下搅拌溶清。将上述溶液在旋转蒸发器上5分钟内迅速浓缩至干，得到浅黄色固体，即阿普斯特的无定型物。该无定型物的X-射线粉末衍射图如图1所示，以度2θ表示的X-射线粉末衍射光谱中无尖锐的衍射峰，在度2θ为2.0～50.0之间有三个宽峰。该无定型物的热失重及差示扫描量热(TGA/DSC)分析图如图2所示，由图2可以看出：差示扫描量热图包含起始温度339℃的吸热事件，热失重图显示加热至378℃后完全失重。
实施例2：
将阿普斯特(50毫克)悬浮于四氢呋喃(750微升)，室温下搅拌溶清。将上述溶液在旋转蒸发器上迅速浓缩至干，得到浅黄色固体，即阿普斯特的无定型物。
实施例3：
将阿普斯特(50毫克)悬浮于乙醇(5000微升)，室温下搅拌溶清。将上述溶液在旋转蒸发器上迅速浓缩至干，得到浅黄色固体，即阿普斯特的无定型物。
实施例4：
将阿普斯特(50毫克)悬浮于乙腈(200微升)，加热下搅拌溶清。将上述溶液在旋转蒸发器上5分钟内迅速浓缩至干，得到浅黄色固体，即阿普斯特的无定型物。
实施例5：
将阿普斯特(50毫克)加入到乙腈(750微升)中，室温下搅拌溶清。将上述溶液加入到冷却到-80℃的正庚烷(10毫升)中，搅拌下析出浅黄色固体，过滤，干燥，得到固体45毫克，即阿普斯特的无定型物。
实施例6：
将阿普斯特(30毫克)加入到N,N-二甲基甲酰胺(60微升)中，室温下搅拌溶清。将上述溶液迅速加入到加热至80℃的水(450微升)中，搅拌下析出浅黄色固体，过滤，干燥，得到固体27毫克，即阿普斯特的无定型物。
实施例7：
将阿普斯特(30毫克)加入到甲醇(300微升)中，室温下搅拌溶清。将上述溶液加入到水(1500微升)中，搅拌下析出浅黄色固体，过滤，干燥，得到固体24毫克，即阿普斯特的无定型物。
实施例8：
将阿普斯特(30毫克)加入到丙酮(300微升)中，室温下搅拌溶清。将上述溶液加入到水(1500微升)中，搅拌下析出浅黄色固体，过滤，干燥，得到固体25毫克，即阿普斯特的无定型物。
实施例9：无定型阿普斯特的影响因素试验
材料：实施例1所得阿普斯特的无定型物
实验条件及结果参见表1。
表1
Figure PCTCN2016106201-appb-000003
Figure PCTCN2016106201-appb-000004
表1说明：无定型阿普斯特在高温、高湿条件下，放置10天，有关物质无显著改变，无阿普斯特结晶析出。
实施例10：无定型阿普斯特的加速试验
材料：实施例1所得阿普斯特的无定型物
实验条件：温度40℃±2℃，湿度75％±5％。
表2
Figure PCTCN2016106201-appb-000005
表2说明：无定型阿普斯特在加速试验条件下，放置6个月，有关物质无显著改变，无阿普斯特结晶析出。
实施例11：测定表观溶解度
比较本发明阿普斯特无定型物与阿普斯特晶型的表观溶解度。
测定对象分别为：本发明实施例8得到的阿普斯特的无定型物；阿普斯特晶型物(Form B)根据专利CN102702070实施例12的方法制备得到)。
表观溶解度的测定：本发明实施例1得到的阿普斯特的无定型物及上述阿普斯特晶型物，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0.45um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＝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。
(2)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。
(3)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。
(4)pH＝5.0的稀释液：取0.2摩尔/升的邻苯二甲酸氢钾100毫升，用0.2摩尔/升的氢氧化钠溶液约50毫升调节pH值至5.0，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 PCTCN2016106201-appb-000006
表3表明：在各个pH值下，阿普斯特无定型物晶型物(Form B)的表观溶解度。
本发明的阿普斯特的无定型物，其溶解度明显增加，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12
将阿普斯特(50毫克)、羟丙基纤维素SSL(50毫克)和聚维酮K30(50毫克)加入到甲醇(800微升)中，加热到60℃搅拌溶清，真空蒸发除去溶剂，得到白色固体，即无定型阿普斯特与羟丙基纤维素SSL及聚维酮K30的固体分散体。该固体分散体的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阿普斯特晶型的特征峰。
实施例13
将阿普斯特(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，真空蒸发除去溶剂，得到白色固体，即无定型阿普斯特与聚丙烯酸树脂Eudragit L100及聚乙二醇4000的固体分散体。该固体分散体的X-射线粉末衍射图中，扣除药用辅料的背景峰后无阿普斯特晶型的特征峰。
实施例14
将阿普斯特(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阿普斯特与乳糖及聚乙二醇8000的固体分散体。该固体分散体的X-射线粉末衍射图中，扣除药用辅料的背景峰后无阿普斯特晶型的特征峰。
实施例15
将阿普斯特(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，即无定型阿普斯特与半乳糖及羟丙甲基纤维素E50的固体分散体。该固体分散体的X-射线粉末衍射图中，扣除药用辅料的背景峰后无阿普斯特晶型的特征峰。
实施例16
将阿普斯特(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，即无定型阿普斯特与尿素及聚乙二醇8000的固体分散体。该固体分散体的X-射线粉末衍射图中，扣除药用辅料的背景峰后无阿普斯特晶型的特征峰。
实施例17
将阿普斯特(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，即无定型阿普斯特与山梨醇及聚乙二醇10000的固体分散体。该固体分散体的X-射线粉末衍射图中，扣除药用辅料的背景峰后无阿普斯特晶型的特征峰。
实施例18
将阿普斯特(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，即无定型阿普斯特与富马酸及脂质体的固体分散体。该固体分散体的X-射线粉末衍射图中，扣除药用辅料的背景峰后无阿普斯特晶型的特征峰。
实施例19
将阿普斯特(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，迅速冷却到-30℃，得到白色固体，即无定型阿普斯特与聚丙烯酸树脂Eudragit L100及甲基丙烯酸共聚物A型的固体分散体。该固体分散体的X-射线粉末衍射图中，扣除药用辅料的背景峰后无阿普斯特晶型的特征峰。
实施例20
将阿普斯特(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，即无定型阿普斯特与预胶化及乙基纤维素的固体分散体。该固体分散体的X-射线粉末衍射图中，扣除药用辅料的背景峰后无阿普斯特晶型的特征峰。
实施例21
将阿普斯特(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，即无定型阿普斯特与木糖醇及羟丙基纤维素SSL的固体分散体。该固体分散体的X-射线粉末衍射图中，扣除药用辅料的背景峰后无阿普斯特晶型的特征峰。
实施例22
将阿普斯特(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，即无定型阿普斯特与枸橼酸及聚醋酸乙烯的固体分散体。该固体分散体的X-射线粉末衍射图中，扣除药用辅料的背景峰后无阿普斯特晶型的特征峰。
实施例23
将阿普斯特(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，真空蒸发除去溶剂，得到白色固体，即无定型阿普斯特与山梨醇及聚丙烯酸树脂Eudragit L100的固体分散体。该固体分散体的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阿普斯特晶型的特征峰。
实施例24
将阿普斯特(50毫克)羧甲基纤维素邻苯二甲酸酯Agucoat CPD(20毫克)和聚丙烯酸树脂Eudragit S100(30毫克)加入到甲醇(4毫升)和乙酸乙酯(1毫升)，在-30℃下搅拌溶清。将上述溶液在旋转蒸发其上浓缩除去溶剂，冷却至室温，得到白色固体，即无定型阿普斯特与羧甲基纤维素邻苯二甲酸酯Agucoat CPD及聚丙烯酸树脂Eudragit S100的固体分散体。该固体分散体的X-射线粉末衍射图中，扣除药用辅料的背景峰后无阿普斯特晶型的特征峰。
实施例25
将阿普斯特(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)，在-30℃下搅拌混合均匀。将上述溶液在旋转蒸发其上浓缩除去溶剂，冷却至室温，得到白色固体，即无定型阿普斯特与糊精及聚羧乙烯Carbomer 940的固体分散体。该固体分散体的X-射线粉末衍射图中，扣除药用辅料的背景峰后无阿普斯特晶型的特征峰。
实施例26
将阿普斯特(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除去溶剂，得到白色固体，即无定型阿普斯特与β-环糊精及预胶化淀粉Pharma-Gel的固体分散体。该固体分散体的X-射线粉末衍射图中，扣除药用辅料的背景峰后无阿普斯特晶型的特征峰。
实施例27
将阿普斯特(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除去溶剂，得到白色固体，即无定型阿普斯特与β-环糊精(100毫克)及高支链交联淀粉的固体分散体。该固体分散体的X-射线粉末衍射图中，扣除药用辅料的背景峰后无阿普斯特晶型的特征峰。
实施例28
将阿普斯特(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，真空蒸发除去溶剂，得到白色固体，进一步真空干燥，即无定型阿普斯特与马来酸及羧甲基纤维素钠SCMC的固体分散体，该固体分散体的X-射线粉末衍射图中，扣除药用辅料的背景峰后无阿普斯特晶型的特征峰。
实施例29
将阿普斯特(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除去溶剂，得到白色固体，即无定型阿普斯特与聚乙二醇4000及几丁聚糖的固体分散体。该固体分散体的X-射线粉末衍射图中，扣除药用辅料的背景峰后无阿普斯特晶型的特征峰。
实施例30
将阿普斯特(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除去溶剂，得到白色固体，即无定型阿普斯特与D-甘露醇及羧甲基淀粉钠Explotab的固体分散体。该固体分散体的X-射线粉末衍射图中，扣除药用辅料的背景峰后无阿普斯特晶型的特征峰。
实施例31
将阿普斯特(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除去溶剂，得到白色固体，即无定型阿普斯特与聚维酮K90及藻酸盐E401的固体分散体。该固体分散体的X-射线粉末衍射图中，扣除药用辅料的背景峰后无阿普斯特晶型的特征峰。
实施例32
将阿普斯特(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，即无定型阿普斯特与L-酒石酸及羧甲基纤维素邻苯二甲酸酯Agucoat CPD的固体分散体。该固体分散体的X-射线粉末衍射图中，扣除药用辅料的背景峰后无阿普斯特晶型的特征峰。
实施例33
将阿普斯特(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，即无定型阿普斯特与树胶Galactosol及卡拉胶E407的固体分散体。该固体分散体的X-射线粉末衍射图中，扣除药用辅料的背景峰后无阿普斯特晶型的特征峰。
实施例34
将阿普斯特(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，即无定型阿普斯特与半乳糖及壳聚糖的固体分散体。该固体分散体的X-射线粉末衍射图中，扣除药用辅料的背景峰后无阿普斯特晶型的特征峰。
实施例35
将阿普斯特(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，得到无定型阿普斯特与脂质体及聚丙烯酸树脂Eudragit E100的固体分散体。该固体分散体的X-射线粉末衍射图中，扣除药用辅料的背景峰后无阿普斯特晶型的特征峰。
实施例36
将阿普斯特(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，得到无定型阿普斯特与木糖醇及胶原蛋白Peptan的固体分散体。该固体分散体的X-射线粉末衍射图中，扣除药用辅料的背景峰后无阿普斯特晶型的特征峰。
实施例37
将阿普斯特(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溶剂，得到白色固体，即得到无定型阿普斯特与D-甘露醇及树胶Galactosol的固体分散体。该固体分散体的X-射线粉末衍射图中，扣除药用辅料的背景峰后无阿普斯特晶型的特征峰。
实施例38
将阿普斯特(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，即无定型阿普斯特与几丁聚糖及羟丙甲基纤维素邻苯二甲酸酯HPMCP的固体分散体。该固体分散体的X-射线粉末衍射图中，扣除药用辅料的背景峰后无阿普斯特晶型的特征峰。
实施例39
将阿普斯特(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，即无定型阿普斯特与D-甘露醇及羧基乙酸内酯的固体分散体。该固体分散体的X-射线粉末衍射图中，扣除药用辅料的背景峰后无阿普斯特晶型的特征峰。
实施例40
将阿普斯特(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，即无定型阿普斯特与β-环糊精及糊精Maltrin M100的固体分散体。该固体分散体的X-射线粉末衍射图中，扣除药用辅料的背景峰后无阿普斯特晶型的特征峰。
实施例41
将阿普斯特(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，即无定型阿普斯特与琥珀酸及羧甲基纤维素钠SCMC的固体分散体。该固体分散体的X-射线粉末衍射图中，扣除药用辅料的背景峰后无阿普斯特晶型的特征峰。
实施例42
将阿普斯特(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，即无定型阿普斯特与山梨醇及聚环氧乙烷Polyox WSR301的固体分散体。该固体分散体的X-射线粉末衍射图中，扣除药用辅料的背景峰后无阿普斯特晶型的特征峰。
实施例43
将阿普斯特(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，即无定型阿普斯特与山梨醇、聚乙二醇8000及聚乙烯醇EG-40的固体分散体。该固体分散体的X-射线粉末衍射图中，扣除药用辅料的背景峰后无阿普斯特晶型的特征峰。
实施例44
将阿普斯特(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除去溶剂，得到白色固体，即无定型阿普斯特与木糖醇及羟丙甲基纤维素醋酸酯琥珀酸酯Agoat MG的固体分散体。该固体分散体的X-射线粉末衍射图中，扣除药用辅料的背景峰后无阿普斯特晶型的特征峰。
实施例45
将阿普斯特(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除去溶剂，得到白色固体，即无定型阿普斯特与山梨醇及羧甲基乙基纤维素的固体分散体。该固体分散体的X-射线粉末衍射图中，扣除药用辅料的背景峰后无阿普斯特晶型的特征峰。
实施例46：无定型阿普斯特与羟丙基纤维素SSL及聚维酮K30的固体分散体的 影响因素试验
材料：实施例12所得无定型阿普斯特与羟丙基纤维素SSL及聚维酮K30的固体分散体。
实验条件及实验结果参见表4。
表4
Figure PCTCN2016106201-appb-000007
表4说明：无定型阿普斯特与羟丙基纤维素SSL及聚维酮K30固体分散体在高温、高湿条件下，放置10天，有关物质无显著改变，无阿普斯特结晶析出。
实施例47：无定型阿普斯特与羟丙基纤维素SSL及聚维酮K30固体分散体的加速试验
材料：实施例12所得无定型阿普斯特与羟丙基纤维素SSL及聚维酮K30的固体分散体
实验条件：温度40℃±2℃，湿度75％±5％
实验结果参见表5。
表5
Figure PCTCN2016106201-appb-000008
Figure PCTCN2016106201-appb-000009
表5说明：本发明的无定型阿普斯特与羟丙基纤维素SSL及聚维酮K30固体分散体在加速试验条件下，放置6个月，有关物质无显著改变，无阿普斯特结晶析出。
实施例48：测定表观溶解度
比较本发明含无定型阿普斯特的固体分散体与阿普斯特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12得到的固体分散体；阿普斯特晶型物的混合物(阿普斯特晶型物(Form B)、羟丙基纤维素SSL及聚维酮K30经过物理混合，重量比为1:1:1，阿普斯特晶型物(Form B)根据专利CN102702070实施例12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12获得的固体分散体及上述阿普斯特晶型物的混合物，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0.45um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值稀释液的配制方法同实施例11。
实验结果如表6所示：
表6
Figure PCTCN2016106201-appb-000010
表6表明：在各个pH值下，本发明的无定型阿普斯特固体分散体与微晶纤维素的组合物的表观溶解度的表观溶解度明显高于晶型物(Form B)与羟丙基纤维素SSL及聚维酮K30的混合物的表观溶解度。
实施例49：无定型阿普斯特与山梨醇及聚丙烯酸树脂Eudragit L100的固体分散 体的影响因素试验
材料：实施例23所得无定型阿普斯特与山梨醇及聚丙烯酸树脂Eudragit L100的固体分散体。
实验条件及实验结果参见表7。
表7
Figure PCTCN2016106201-appb-000011
表7说明：无定型阿普斯特与山梨醇及聚丙烯酸树脂Eudragit L100的固体分散体在高温、高湿条件下，放置10天，有关物质无显著改变，无阿普斯特结晶析出。
实施例50：无定型阿普斯特与山梨醇及聚丙烯酸树脂Eudragit L100的固体分散体的加速试验
材料：实施例23所得无定型阿普斯特与山梨醇及聚丙烯酸树脂Eudragit L100的固体分散体
实验条件：温度40℃±2℃，湿度75％±5％
实验结果参见表8。
表8
Figure PCTCN2016106201-appb-000012
Figure PCTCN2016106201-appb-000013
表8说明：本发明的无定型阿普斯特与山梨醇及聚丙烯酸树脂Eudragit L100的固体分散体在加速试验条件下，放置6个月，有关物质无显著改变，无阿普斯特结晶析出。
实施例51：测定表观溶解度
比较本发明含无定型阿普斯特的固体分散体与阿普斯特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23得到的固体分散体；阿普斯特晶型物的混合物(阿普斯特晶型物(Form B)、山梨醇和聚丙烯酸树脂Eudragit L100经过物理混合，重量比为1:2:2，阿普斯特晶型物(Form B)根据专利CN102702070实施例12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23获得的固体分散体及上述阿普斯特晶型物的混合物，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0.45um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值稀释液的配制方法同实施例11。
实验结果如表9所示：
表9
Figure PCTCN2016106201-appb-000014
表9表明：在各个pH值下，本发明的无定型阿普斯特山梨醇及聚丙烯酸树脂Eudragit L100的固体分散体的表观溶解度的表观溶解度明显高于晶型物(Form B)与山梨醇和聚丙烯酸树脂Eudragit L100的混合物的表观溶解度。
本发明的阿普斯特与药用辅料的无定型固体分散体，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. 一种阿普斯特的无定型物，其特征在于，使用Cu-Kα辐射，以度2θ表示的X-射线粉末衍射光谱中无尖锐的衍射峰。
  2. 根据权利要求1所述阿普斯特的无定型物，其特征在于：其X-射线粉末衍射光谱，在度2θ为2.0～50.0之间有三个宽峰。
  3. 如权利要求1或2所述阿普斯特的无定型物的制备方法，其特征在于，包括如下步骤：
    1)将阿普斯特溶于溶剂I中，形成浓度为0.01～1克/毫升的溶液；
    2)将步骤1)得到的溶液加入溶剂II中，温度为-80～100℃，形成悬浊液，其中，溶剂I和溶剂II不同，所述步骤1)得到的溶液和溶剂II的体积比为1:1～200；
    3)将步骤2)形成的悬浊液过滤，干燥滤饼，得到阿普斯特的无定型物。
  4. 根据权利要求3所述阿普斯特的无定型物的制备方法，其特征在于，所述溶剂I选自含8个以下碳原子的醇类、酮类、醚类、卤代烃、酰胺、砜或亚砜中的至少一种。
  5. 根据权利要求3所述阿普斯特的无定型物的制备方法，其特征在于，溶剂II选自含8个以下碳原子的烃类、芳烃类或水中的至少一种。
  6. 如权利要求1或2所述阿普斯特的无定型物的制备方法，其特征在于，包括：
    1)将阿普斯特溶于有机溶剂中，形成浓度为0.01～1克/毫升的溶液；
    2)将步骤1)所得的溶液的溶剂除去，得到阿普斯特的无定型物。
  7. 根据权利要求6所述阿普斯特的无定型物的制备方法，其特征在于，所述有机溶剂选自含8个及以下碳原子的醇类、醚类、酮类或腈类溶剂中的至少一种。
  8. 根据权利要求6所述阿普斯特的无定型物的制备方法，其特征在于，所述步骤2)中除去溶剂的方法为溶剂蒸发法。
  9. 一种药用组合物，其特征在于，所述药用组合物含有无定型态的阿普斯特和至少一种药学上可接受的辅料。
  10. 如权利要求9所述的药用组合物在制备治疗银屑病关节炎药物和治疗中度至重度斑块银屑病药物的用途。
  11. 一种阿普斯特与药用辅料的固体分散体，其特征在于，所述固体分散体包含阿普斯特与两种或两种以上的药用辅料，阿普斯特与全部药用辅料的重量比为1:0.1～100，其中，所述固体分散体中的阿普斯特为无定型态，所述固体分散体的X-射线粉末衍射光谱中，扣除药用辅料的背景峰后无阿普斯特晶体的特征峰。
  12. 根据权利要求11所述阿普斯特与药用辅料的固体分散体，其特征在于，所述药用辅料中的至少一种选自稀释剂、润滑剂、粘合剂、崩解剂、表面活性剂、成膜材料、包衣材料和胶囊材料中的至少一种。
  13. 根据权利要求11所述阿普斯特与药用辅料的固体分散体，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、微晶纤维素、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。
  14. 一种阿普斯特与药用辅料的固体分散体的制备方法，包括如下步骤：
    1)将阿普斯特与药用辅料混合，加热至药用辅料熔融；其中，阿普斯特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，得到无定型态的阿普斯特与药用辅料的固体分散体。
  15. 根据权利要求14所述阿普斯特与药用辅料的固体分散体的制备方法，其特征在于，所述药用辅料中的至少一种选自稀释剂、润滑剂、粘合剂、崩解剂、表面活性剂、成膜材料、包衣材料和胶囊材料中的至少一种。
  16. 根据权利要求14所述阿普斯特与药用辅料的固体分散体的制备方法，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、微晶纤维素、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。
  17. 一种阿普斯特与药用辅料的固体分散体的制备方法，包括如下步骤：
    1)将阿普斯特和药用辅料在溶剂中混合，混合温度为-50～150℃，形成含阿普斯特和药用辅料的溶液或悬浮液，其中，阿普斯特与溶剂的重量比为0.001～100:1，阿普斯特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，得到无定型态的阿普斯特与药用辅料的固体分散体。
  18. 根据权利要求17所述的阿普斯特与药用辅料的固体分散体的制备方法，其特征在于，所述药用辅料中的至少一种选自稀释剂、润滑剂、粘合剂、崩解剂、表面活性剂、成膜材料、包衣材料和胶囊材料中的至少一种。
  19. 根据权利要求17所述的阿普斯特与药用辅料的固体分散体的制备方法，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、微晶纤维素、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所述阿普斯特与药用辅料的固体分散体的制备方法，其特征在于，步骤1)所述溶剂选自含12个以下碳原子的醇类、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。
  21. 一种药用组合物，其特征在于，所述药用组合物含有无定型阿普斯特和两种或两种以上药用辅料，所述药用辅料中的至少一种选自稀释剂、润滑剂、粘合剂、崩解剂、表面活性剂、成膜材料、包衣材料和胶囊材料中的至少一种。
  22. 根据权利要求21所述的药用组合物，其特征在于，所述药用组合物中的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、微晶纤维素、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。
  23. 如权利要求21或22的所述的组合物用于制备治疗银屑病关节炎药物的用途。
  24. 如权利要求21或22的所述的组合物用于制备治疗中度至重度斑块银屑病药物的用途。
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