[go: up one dir, main page]

WO2023138366A1 - Dispersion solide, son procédé de préparation et composition pharmaceutique la contenant - Google Patents

Dispersion solide, son procédé de préparation et composition pharmaceutique la contenant Download PDF

Info

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
Authority
WO
WIPO (PCT)
Prior art keywords
matrix
solid dispersion
cellulose
solubilizing
pharmaceutical composition
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/CN2023/070319
Other languages
English (en)
Chinese (zh)
Inventor
邓蓝进
谭冲
崔保清
徐上虎
徐飞
沈利
赵栋
刘思川
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Sichuan Kelun Pharmaceutical Research Co Ltd
Sichuan Kelun Pharmaceutical Research Institute Co Ltd
Original Assignee
Sichuan Kelun Pharmaceutical Research Co Ltd
Sichuan Kelun Pharmaceutical Research Institute Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Sichuan Kelun Pharmaceutical Research Co Ltd, Sichuan Kelun Pharmaceutical Research Institute Co Ltd filed Critical Sichuan Kelun Pharmaceutical Research Co Ltd
Priority to CN202380014610.4A priority Critical patent/CN118251213A/zh
Publication of WO2023138366A1 publication Critical patent/WO2023138366A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Images

Classifications

    • 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.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Inorganic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Medicinal Preparation (AREA)

Abstract

Dispersion solide, son procédé de préparation et composition pharmaceutique la contenant. Le procédé de préparation de la dispersion solide comprend les étapes suivantes : après le mélange d'un ingrédient pharmaceutique actif avec une matrice de solubilisation, la réalisation d'une extrusion à chaud, et la réalisation d'un broyage à basse température sur un extrudat, ce qui permet d'obtenir la dispersion solide. Le D90 de la dispersion solide est inférieur ou égal à 100 µm. La dispersion solide a une petite taille de particule, a une bonne fluidité, et peut être facilement mise en comprimés après avoir été mélangée avec une petite quantité d'adjuvants ou peut être utilisée pour remplir une capsule après avoir été mélangée avec une petite quantité d'adjuvants, de telle sorte que la quantité d'utilisation de l'adjuvant est considérablement réduite, la masse d'un comprimé ou d'une capsule peut ensuite être réduite, la taille du comprimé ou de la capsule est réduite, et il est plus facile pour un patient d'avaler ; et il est également propice à améliorer la spécification de formulation.
PCT/CN2023/070319 2022-01-19 2023-01-04 Dispersion solide, son procédé de préparation et composition pharmaceutique la contenant Ceased WO2023138366A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202380014610.4A CN118251213A (zh) 2022-01-19 2023-01-04 固体分散体及其制备方法和包含其的药物组合物

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202210060860.9 2022-01-19
CN202210060860 2022-01-19

Publications (1)

Publication Number Publication Date
WO2023138366A1 true WO2023138366A1 (fr) 2023-07-27

Family

ID=87347754

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2023/070319 Ceased WO2023138366A1 (fr) 2022-01-19 2023-01-04 Dispersion solide, son procédé de préparation et composition pharmaceutique la contenant

Country Status (2)

Country Link
CN (1) CN118251213A (fr)
WO (1) WO2023138366A1 (fr)

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103169676A (zh) * 2011-12-23 2013-06-26 石药集团中奇制药技术（石家庄）有限公司 一种丁苯酞舌下片及其制备方法
CN108066289A (zh) * 2017-12-28 2018-05-25 广州玻思韬控释药业有限公司 一种泊沙康唑固体分散体及其制备方法和泊沙康唑肠溶制剂
CN109897004A (zh) * 2012-09-11 2019-06-18 麦迪威森前列腺医疗有限责任公司 恩杂鲁胺制剂
CN110198704A (zh) * 2016-11-07 2019-09-03 默克专利股份有限公司 基于聚乙烯醇的控释片剂及其制备
CN113230217A (zh) * 2020-10-12 2021-08-10 哈药集团三精明水药业有限公司 一种拉西地平组合物的制备方法

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103169676A (zh) * 2011-12-23 2013-06-26 石药集团中奇制药技术（石家庄）有限公司 一种丁苯酞舌下片及其制备方法
CN109897004A (zh) * 2012-09-11 2019-06-18 麦迪威森前列腺医疗有限责任公司 恩杂鲁胺制剂
CN110198704A (zh) * 2016-11-07 2019-09-03 默克专利股份有限公司 基于聚乙烯醇的控释片剂及其制备
CN108066289A (zh) * 2017-12-28 2018-05-25 广州玻思韬控释药业有限公司 一种泊沙康唑固体分散体及其制备方法和泊沙康唑肠溶制剂
CN113230217A (zh) * 2020-10-12 2021-08-10 哈药集团三精明水药业有限公司 一种拉西地平组合物的制备方法

Also Published As

Publication number Publication date
CN118251213A (zh) 2024-06-25

Similar Documents

Publication Publication Date Title
EP1985310B1 (fr) Formes de dosage solide
Ekdahl et al. Effect of spray-dried particle morphology on mechanical and flow properties of felodipine in PVP VA amorphous solid dispersions
CN110650730A (zh) 维生素d类似物制剂及其制备方法
JP2011063611A (ja) シロスタゾール製剤
CN108135854A (zh) 含有药物的立即释放片剂和用于形成片剂的方法
CN103191023B (zh) 一种快速崩解片剂的低温压制方法
WO2022013360A1 (fr) Composition pharmaceutique comprenant un ivacaftor
US20210220283A1 (en) Method for manufacturing acetaminophen preparation
WO2022037544A1 (fr) Préparation solide médicinale de tolvaptan et procédé de préparation s'y rapportant
CN101961306B (zh) 一种低熔点药物固体分散体的制备方法
CN105832680A (zh) 一种改善螺内酯体外溶出及流动性的药物组合物
JP2012193177A (ja) 水難溶性薬物と賦形剤との粉砕物およびその製造方法、造粒粒子、錠剤
CN112351772B (zh) 颗粒尺寸不一致的原料药颗粒的处理方法
CN103239719A (zh) 二甲双胍复方药物组合物及其制备方法
CN103877051A (zh) 一种依折麦布片的制备方法
CN105434386B (zh) 一种含有高水溶性活性成分的缓释片剂及其制备方法
CN114469879B (zh) 一种丁溴东莨菪碱微片及其制备方法和制剂
WO2023138366A1 (fr) Dispersion solide, son procédé de préparation et composition pharmaceutique la contenant
CN102657617A (zh) 一种尼美舒利的热熔挤出速释制剂及其热熔挤出方法
CN109125270B (zh) 一种固体制剂及其制备方法
CN111343974B (zh) 对乙酰氨基酚制剂及其制造方法
JP5669751B2 (ja) 低い経口生物学的利用能を有する化合物のプレ圧縮崩壊性製剤
JP5900702B2 (ja) 経口投与用医薬組成物
CN111888477A (zh) 一种贝达喹啉药物制剂
CN105106250A (zh) 一种灵芝总三萜组合物及其制备方法

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 23742682

Country of ref document: EP

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: 202380014610.4

Country of ref document: CN

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 23742682

Country of ref document: EP

Kind code of ref document: A1