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WO2023138366A1 - 固体分散体及其制备方法和包含其的药物组合物 - Google Patents

固体分散体及其制备方法和包含其的药物组合物 Download PDF

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Publication number
WO2023138366A1
WO2023138366A1 PCT/CN2023/070319 CN2023070319W WO2023138366A1 WO 2023138366 A1 WO2023138366 A1 WO 2023138366A1 CN 2023070319 W CN2023070319 W CN 2023070319W WO 2023138366 A1 WO2023138366 A1 WO 2023138366A1
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matrix
solid dispersion
cellulose
solubilizing
pharmaceutical composition
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English (en)
French (fr)
Inventor
邓蓝进
谭冲
崔保清
徐上虎
徐飞
沈利
赵栋
刘思川
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Sichuan Kelun Pharmaceutical Research Co Ltd
Sichuan Kelun Pharmaceutical Research Institute Co Ltd
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Sichuan Kelun Pharmaceutical Research Co Ltd
Sichuan Kelun Pharmaceutical Research Institute Co Ltd
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Priority to CN202380014610.4A priority Critical patent/CN118251213A/zh
Publication of WO2023138366A1 publication Critical patent/WO2023138366A1/zh
Anticipated expiration legal-status Critical
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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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4166—1,3-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. phenytoin
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the invention belongs to the field of pharmaceutical preparations, and in particular relates to a solid dispersion, a preparation method thereof and a pharmaceutical composition containing the same.
  • Hypromellose acetate succinate HPMCAS
  • HPMC hypromellose
  • HPMC hypromellose phthalate
  • HPC hypromellose phthalate
  • the spray drying technology uses the high pressure of the high-pressure pump to atomize the organic solution of the material into mist droplets through the atomizer, and then directly contacts with the hot air for heat exchange, and completes the drying in a short time. Due to the very small spray drying technology, the atomized liquid droplets are very small, and the solid dispersion particles obtained by direct drying are very fine, so the dissolution is fast. Disadvantages of spray drying technology include: 1) A large amount of flammable and explosive organic solvents need to be used, and they are also easy to leak and pollute the environment. 2) The particles obtained by spray drying are fine, fluffy, poor in fluidity, and poor in compressibility. They need to be mixed with more external auxiliary materials or granulated to improve fluidity.
  • patent WO2014043208 discloses that the enzalutamide solid dispersion particle Carr coefficient prepared by spray drying is 33.3%, and its fluidity is very poor. Excipients such as 316 are mixed many times and sieved many times to obtain tablet powder with general fluidity, which is extremely cumbersome.
  • the preparation prescription of this patent uses more than 40% of auxiliary materials except hypromellose acetate succinate. It can be seen that in order to improve its fluidity and facilitate direct tablet compression, a large amount of auxiliary materials and glidants with good fluidity need to be added; and none of them can be directly mixed for tablet compression, and grinding or dry granulation is required to improve fluidity.
  • Spray granules use a large amount of excipients to improve fluidity, which will inevitably lead to large tablet weight. At the same time, the granules are too fine, the specific surface area is large, there is more air, and the compression space is limited, which will inevitably lead to excessive tablet size. Larger tablets have poor medication compliance for the elderly and children who have difficulty swallowing.
  • Co-precipitation to prepare solid dispersed particles is to deposit the organic solution of the raw material drug and the solubilizing matrix on the surface of the excipients through spraying and hot air drying.
  • the advantage of this process is that the equipment requirements are low, and the fluidized bed can meet the requirements.
  • the obtained particles are fluffy, have a large surface area, and can be dissolved quickly.
  • the disadvantage is that a large amount of auxiliary materials need to be added as co-precipitation carriers in the fluidized bed granulation.
  • Patent WO2021064123 discloses the preparation of enzalutamide solid dispersion granules by fluidized bed granulation, which needs to add a large amount of microcrystalline cellulose and croscarmellose sodium to granulate, and at the same time, dry granulate with external excipients to obtain granules that meet the requirements of fluidity and can be used for tableting.
  • the use of a large number of excipients will inevitably make it difficult to reduce the size of the tablet, and the size of the tablet is too large for the elderly and children who have difficulty swallowing and poor medication compliance.
  • Hot-melt extrusion is a technology in which drugs and solubilized matrix materials are added to a screw machine to obtain extrudates with uniform shapes through heating-melting-mixing-extrusion processes. Compared with the spray drying and co-precipitation methods, this process has the advantages of continuous production, no use of organic solvents, more environmental protection, and the obtained extrudates are compact, compact, small in size and high in bulk density. Although the extrudate is dense and compact, it is very difficult to crush the extrudate of the cellulose-containing solid dispersion, and it is easy to generate a large amount of heat during the crushing, which may even cause the solid dispersion to melt in the crushing equipment.
  • Patent CN104983701A discloses the preparation of posaconazole-containing cellulose-containing hot-melt extruded solid dispersion particles, which are sieved through 200 mesh and 75 mesh to obtain particles with a particle size distribution between 75 microns and 300 microns, and the pulverization of hot-melt extruded particles below 100 ⁇ m has not been studied.
  • Patent WO2014043208 discloses using a mortar and pestle to manually grind the extrudate, and then sieve it to obtain hot-melt extrudate particles with D90 ⁇ 100 ⁇ m. None of the above methods is suitable for industrial production, and it does not actually solve the problem of difficult crushing of cellulose-containing solid dispersions.
  • Patent WO2019030691 discloses the preparation of enzalutamide-containing hypromellose acetate succinate solid dispersion particles by hot-melt extrusion. After crushing, the solid dispersion particles need to be dry granulated with auxiliary materials, and finally compressed into tablets. The purpose of the dry granulation is to improve the fluidity of the crushed solid dispersion particles.
  • the particle size of the cellulose-containing solid dispersion obtained by the spray-drying technology and co-precipitation technology reported at present is fine or fluffy, but the fluidity is poor. It needs to add a large amount of excipients to granulate, or to improve the fluidity after multiple times of mixing and sieving. The operation is cumbersome, which is not conducive to direct compression and direct filling of capsules. At the same time, the use of a large number of excipients will inevitably lead to large tablet weight, and it is difficult to reduce the size of the tablet. If the tablet size is too large, the medication compliance of the elderly and children with dysphagia will be poor. However, the cellulose-containing solid dispersion prepared by hot-melt extrusion is difficult to pulverize.
  • the solid dispersion particles with D 90 ⁇ 100 ⁇ m cannot be directly pulverized and must be sieved.
  • the cellulose-containing solid dispersion particles need to be granulated to improve fluidity.
  • a large number of excipients are required, which will also lead to large tablet weight and large tablet size, which is not conducive to medication for the elderly and children who have difficulty swallowing. It is also not conducive to direct compression and direct filling of capsules.
  • Patent WO2014043208 discloses cellulose-containing solid dispersion particles of enzalutamide.
  • the particle size affects its supersaturation maintenance capacity.
  • the finer the particle size the better the supersaturation maintenance capacity, which in turn promotes drug absorption. Therefore, the preparation of fine particle size solid dispersion particles can be used to improve the bioavailability of drugs, which is of positive significance for drug development.
  • the fluidity of powder is part of the development of solid preparations. Good fluidity can ensure uniform mixing, smooth feeding during tablet compression and stable tablet weight. At the same time, materials with good fluidity can be used for direct tablet compression, and can also be directly filled into capsules, which simplifies the process.
  • the preparation of cellulose-containing solid dispersion particles with fine particle size and good fluidity not only helps to improve the bioavailability of drugs, but also facilitates the process of direct compression and direct filling of capsules, which is of great significance in drug development and production.
  • the first aspect of the present invention is to provide a method for preparing a solid dispersion, which comprises the following steps: after the active pharmaceutical ingredient is mixed with a solubilizing matrix, hot-melt extrusion is performed, and the extruded product is pulverized at a low temperature to obtain the solid dispersion, and the solubilizing matrix is selected from a cellulose solubilizing matrix and/or a non-cellulose solubilizing matrix.
  • the low-temperature pulverization is pulverization by mixing the extrudate with a low-temperature medium, for example, the low-temperature medium is dry ice or liquid nitrogen, preferably liquid nitrogen.
  • the pharmaceutically active ingredient is selected from enzalutamide, ARN-509 or posaconazole.
  • the solubilization matrix comprises a cellulosic solubilization matrix and a non-cellulosic solubilization matrix.
  • the solubilization matrix is a cellulosic solubilization matrix.
  • the cellulose-based solubilizing matrix is selected from one or more of hypromellose acetate succinate, hypromellose or hypromellose phthalate.
  • the non-cellulosic solubilizing matrix is selected from one or more of povidone, copovidone or polyethylene glycol.
  • the mass ratio of the active pharmaceutical ingredient to the solubilizing matrix is 1:2-1:5, such as 1:2, 1:2.5, 1:2.7, 1:3, 1:4, 1:5, especially 1:2, 1:2.5, 1:2.7, 1:3, 1:4 or 1:5.
  • the rotational speed of the low-temperature pulverization is above 10,000 rpm; preferably, the rotational speed of the low-temperature pulverization is above 12,000 rpm; for example, above 16,000 rpm, such as 16,000 rpm, 18,000 rpm, 20,000 rpm, especially 16,000 rpm, 18,000 rpm or 20,000 rpm.
  • the number of low-temperature pulverization is more than 1 time; preferably, the number of times of low-temperature pulverization is more than 1 time and less than 4 times, such as 1 time, 2 times or 3 times.
  • the temperature of the hot melt extrusion is 140-200° C.
  • the screw speed is 200-600 rpm.
  • the temperature of the hot melt extrusion is 140°C, 150°C, 160°C, 170°C, 175°C, 180°C, 185°C, 190°C, 195°C, especially 140°C, 150°C, 160°C, 170°C, 175°C, 180°C, 185°C, 190°C or 195°C
  • the screw speed of the hot melt extrusion is 200rpm, 300rpm, 400rpm, 500rpm and 600rpm, especially 200rpm, 300rpm, 400rpm, 500rpm or 600rpm.
  • the second aspect of the present invention is to provide a solid dispersion, which is obtained by the preparation method of the first aspect of the present invention, comprising a pharmaceutical active ingredient and a solubilizing matrix, the solubilizing matrix is selected from cellulose solubilizing matrix and/or non-cellulose solubilizing matrix, the D90 of the solid dispersion is 50-100 ⁇ m; preferably, the D50 of the solid dispersion is 25-60 ⁇ m, and the D10 is 8-30 ⁇ m.
  • the solubilization matrix comprises a cellulosic solubilization matrix and a non-cellulosic solubilization matrix.
  • the solubilization matrix is a cellulosic solubilization matrix.
  • the pharmaceutically active ingredient is selected from enzalutamide, ARN-509 or posaconazole.
  • the mass ratio of the active pharmaceutical ingredient to the solubilizing matrix is 1:2-1:5, such as 1:2, 1:2.5, 1:2.7, 1:3, 1:4, 1:5, especially 1:2, 1:2.5, 1:2.7, 1:3, 1:4 or 1:5.
  • the cellulose-based solubilizing matrix is selected from one or more of hypromellose acetate succinate, hypromellose or hypromellose phthalate.
  • the non-cellulosic solubilizing matrix is selected from one or more of povidone, copovidone or polyethylene glycol.
  • a third aspect of the present invention provides a pharmaceutical composition, which includes the solid dispersion of the second aspect of the present invention; preferably, the pharmaceutical composition also includes a disintegrant and a lubricant, the disintegrator is selected from one or more of croscarmellose sodium, crospovidone or sodium starch glycolate, and the lubricant is selected from one or more of magnesium stearate, calcium stearate or sodium stearyl fumarate.
  • the pharmaceutical composition further includes one or more of fillers, glidants or binders.
  • the filler is selected from microcrystalline cellulose or silicified microcrystalline cellulose; the glidant is selected from silicon dioxide or colloidal silicon dioxide; and the binder is selected from hydroxypropyl cellulose.
  • the pharmaceutical composition includes the following components by mass: 10-30 parts of active ingredients (especially active pharmaceutical ingredients), 55-80 parts of cellulose solubilizing base, 3-12 parts of disintegrant, 0.1-2 parts of lubricant, especially 10-30 parts of active pharmaceutical ingredient, 55-80 parts of cellulose solubilizing base, 3-12 parts of disintegrating agent and 0.1-2 parts of lubricant.
  • the present invention has the following beneficial effects:
  • the preparation method of the solid dispersion of the present invention adopts hot-melt extrusion and low-temperature pulverization to directly pulverize to obtain a solid dispersion with a D 90 ⁇ 100 ⁇ m, and has a relatively high yield.
  • the method can be applied to the pulverization of solid dispersions of enzalutamide, posaconazole, and ARN-509. At the same time, the method can also realize the pulverization of hot-melt extrusion solid dispersions with different ratios of cellulose solubilizing matrix and active ingredients.
  • the method has strong durability and is suitable for industrialization.
  • the D 90 of the solid dispersion prepared by the invention is less than or equal to 100 ⁇ m, and has a finer particle size, and the prepared pharmaceutical composition shows faster dissolution. Therefore, the solid dispersion prepared by the invention can improve the bioavailability of the drug.
  • the D 90 of the solid dispersion prepared by the present invention is ⁇ 100 ⁇ m, and has a finer particle size. At the same time, because the particle size distribution of the solid dispersion prepared by the present invention is relatively concentrated, the D 50 is 25-60 ⁇ m, and the D 10 is 8-30 ⁇ m. Therefore, the particles have good fluidity at the same time.
  • the solid dispersion prepared by the present invention has good fluidity, it can be smoothly compressed into tablets or filled into capsules by mixing with a small amount of auxiliary materials, which can greatly reduce the amount of auxiliary materials, thereby reducing the quality of tablets or capsules and reducing the size of tablets or capsules, which is more conducive to swallowing by patients; meanwhile, it is also conducive to improving the specifications of the preparation.
  • Fig. 1 is the dissolution curve of the posaconazole tablet obtained in Example 4 and Comparative Example 1.
  • Fig. 2 is the dissolution curve of ARN-509 tablets obtained in Example 5 and Comparative Example 2.
  • Test method for the angle of repose slowly add powder from the top of the funnel, and the material leaked from the bottom of the funnel forms the inclination angle of a conical pile on the horizontal plane.
  • the particle size distribution was detected by a Malvern laser particle size analyzer.
  • ARN-509 solid dispersion Take 240g of ARN-509 solid dispersion, 9.1g of colloidal silicon dioxide, 35g of croscarmellose sodium, 412.4g of silicified microcrystalline cellulose, mix for 5min, add 3.5g of magnesium stearate, mix for 1min, compress into tablets, the tablet weight is 690mg.
  • Embodiment 6 is a diagrammatic representation of Embodiment 6
  • Embodiment 7 is a diagrammatic representation of Embodiment 7:
  • Embodiment 8 is a diagrammatic representation of Embodiment 8
  • Example 6 Take 1.995 kg of the enzalutamide solid dispersion in Example 6, add 5 g of magnesium stearate, mix for 1 min, and fill the capsules with a capsule filling machine.
  • the target filling volume is 321.6 mg, and the filling volume difference during the filling process is within 5%, and the filling is smooth.
  • Embodiment 9 is a diagrammatic representation of Embodiment 9:
  • the target filling volume is 321.6 mg.
  • the filling volume difference during the filling process is within 5%, and the filling is smooth.
  • the tablet size is 13 ⁇ 6 mm, the tablet weight is 350 mg, and the specification is 80 mg.
  • the tablet weight is 251 mg, and the specification is 60 mg. Within 5%, tablet compression is smooth.
  • the tablet weight is 250.5 mg, and the specification is 60 mg.
  • the tablet weight is 250.5 mg, and the specification is 60 mg.
  • the particle angle of repose is 45°.
  • the particle angle of repose is 46°.
  • Example 1 The extrudates of Example 1, Example 2, Example 3 and Comparative Example 5 were all transparent strips, and were all amorphous through X-ray diffraction analysis, indicating that the solid dispersion prepared by this method was amorphous.
  • Example 1 shows that the fluidity of the solid dispersion obtained in Examples 1-1 to 1-5 is better than that of the particles of Comparative Examples 3 and 4, indicating that the solid dispersion obtained by the preparation method of the present invention has good fluidity.
  • the D90 of the solid dispersion of the present invention is 50-100 ⁇ m, and has good fluidity. The reason is that the particle size distribution of the solid dispersion of the present invention is relatively concentrated. Compared with conventional materials, the solid dispersion of the present invention has greater D50 and D10 under the same D90 , ensuring the fluidity of the product. Therefore, in order to ensure that the solid dispersion has good fluidity while taking into account relatively rapid dissolution, the D90 of the solid dispersion of the present invention is preferably 50-100 ⁇ m, the D50 is preferably 25-60 ⁇ m, and the D10 is preferably 8-30 ⁇ m.
  • the solid dispersion of the present invention has good fluidity, does not need granulation, repeated sieving and mixing, can greatly simplify the process, and only needs to add a small amount of additional auxiliary materials to meet the needs of powder direct compression, thus greatly reducing the amount of auxiliary materials.
  • the tablet weight of the ARN-509 tablet (60 mg specification) of Example 13 is 251 mg, which is 690 mg compared to the tablet weight 690 mg of the tablet of Example 5.2 (60 mg specification) in CN106999431A, which greatly reduces the amount of auxiliary materials and the size of the tablet.
  • the tablet weight of the 120 mg tablet in Example 13 is 502 mg, which is still lower than the 690 mg tablet weight of the 60 mg tablet in Example 5.2 of CN106999431A, which can reduce the number of tablets taken by patients and improve medication compliance.
  • the dissolution curves of the posaconazole tablets obtained in Example 4 and Comparative Example 1 and the ARN-509 tablets obtained in Example 5 and Comparative Example 2 were compared, as shown in Fig. 1 and Fig. 2 for details.
  • the results show that Example 4 dissolves faster than Comparative Example 1, and Example 5 dissolves faster than Comparative Example 2, indicating that the tablet prepared by the solid dispersion of the present invention can accelerate the dissolution rate.

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Abstract

一种固体分散体及其制备方法和包含其的药物组合物。固体分散体的制备方法包括如下：药物活性成分与增溶基质混合后，经热熔挤出，挤出物经低温粉碎，得到所述固体分散体。固体分散体的 D90≤100 um，具有较细的粒径，同时具有良好的流动性，与少量辅料混合即可顺畅压片或与少量辅料混合即可充填胶囊，大大减少辅料的用量，进而可减少片剂或胶囊的质量，缩小片剂或胶囊的尺寸，更利于患者的吞服；同时也有利于提高制剂规格。

Description

固体分散体及其制备方法和包含其的药物组合物
相关申请的引用
本发明要求2022年1月19日在中国提交的、名称为“固体分散体及其制备方法和包含其的药物组合物”、申请号为202210060860.9的发明专利申请的优先权，通过引用的方式将该专利申请的全部内容并入本文。
技术领域
本发明属于药物制剂领域，具体涉及固体分散体及其制备方法和包含其的药物组合物。
背景技术
醋酸羟丙甲纤维素琥珀酸酯(HPMCAS)、羟丙甲纤维素(HPMC)、羟丙甲纤维素邻苯二甲酸酯(HPMCP)为制备固体分散体的常用纤维素类增溶基质，已广泛应用于药物制剂开发中，如恩扎卢胺片、特拉匹韦片、阿帕他胺、他克莫司等。
固体分散体颗粒的制备技术主要有三种：1)喷雾干燥技术；2)共沉淀技术；3)热熔挤出技术。
喷雾干燥技术利用高压泵较大的气压将物料的有机溶液通过雾化器雾化成雾状液滴，然后与热空气直接接触，进行热交换，短时间完成干燥。喷雾干燥技术因雾化液滴非常小，直接干燥制得的固体分散体颗粒非常细，因而溶出快。喷雾干燥技术缺点包括：1)需采用大量易燃易爆的有机溶剂，并且也易泄露污染环境。2)喷雾干燥得到的颗粒细，很蓬松、流动性差，可压缩性差，需与较多的外加辅料混合或制粒改善流动性，如专利WO2014043208公布喷雾干燥制备的恩扎卢胺固体分散体颗粒卡尔系数为33.3％，流动性非常差，为了实现直压，需与助流剂胶态二氧化硅、流动性较好的微晶纤维素Avicel PH102和一水乳糖Fast Flo 316等辅料经多次混合，多次过筛得到流动性一般的压片粉末，该操作极其繁琐。该专利的制剂处方除醋酸羟丙甲纤维素琥珀酸酯外的辅料用量超过40％，可见为了改善其流动性，便于直接压片，需加入大量流动性好的辅料和助流剂；且均不能通过直接混合用于压片，需要研磨或干法制粒改善流动性。3)喷雾颗粒使用大量辅料改善流动性必然导致片重偏大，同时颗粒过细，比表面积大，空气较多，压缩空间有限，必然导致片形尺寸过大，较大尺寸的片子对有吞咽困难的老人和儿童用药依从性差。
共沉淀制备固体分散颗粒是将原料药与增溶基质的有机溶液经喷雾和热风干燥沉结于辅料表面。该工艺的优点是设备要求较低，流化床即可满足要求，所得颗粒蓬松、表面积大，能快速溶出，缺点是流化床制粒中需加入大量辅料作为共沉淀载体，这必然导致所得片剂的片重偏大，同时颗粒流动性差、蓬松，需经制粒改善流动性。专利WO2021064123公布流化床制粒制备恩扎卢胺的固体分散体颗粒，需内加大量微晶纤维素和交联羧甲纤维素钠制粒，同时需与外加辅料进行干法制粒，进而获得流动性符合要求的可用于压片的颗粒。大量辅料的使用必然导致片形尺寸较难缩小，片形尺寸过大对有吞咽困难的老人和儿童用药依从性差。
热熔挤出是将药物与增溶基质材料加入螺杆机中通过加热—熔融—混合—挤出工序制得 具有均匀形态的挤出物的技术。该工艺相对喷雾干燥和共沉淀法优点是连续化生产，不使用有机溶剂，较环保，所得挤出物致密、紧实、体积小、堆密度大。虽然挤出物致密、紧实，但是对于含纤维素类的固体分散体挤出物进行粉碎却很困难，粉碎中易大量产热，甚至可能导致固体分散体在粉碎设备中发生熔化，因此，很难直接粉碎获得D90≤100μm的含纤维素类的热熔挤出固体分散体颗粒。专利CN104983701A公布了泊沙康唑含纤维素类热熔挤出固体分散体颗粒的制备，其通过200目和75目筛分获得粒度分布在75微米到300微米之间颗粒，未对100μm以下的热熔挤出颗粒粉碎进行研究。专利WO2014043208公布了采用研钵和研杵，手工研磨挤出物，随后过筛得到D90≤100μm的热熔挤出物颗粒，以上方法均不适用于工业化生产，并未实际解决含纤维素类固体分散体粉碎难的问题。专利WO2019030691公布了热熔挤出制备恩扎卢胺的含醋酸羟丙甲纤维素琥珀酸酯的固体分散体颗粒，其粉碎后固体分散体颗粒需与辅料进行干法制粒，最终压片，其干法制粒的目的是为了改善粉碎后固体分散体颗粒的流动性。
现有报道的喷雾干燥技术和共沉淀技术得到的含纤维素类固体分散体颗粒粒径细或蓬松，但流动性差，需要加入大量辅料制粒，或经多次混合并过筛改善流动性，操作繁琐，不利于直接压片和直接充填胶囊，同时大量辅料的使用必然导致片重偏大，片形尺寸较难缩小，片形尺寸若过大对有吞咽困难的老人和儿童用药依从性差。而热熔挤出制备的含纤维素类固体分散体，粉碎难度大，对于D 90≤100μm以下的固体分散体颗粒不能直接粉碎获得，需过筛，同时含纤维素类固体分散体颗粒还需制粒改善流动性，需使用大量辅料，也会导致片重偏大，片形尺寸偏大，不利于有吞咽困难的老人和儿童用药，同时也不利于直接压片和直接灌装胶囊。
专利WO2014043208公布了恩扎卢胺含纤维素类的固体分散体颗粒，其粒径影响其过饱和维持能力，粒径越细过饱和维持能力越好，进而促进药物的吸收，因此制备细粒径的固体分散体颗粒可用于提高药物的生物利用度，对于药物开发具有积极意义。粉体流动性是固体制剂开发的一部分，良好的流动性可确保混合均匀、压片中加料顺畅以及片重稳定。同时良好流动性的物料可用于直接压片，也可直接充填胶囊，简化工艺。
因此，制备细粒径兼具良好流动性的含纤维素类的固体分散体颗粒，不仅有利于提高药物生物利用度，同时还有利于直接压片和直接充填胶囊简化工艺，在药物开发和生产上具有较大的意义。
发明内容
本发明的第一方面是提供一种固体分散体的制备方法，其包括如下：药物活性成分与增溶基质混合后，经热熔挤出，挤出物经低温粉碎，得到所述固体分散体，所述增溶基质选自纤维素类增溶基质和/或非纤维素类增溶基质。
在本发明第一方面的一些实施方案中，所述低温粉碎是将所述挤出物与低温介质混合共同进行粉碎，例如，所述低温介质为干冰或液氮，优选为液氮。
在本发明第一方面的一些实施方案中，所述药物活性成分选自恩扎卢胺、ARN-509或泊沙康唑。
在本发明第一方面的一些实施方案中，所述增溶基质包括纤维素类增溶基质和非纤维素类增溶基质。
在本发明第一方面的一些实施方案中，所述增溶基质为纤维素类增溶基质。
在本发明第一方面的一些实施方案中，所述纤维素类增溶基质选自醋酸羟丙甲纤维素琥珀酸酯、羟丙甲纤维素或羟丙甲纤维素邻苯二甲酸酯中的一种或多种。
在本发明第一方面的一些实施方案中，所述非纤维素类增溶基质选自聚维酮、共聚维酮或聚乙二醇中的一种或多种。
在本发明第一方面的一些实施方案中，所述药物活性成分与所述增溶基质的质量比为1:2-1:5，例如1:2，1:2.5，1:2.7，1:3，1:4，1:5，特别是1:2，1:2.5，1:2.7，1:3，1:4或1:5。
在本发明第一方面的一些实施方案中，所述低温粉碎的转速为10000rpm以上；优选地，所述低温粉碎的转速为12000rpm以上；例如16000rpm以上，例如16000rpm、18000rpm、20000rpm，特别是16000rpm、18000rpm或20000rpm。
在本发明第一方面的一些实施方案中，所述低温粉碎的次数为1次以上；优选地，所述低温粉碎次数为1次以上，4次以下，例如1次、2次或3次。
在本发明第一方面的一些实施方案中，所述热熔挤出的温度为140-200℃，螺杆转速为200-600rpm。例如，所述热熔挤出的温度为140℃、150℃、160℃、170℃、175℃、180℃、185℃、190℃、195℃，特别是140℃、150℃、160℃、170℃、175℃、180℃、185℃、190℃或195℃；所述热熔挤出的螺杆转速为200rpm、300rpm、400rpm、500rpm和600rpm，特别是200rpm、300rpm、400rpm、500rpm或600rpm。
本发明的第二方面是提供一种固体分散体，所述固体分散体采用本发明第一方面的制备方法获得，包括药物活性成分与增溶基质，所述增溶基质选自纤维素类增溶基质和/或非纤维素类增溶基质，所述固体分散体的D 90为50-100μm；优选地，所述固体分散体的D 50为25-60μm，D 10为8-30μm。
在本发明第二方面的一些实施方案中，所述增溶基质包括纤维素类增溶基质和非纤维素类增溶基质。
在本发明第二方面的一些实施方案中，所述增溶基质为纤维素类增溶基质。
在本发明第二方面的一些实施方案中，所述药物活性成分选自恩扎卢胺、ARN-509或泊沙康唑。
在本发明第二方面的一些实施方案中，所述药物活性成分与所述增溶基质的质量比为1:2-1:5，例如1:2，1:2.5，1:2.7，1:3，1:4，1:5，特别是1:2，1:2.5，1:2.7，1:3，1:4或1:5。
在本发明第二方面的一些实施方案中，所述纤维素类增溶基质选自醋酸羟丙甲纤维素琥珀酸酯、羟丙甲纤维素或羟丙甲纤维素邻苯二甲酸酯中的一种或多种。
在本发明第二方面的一些实施方案中，所述非纤维素类增溶基质选自聚维酮、共聚维酮或聚乙二醇中的一种或多种。
本发明的第三方面提供一种药物组合物，其包括本发明第二方面的固体分散体；优选地，所述药物组合物还包括崩解剂和润滑剂，所述崩解剂选自交联羧甲纤维素钠、交联聚维酮或羧甲淀粉钠中的一种或多种，所述润滑剂选自硬脂酸镁、硬脂酸钙或硬脂富马酸钠中的一种 或多种。
本发明第三方面的一些实施方案中，所述药物组合物还包括填充剂、助流剂或粘合剂中的一种或多种。优选地，所述填充剂选自微晶纤维素或硅化微晶纤维素；所述助流剂选自二氧化硅或胶态二氧化硅；所述粘合剂选自羟丙基纤维素。
在本发明第三方面的一些实施方案中，所述药物组合物包括下述质量份的组分：活性成分(特别是药物活性成分)10-30份，纤维素类增溶基质55-80份，崩解剂3-12份，润滑剂0.1-2份，特别是药物活性成分10-30份，纤维素类增溶基质55-80份，崩解剂3-12份和润滑剂0.1-2份。
与现有技术相比，本发明具有以下的有益效果：
本发明的固体分散体的制备方法，采用热熔挤出和低温粉碎可直接粉碎得到D 90≤100μm的固体分散体，并且具有较高的收率。本方法可应用于恩扎卢胺、泊沙康唑、ARN-509的固体分散体的粉碎中，同时该方法也能实现纤维素类增溶基质与活性成分不同比例的热熔挤出固体分散体的粉碎，该方法耐用性较强，且适于产业化。
本发明制备的固体分散体的D 90≤100μm，具有较细的粒径，制备的药物组合物表现出更快速的溶出，因此，本发明制备的固体分散体可提高药物生物利用度。
本发明制备的固体分散体的D 90≤100μm，具有较细的粒径，同时由于本发明制备的固体分散体颗粒粒径分布较集中，D 50为25-60μm，D 10为8-30μm，因此，该颗粒同时具有良好的流动性。
本发明制备的固体分散体由于具有良好的流动性，与少量辅料混合即可顺畅压片或与少量辅料混合即可充填胶囊，大大减少辅料的用量，进而可减少片剂或胶囊的质量，缩小片剂或胶囊的尺寸，更利于患者的吞服；同时也有利于提高制剂规格。
附图说明
图1为实施例4、对比例1所获得泊沙康唑片的溶出曲线。
图2为实施例5、对比例2所获得ARN-509片的溶出曲线。
具体实施方式
以下通过具体实施例对本发明的上述内容做进一步的详细说明。但不应该将此理解为本发明上述主题的范围仅限于以下的实例。凡基于本发明上述内容所实现的技术方案均属于本发明的范围。
休止角的测试方法：将粉体从漏斗上方慢慢加入，从漏斗底部漏出的物料在水平面上形成圆锥状堆积体的倾斜角。
粒径分布采用马尔文激光粒度仪检测。
实施例1：
将2kg恩扎卢胺与6kg醋酸羟丙甲纤维素琥珀酸酯于195℃、螺杆转速300rpm进行热熔挤出，挤出物冷却后，经冷辊制备薄片，破碎物料，得初粉碎挤出物。
实施例1-1：取1.2kg初粉碎挤出物与干冰混合，用粉碎机于转速16000rpm粉碎二次， 得D 90＝163μm、D 50＝95μm、D 10＝31μm，休止角为32°的固体分散体1.06kg。取固体分散体300g采用150目筛网筛分，得筛下物143.4g，收率47.8％，所得筛下物为D 90＝97μm、D 50＝59μm、D 10＝27μm，休止角为36°的恩扎卢胺固体分散体。
实施例1-2：取1.2kg初粉碎挤出物与液氮混合，用粉碎机于转速10000rpm下共粉二次，得D 90＝131μm、D 50＝72μm、D 10＝21μm，休止角为34°的恩扎卢胺固体分散体1.14kg。
实施例1-3：取1.2kg初粉碎挤出物同液氮混合，用粉碎机于转速16000rpm下共粉一次，得D 90＝89μm、D 50＝46μm、D 10＝22μm，休止角为36°的恩扎卢胺固体分散体1.13kg。
实施例1-4：取1.2kg初粉碎挤出物同液氮混合，用粉碎机于转速16000rpm下共粉二次，得D 90＝75μm、D 50＝40μm、D 10＝18μm，休止角为38°的恩扎卢胺固体分散体1.10kg。
实施例1-5：取1.2kg初粉碎挤出物同液氮混合，用粉碎机于转速18000rpm下共粉二次，得D 90＝51μm、D 50＝25μm、D 10＝8μm，休止角为38°的恩扎卢胺固体分散体1.08kg。
实施例1-6：将上述实施例1-4中的粉碎后固体分散体进一步同液氮混合，用粉碎机于转速18000rpm粉碎二次，得D 90＝35μm、D 50＝14μm、D 10＝5μm，休止角为46°的恩扎卢胺固体分散体。
实施例2：
将0.5kg恩扎卢胺、1.35kg醋酸羟丙甲纤维素琥珀酸酯和0.15kg共聚维酮于195℃、螺杆转速300rpm进行热熔挤出，挤出物冷却后，经冷辊制备薄片，破碎物料后，再与液氮混合，用粉碎机于转速16000rpm粉碎一次，得D 90＝87μm、D 50＝47μm、D 10＝21μm，休止角为35°的恩扎卢胺固体分散体。
实施例3：
将0.5kg恩扎卢胺、1.35kg醋酸羟丙甲纤维素琥珀酸酯和0.15kg羟丙甲纤维素于195℃、螺杆转速300rpm进行热熔挤出，挤出物冷却后，经冷辊制备薄片，破碎物料后，再与液氮混合，用粉碎机于转速16000rpm粉碎一次，得D 90＝82μm、D 50＝43μm、D 10＝19μm，休止角为37°的恩扎卢胺固体分散体。
实施例4：
将1.0kg泊沙康唑与3.0kg醋酸羟丙甲纤维素琥珀酸酯预混5min，于140℃、螺杆转速300rpm进行热熔挤出，挤出物冷却后，经冷辊制备薄片，破碎物料后，得初粉碎颗粒3.62kg。取2.5kg初粉碎颗粒与液氮混合，用粉碎机于转速16000rpm粉碎一次，得D 90＝93μm、D 50＝50μm、D 10＝24μm，休止角为36°的泊沙康唑固体分散体。
取2.0kg泊沙康唑固体分散体、0.1925kg醋酸羟丙甲纤维素琥珀酸酯、0.25kg微晶纤维素、0.2kg低取代的羟丙基纤维素，0.11kg二氧化硅混合5min，再加入12.5g硬脂酸镁，总混1min，压片，片重550mg。
对比例1：
取实施例4中的初粉碎颗粒1kg筛分，收集50目与250目之间的颗粒，获得D 90＝260μm、D 50＝143μm、D 10＝46μm的泊沙康唑固体分散体颗粒。取0.2kg粉碎后泊沙康唑的固体分散体，采用与实施例4相同的处方制备片剂，片重550mg。
实施例5：
将1.0kg ARN-509与3.0kg醋酸羟丙甲纤维素琥珀酸酯预混5min，于195℃、螺杆转速300rpm进行热熔挤出，挤出物冷却后，经冷辊制备薄片，破碎物料，得初粉碎颗粒3.72kg。取2.82kg初粉碎颗粒与液氮混合，用粉碎机于转速16000rpm粉碎一次，得D 90＝97μm、D 50＝52μm、D 10＝26μm，休止角为38°的ARN-509固体分散体。
取ARN-509固体分散体240g，胶态二氧化硅9.1g，交联羧甲纤维素钠35g，硅化微晶纤维素412.4g，混合5min，加入硬脂酸镁3.5g，总混1min，压片，片重690mg。
对比例2：
取实施例5中的初粉碎颗粒0.9kg，用孔径为250μm的筛网筛分，收集筛下物，得D 90＝200μm、D 50＝129μm、D 10＝50μm的ARN-509固体分散体。
取筛分后ARN-509固体分散体240g，按实施例5中处方制备片剂，片重690mg。
实施例6：
将1.0kg恩扎卢胺与3.0kg羟丙甲纤维素预混5min，于195℃、螺杆转速300rpm进行热熔挤出，挤出物冷却后，经冷辊制备薄片，破碎物料后，再与液氮混合，用粉碎机于转速16000rpm粉碎二次，得D 90＝89μm、D 50＝45μm、D 10＝22μm，休止角为37°的恩扎卢胺固体分散体。
实施例7：
将1.0kg恩扎卢胺与3.0kg羟丙甲纤维素邻苯二甲酸酯预混5min，于195℃、螺杆转速300rpm进行热熔挤出，挤出物冷却后，经冷辊制备薄片，破碎物料后，再与液氮混合，用粉碎机于转速16000rpm粉碎一次，得D 90＝91μm、D 50＝43μm、D 10＝24μm，休止角为34°的恩扎卢胺固体分散体。
实施例8：
取实施例6中的恩扎卢胺固体分散体1.995kg，加入5g硬脂酸镁，混合1min，采用胶囊灌装机灌装胶囊，目标装量为321.6mg，灌装过程中装量差异在5％以内，灌装顺畅。
实施例9：
取实施例1-3中的恩扎卢胺固体分散体(D 90＝89μm、D 50＝46μm、D 10＝22μm)0.998kg，加入2.5g硬脂酸镁，混合1min，采用胶囊灌装机灌装胶囊，目标装量为321.6mg，灌装过程中装量差异在5％以内，灌装顺畅。
实施例10：
取实施例1-5中的恩扎卢胺固体分散体(D 90＝51μm、D 50＝25μm、D 10＝8μm)320g与交联羧甲纤维素钠27g、二氧化硅2g，混合5min，加入硬脂酸镁1g，总混1min，压片，压片模具为13×6mm，片重为350mg，规格为80mg。
实施例11：
将0.5kg恩扎卢胺与1.0kg醋酸羟丙甲纤维素琥珀酸酯预混5min，于195℃、螺杆转速300rpm进行热熔挤出，挤出物冷却后，经冷辊制备薄片，破碎后，再与液氮混合，用粉碎机于16000rpm粉碎一次，得D 90＝89μm、D 50＝43μm、D 10＝24μm的恩扎卢胺固体分散体。
将恩扎卢胺固体分散体240g与交联羧甲纤维素钠29g混合5min，加入硬脂酸镁1.0g，总混1min，压片，压片模具为14.8×7.8mm，片重为540mg，规格为160mg。
实施例12：
将0.5kg恩扎卢胺与2.0kg醋酸羟丙甲纤维素琥珀酸酯预混5min，于195℃、螺杆转速300rpm进行热熔挤出，挤出物冷却后，经冷辊制备薄片，破碎后，再与液氮混合，用粉碎机于转速16000rpm粉碎二次，得D 90＝85μm、D 50＝46μm、D 10＝19μm，休止角为39°的恩扎卢胺固体分散体。
实施例13：
取实施例5中的ARN-509固体分散体(D 90＝97μm，D 50＝52μm，D 10＝26μm)240g，加入10.125g交联羧甲纤维素钠、0.5g二氧化硅，混合5min，加入0.375g硬脂酸镁，混合1min，压片，片重为251mg，规格为60mg，压片中片重差异在5％以内，压片顺畅。
另取部分上述总混颗粒，压片，片重502mg，规格120mg，压片中片重差异在5％以内，压片顺畅。
实施例14：
取实施例5中的ARN-509固体分散体(D 90＝97μm，D 50＝52μm，D 10＝26μm)240g，加入10g交联聚维酮，混合5min，加入0.5g硬脂富马酸钠，混合1min，压片，片重为250.5mg，规格为60mg，压片中片重差异在5％以内，压片顺畅。
实施例15：
取实施例5中的ARN-509固体分散体(D 90＝97μm，D 50＝52μm，D 10＝26μm)240g，加入10g羧甲淀粉钠，混合5min，加入0.5g硬脂酸镁，混合1min，压片，片重为250.5mg，规格为60mg，压片中片重差异在5％以内，压片顺畅。
对比例3：
将16g恩扎卢胺与48g醋酸羟丙甲纤维素琥珀酸酯溶于320g丙酮，与50.84g微晶纤维素、8.8g交联羧甲纤维素钠进行流化床制粒，经干燥后，得流化床颗粒。颗粒休止角为45°。
对比例4：
将16g恩扎卢胺与48g醋酸羟丙甲纤维素琥珀酸酯溶于320g丙酮，经喷雾干燥，得喷雾干燥颗粒。颗粒休止角为46°。
对比例5：
将0.5kg恩扎卢胺与2.5kg醋酸羟丙甲纤维素琥珀酸酯于185℃、螺杆转速400rpm进行热熔挤出，挤出物冷却后，经冷辊制备薄片，破碎后，得初粉碎挤出物，取0.8kg初粉碎挤出物，用粉碎机于转速16000rpm粉碎一次，D 90＝243μm、D 50＝151μm、D 10＝59μm，休止角为30°；另取0.8kg初粉碎挤出物，用粉碎机于转速16000rpm粉碎二次，D 90＝203μm、D 50＝138μm、D 10＝46μm，休止角为32°。
实施例1、实施例2、实施例3和对比例5的挤出物均为透明的条状物，经X-射线衍射分析均为无定形，表明本方法制备的固体分散体为无定形。
固体分散体颗粒粒径和流动性对比：
实施例1和对比例5对比可知，挤出物采用常温粉碎，即使采用粉碎机在较高的转速下粉碎两次，所得固体分散体的D 90仍然大于200μm，不能获得D 90≤100μm的固体分散体。而采用低温粉碎，特别是与液氮混合后粉碎一次或两次，即可得到D 90≤100μm的固体分散体。
实施例1和对比例3-4对比可知，实施例1-1至1-5中获得的固体分散体的流动性优于对比例3和4颗粒的流动性，表明通过本发明的制备方法获得的固体分散体具有良好的流动性。
本发明的固体分散体的D 90为50-100μm，具有良好的流动性，原因在于本发明的固体分散体的粒径分布较集中，相比于常规物料，本发明的固体分散体在相同的D 90下具有更大的D 50与D 10，确保了产品的流动性。因此，为保证固体分散体具有良好的流动性，同时兼顾较快速的溶出，本发明的固体分散体的D 90优选为50-100μm，D 50优选为25-60μm，D 10优选为8-30μm。
片重、片形尺寸对比：
本发明的固体分散体具有良好的流动性，不需制粒和反复过筛、混合，可大大简化工艺，仅需加入少量的外加辅料即可满足粉末直压需要，因而可大大减少辅料用量。
将实施例10的恩扎卢胺片剂与CN105358535A中实施例16的片剂进行比较，可见采用本发明的固体分散体制备的片剂的片重和尺寸可明显减小。
  CN105358535A中实施例16 实验例10
规格 80mg 80mg
片形 14.8mm*7.8mm 13*6mm
片重 540mg 350mg
除增溶基质外辅料在片中占比 40.7％ 8.6％
将实施例13的ARN-509片剂与CN106999431A中实施例5.2的片剂相比，实施例13的ARN-509片剂(规格为60mg)的片重为251mg，相比于CN106999431A中实施例5.2(规格为60mg)的片剂的片重690mg，大大降低了辅料的用量，片剂尺寸也大大缩小。实施例13中规格为120mg的片剂的片重为502mg，仍低于CN106999431A中实施例5.2中规格为60mg的片剂的片重690mg，可减少患者的服药片数，提高用药顺应性。
溶出速率对比：
根据中国药典2015版溶出度测定第二法(桨法)，对实施例4、对比例1所获得的泊沙康唑片和实施例5、对比例2所获得的ARN-509片进行溶出曲线对比，具体见图1和图2。结果显示，实施例4比对比例1溶出更快速，实施例5比对比例2溶出更快速，表明采用本发明的固体分散体制得的片剂可加快溶出速率。
以上所述实施例的各技术特征可以进行任意的组合，为使描述简洁，未对上述实施例中的各个技术特征所有可能的组合都进行描述，然而，只要这些技术特征的组合不存在矛盾，都应当认为是本说明书记载的范围。
以上所述实施例仅表达了本发明的几种实施方式，便于具体和详细地理解本发明的技术方案，但并不能因此而理解为对发明保护范围的限制。应当指出的是，对于本领域的普通技术人员来说，在不脱离本发明构思的前提下，还可以做出若干变形和改进，这些都属于本发明的保护范围。应当理解，本领域技术人员在本发明提供的技术方案的基础上，通过合乎逻辑的分析、推理或者有限的试验得到的技术方案，均在本发明所附权利要求的保护范围内。因此，本发明的保护范围应以所附权利要求的内容为准，说明书可以用于解释权利要求的内容。

Claims (10)

  1. 一种固体分散体的制备方法，所述制备方法包括如下：药物活性成分与增溶基质混合后，经热熔挤出，挤出物经低温粉碎，得到所述固体分散体，所述增溶基质选自纤维素类增溶基质和/或非纤维素类增溶基质。
  2. 根据权利要求1所述的制备方法，其特征在于，所述低温粉碎是将所述挤出物与低温介质混合共同进行粉碎，例如，所述低温介质为干冰或液氮，优选为液氮。
  3. 根据权利要求1或2所述的制备方法，其特征在于，满足以下条件中的一个或多个：
    所述药物活性成分选自恩扎卢胺、ARN-509或泊沙康唑；或，
    所述增溶基质包括纤维素类增溶基质和非纤维素类增溶基质，或，所述增溶基质为纤维素类增溶基质；或，
    所述纤维素类增溶基质选自醋酸羟丙甲纤维素琥珀酸酯、羟丙甲纤维素或羟丙甲纤维素邻苯二甲酸酯中的一种或多种；或，
    所述非纤维素类增溶基质选自聚维酮、共聚维酮或聚乙二醇中的一种或多种；或
    所述药物活性成分与所述增溶基质的质量比为1:2-1:5，例如1:2，1:2.5，1:2.7，1:3，1:4或1:5。
  4. 根据权利要求1-3任一项所述的制备方法，其特征在于，满足以下条件中的一个或多个：
    所述低温粉碎的转速为10000rpm以上；优选地，所述低温粉碎的转速为12000rpm以上；例如16000rpm以上，例如16000rpm、18000rpm或20000rpm；或，
    所述低温粉碎的次数为1次以上；优选地，所述低温粉碎的次数为1次以上，4次以下，优选为1次、2次或3次；或，
    所述热熔挤出的温度为140-200℃，螺杆转速为200-600rpm；优选地，所述热熔挤出的温度为140℃、150℃、160℃、170℃、175℃、180℃、185℃、190℃或195℃；所述热熔挤出的螺杆转速为200rpm、300rpm、400rpm、500rpm或600rpm。
  5. 一种固体分散体，所述固体分散体采用根据权利要求1-4任一项所述的制备方法获得，包括药物活性成分与增溶基质，所述增溶基质选自纤维素类增溶基质和/或非纤维素类增溶基质，所述固体分散体的D 90为50-100μm；优选地，所述固体分散体的D 50为25-60μm，D 10为8-30μm。
  6. 根据权利要求5所述的固体分散体，其特征在于，所述增溶基质包括纤维素类增溶基质和非纤维素类增溶基质；或，所述增溶基质为纤维素类增溶基质。
  7. 根据权利要求5或6所述的固体分散体，其特征在于，满足以下条件中的一个或多个：
    所述药物活性成分选自恩扎卢胺、ARN-509或泊沙康唑；或，
    所述药物活性成分与所述增溶基质的质量比为1:2-1:5，例如1:2，1:2.5，1:2.7，1:3，1:4或1:5；或，
    所述纤维素类增溶基质选自醋酸羟丙甲纤维素琥珀酸酯、羟丙甲纤维素或羟丙甲纤维素邻苯二甲酸酯中的一种或多种；或，
    所述非纤维素类增溶基质选自聚维酮、共聚维酮或聚乙二醇中的一种或多种。
  8. 一种药物组合物，所述药物组合物包括根据权利要求5-7任一项所述的固体分散体；优选地，所述药物组合物还包括崩解剂和润滑剂，所述崩解剂选自交联羧甲纤维素钠、交联聚维酮或羧甲淀粉钠中的一种或多种，所述润滑剂选自硬脂酸镁、硬脂酸钙或硬脂富马酸钠中的一种或多种。
  9. 根据权利要求8所述的药物组合物，其特征在于，所述药物组合物还包括填充剂、助流剂或粘合剂中的一种或多种；优选地，所述填充剂选自微晶纤维素或硅化微晶纤维素；所述助流剂选自二氧化硅或胶态二氧化硅；所述粘合剂选自羟丙基纤维素。
  10. 根据权利要求8或9所述的药物组合物，其特征在于，所述药物组合物包括下述质量份的组分：药物活性成分10-30份，纤维素类增溶基质55-80份，崩解剂3-12份和润滑剂0.1-2份。
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