WO2023125724A1 - 一种固体药物组合物 - Google Patents

一种固体药物组合物 Download PDF

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Publication number
WO2023125724A1
WO2023125724A1 PCT/CN2022/143030 CN2022143030W WO2023125724A1 WO 2023125724 A1 WO2023125724 A1 WO 2023125724A1 CN 2022143030 W CN2022143030 W CN 2022143030W WO 2023125724 A1 WO2023125724 A1 WO 2023125724A1
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WIPO (PCT)
Prior art keywords
pharmaceutical composition
solid pharmaceutical
total weight
cancer
pharmaceutically acceptable
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
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PCT/CN2022/143030
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English (en)
French (fr)
Inventor
陈梁
刘世峰
赵艳慧
杨东晖
路杨
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.)
Adlai Nortye Biopharma Co Ltd
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Adlai Nortye Biopharma 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
Priority to US18/725,505 priority Critical patent/US20250381143A1/en
Priority to MX2024008180A priority patent/MX2024008180A/es
Priority to IL313976A priority patent/IL313976A/en
Priority to CA3242313A priority patent/CA3242313A1/en
Priority to CN202280013622.0A priority patent/CN116887817A/zh
Priority to AU2022426506A priority patent/AU2022426506B2/en
Application filed by Adlai Nortye Biopharma Co Ltd filed Critical Adlai Nortye Biopharma Co Ltd
Priority to JP2024538350A priority patent/JP2024544423A/ja
Priority to EP22914974.5A priority patent/EP4438036A4/en
Priority to KR1020247021645A priority patent/KR20240110883A/ko
Publication of WO2023125724A1 publication Critical patent/WO2023125724A1/zh
Priority to ZA2024/04874A priority patent/ZA202404874B/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • 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
    • A61K31/415—1,2-Diazoles
    • 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
    • A61K9/1682—Processes
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/282—Organic compounds, e.g. fats
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2893—Tablet coating processes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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 technical field of medicine, in particular to a novel selective EP4 antagonist 4- ⁇ (1S)-1-[( ⁇ 3-(difluoromethyl)-1-methyl-5-[3-(trifluoromethyl)
  • the most abundant type of immune cells infiltrating solid tumors includes myeloid cells, primarily TAMs and MDSCs, and depletion of monocytic cells, including TAMs and MDSCs, significantly inhibits tumor growth in established tumors in animal models (Zeisberger, et al ., 2006; Srivastava, et al., 2012).
  • TAMs and MDSCs significantly inhibit tumor growth in established tumors in animal models.
  • the presence and accumulation of TAMs and MDSCs in tumors is well documented in the literature and is associated with poorer prognosis in patients with breast, pancreatic or other types of cancer (Joyce and Pollard, 2009; Ding, et al., 2009; Ganjoo, et al., 2011; Medrek, et al., 2012; Zhang, et al., 2012).
  • EP4 is one of the four PGE2 receptors, expressed on myeloid cells (Wang and DuBois, 2010), and plays a key role in promoting the differentiation of monocytes into TAMs and MDSCs in the tumor microenvironment (Lechner, et al. , 2011; Mao, et al., 2014; Majumder, et al., 2014). Therefore, EP4 antagonism is a potential anticancer therapy, and the mechanism of action is to attenuate the formation and function of immunosuppressive TAMs and MDSCs.
  • ethyl ⁇ benzoic acid has a structure as shown in formula 1, which is hereinafter referred to as AN0025 for short in the application, and is a highly selective, strong Potent antagonists exhibit antitumor activity by modulating the accumulation and function of immunosuppressive myeloid cells, including tumor-associated macrophages [TAM] and myeloid-derived suppressor cells [MDSC], in the tumor microenvironment.
  • TAM tumor-associated macrophages
  • MDSC myeloid-derived suppressor cells
  • Oral administration is a more convenient and safer route of administration, superior to other routes of administration (such as intramuscular injection, intravenous injection, etc.), and is the preferred method of administration in the drug development process.
  • AN0025 capsules have been developed for phase I clinical research.
  • the capsules involve AN0025 and pharmaceutically acceptable carriers.
  • the granules containing the active ingredient AN0025 are prepared by dry granulation technology, and the granules are then filled into hypromellose hollow inside the capsule. Further details of this capsule are described below as "Comparative Example 1".
  • the present invention relates to compound 4- ⁇ (1S)-1-[( ⁇ 3-(difluoromethyl)-1-methyl-5-[3-(trifluoromethyl)phenoxy]-4 - a quality-controlled solid dosage form of 1H-pyrazolyl ⁇ carbonyl)amino]ethyl ⁇ benzoic acid (compound AN0025) and optionally at least one pharmaceutically acceptable carrier and its preparation process.
  • AN0025 belongs to Class IV drugs of the biopharmaceutical classification system, that is, low solubility and poor permeability.
  • the inventor unexpectedly found in the experiment that the AN0025 tablets prepared by different processes can show better uniformity in the in vitro dissolution test, and the AN0025 tablets prepared with different raw material particle sizes have similar in vitro dissolution behavior and in vivo exposure. .
  • the bioavailability of the AN0025 tablet provided by the present invention in Beagle dogs is equivalent to that of the clinical capsule, but the individual differences in the exposure in vivo (AUC) are small.
  • the present invention provides a solid pharmaceutical composition, which comprises: the compound described in Formula 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, wherein the compound described in Formula 1 or a pharmaceutically acceptable salt thereof The acceptable salt accounts for about 30% to about 80% of the total weight of the solid pharmaceutical composition; the dosage form of the solid pharmaceutical composition is a tablet.
  • the compound of Formula 1 or a pharmaceutically acceptable salt thereof accounts for about 40% to about 60% of the total weight of the solid pharmaceutical composition.
  • the pharmaceutically acceptable carrier includes one or more selected from fillers, binders, lubricants, disintegrants and glidants.
  • the pharmaceutically acceptable carrier includes:
  • a filler comprising from about 5% to about 60% of the total weight of the solid pharmaceutical composition
  • a binder comprising from about 0% to about 8% of the total weight of the solid pharmaceutical composition
  • a disintegrant comprising from about 0% to about 30% of the total weight of the solid pharmaceutical composition
  • a lubricant comprising from about 0.1% to about 10% of the total weight of the solid pharmaceutical composition
  • a glidant comprising from about 0% to about 5% of the total weight of the solid pharmaceutical composition.
  • the pharmaceutically acceptable carrier includes:
  • a filler comprising from about 10% to about 50% of the total weight of the solid pharmaceutical composition
  • a binder comprising from about 2% to about 6% of the total weight of the solid pharmaceutical composition
  • a disintegrant comprising about 0.1% to about 25% of the total weight of the solid pharmaceutical composition
  • a lubricant comprising from about 0.5% to about 8% of the total weight of the solid pharmaceutical composition
  • a glidant comprising from about 0% to about 3% of the total weight of the solid pharmaceutical composition.
  • the pharmaceutically acceptable carrier includes:
  • a filler comprising from about 20% to about 40% of the total weight of the solid pharmaceutical composition
  • a binder comprising from about 3% to about 5% of the total weight of the solid pharmaceutical composition
  • a disintegrant comprising about 1% to about 25% of the total weight of the solid pharmaceutical composition
  • a lubricant comprising from about 1% to about 6% of the total weight of the solid pharmaceutical composition
  • a glidant comprising from about 0% to about 1% of the total weight of the solid pharmaceutical composition.
  • the filler is selected from the group comprising: microcrystalline cellulose, calcium phosphate, calcium hydrogen phosphate, starch, dextrin, pregelatinized starch, mannitol, sorbitol, lactose, dextran , sucrose, dextrose and combinations thereof;
  • the binder is selected from the group comprising cellulose ethers, povidone, copovidone, starch, corn syrup and combinations thereof; wherein the cellulose ether Classes include but are not limited to hypromellose, hydroxypropyl cellulose, methyl cellulose, hydroxyethyl cellulose;
  • the disintegrant is selected from the group comprising: croscarmellose sodium, croscarmellose Lopovidone, sodium carboxymethyl starch, calcium carboxymethylcellulose, low-substituted hydroxypropyl cellulose and combinations thereof;
  • the lubricant is selected from the group comprising: magnesium stearate, stearyl fumaric acid Sodium, macrogol,
  • the filler is selected from microcrystalline cellulose, lactose, mannitol, sorbitol and combinations thereof;
  • the binder is selected from hydroxypropyl cellulose, hypromellose, polyvinylcellulose Ketone, copovidone and combinations thereof;
  • the disintegrating agent is selected from croscarmellose sodium, crospovidone, sodium carboxymethyl starch, carboxymethylcellulose calcium, low-substituted hydroxypropyl fiber Primers and combinations thereof;
  • the lubricant is selected from magnesium stearate, sodium stearyl fumarate and combinations thereof.
  • the solid pharmaceutical composition of the invention comprises particles having an internal phase.
  • the solid pharmaceutical composition of the present invention further comprises an external phase adjacent to said particles having an internal phase.
  • AN0025 and other pharmaceutically acceptable carriers are prepared into granules with good fluidity and compressibility through a granulation process, and then compressed into tablets. All other pharmaceutically acceptable carriers in the solid pharmaceutical composition can be added internally to participate in the granulation process, or partly added as an external phase.
  • the particles with an internal phase are prepared by a dry preparation process, comprising the following steps: screening and weighing compound AN0025 and various pharmaceutically acceptable carriers; compounding compound AN0025 and pharmaceutically acceptable carriers blending for an appropriate amount of time; rolling the blend into ribbons and grinding the ribbons into granules; blending the granules with extragranular excipients for an appropriate amount of time; compressing the blend into tablets agent.
  • the granules with an internal phase are prepared by a wet preparation process, comprising the following steps: screening and weighing compound AN0025 and each pharmaceutically acceptable carrier; Simultaneously with the granulation fluid, the compound AN0025 and the pharmaceutically acceptable carrier are mixed for an appropriate amount of time at a suitable mixing speed and the mixture is chopped into granules, wherein the granulation fluid can be obtained by dispersing the binder in a solvent ( water), or just a wetting agent such as water; dry the granules; blend the granules with extragranular excipients for an appropriate amount of time; compress the blend into tablets .
  • a wet preparation process comprising the following steps: screening and weighing compound AN0025 and each pharmaceutically acceptable carrier; Simultaneously with the granulation fluid, the compound AN0025 and the pharmaceutically acceptable carrier are mixed for an appropriate amount of time at a suitable mixing speed and the mixture is chopped into granules, wherein the granulation fluid can
  • the solid pharmaceutical composition further comprises a coating.
  • the compound of Formula 1 has a particle size D90 of less than about 200 microns.
  • the compound of Formula 1 has a particle size D90 of less than about 100 microns.
  • the solid pharmaceutical composition of the present invention contains about 50 mg to about 500 mg of the compound of formula 1.
  • the solid pharmaceutical composition of the present invention contains about 100 mg to about 300 mg of the compound of formula 1.
  • the present invention provides the use of the solid pharmaceutical composition in the preparation of medicines for the treatment of multiple sclerosis, rheumatoid arthritis, or cancer
  • the cancer includes: skin cancer, breast cancer, colorectal cancer cancer, prostate cancer, kidney cancer, ovarian cancer, cervical cancer, endometrial cancer, glioblastoma, lung cancer, head and neck cancer, medulloblastoma and urethral cancer.
  • Fig. 3 capsule (comparative example 1) AN0025 drug-time curve (750mg/ only) in Beagle dog
  • Fig. 4 tablet (embodiment example 4) AN0025 drug time curve (750mg/ only) in Beagle dog
  • Fig. 5 capsule (comparative example 1) AN0025 drug time curve (250mg/ only) in Beagle dog
  • Fig. 6 tablet (embodiment example 4) AN0025 drug time curve (250mg/ only) in Beagle dog
  • Fig. 7 tablet (embodiment example 4a) AN0025 drug-time curve (750mg/ only) in Beagle dog
  • the present invention provides a compound 4- ⁇ (1S)-1-[( ⁇ 3-(difluoromethyl)-1-methyl-5-[3-(trifluoromethyl)phenoxy]- 4-1H-pyrazolyl ⁇ carbonyl)amino]ethyl ⁇ benzoic acid (AN0025) and pharmaceutically acceptable salts thereof, and optionally at least one pharmaceutically acceptable carrier in a quality-controlled solid pharmaceutical combination substances, solid pharmaceutical preparations, and their preparation processes.
  • composition refers to a composition comprising a composition intended to be administered to an individual (e.g., a human) for the prevention, treatment, or management of a particular disease or condition affecting that individual.
  • a composition intended to be administered to an individual (e.g., a human) for the prevention, treatment, or management of a particular disease or condition affecting that individual.
  • a physical mixture of therapeutic compounds e.g., the terms “pharmaceutical composition” or “formulation” as used herein also encompass intimate physical mixtures formed at high temperature and pressure.
  • pharmaceutically acceptable refers to those substances which, within the scope of sound medical judgment, are suitable for contact with the tissues of individuals, especially humans, without undue toxicity, irritation, allergic reactions and other problematic complications and with a reasonable benefit/risk ratio.
  • Compound, material, composition, carrier and/or dosage form are suitable for contact with the tissues of individuals, especially humans, without undue toxicity, irritation, allergic reactions and other problematic complications and with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable carrier and “carrier” refer to any pharmaceutically acceptable inert material that is substantially inactive in biological activity and that constitutes a substantial part of the formulation.
  • terapéuticaally effective amount refers to an amount or concentration effective to reduce, eliminate, treat, prevent or manage the symptoms of a disease or condition affecting an individual.
  • control refers to all processes by which the progression of diseases and conditions affecting mammals can be slowed, interrupted, arrested or stopped. However, “controlling” does not necessarily indicate complete elimination of all symptoms of a disease or condition.
  • treatment includes prophylactic and/or therapeutic treatment as well as delaying the progression of a disease or condition.
  • treatment refers to therapeutic treatment as well as delaying the progression of a disease or condition.
  • Delayed progression refers to the administration of the pharmaceutical composition to an individual who is at a pre- or early stage of the cancer to be treated, in whom, for example, a pre-formation of the corresponding disease is diagnosed, or where the individual is in a situation where it is likely that the corresponding disease will develop.
  • oral dosage form refers to a pharmaceutical composition prepared for administration to an individual by the oral route of administration.
  • known oral dosage forms include, but are not limited to, tablets, capsules, caplets, powders, pills, granules, solutions, suspensions, solutions and solution pre-concentrates, emulsions and emulsion pre-concentrates, and the like.
  • powders, pills, granules and tablets may be coated with suitable polymers or commonly used coating materials to achieve, for example, greater stability in the gastrointestinal tract or to achieve a desired rate of release.
  • capsules containing powders, pills or granules may be further coated. Tablets may be scored to facilitate divided dosing.
  • dosage forms of the invention may be unit dosage forms, wherein one unit dosage form is intended to deliver one therapeutic dose per administration, or wherein multiple unit dosage forms are intended to deliver a total therapeutic dose per administration.
  • administering refers to the manner in which a therapeutic compound is presented to an individual.
  • oral administration denotes any method of administration in which a therapeutic compound can be administered by the oral route by swallowing, chewing or sucking an oral dosage form.
  • Solid oral dosage forms are traditionally intended to substantially release and/or deliver the active drug in the oral cavity and/or in the gastrointestinal tract behind the buccal cavity. Examples of solid dosage forms include commonly used tablets, capsules, caplets and the like.
  • the term "individual” or “patient” is intended to include animals. Examples of individuals include mammals such as humans, dogs, cows, horses, pigs, sheep, goats, cats, mice, rabbits, rats, and transgenic non-human animals. In certain embodiments, the individual is a human, e.g., a human having, at risk of, or potentially capable of developing cancer (including male and female subjects, and including newborns, infants, juveniles, adolescents, adults, and elderly subjects).
  • the terms “about” and “approximately” are used to provide flexibility in the endpoints of numerical ranges by providing that a given value may be “slightly above” or “slightly below” the endpoint to account for differences in instruments, samples, and sample preparations. Visible differences in the measurements between.
  • the term “about” or “approximately” generally means within 10%, more preferably within 5%, and most preferably within 1% of a given value or range.
  • Azolyl ⁇ carbonyl)amino]ethyl ⁇ benzoic acid (AN0025) and pharmaceutically acceptable salts thereof are intended for use in the pharmaceutical compositions of the present invention.
  • the compound, its pharmaceutically acceptable salt and its preparation are disclosed in WO2012039972A, which is incorporated herein by reference in its entirety.
  • the compound of formula 1 may exist in the pharmaceutical composition of the present invention in the form of its free acid or a pharmaceutically acceptable salt. These salts can be prepared in situ during the final isolation and purification of the compounds, or by separately reacting a base or acid function with a suitable organic or inorganic acid or base, respectively.
  • acid addition salts which can be used to form pharmaceutically acceptable salts include inorganic acids such as hydrochloric, hydroboric, nitric, sulfuric and phosphoric, and organic acids such as formic, acetic, trifluoroacetic, fumaric, tartaric, oxalic, , maleic acid, methanesulfonic acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid, citric acid) and acidic amino acids (such as aspartic acid and glutamic acid).
  • inorganic acids such as hydrochloric, hydroboric, nitric, sulfuric and phosphoric
  • organic acids such as formic, acetic, trifluoroacetic, fumaric, tartaric, oxalic, , maleic acid, methanesulfonic acid, succinic acid, malic acid, methanesulfonic acid, benzene
  • Pharmaceutically acceptable base salts include, but are not limited to, alkali metal and alkaline earth metal based cations, such as sodium, lithium, potassium, calcium, magnesium, aluminum salts, etc.; and non-toxic ammonium, quaternary ammonium and ammonia cations, including but not limited to Ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, etc.
  • alkali metal and alkaline earth metal based cations such as sodium, lithium, potassium, calcium, magnesium, aluminum salts, etc.
  • non-toxic ammonium, quaternary ammonium and ammonia cations including but not limited to Ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, etc.
  • the compound of formula 1 or its pharmaceutically acceptable salt can range from about 20% to about 90%, about 30% to about 80%, about 35% to about 70% relative to the total weight of the total composition
  • the amount within is present in the pharmaceutical composition.
  • the compound of Formula 1, or a pharmaceutically acceptable salt thereof is present in a therapeutically effective amount ranging from about 40% to about 60% relative to the total weight of the total composition.
  • the compound of formula 1 or a pharmaceutically acceptable salt thereof relative to the total weight of the total composition is between about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55% %, about 60%, about 65%, about 70%, about 75%, about 80%, or about 85%.
  • the solid pharmaceutical composition of the present invention further comprises at least one pharmaceutically acceptable carrier for medicine.
  • these carriers include, but are not limited to, fillers (or diluents), disintegrants, glidants, binders, stabilizers, colorants, flavor enhancers, preservatives or combinations thereof.
  • fillers or diluents
  • disintegrants include, but are not limited to, fillers (or diluents), disintegrants, glidants, binders, stabilizers, colorants, flavor enhancers, preservatives or combinations thereof.
  • Fillers suitable for use in the present invention are compatible with the ingredients of the pharmaceutical composition, ie, they do not substantially reduce the chemical stability, physical stability or biological activity of the pharmaceutical composition.
  • Examples of pharmaceutically acceptable fillers include, but are not limited to, cellulose, modified cellulose (e.g.
  • the filler is preferably microcrystalline cellulose, mannitol and/or lactose.
  • the filler may be from about 5% to about 60%, from about 10% to about 50%, from about 15% to about 45%, from about 20% to about 40%, based on the total weight of the composition. Quantity exists. In a preferred embodiment of the present invention, the filler can be about 5%, about 10%, about 15%, about 20%, about 22%, about 25%, about 27.5%, about 30% based on the total weight of the composition , about 33%, about 34%, about 35%, about 37%, about 40%, about 42%, about 44%, about 46%, about 48%, about 50%, about 55%, or about 60%.
  • disintegrants examples include, but are not limited to, starch; cellulose; calcium carboxymethylcellulose; alginates; gums; sodium carboxymethyl starch; croscarmellose sodium or croscarmellose sodium; carmellose calcium; low-substituted hydroxypropyl cellulose; soybean polysaccharides; sodium starch glycolate; and guar glue or a combination thereof.
  • the disintegrant is preferably croscarmellose sodium, low-substituted hydroxypropyl cellulose and/or crospovidone.
  • the disintegrant may be from about 0% to about 30%, from about 0.1% to about 25%, from about 1% to about 25%, from about 1% to about 22.5%, based on the total weight of the composition , present in an amount from about 5% to about 20%.
  • the disintegrant can be about 0.5%, about 1%, about 2.5%, about 5%, about 7.5%, about 10%, about 12%, about 14%, based on the total weight of the composition. %, about 16%, about 18%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 27.5%, or about 30%.
  • binders examples include, but are not limited to, starch; cellulose and its derivatives, such as microcrystalline cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hypromellose; sucrose; Glucose; corn syrup; polysaccharides; povidone; copovidone neutralized gelatin or combinations thereof.
  • the binder is preferably hydroxypropyl cellulose, hypromellose, povidone and/or copovidone.
  • the binder may be from about 0% to about 10%, from about 0% to about 8%, from about 2% to about 6%, from about 3% to about 5%, based on the total weight of the composition amount exists.
  • the binder can be about 0.5%, about 1%, about 2%, about 3%, about 3.5%, about 4%, about 4.5%, about 5%, based on the total weight of the composition. %, about 5.5%, about 6%, about 7%, about 8%, about 9%, or about 10%.
  • Examples of pharmaceutically acceptable lubricants include, but are not limited to, magnesium stearate, sodium stearyl fumarate, talc, polyethylene glycol, glyceryl behenate, and combinations thereof.
  • the lubricant is magnesium stearate and/or sodium stearyl fumarate.
  • the lubricant may be present in an amount of about 0.1% to about 10%, about 0.5% to about 8%, about 1% to about 6%, based on the total weight of the composition.
  • the slip agent is based on the total weight of the composition at about 0.5%, about 1%, about 2%, about 2.5%, about 3%, about 4%, about 5%, about 6%, About 7%, about 8%, about 9%, or about 10%.
  • a pharmaceutically acceptable glidant refers to a pharmaceutical excipient whose main function is to improve product fluidity by reducing intergranular friction.
  • Glidants may be selected from silicon-containing materials such as fumed micronized silica gel, pyrogenic silica gel, and hydrated sodium aluminosilicate and talc.
  • the pharmaceutical composition of the invention includes a glidant, preferably colloidal silicon dioxide.
  • the glidant may be from about 0% to about 5%, from about 0% to about 3%, from about 0% to about 1%, based on the total weight of the composition.
  • no glidants are present.
  • the glidant is about 0.5%, about 1%, about 1.5%, about 2%, about 2.5%, about 3%, about 3.5%, about 4%, about 4.5%, about 5%.
  • the solid pharmaceutical composition of the present invention comprises at least one pharmaceutically acceptable carrier selected from the group consisting of fillers present in an amount of about 5% to about 60% by weight of the composition,
  • the disintegrating agent present in the amount of about 0% to about 30% by weight of the composition, the binder present in the amount of about 0% to about 8% by weight of the composition, the A lubricant present in an amount of about 0% to about 5% by weight of the composition, a glidant, or a combination thereof.
  • the glidant can be colloidal silicon dioxide.
  • the solid pharmaceutical composition of the present invention comprises at least one pharmaceutically acceptable carrier selected from the group consisting of fillers present in an amount of about 10% to about 50% by weight of the composition,
  • the disintegrating agent present in the amount of about 0.1% to about 25% by weight of the composition, the binder present in the amount of about 2% to about 6% by weight of the composition, the binder in the amount of about 0.5% to about 8% by weight of the composition
  • a lubricant present in an amount of about 0% to about 3% by weight of the composition, a glidant present, or a combination thereof.
  • the glidant can be colloidal silicon dioxide.
  • the filler is selected from microcrystalline cellulose, calcium phosphate, calcium hydrogen phosphate, starch, dextrin, pregelatinized starch, mannitol, sorbitol, lactose, dextran, sucrose, dextrose or combinations thereof;
  • the binder is selected from cellulose ethers, povidone, copovidone, starch, corn syrup or combinations thereof, wherein the cellulose ethers include but not limited to hypromellose, hydroxypropyl cellulose, Methyl cellulose, hydroxyethyl cellulose; disintegrants are selected from croscarmellose sodium, crospovidone, sodium carboxymethyl starch, carboxymethyl cellulose calcium, low-substituted hydroxypropyl fiber element or a combination thereof; the lubricant is selected from magnesium stearate, sodium stearyl fumarate, polyethylene glycol, glycerin, behenate, talc or a combination thereof.
  • the filler is selected from microcrystalline cellulose, lactose, mannitol, sorbitol or combinations thereof, and the binder is selected from hydroxypropyl cellulose, hypromellose, povidone, copovidone or Combination, the disintegrant is selected from croscarmellose sodium, crospovidone, sodium carboxymethyl starch, carmellose calcium, low-substituted hydroxypropyl cellulose or a combination thereof, and the lubricant is selected from Magnesium stearate, sodium stearyl fumarate, or combinations thereof.
  • the dissolution RSD of the solid pharmaceutical composition at any time point from 5 minutes to 60 minutes is less than 20%. More preferably, the dissolution RSD of the solid pharmaceutical composition at any time point from 5 minutes to 60 minutes is less than 10%.
  • the solid pharmaceutical composition of the present invention comprises granules having an inner phase made by the granulation part and an outer phase adjacent to the granules made by the adding part.
  • the constituents of the particles and the outer phase and the content of each constituent may be the same or different.
  • the respective proportions of the granules and the external phase to the total weight of the solid pharmaceutical composition can be appropriately adjusted by researchers according to the selected auxiliary materials and process requirements.
  • the invention relates to a manufacturing process of a solid pharmaceutical composition.
  • the pharmaceutical composition of the present invention is prepared by dry granulation process.
  • the pharmaceutical composition can be prepared by a method comprising the steps of: milling the granulated fraction comprising Compound 1 or a pharmaceutically acceptable salt thereof together with at least one pharmaceutically acceptable carrier, milling
  • the material is compacted to form a plurality of granules with an internal phase, the granules are mixed with the additional portion, and the final mixture is optionally compressed into tablets.
  • Laminating uses a device that basically utilizes two rollers rolling towards each other. The ground particles fed into the roller compactor by a screw conveyor system exert compaction force.
  • “granulation part” refers to the raw material part used to prepare granules with an internal phase;
  • the particles of the solid pharmaceutical preparation are mixed to prepare the excipient part of the solid pharmaceutical preparation, which constitutes the outer phase of the solid pharmaceutical preparation adjacent to the particles with the inner phase.
  • the sieving or sifting step can be accomplished using any suitable means, for example using vibratory sieving or hand/vibrating sieves or commercially available sifting mills fitted with screens of suitable size.
  • suitable means for example using vibratory sieving or hand/vibrating sieves or commercially available sifting mills fitted with screens of suitable size.
  • Those of ordinary skill in the art will have the experience and knowledge how to determine and select the appropriate size screen for use in the sieving or screening step.
  • the sieving or sifting step can be carried out using a screening mill equipped with a suitable sized screen.
  • the rolling step is accomplished using a rolling machine with a compaction force in the range of about 3.6 MPa to about 19.4 MPa, preferably about 4.0 MkPa to 10.0 MPa, most preferably about 7.0 MPa.
  • the device used is preferably a roller compactor.
  • the screw speed of the equipment is properly adjusted to ensure the proper quality of the rolled material.
  • the speed of the rolls is properly adjusted to ensure the proper quality of the rolled material.
  • the milling/screening step can be accomplished using any suitable means.
  • the milled material (which forms particles with an internal phase) is passed through a screening mill or vibrating sieve/mill having a mesh with a mesh size of at least 0.5 mm, such as 0.6 mm, 0.8 mm, 1.2 mm or 2 mm mill.
  • This milling/screening step produces a plurality of particles.
  • the step of mixing the granules together with the extra portion can be done in a hopper mixer. Tablet solid dosage forms can then be compressed using a suitable rotary press at the desired target tablet weight.
  • the present invention relates to a solid oral dosage form comprising the pharmaceutical composition of the present invention and coated with a coating.
  • Suitable coatings are known in the art and are commercially available or may be manufactured according to known methods.
  • the coating material is a hydrophilic polymer such as polyvinyl alcohol, hydroxypropyl cellulose, hydroxymethyl cellulose, hypromellose, and the like.
  • Coating composition ingredients may include plasticizers, such as polyethylene glycol, triethyl citrate, diethyl phthalate, propylene glycol, glycerin; and opacifiers, such as titanium dioxide; and/or coloring agents in usual amounts , such as iron oxide, aluminum lake, etc.
  • the coating material is applied, for example, in an amount to provide a coating in the range of about 1% to about 6% of the total solid oral dosage form.
  • These products are individually prepared dry premixes of film-forming polymers, opacifiers, colorants and plasticizers, which are further processed into aqueous coating suspensions.
  • the coating is applied to achieve a weight gain of about 1% to 10% and preferably about 2% to 6% of the total composition of the solid oral dosage form.
  • the coating material is The weight of the coating is about 3% to 4% of the total weight of the solid oral dosage form.
  • the present invention relates to a process for manufacturing a solid pharmaceutical composition, comprising the steps of:
  • the present invention may also include a process for manufacturing coated tablets, after compressing the final mixture into tablets according to the steps described above, further comprising the step of optionally applying a coating to the tablets.
  • the pharmaceutical composition of the present invention is prepared by wet granulation process.
  • the pharmaceutical composition can be prepared by a method comprising the following steps: screening and weighing compound AN0025 and various pharmaceutically acceptable carriers; Mixing Speed Compound AN0025 and pharmaceutically acceptable carrier are mixed for an appropriate amount of time and the mixture is chopped into granules, wherein the granulation fluid may be prepared by dispersing the binder in a solvent (water) solution, or just a wetting agent such as water; dry the granules; blend the granules with extragranular excipients for an appropriate amount of time; then compress into tablets using a suitable rotary press at the desired target tablet weight solid dosage form.
  • the present invention relates to a process for manufacturing a solid pharmaceutical composition, comprising the steps of:
  • the particle size of the compound of formula 1 in the solid pharmaceutical composition tablet of the present invention is D90 less than about 200 microns;
  • the particle size D90 is less than about 100 microns; in a preferred embodiment, the compound of formula 1 in the solid pharmaceutical composition tablet of the present invention has a particle size D90 of about 10 microns to about 80 microns.
  • the present invention may also include a process for manufacturing coated tablets, after compressing the final mixture into tablets according to the steps described above, further comprising the step of optionally applying a coating to the tablets.
  • the solid pharmaceutical composition tablet of the present invention contains about 50 mg to about 500 mg of the compound of formula 1; in another embodiment, the solid pharmaceutical composition tablet of the present invention contains about 100 mg to about 300 mg of the compound of formula 1 The compound of formula 1; preferably, the solid pharmaceutical composition tablet of the present invention contains about 125 mg to about 250 mg of the compound of formula 1.
  • the formulation of the pharmaceutical composition has a fast dissolution rate
  • composition of the pharmaceutical composition is suitable for raw materials of different particle sizes
  • the pharmaceutical composition of the present invention and its solid dosage form can be used to treat cancer, especially multiple sclerosis, rheumatoid arthritis, or cancer that can be beneficially treated by inhibiting EP4.
  • cancers suitable for treatment with the solid pharmaceutical composition of the present invention include, but are not limited to, e.g., skin cancer, breast cancer, colorectal cancer, prostate cancer, kidney cancer, ovarian cancer, cervical cancer, endometrial cancer, colloid Blastoma, lung cancer, head and neck cancer, medulloblastoma and urethral cancer.
  • Other diseases that can be treated with the solid pharmaceutical composition of the present invention are disclosed in WO2012039972A, which is incorporated herein by reference in its entirety.
  • the present invention provides a solid pharmaceutical composition of the present invention for use in the treatment of cancer.
  • the present invention provides the use of the solid pharmaceutical composition of the present invention in the manufacture of a medicament for treating cancer.
  • the present invention provides a method of treating cancer, comprising administering a solid composition of the present invention comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to a patient suffering from the cancer.
  • Dissolution medium pH 6.8 phosphate buffer solution
  • Solvent A water/70% perchloric acid (1000/1, v/v)
  • Solvent B acetonitrile/70% perchloric acid (1000/1, v/v)
  • the pharmacokinetic parameters of the comparative examples and examples are measured by chromatography and mass spectrometry, and the details of the test conditions are listed in Table 1a and Table 1b.
  • AN00251001 is the deuterated compound of AN0025.
  • the capsules of Comparative Example 1 were prepared according to the ingredients and contents as described in Table 2a.
  • the AN0025 capsule of comparative example 1 its manufacturing process is made up of six steps: mix, lubricate, granulate, granulate, capsule filling and weight sorting.
  • Magnesium stearate is then added to the above mixture for lubrication. Press the mixture into long strips using a roller compactor. Long strips are sieved and granulated (the mesh aperture is 1.5 mm).
  • Use a capsule filling machine to fill the sized granules into hypromellose (HPMC) capsules, and use a checkweigher to remove overweight and insufficiently filled capsules.
  • HPMC hypromellose
  • Table 2b shows the mean values of the dissolution profiles during the stability study of the 125 mg capsules of Comparative Example 1. Under different storage conditions (25°C/60% relative humidity for long-term stability, 40°C/75% relative humidity for accelerated stability), there are large differences in the results measured at different time points from 1 to 36 months. This difference is not a trend, but fluctuates up and down, indicating that even the average dissolution value cannot reflect the true dissolution state of the drug.
  • the dissolution curve measurement results of another batch of Comparative Example 1 are shown in Table 2c, wherein SD is the standard deviation, and RSD is the relative standard deviation. Unless stated otherwise, the SD and RSD recorded in this article have the same definitions and calculation methods as those in Table 2c. Figure 2c shows that the detection results of different capsule samples at the same time point are quite different, and the RSD is relatively large.
  • the general acceptable standard for technicians in the industry to measure the dissolution curve is that the RSD of the dissolution measurement value at the first time point is not greater than 20%, and the RSD of the dissolution measurement value at the other time points is not greater than 10%.
  • Comparative Example 2 The capsules of Comparative Example 2 were prepared according to the ingredients and contents as described in Table 3. Comparative Example 2 uses the same components and contents as Comparative Example 1, and is filled into different hollow capsules.
  • the AN0025 capsule of comparative example 2 its manufacturing process is made up of six steps: mix, lubricate, granulate, granulate, capsule filling and weight sorting.
  • the magnesium stearate was mixed with the mixture using a high shear mixer. Press the mixture into long strips using a roller compactor. Long strips are sieved and granulated (the mesh aperture is 1.5 mm).
  • Use a capsule filling machine to fill the whole granules into gelatin hollow capsules, and use a checkweigher to remove overweight and insufficiently filled capsules.
  • Table 3b shows that compared with Comparative Example 1 using HPMC capsules, Comparative Example 2 using gelatin capsules can be dissolved faster, and its dissolution RSD is also greatly improved, but the RSD in 5 minutes is still more than 20%. Moreover, during the accelerated stability investigation at 40° C./75% relative humidity, the capsule of Comparative Example 2 had a relatively obvious drop in dissolution.
  • the preparation process is as follows:
  • the wet granules obtained in the above steps are dried to remove moisture.
  • the granules obtained after drying are sieved again to obtain granules with an internal phase.
  • the lubricated material is filled into hypromellose (HPMC) capsules to obtain the product.
  • HPMC hypromellose
  • the capsules prepared by the wet granulation process still had a high RSD.
  • Embodiment 1 of the present invention In order to fundamentally solve the problem of high RSD of the compound AN0025 preparation, the inventors implemented the following specific examples. 5. Embodiment 1 of the present invention
  • Example 1 of the present invention was prepared according to the ingredients and contents as described in Table 5a.
  • the preparation process is as follows:
  • the weighed compound AN0025, mannitol, low-substituted hydroxypropyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose calcium and microcrystalline cellulose were uniformly mixed.
  • the strips are respectively sieved and sized through a coarse screen (aperture 2.0 mm) and a fine screen (aperture 0.6 mm) to obtain granules with an internal phase.
  • the granules prepared above are mixed with an additional part of magnesium stearate.
  • tablets of suitable shape were compressed using a tablet press.
  • the prescription component of implementation example 1 is the same as comparative example 1, comparative example 2 and the same, and the difference is that it is prepared into different dosage forms. Its dissolution data are shown in Table 5b, and the dissolution RSD at all time points is not more than 10%, which is significantly improved compared with Comparative Example 1 and Comparative Example 2. In addition, accompanying drawing 2 also shows that the drug dissolution rate of the tablet of implementation example 1 is higher than the capsule of comparative example 1.
  • Example 2 of the present invention was prepared according to the ingredients and contents as described in Table 6a.
  • the preparation process is as follows:
  • the wet granules obtained in the above steps are dried to remove moisture.
  • the granules obtained after drying are sieved again to obtain granules with an internal phase.
  • a tablet press to compress tablets into suitable shapes.
  • the prescription components of implementation example 2 and comparative example 3 are the same as the preparation process, and the difference is that they are prepared into different dosage forms.
  • the dissolution curve of embodiment example 2 is compared as shown in accompanying drawing 2 of specification sheet, is similar to the experimental result of embodiment 1, and the drug dissolution rate of the tablet of embodiment example 2 is also higher than the capsule of comparative example 3.
  • Implementation example 2 is relatively stable during the stability investigation process, without significant decline, as shown in Table 6c.
  • the dissolution rate of Comparative Example 2 decreased significantly during the stability investigation, as shown in Table 3b. This result demonstrates the advantages of tablets from a stability point of view.
  • Examples 1 and 2 show that no matter dry granulation or wet granulation, the tablet of the present invention can significantly improve the problem of high RSD of capsules, and this improvement has nothing to do with the preparation process.
  • Example 3 of the present invention was prepared according to the ingredients and contents as described in Table 7a.
  • the preparation process is as follows:
  • the mixture is pressed into long strips using a rolling machine, and the rolling parameters are: compaction force: 7Mpa; roll speed: 2rpm; gap width: 1.5mm.
  • the granules prepared above are mixed with an additional part of magnesium stearate.
  • a tablet machine is used to compress tablets into suitable shapes.
  • the dissolution data are shown in Table 7b, except that the dissolution RSD of the first time point is slightly higher (but not more than 20%), and the dissolution RSDs of the other points are all no more than 10%.
  • the coated tablet of Example 4 was prepared according to the ingredients and contents as described in Table 8a.
  • the preparation process is as follows:
  • the mixture is pressed into long strips using a rolling machine, and the rolling parameters are: compaction force: 7Mpa; roll speed: 2rpm; gap width: 1.5mm.
  • the granules prepared above are mixed with an additional part of magnesium stearate.
  • a tablet machine is used to compress tablets into suitable shapes.
  • the dissolution data are shown in Table 8b, and the dissolution RSDs at all time points are not more than 10%.
  • AUC 0-t represents the time from 0 to the last time selected
  • AUC 0-t_dose represents the ratio of the area under the plasma concentration-time curve from 0 to the selected last time point to the administered dose.
  • AUC 0-t and AUC 0-t_dose described herein have the same definitions and calculation methods as those in Table 8d.
  • the in vivo exposure (AUC) of embodiment example 3 and embodiment example 4 tablet is equivalent, but inter-individual difference (SD) is smaller, more consistent with in vitro dissolution data, suggesting that tablet may be clinically Have better effectiveness and safety.
  • SD inter-individual difference
  • Comparative example 1 the drug-time curve in the beagle dog body under 750mg/ dose of embodiment example 4 is shown in Figure 3 and Figure 4 respectively.
  • the tablet of the present invention has a similar in vivo exposure to the capsule, but the inter-individual variation is significantly reduced, and the RSD is reduced, and this improvement is not affected by the dose.
  • Implementation example 4a's prescription component and preparation process are completed identical with implementation example 4, but used the crude drug of different granularity.
  • the difference between the particle size of the bulk drug used in Example 4 and Example 4a is shown in Table 9a, wherein D50 represents the particle size corresponding to when the cumulative particle size distribution percentage of a sample reaches 50%, that is, the particles with a particle size smaller than it account for 50% ; D90 means the particle size corresponding to when the cumulative particle size distribution percentage of a sample reaches 90%, that is, the particles with a particle size smaller than it account for 90%.
  • D50 and D90 described herein for particle size have the same definitions as those in this embodiment.
  • Embodiment 4 and Embodiment 4a exhibit similar dissolution behaviors, and their in vitro dissolution similarity factor f2 is 52 (if f2 is greater than 50, it is considered that the dissolution is similar).
  • the dissolution curve of embodiment example 4a is shown in Table 9b for details.
  • the pharmacokinetic data in the beagle dog body further reached a similar conclusion: AN0025 APIs with different particle sizes had no effect on product quality.
  • the tablet provided by the invention has good durability to raw materials with different particle sizes.
  • the comparison of in vivo pharmacokinetic parameters between Example 4 and Example 4a is shown in Table 9c.
  • the drug-time curve in Beagle dogs in Example 4a is shown in Figure 7 at a dose of 750mg/only.
  • Example 5 of the present invention was prepared according to the ingredients and contents as described in Table 10a.
  • the preparation process is as follows:
  • the mixture is pressed into long strips using a rolling machine, and the rolling parameters are: compaction force: 7Mpa; roll speed: 2rpm; gap width: 1.5mm.
  • the granules prepared above are mixed with an additional part of sodium stearyl fumarate.
  • a tablet machine is used to compress tablets into suitable shapes.
  • the dissolution data are shown in Table 10b, and the dissolution RSDs at all time points are not more than 10%.

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Abstract

一种固体药物组合物，其包含式1所示化合物或其药学上可接受的盐以及药学上可接受的载体，其中式1所示化合物或其药学上可接受的盐占所述固体药物组合物总重量的约30%至约80%。

Description

一种固体药物组合物
本申请要求于2021年12月30日提交到中国国家知识产权局、申请号为202111661891.1、发明名称为“一种固体药物组合物”的中国专利申请的优先权，且其全部内容通过引用结合在本申请中。
技术领域
本发明属于医药技术领域，具体涉及新颖的选择性的EP4拮抗剂4-{(1S)-1-[({3-(二氟甲基)-1-甲基-5-[3-(三氟甲基)苯氧基]-4-1H-吡唑基}羰基)氨基]乙基}苯甲酸和任选的至少一种药学上可接受的载体的固体药物组合物，及其制备方法。
背景技术
浸润实体瘤的最富集型免疫细胞包括髓细胞，主要为TAM和MDSC，在动物模型中，单核系细胞(包括TAM和MDSC)耗尽可显著抑制既定肿瘤的肿瘤生长(Zeisberger,et al.,2006；Srivastava,et al.,2012)。文献详细记录了肿瘤中存在TAM和MDSC以及出现TAM和MDSC蓄积，这与伴有乳腺癌、胰腺癌或其他类型癌症的患者的预后较差相关(Joyce and Pollard,2009；Ding,et al.,2009；Ganjoo,et al.,2011；Medrek,et al.,2012；Zhang,et al.,2012)。
TAM和MDSC均衍生自未成熟单核细胞前体。EP4为4种PGE2受体中的1种，在髓细胞上表达(Wang and DuBois,2010)，且在促进肿瘤微环境中单核细胞分化为TAM和MDSC方面起关键作用(Lechner,et al.,2011；Mao,et al.,2014；Majumder,et al.,2014)。因此EP4拮抗为一种潜在抗癌治疗方法，且作用机制为衰减免疫抑制性TAM和MDSC的形成和功能。
4-{(1S)-1-[({3-(二氟甲基)-1-甲基-5-[3-(三氟甲基)苯氧基]-4-1H-吡唑基}羰基)氨基]乙基}苯甲酸的结构如式1所示，在本申请下文中简称为AN0025，是前列腺素E2(PGE2)受体4(EP4)(PGE2-EP4)的高选择性、强效拮抗剂，通过调节肿瘤微环境中免疫抑制性髓细胞(包括肿瘤相关巨噬细胞[TAM]和髓源性抑制细胞[MDSC])的蓄积和功能表现出抗肿瘤活性。
Figure PCTCN2022143030-appb-000001
口服给药是一种更加方便，更加安全的给药途径，优于其他给药途径(如肌肉注射、静脉注射等)，是药物开发过程中首选的给药方式。
AN0025胶囊曾被开发用于I期临床研究，该胶囊涉及AN0025与药学上可接受的载体，通过干法制粒技术制备得到含有活性成分AN0025的颗粒，该颗粒然后被填充至羟丙甲纤维素空心胶囊内。该胶囊剂的其他细节在下文中被描述为“比较实例1”。
然而，上述AN0025胶囊剂溶出的批内差异(RSD)较大(图1)，导致溶出测定结果不可靠，难以通过溶出的手段建立良好的质量评价方式来评估不同物料变量、工艺变量对产品质量的影响；也难以建立良好的质量控制手段来保证工艺稳健性和不同批次间AN0025制剂的质量一致性。因此，需要开发适宜且稳健的固体药物组合物，以克服上述溶出变异较大的问题。
发明内容
本发明涉及包含式1化合物4-{(1S)-1-[({3-(二氟甲基)-1-甲基-5-[3-(三氟甲基)苯氧基]-4-1H-吡唑基}羰基)氨基]乙基}苯甲酸(化合物AN0025)和任选的至少一种药学上可接受的载体的质量可控的固体剂型及其制备工艺。AN0025属于生物药剂学分类系统IV类药物，即溶解度低、渗透性差。发明人在实验过中意外地发现，通过不同的工艺制备得到AN0025片剂均可以在体外溶出实验中表现出较好的均一性，不同原料药粒度制备AN0025片具有相似的体外溶出行为和体内暴露。本发明提供的AN0025片剂在比格犬内的生物利用度与临床胶囊剂相当，但是体内暴露量(AUC)的个体差异小。这些结果表明AN0025片剂是在商业化生产上具有更好的可控性，在临床应用上具有更好的有效性和安全性。
Figure PCTCN2022143030-appb-000002
在一个方面，本发明提供了一种固体药物组合物，其包括：式1所述化合物或其药学上可接受的盐以及药学上可接受的载体，其中式1所述化合物或其药学上可接受的盐占所述固体药物组合物总重量的约30％至约80％；该固体药物组合物的剂型为片剂。
在一个实施方式中，式1所述化合物或其药学上可接受的盐占所述固体药物组合物总重量的约40％至约60％。
在一个实施方式中，所述药学上可接受的载体包括选自填充剂、粘合剂、润滑剂、崩解剂和助流剂的一种或者多种。
在一个实施方式中，所述药学上可接受的载体包括：
a.填充剂，其占所述固体药物组合物总重量的约5％至约60％；
b.粘合剂，其占所述固体药物组合物总重量的约0％至约8％；
c.崩解剂，其占所述固体药物组合物总重量的约0％至约30％；
d.润滑剂，其占所述固体药物组合物总重量的约0.1％至约10％；
e.助流剂，其占所述固体药物组合物总重量的约0％至约5％。
在又一个实施方式中，所述药学上可接受的载体包括：
a.填充剂，其占所述固体药物组合物总重量的约10％至约50％；
b.粘合剂，其占所述固体药物组合物总重量的约2％至约6％；
c.崩解剂，其占所述固体药物组合物总重量的约0.1％至约25％；
d.润滑剂，其占所述固体药物组合物总重量的约0.5％至约8％；
e.助流剂，其占所述固体药物组合物总重量的约0％至约3％。
在一个优选实施方式中，所述药学上可接受的载体包括：
a.填充剂，其占所述固体药物组合物总重量的约20％至约40％；
b.粘合剂，其占所述固体药物组合物总重量的约3％至约5％；
c.崩解剂，其占所述固体药物组合物总重量的约1％至约25％；
d.润滑剂，其占所述固体药物组合物总重量的约1％至约6％；
e.助流剂，其占所述固体药物组合物总重量的约0％至约1％。
在一个实施方式中，所述填充剂选自包含以下的组：微晶纤维素、磷酸钙、磷酸氢钙、淀粉、糊精、预胶化淀粉、甘露醇、山梨醇、乳糖、葡聚糖、蔗糖、右旋糖及其组合；所述粘合剂选自包含以下的组：纤维素醚类、聚维酮、共聚维酮、淀粉、玉米糖浆及其组合；其中，所述纤维素醚类包括但不限于羟丙甲纤维素、羟丙基纤维素、甲基纤维素、羟乙基 纤维素；所述崩解剂选自包含以下的组：交联羧甲基纤维素钠、交联聚维酮、羧甲基淀粉钠、羧甲基纤维素钙、低取代羟丙基纤维素及其组合；所述润滑剂选自包含以下的组：硬脂酸镁、硬脂富马酸钠、聚乙二醇、甘油、山嵛酸酯、滑石粉及其组合。
在有一个实施方式中，所述填充剂选自微晶纤维素、乳糖、甘露醇、山梨醇及其组合；所述粘合剂选自羟丙基纤维素、羟丙甲纤维素、聚维酮、共聚维酮及其组合；所述崩解剂选自交联羧甲基纤维素钠、交联聚维酮、羧甲基淀粉钠、羧甲基纤维素钙、低取代羟丙基纤维素及其组合；所述润滑剂选自硬脂酸镁、硬脂富马酸钠及其组合。
在一个实施方式中，本发明的固体药物组合物包括具有内相的颗粒。
在一个实施方式中，本发明的固体药物组合物还包括与所述具有内相的颗粒相邻的外相。
在一个实施方式中，本发明提供的固体药物组合物，通过制粒工艺将AN0025与药学上可接受的其他载体制备成流动性、可压性较好的颗粒，再压制成片剂。固体药物组合物中各个药学上可接受的其他载体，可以全部内加参与制粒过程，也可以部分作为外相加入。
在一个实施方式中，所述具有内相的颗粒通过干法制备工艺来制备，包括以下步骤：筛选并称取化合物AN0025和各个药学上可接受的载体；将化合物AN0025和药学上可接受的载体共混适当量的时间；将共混物辊压成带状物并将该带状物磨成颗粒；将颗粒与颗粒外的赋形剂共混适当量的时间；将共混物压成片剂。
在一个实施方式中，所述具有内相的颗粒通过湿法制备工艺来制备，包括以下步骤：筛选并称取化合物AN0025和各个药学上可接受的载体；在添加含有或不含有粘合剂的制粒流体的同时，以合适的混合速度使化合物AN0025和药学上可接受的载体混合适当量的时间并将混合物切碎成颗粒，其中，制粒流体可以是通过将粘合剂分散在溶剂(水)中而制备得粘合剂溶液，也可以仅仅是润湿剂，比如说水；干燥颗粒；将颗粒与颗粒外的赋形剂共混适当量的时间；将共混物压成片剂。
在一个实施方式中，所述固体药物组合物还包括包衣。
在一个实施方式中，式1化合物的粒度为D90小于约200微米。
在优选的实施方式中，式1化合物的粒度为D90小于约100微米。
在一个实施方式中，本发明固体药物组合物含有约50mg至约500mg所述式1化合物。
在优选的实施方式中，本发明的固体药物组合物含有约100mg至约300mg所述式1化合物。
在另一个方面，本发明提供了所述的固体药物组合物用于制备治疗多发性硬化、类风湿性关节炎、或者癌症的药物中用途，所述癌症包括：皮肤癌、乳腺癌、结直肠癌、前列腺癌、肾癌、卵巢癌、子宫颈癌、子宫内膜癌、胶质母细胞瘤、肺癌、头颈癌、髓母细胞瘤和尿道癌。
附图说明
图1对比实例1、实施实例1、实施实例2的溶出RSD对比
图2对比实例1、2、3及实施实例1、2的溶出曲线对比
图3胶囊剂(对比实例1)在比格犬内AN0025药时曲线(750mg/只)
图4片剂(实施实例4)在比格犬内AN0025药时曲线(750mg/只)
图5胶囊剂(对比实例1)在比格犬内AN0025药时曲线(250mg/只)
图6片剂(实施实例4)在比格犬内AN0025药时曲线(250mg/只)
图7片剂(实施实例4a)在比格犬内AN0025药时曲线(750mg/只)
具体实施方式
定义
本发明提供了一种包含化合物4-{(1S)-1-[({3-(二氟甲基)-1-甲基-5-[3-(三氟甲基)苯氧基]-4-1H-吡唑基}羰基)氨基]乙基}苯甲酸(AN0025)和其药学上可接受的盐，和任选的至少一种药学上可接受的载体的质量可控的固体药物组合物、固体药物制剂、及其制备工艺。
除非另外指明，否则如本文所用的以下术语具有以下含义：术语“药物组合物”或“制剂”指含有欲施用于个体(例如人类)以预防、治疗或控制影响该个体的具体疾病或病况的治疗化合物的物理混合物。例如，如本文所用术语“药物组合物”或“制剂”也涵盖在高温和高压下形成的紧密物理混合物。
术语“药物上可接受的”是指那些在合理医学判断范围内适于与个体(尤其人类)的组织接触而无过度毒性、刺激、过敏反应和其他问题并发症且具有合理益处/风险比的化合物、材料、组合物、载体和/或剂型。
术语“药学上可接受的载体”和“载体”是指实质上不具有生物活性且构成制剂的实质性部分的任何药学上可接受的惰性材料。
术语“治疗有效量”是指有效降低、消除、治疗、预防或控制影响个体的疾病或病况的症状的量或浓度。术语“控制”指其中可减慢、中断、阻止或停止影响哺乳动物的疾病和病况的进展的所有过程。然而，“控制”不一定指示完全消除疾病和病况的所有症状。
术语“治疗”包括预防性和/或治疗性治疗以及延迟疾病或病症的进展。优选地，术语“治疗”是指治疗性治疗以及延迟疾病或病症的进展。“延迟进展”指向处于欲治疗癌症 的前期或早期的个体施用药物组合物，在这些患者中(例如)诊断相应疾病的预形成，或其中个体处于可能将发生相应疾病的情况下。
术语“口服剂型”是指经制备用于通过口服施用途径施用于个体的药物组合物。已知口服剂型的实例包括但不限于片剂、胶囊、小胶囊、粉末、丸剂、颗粒、溶液、悬浮液、溶液和溶液预浓缩剂、乳液和乳液预浓缩剂等。在一些方面中，粉末、丸剂、颗粒和片剂可经适宜聚合物或常用包衣材料包被以达到(例如)在胃肠道中的更高稳定性或达到期望释放速率。此外，含有粉末、丸剂或颗粒的胶囊可经进一步包被。片剂可加刻痕以促进给药分割。或者，本发明剂型可为单位剂型，其中一个单位剂型意欲每次施用递送一个治疗剂量，或其中多个单位剂型意欲每次施用递送总治疗剂量。
术语“施用”是指将治疗化合物呈递至个体的方式。
术语“口服施用”代表任何施用方法，其中可通过口服途径通过吞服、咀嚼或吮吸口服剂型来施用治疗化合物。固体口服剂型传统上意欲在口腔和/或颊腔后方的胃肠道中实质上释放和/或递送活性药物。固体剂型的实例包括常用片剂、胶囊、小胶囊等。
术语“个体”或“患者”意欲包括动物。个体的实例包括哺乳动物，例如人类、犬、牛、马、猪、绵羊、山羊、猫、小鼠、兔、大鼠和转基因非人类动物。在某些实施方式中，个体是人类，例如患有癌症、具有患癌症的风险或可能能够患癌症的人类(包括雄性和雌性受试者，且包括新生儿、婴儿、少年、青年、成年和老年受试者)。
除非另外说明，否则如本文所用术语“包含”和“包括”具有开放性和非限制性含义。
除非本文另有指示或上下文明显矛盾，否则在阐述本发明的情况(尤其在下文权利要求范围的情况)中，术语“一”和“该”和类似用词应视为涵盖单数与复数。
如本文所用术语“约”和“大约”用于通过提供给定值可“略高于”或“略低于”端点来提供数字范围端点的灵活性，以解释在不同仪器、样品和样品制备之间的测量中可见的差异。术语“约”或“大约”通常指在给定值或范围的10％内，更优选在5％内，且最优选在1％内。
为方便起见，如本文所用的多个项目、结构要素、组成要素和/或材料可呈现于列表中。然而，这些列表应视为列表中的每一成员个别地被鉴别为单独且唯一的成员。因此，不应仅基于列表中的个别成员与同一列表中的任何另一成员呈现于共同组中且未指示相反含义即将其解释为事实上等效。
Figure PCTCN2022143030-appb-000003
化合物：化合物或者药学上可接受的盐或酯，以及他们的各种存在形态。
式1化合物4-{(1S)-1-[({3-(二氟甲基)-1-甲基-5-[3-(三氟甲基)苯氧基]-4-1H-吡唑基}羰基)氨基]乙基}苯甲酸(AN0025)和其药学上可接受的盐意欲用于本发明的药物组合物中。该化合物、其药学上可接受的盐和其制备公开于WO2012039972A，其全文以引用方式并入本文中。
式1化合物可以其游离酸或药学上可接受的盐形式存在于本发明的药物组合物中。这些盐可在化合物的最终分离和纯化期间原位制备，或通过使碱或酸官能团分别与适宜有机或无机酸或碱单独反应来制备。可用于形成药学上可接受的酸加成盐的实例包括无机酸(例如盐酸、氢硼酸、硝酸、硫酸和磷酸)和有机酸(例如甲酸、乙酸、三氟乙酸、富马酸、酒石酸、草酸、马来酸、甲烷磺酸、琥珀酸、苹果酸、甲烷磺酸、苯磺酸和对甲苯磺酸、柠檬酸)和酸性氨基酸(例如天冬氨酸和谷氨酸)。药学上可接受的碱盐包括但不限于基于碱金属和碱土金属的阳离子，例如钠、锂、钾、钙、镁、铝盐等；以及无毒铵、季铵和氨阳离子，包括但不限于铵、四甲基铵、四乙基铵、甲基胺、二甲基胺、三甲基胺、三乙基胺、乙基胺等。可用于形成碱加成盐的其他代表性有机胺包括二乙基胺、乙二胺、乙醇胺、二乙醇胺、六氢吡嗪、吡啶、甲基吡啶、三乙醇胺等；和碱性氨基酸，例如精氨酸、赖氨酸和鸟氨酸。
根据本发明，式1化合物或其药学上可接受的盐可以相对于总组合物的总重量介于约20％至约90％、约30％至约80％、约35％至约70％范围内的量存在于药物组合物中。在一个实施方式中，式1化合物或其药学上可接受的盐是以相对于总组合物的总重量介于约40％至约60％范围内的治疗有效量存在。优选地，式1化合物或其药学上可接受的盐相对于总组合物的总重量介于约25％、约30％、约35％、约40％、约45％、约50％、约55％、约60％、约65％、约70％、约75％、约80％或者约85％。
除了式1化合物或其药学上可接受的盐以外，本发明的固体药物组合物进一步包含至少一种用于药物的药学上可接受的载体。这些载体的实例包括但不限于填充剂(或者稀释剂)、崩解剂、助流剂、粘合剂、稳定剂、着色剂、增味剂、防腐剂或其组合。本领域普 通技术人员通过常规实验且无需任何过多负荷即可针对固体药物组合物的具体期望性质选择前文所提及赋形剂中之一或多者。所用每一载体的量可在本领域内常用范围内变化。
适用于本发明的填充剂与药物组合物的成分相容，即，它们基本上不会降低药物组合物的化学稳定性、物理稳定性或生物活性。药学上可接受的填充剂的实例包括但不限于纤维素、改性纤维素(例如羧甲基纤维素钠、乙基纤维素、羟甲基纤维素、羟丙基纤维素)、醋酸纤维素、微晶纤维素、纤维素粉末、磷酸钙、磷酸氢钙、淀粉(例如玉米淀粉、马铃薯淀粉)、糊精、预胶化淀粉、糖(例如甘露醇、山梨醇、乳糖、葡聚糖、蔗糖、右旋糖、粉糖、可压制糖、等等)、滑石粉或它们的任何组合。在本发明的一个实施方式中，填充剂优选是微晶纤维素、甘露醇和/或乳糖。在本发明的一个实施方式中，填充剂可以基于组合物的总重量约5％至约60％、约10％至约50％、约15％至约45％、约20％至约40％的量存在。在本发明的一个优选实施方式中，填充剂可以基于组合物的总重量约5％、约10％、约15％、约20％、约22％、约25％、约27.5％、约30％、约33％、约34％、约35％、约37％、约40％、约42％、约44％、约46％、约48％、约50％、约55％或者约60％。
药学上可接受的崩解剂的实例包括但不限于淀粉；纤维素；羧甲基纤维素钙；藻酸盐；树胶；羧甲基淀粉钠；交联聚合物，例如交联聚乙烯吡咯啶酮或交聚维酮；交联羧甲基纤维素钠或交联羧甲纤维素钠；羧甲基纤维素钙；低取代羟丙基纤维素；大豆多糖；淀粉羟乙酸钠；和瓜尔胶或其组合。在本发明的一个实施方式中，崩解剂优选是交联羧甲基纤维素钠、低取代羟丙基纤维素和/或交聚维酮。在本发明的一个实施方式中，崩解剂可以基于组合物的总重量约0％至约30％、约0.1％至约25％、约1％至约25％、约1％至约22.5％、约5％至约20％的量存在。在本发明的一个优选实施方式中，崩解剂可以基于组合物的总重量约0.5％、约1％、约2.5％、约5％、约7.5％、约10％、约12％、约14％、约16％、约18％、约20％、约21％、约22％、约23％、约24％、约25％、约27.5％或者约30％。
药学上可接受的粘合剂的实例包括但不限于淀粉；纤维素和其衍生物，例如微晶纤维素，羟丙基纤维素、羟乙基纤维素、羟丙甲纤维素；蔗糖；右旋糖；玉米糖浆；多糖；聚维酮；共聚维酮中和明胶或其组合。在本发明的一个实施方式中，粘合剂优选为羟丙基纤维素、羟丙甲纤维素、聚维酮和/或共聚维酮。在本发明的一个实施方式中，粘合剂可以基于组合物的总重量约0％至约10％、约0％至约8％、约2％至约6％、约3％至约5％的量存在。在本发明的一个优选实施方式中，粘合剂可以基于组合物的总重量约0.5％、约1％、约2％、约3％、约3.5％、约4％、约4.5％、约5％、约5.5％、约6％、约7％、约8％、约9％或者约10％。
药学上可接受的润滑剂的实例包括但不限于硬脂酸镁、硬脂富马酸钠、滑石粉、聚乙二醇、山嵛酸甘油酯和其组合。在本发明的一个实施方式中，润滑剂为硬脂酸镁和/或硬脂富马酸钠。在本发明的一个实施方式中，润滑剂可以基于组合物的总重量约0.1％至约10％、约0.5％至约8％、约1％至约6％的量存在。在本发明的一个优选实施方式中，滑剂基于组 合物的总重量约0.5％、约1％、约2％、约2.5％、约3％、约4％、约5％、约6％、约7％、约8％、约9％或者约10％。
药学上可接受的助流剂指主要功能是通过降低粒间摩擦来提高产品流动性的药物赋形剂。助流剂可选自含硅材料，如气相微粉硅胶、热解硅胶、以及水合硅铝酸钠和滑石。优选地，本发明的药物组合物包括助流剂，所述助流剂优选胶态二氧化硅。在本发明的一个实施方式中，助流剂可以基于组合物的总重量的约0％至约5％、约0％至约3％、约0％至约1％。在本发明的一个优选实施方式中，不含有助流剂。在另一个优选实施方式中，助流剂基于组合物的总重量约0.5％、约1％、约1.5％、约2％、约2.5％、约3％、约3.5％、约4％、约4.5％、约5％。
在一个实施方式中，本发明的固体药物组合物包含至少一种选自以下的药学上可接受的载体：以占组合物重量约5％至约60％的量存在的填充剂、以占组合物重量约0％至约30％的量存在的崩解剂、以占组合物重量约0％至约8％的量存在的粘合剂、以占组合物重量约0.1％至约10％的量存在的润滑剂、以占组合物重量约0％至约5％的量存在的助流剂或其组合。助流剂可以是胶态二氧化硅。
在一个实施方式中，本发明的固体药物组合物包含至少一种选自以下的药学上可接受的载体：以占组合物重量约10％至约50％的量存在的填充剂、以占组合物重量约0.1％至约25％的量存在的崩解剂、以占组合物重量约2％至约6％的量存在的粘合剂、以占组合物重量约0.5％至约8％的量存在的润滑剂、以占组合物重量约0％至约3％的量存在的助流剂或其组合。助流剂可以是胶态二氧化硅。
优选地，填充剂选自微晶纤维素、磷酸钙、磷酸氢钙、淀粉、糊精、预胶化淀粉、甘露醇、山梨醇、乳糖、葡聚糖、蔗糖、右旋糖或其组合；粘合剂选自纤维素醚类、聚维酮、共聚维酮、淀粉、玉米糖浆或其组合，其中，所述纤维素醚类包括但不限于羟丙甲纤维素、羟丙基纤维素、甲基纤维素、羟乙基纤维素；崩解剂选自交联羧甲基纤维素钠、交联聚维酮、羧甲基淀粉钠、羧甲基纤维素钙、低取代羟丙基纤维素或其组合；润滑剂选自硬脂酸镁、硬脂富马酸钠、聚乙二醇、甘油、山嵛酸酯、滑石粉或其组合。更优选地，填充剂选自微晶纤维素、乳糖、甘露醇、山梨醇或其组合，粘合剂选自羟丙基纤维素、羟丙甲纤维素、聚维酮、共聚维酮或其组合，崩解剂选自交联羧甲基纤维素钠、交联聚维酮、羧甲基淀粉钠、羧甲基纤维素钙、低取代羟丙基纤维素或其组合，润滑剂选自硬脂酸镁、硬脂富马酸钠或其组合。优选地，该固体药物组合物在5分钟至60分钟的任意时间点的溶出RSD小于20％。更优选地，该固体药物组合物在5分钟至60分钟的任意时间点的溶出RSD小于10％。
在另一个实施方式中，本发明的固体药物组合物包括由制粒部分制得的具有内相的颗粒和由外加部分制得的与该颗粒相邻的外相。所述颗粒和所述外相的组成成分以及各组成 成分的含量可以相同或者不同。所述颗粒和所述外相分别占固体药物组合物的总重量的比重可以由研究人员根据所选辅料与工艺需要适量调整。
本发明涉及固体药物组合物的制造工艺。
在一个实施例中，通过干法制粒工艺来制备本发明的药物组合物。根据本发明，药物组合物可通过包含以下步骤的方法来制备：将包含化合物1或其药学上可接受的盐与至少一种药学上可接受的载体的制粒部分一起碾压，碾磨经压实材料以形成多个具有内相的颗粒，将所述颗粒与外加部分混合，和任选地将最终混合物压制成片剂。碾压使用基本上利用两个朝向彼此滚动的辊的装置。通过螺旋输送机系统进料至碾压机中的经研磨粒子施加压实力。
在本发明中，如无相反指示，“制粒部分”指的是用于制备具有内相的颗粒的原料部分；“外加部分”指的是用于与由制粒部分制备得到的具有内相的颗粒混合进而制备得到固体药物制剂的辅料部分，其构成固体药物制剂的与具有内相的颗粒相邻的外相。
已知多种本领域内采用的造粒、筛分和混合方法，例如自由下落混合或滚筒式混合，在单冲头或旋转压片机上压制成片剂，或在碾压设备上压实。
筛分或筛选步骤可使用任何适宜方式来完成，例如使用振荡筛分或手动/振动筛或装配有适宜大小筛网的市售筛选磨机。本领域普通技术人员将具有如何确定并选择用于筛分或筛选步骤的适宜大小筛网的经验和知识。例如，筛分或筛选步骤可使用装配有适宜大小筛网筛选磨机来实施。
碾压步骤是使用压实力介于约3.6MPa至约19.4MPa、优选约4.0MkPa至10.0MPa、最优选约7.0MPa范围内的碾压机来完成。所用器件优选是碾压机。适当调节设备的螺杆转速以确保经碾压材料的适当品质。适当调节辊速以确保经碾压材料的适当品质。
碾磨/筛选步骤可使用任何适宜方式来完成。通常，经碾压材料(其形成具有内相的颗粒)是通过具有筛孔大小为至少0.5mm、例如0.6mm、0.8mm、1.2mm或者2mm的筛网的筛选磨机或振荡筛/磨机碾磨。该碾磨/筛选步骤产生多个颗粒。
将颗粒与外加部分混合在一起的步骤可在料斗混合机中完成。然后可以所需目标片剂重量使用适宜旋转压机压制成片剂固体剂型。
在优选实施例中，本发明涉及固体口服剂型，包含本发明的药物组合物且被包衣包被。适宜包衣为本领域内已知且可自市场购得或可根据已知方法来制造。通常，包衣材料是亲水聚合物，例如聚乙烯醇、羟丙基纤维素、羟甲基纤维素和羟丙甲纤维素等。包衣组合物成份可包括常用量的增塑剂，例如聚乙二醇、柠檬酸三乙酯、邻苯二甲酸二乙酯、丙二醇、甘油；以及遮光剂，例如二氧化钛；和/或着色剂，例如氧化铁、铝色淀等。通常，包衣材料是以例如可提供介于总固体口服剂型的约1％至约6％范围内的包衣的量来施加。这些产品是个别制备的膜形成聚合物、遮光剂、着色剂和增塑剂的干燥预混物，将其进一步处理为水性包衣悬浮液。优选地，施加包衣以达到固体口服剂型占总组合物约1％至10％且 优选占总组合物约2％至6％的重量增加。在本发明一个实施例中，包衣材料为
Figure PCTCN2022143030-appb-000004
包衣重量占固体口服剂型总重量的约3％至4％。
在另一个实施方式中，本发明涉及制造固体药物组合物的工艺，包含以下步骤：
(a)将化合物1或其药学上可接受的盐与至少一种药学上可接受的载体混合在一起混合均匀，
(b)碾压经筛分或筛选材料以形成经压实材料，
(c)碾磨经压实材料以形成多个颗粒，
(d)将所述颗粒与外加部分混合以形成最终混合物，和
(e)任选地将最终混合物压制成片剂。
在一个实施方式中，本发明还可以包括制造包衣片剂的工艺，在根据如上所述步骤将最终混合物压制成片剂后，还包含以下步骤：任选地将包衣施加至片剂。
在另一个实施例中，通过湿法制粒工艺来制备本发明的药物组合物。根据本发明，药物组合物可通过包含以下步骤的方法来制备：筛选并称取化合物AN0025和各个药学上可接受的载体；加入含有或不含有粘合剂的制粒流体的同时，以合适的混合速度使化合物AN0025和药学上可接受的载体混合适当量的时间并将混合物切碎成颗粒，其中，制粒流体可以是通过将粘合剂分散在溶剂(水)中而制备得粘合剂溶液，也可以仅仅是润湿剂，比如说水；干燥颗粒；将颗粒与颗粒外的赋形剂共混适当量的时间；然后可以所需目标片剂重量使用适宜旋转压机压制成片剂固体剂型。
在另一个实施方式中，本发明涉及制造固体药物组合物的工艺，包含以下步骤：
(a)将化合物1或其药学上可接受的盐与至少一种药学上可接受的载体混合在一起混合均匀，
(b)加入制粒流体的同时，以合适的混合速度使化合物AN0025和药学上可接受的载体混合适当量的时间并将混合物切碎成颗粒，
(c)干燥颗粒，
(d)经筛分获得目标粒度的干颗粒；
(e)将所述颗粒与外加部分混合以形成最终混合物，和
(f)任选地将最终混合物压制成片剂。
在一个实施方式中，本发明的固体药物组合物片剂中的式1化合物的粒度为D90小于约200微米；在一个实施方式中，本发明的固体药物组合物片剂中的式1化合物的粒度为D90小于约100微米；在优选的实施方式中，本发明的固体药物组合物片剂中的式1化合物的粒度为D90介于约10微米至约80μm。
在一个实施方式中，本发明还可以包括制造包衣片剂的工艺，在根据如上所述步骤将最终混合物压制成片剂后，还包含以下步骤：任选地将包衣施加至片剂。
在一个实施方式中，本发明的固体药物组合物片剂含有约50mg至约500mg所述式1化合物；在另一个实施方式中，本发明的固体药物组合物片剂含有约100mg至约300mg所述式1化合物；优选地，本发明的固体药物组合物片剂含有约125mg至约250mg所述式1化合物。
通过干法制粒或者湿法制粒所得到的本发明的片剂固体药物组合物显示以下优点：
(1)药物组合物的制剂具有快速溶出速率；
(2)药物组合物的制剂具有较低的溶出RSD；
(3)药物组合物的制剂适用于不同粒度的原料药；
(4)药物组合物的制剂在体内的暴露量，具有较低的个体差异。
本发明的药物组合物和其固体剂型可用于治疗癌症，尤其可通过抑制EP4有益治疗的多发性硬化、类风湿性关节炎、或者癌症。适合用本发明的固体药物组合物治疗的癌症的实例包括但不限于例如：皮肤癌、乳腺癌、结直肠癌、前列腺癌、肾癌、卵巢癌、子宫颈癌、子宫内膜癌、胶质母细胞瘤、肺癌、头颈癌、髓母细胞瘤和尿道癌。可用本发明的固体药物组合物治疗的其他疾病公开于WO2012039972A中，其全文以引用方式并入本文中。
在一个实施方式中，本发明提供用于治疗癌症的本发明的固体药物组合物。
在一个实施方式中，本发明提供本发明的固体药物组合物在制造用于治疗癌症的药物中的用途。
在一个实施方式中，本发明提供治疗癌症的方法，包括将包含治疗有效量的式(I)化合物或其药学上可接受的盐的本发明固体组合物施用于患有该癌症的患者。
本发明之一或多个实施例的细节阐述于上述附随的说明中。尽管可在本发明的实践或测试中使用那些与本文所述类似或等效的方法和材料，但现在阐述优选的方法和材料。根据说明书和权利要求书可了解本发明的其他特征、目标和优点。在说明书和附随权利要求书中，除非上下文明确指示其他含义，否则单数形式包含多个指示物。除非另外定义，否则本文所用的所有技术和科学术语都具有与熟悉本发明所属领域技术人员通常所理解相同的意义。本说明书中引用的所有专利和出版物都是以引用方式并入。呈现以下实施例以更全面地阐释本发明的优选实施例。这些实施例绝不应解释为限制如附随权利要求书所定义的所公开专利的范围。
实施例
1、溶出度检测方法：
溶出参数
装置：美国药典和中国药典装置二(浆法)
转速：50转/分钟
溶出介质：pH 6.8磷酸盐缓冲溶液
溶出体积：900mL
温度:37±0.5℃
HPLC检测条件
检测波长：234nm
色谱柱：YMC-Triart C 18 75×4.6mm,3μm
柱温：40℃
溶剂A：水/70％高氯酸(1000/1，v/v)
溶剂B：乙腈/70％高氯酸(1000/1，v/v)
洗脱梯度：
Figure PCTCN2022143030-appb-000005
药动学参数测试方法
本发明通过色谱和质谱测得对比实例和实施例的药动学参数，测试条件详情列于表1a和表1b中。
表1a、色谱条件
Figure PCTCN2022143030-appb-000006
Figure PCTCN2022143030-appb-000007
注：AN00251001为AN0025的氘代化合物。
表1b、质谱条件
Figure PCTCN2022143030-appb-000008
Figure PCTCN2022143030-appb-000009
2、对比实例1
根据如表2a所述的成分和含量制备对比实例1的胶囊剂。
表2a、对比实例1的处方组成
Figure PCTCN2022143030-appb-000010
对比实例1的AN0025胶囊剂，其制造过程由六个步骤组成：混合，润滑，制粒，整粒，胶囊灌装和重量分选。将AN0025原料药，甘露醇，低取代羟丙基纤维素，羟丙基纤维素，羧甲基纤维素钙和微晶纤维素混合到高剪切混合器或料斗混合机中混合均匀。再将硬脂酸镁加入到上述混合物中润滑。使用碾压机将混合物压成长条。长条过筛整粒(筛网孔径为1.5毫米)。使用胶囊灌装机将整粒后的颗粒填充到羟丙甲纤维素(HPMC)胶囊中，使用检重秤剔除超重和灌装量不足的胶囊。
表2b、125mg胶囊剂(对比实例1)稳定性考察期间的溶出曲线均值
Figure PCTCN2022143030-appb-000011
Figure PCTCN2022143030-appb-000012
ND:由于实验操作失误，未测定
表2b示出了对比实例1的125mg胶囊剂稳定性考察期间的溶出曲线均值。在不同的储存条件下(长期稳定性条件25℃/60％相对湿度，加速稳定性条件40℃/75％相对湿度)，1～36个月不同时间点测得的结果存在较大差异。这种差异不是趋势性的，而是上下波动的，说明即便是溶出均值也不能反应药品真实的溶出状态。
其中，另外一批对比实例1的溶出曲线测定结果如表2c所示，其中，SD为标准偏差，RSD为相对标准偏差。如无相反说明，本文中记载的SD、RSD均具有与表2c相同的定义和计算方法。图2c表明，相同时间点不同胶囊剂样品检测结果有较大不同，RSD较大。行业内技术人员测定溶出曲线时通用的可接受标准为第一个时间点的溶出测定值的RSD不大于20％，其余时间点溶出测定值的RSD不大于10％。
表2c、对比实例1的溶出曲线
Figure PCTCN2022143030-appb-000013
Figure PCTCN2022143030-appb-000014
以上结果表明，该胶囊剂的溶出的RSD较大，不同批次或者相同批次在不同时间的检测结果存在较大的波动。
3、对比实例2
根据如表3所述的成分和含量制备对比实例2的胶囊剂。对比例2使用与对比例1相同的组分和含量，灌装入不同的空心胶囊中。
表3a、对比实例2的处方组成
Figure PCTCN2022143030-appb-000015
对比实例2的AN0025胶囊剂，其制造过程由六个步骤组成：混合，润滑，制粒，整粒，胶囊灌装和重量分选。将AN0025原料药，甘露醇，低取代羟丙基纤维素，羟丙基纤维素，羧甲基纤维素钙和微晶纤维素混合到高剪切混合器中。使用高剪切混合器将硬脂酸镁与混合物混合。使用碾压机将混合物压成长条。长条过筛整粒(筛网孔径为1.5毫米)。使用胶囊灌装机将整粒后的颗粒填充到明胶空心胶囊中，使用检重秤剔除超重和灌装量不足的胶囊。
表3b、对比实例2稳定性考察中的溶出行为
Figure PCTCN2022143030-appb-000016
Figure PCTCN2022143030-appb-000017
表3b表明，与使用HPMC胶囊的对比实例1相比，使用明胶胶囊的对比实例2可以较快溶出，其溶出RSD也有较大改善，但是5min时间的RSD仍超过20％。而且在40℃/75％相对湿度的加速稳定性考察过程中，对比实例2的胶囊剂存在较为明显的溶出下降。
4、对比实例3
为了改善对比实例1较高的RSD，发明人采用不同的制备工艺，根据如表4a所述的成分和含量制备对比实例3的胶囊剂。
表4a、对比实例3的处方组成
Figure PCTCN2022143030-appb-000018
制备工艺如下：
步骤1混合
将称量后的化合物AN0025，一水乳糖，羟丙基纤维素和微晶纤维素加入到高剪切制粒机中300转/分钟混合2分钟。
步骤2制粒
将高剪切制粒机的参数设定为搅拌速度200转/分钟，剪切速度800转/分钟，缓缓加入纯化水作为润湿剂制备软材。润湿剂全部加入完毕后再继续运行相同的搅拌速度和剪切速度2～3分钟，出料。软材过孔径2.0mm的筛网制得湿颗粒。
步骤3干燥
将上述步骤中得到的湿颗粒干燥去除水分。
步骤4整粒
干燥后得到的颗粒再次过筛整粒，得到具有内相的颗粒。
步骤5混合II
将上述制备得到的颗粒与低取代羟丙纤维素混合均匀。
步骤6润滑II
将上述制备得到的混合物再与硬脂酸镁混合均匀。
步骤7胶囊填充
按照目标重量，将润滑后物料填充入羟丙甲纤维素(HPMC)胶囊中，即得。
然而，如表4b所示，采用湿法制粒工艺制备的胶囊依然具有高的RSD。
表4b、对比实例3的溶出曲线
Figure PCTCN2022143030-appb-000019
为了从根本上解决化合物AN0025制剂高RSD的问题，本发明人实施以下具体实施例。 5、本发明实施实例1
根据如表5a所述的成分和含量制备本发明实施例1的片剂。
表5a、实施实例1的处方组成
Figure PCTCN2022143030-appb-000020
制备工艺如下：
步骤1混合
将称量后的化合物AN0025，甘露醇，低取代羟丙基纤维素，羟丙基纤维素，羧甲基纤维素钙和微晶纤维素均匀混合。
步骤2润滑I
将制粒部分的硬脂酸镁加入到步骤1的混合物中，混合均匀。
步骤3制粒
使用碾压机将混合物压成长条，碾压参数为：压实力10Mpa；辊速：4rpm；间隙宽度1.5mm。
步骤4整粒
长条分别通过粗筛网(孔径2.0mm)和细筛网(孔径0.6mm)过筛整粒，得到具有内相的颗粒。
步骤5润滑II
将上述制备得到的颗粒与外加部分硬脂酸镁混合。
步骤6压片
以250mg的所需的目标片重，使用压片机压制成适合形状的片剂。
实施实例1的处方组分与对比实例1、对比实例2和一样，差别在于制备成不同剂型。其溶出数据如表5b所示，所有时间点的溶出RSD不超过10％，相较于对比实例1和对比实例2具有明显的改善。此外，附图2还表明，实施实例1的片剂的药物溶出速度高于对比实例1的胶囊剂。
表5b、实施实例1的溶出曲线
Figure PCTCN2022143030-appb-000021
6、本发明实施实例2
根据如表6a所述的成分和含量制备本发明实施例2的片剂。
表6a、实施实例2的处方组成
Figure PCTCN2022143030-appb-000022
制备工艺如下：
步骤1混合
将称量后的化合物AN0025，一水乳糖，羟丙基纤维素和微晶纤维素加入到高剪切制粒机中300转/分钟混合2分钟。
步骤2制粒
将高剪切制粒机的参数设定为搅拌速度200转/分钟，剪切速度800转/分钟，缓缓加入纯化水作为润湿剂制备软材。润湿剂全部加入完毕后再继续运行相同的搅拌速度和剪切速度2～3分钟，出料。软材过孔径2.0mm的筛网制得湿颗粒。
步骤3干燥
将上述步骤中得到的湿颗粒干燥去除水分。
步骤4整粒
干燥后得到的颗粒再次过筛整粒，得到具有内相的颗粒。
步骤5混合II
将上述制备得到的颗粒与低取代羟丙纤维素混合均匀。
步骤6润滑II
将上述制备得到的混合物再与硬脂酸镁混合均匀。
步骤7压片
根据目标片重重量，使用压片机压制成适合形状的片剂。
其溶出数据如表6b所示，所有时间点的溶出RSD不超过10％。
表6b、实施实例2的溶出曲线
Figure PCTCN2022143030-appb-000023
Figure PCTCN2022143030-appb-000024
表6c、实施实例2稳定性考察中的溶出行为
Figure PCTCN2022143030-appb-000025
实施实例2与对比实例3的处方组分与制备工艺一样，差别在于制备成不同剂型。实施实例2的溶出曲线对比如说明书附图2所示，与实施例1的实验结果类似，实施实例2的片剂的药物溶出速度亦高于对比实例3的胶囊剂。
实施实例2在稳定性考察过程中相对稳定，无显著性下降，如表6c所示。而对比实例2在稳定性考察过程中溶出明显下降，如表3b所示。该结果从稳定性的角度证明了片剂的优势。
实施例1和实施例2表明，无论是干法制粒还是湿法制粒，本发明的片剂均可以明显改善胶囊剂的RSD高的问题，这种改善与制剂制备工艺无关。
7、本发明实施实例3
改变配方中各成分的比例，根据如表7a所述的成分和含量制备本发明实施例3的片剂。
表7a、实施实例3的处方组成
Figure PCTCN2022143030-appb-000026
Figure PCTCN2022143030-appb-000027
制备工艺如下：
步骤1混合
将称量后的化合物AN0025，甘露醇，羟丙基纤维素，羧甲基纤维素钙和微晶纤维素加入到料斗混合机中均匀混合。
步骤2润滑I
使用料斗混合机将制粒部分的硬脂酸镁与步骤1中的混合物混合均匀。
步骤3制粒
使用碾压机将混合物压成长条，碾压参数为：压实力7Mpa；辊速：2rpm；间隙宽度1.5mm。
步骤4整粒
长条打碎后通过0.8mm筛网过筛整粒，得到具有内相的颗粒。
步骤5润滑II
将上述制备得到的颗粒与外加部分硬脂酸镁混合。
步骤6压片
以500mg的所需的目标片重重量，使用压片机压制成适合形状的片剂。
步骤7包衣
将欧巴代充分分散在纯化水中，配置包衣液，通过包衣机进行薄膜包衣，目标包衣增重为4％。
其溶出数据如表7b所示，除第一个时间点的溶出RSD稍高(但不超过20％)，其余点溶出RSD均不超过10％。
表7b、实施实例3的溶出曲线
Figure PCTCN2022143030-appb-000028
8、实施实例4
根据如表8a所述的成分和含量制备实施例4的含有包衣的片剂。
表8a、实施实例4的处方组成
Figure PCTCN2022143030-appb-000029
制备工艺如下：
步骤1混合
将称量后的化合物AN0025，甘露醇，羟丙基纤维素，交联羧甲基纤维素钠和微晶纤维素加入到料斗混合机中均匀混合。
步骤2润滑I
使用料斗混合机将制粒部分的硬脂酸镁与步骤1中的混合物混合均匀。
步骤3制粒
使用碾压机将混合物压成长条，碾压参数为：压实力7Mpa；辊速：2rpm；间隙宽度1.5mm。
步骤4整粒
长条打碎后通过0.8mm筛网过筛整粒，得到具有内相的颗粒。
步骤5润滑II
将上述制备得到的颗粒与外加部分硬脂酸镁混合。
步骤6压片
以500mg的所需的目标片重重量，使用压片机压制成适合形状的片剂。
步骤7包衣
将欧巴代充分分散在纯化水中，配制包衣液，通过包衣机进行薄膜包衣，目标包衣增重为4％。
其溶出数据如表8b所示，所有时间点的溶出RSD不超过10％。
表8b、实施实例4的溶出曲线
Figure PCTCN2022143030-appb-000030
Figure PCTCN2022143030-appb-000031
在40℃/75％相对湿度条件下放置1个月，其溶出度也未见明显变化，如表8c所示。
表8c、实施实例4稳定性考察中的溶出行为
时间点/分 5 10 15 20 30 45 60
初始 56 75 83 87 91 93 94
40℃/75％RH，1个月 50 71 82 88 94 97 98
对比实例1、实施例3与实施例4的片剂被用于动物测试。
比格犬的给药剂量为750mg/只时，不同制剂处方在比格犬内的药动学参数比较如表8d所示，其中，AUC 0-t表示时间从0到所选择的最后一个时间点时血药浓度时间曲线下面积，AUC 0-t_dose表示时间从0到所选择的最后一个时间点时血药浓度时间曲线下面积与给药剂量的比值。如无相反说明，本文中记载的AUC 0-t、AUC 0-t_dose均具有与表8d相同的定义和计算方法。与对比实例1相比，实施实例3和实施实例4片剂的体内暴露量(AUC)相当，但是个体间的差异(SD)更小，与体外溶出数据较为一致，提示片剂在临床上可能有更好的有效性和安全性。对比实例1，实施实例4在750mg/只剂量下比格犬体内的药时曲线分别如附图3、图4所示。
表8d、750mg剂量下不同制剂在比格犬内的药动学参数对比
Figure PCTCN2022143030-appb-000032
比格犬的给药剂量为250mg/只时，不同制剂处方在比格犬内的药动学参数比较如表8e所示。与对比实例1的胶囊剂相比，实施实例4片剂的体内暴露量(AUC)相当，但是个体间的差异(SD)更小，与体外溶出数据较为一致，提示片剂在临床上具有更好的有效性 和安全性。对比实例1，实施实例4在250mg/只剂量下比格犬体内的药时曲线分别如附图5、图6所示。
表8e、250mg剂量下不同制剂在比格犬内的药动学参数对比
Figure PCTCN2022143030-appb-000033
上述结果表明，本发明的片剂具有与胶囊剂相似的体内暴露量，但是个体间的差异明显降低，RSD减小，且这种改善不受给药剂量的影响。
9、实施实例4a
实施实例4a的处方组分和制备工艺与实施实例4完成相同，但是使用了不同粒度的原料药。实施实例4与实施实例4a所用的原料药粒度差别如表9a所示，其中，D50表示一个样品的累计粒度分布百分数达到50％时所对应的粒径，即粒径小于它的颗粒占50％；D90表示一个样品的累计粒度分布百分数达到90％时所对应的粒径，即粒径小于它的颗粒占90％。如无相反说明，本文中记载描述粒度的D50、D90均具有与本实施例相同的定义。
表9a、实施实例4和实施实例4a的原料药粒度信息
原料药粒度 实施实例4 实施实例4a
D50 9.18μm 31μm
D90 22.0μm 76μm
表9b、实施实例4a的溶出曲线
Figure PCTCN2022143030-appb-000034
Figure PCTCN2022143030-appb-000035
一般来说，对于难溶性药物而言，原料药的粒度常常是制剂开发中需要考虑的关键性因素。不同粒度的药物，由于其比表面积的差异，常常表现出小粒度的原料药有更快的体外溶出和更好的体内吸收行为。然而令人意外的是，实施实例4和实施实例4a表现除了相似的溶出行为，其体外溶出的相似因子f2为52(f2大于50则认为溶出相似)。实施实例4a的溶出曲线详见表9b所示。
表9c、250mg剂量下不同粒度原料药在比格犬内的药动学参数对比
Figure PCTCN2022143030-appb-000036
比格犬体内的药动学数据也进一步得出了类似的结论：不同粒度的AN0025原料药对产品质量无影响。本发明所提供的片剂对不同粒度的原料药具有较好的耐用性。实施实例4和实施实例4a的体内药动学参数对比如表9c所示。实施实例4a在750mg/只剂量下比格犬体内的药时曲线如附图7所示。
10、本发明实施实例5
根据如表10a所述的成分和含量制备本发明实施例5的片剂。
表10a、实施实例5的处方组成
Figure PCTCN2022143030-appb-000037
Figure PCTCN2022143030-appb-000038
制备工艺如下：
步骤1混合
将称量后的化合物AN0025，甘露醇，低取代羟丙基纤维素，羟丙基纤维素，羧甲基纤维素钙、微晶纤维素加入到料斗混合机中均匀混合。
步骤2润滑I
使用料斗混合机将制粒部分的硬脂富马酸钠与步骤1中的混合物混合均匀。
步骤3制粒
使用碾压机将混合物压成长条，碾压参数为：压实力7Mpa；辊速：2rpm；间隙宽度1.5mm。
步骤4整粒
长条打碎后通过0.8mm筛网过筛整粒，得到具有内相的颗粒。
步骤5润滑II
将上述制备得到的颗粒与外加部分硬脂富马酸钠混合。
步骤6压片
以500mg的所需的目标片重重量，使用压片机压制成适合形状的片剂。
步骤7包衣
将欧巴代充分分散在纯化水中，配制包衣液，通过包衣机进行薄膜包衣，目标包衣增重为4％。
其溶出数据如表10b所示，所有时间点的溶出RSD不超过10％。
表10b、实施实例5的溶出曲线
Figure PCTCN2022143030-appb-000039

Claims (19)

  1. 一种固体药物组合物，其包括：式1所述化合物或其药学上可接受的盐以及药学上可接受的载体，其中式1所述化合物或其药学上可接受的盐占所述固体药物组合物总重量的约30％至约80％；该固体药物组合物的剂型为片剂。
    Figure PCTCN2022143030-appb-100001
  2. 如权利要求1所述的固体药物组合物，其中，式1所述化合物或其药学上可接受的盐占所述固体药物组合物总重量的约40％至约60％。
  3. 如前述任一权利要求所述的固体药物组合物，其中，所述药学上可接受的载体包括选自填充剂、粘合剂、润滑剂、崩解剂和助流剂的一种或者多种。
  4. 如前述任一权利要求所述的固体药物组合物，其中，所述药学上可接受的载体包括：
    a.填充剂，其占所述固体药物组合物总重量的约5％至约60％；
    b.粘合剂，其占所述固体药物组合物总重量的约0％至约8％；
    c.崩解剂，其占所述固体药物组合物总重量的约0％至约30％；
    d.润滑剂，其占所述固体药物组合物总重量的约0.1％至约10％；
    e.助流剂，其占所述固体药物组合物总重量的约0％至约5％。
  5. 如前述任一权利要求所述的固体药物组合物，其中，所述药学上可接受的载体包括：
    a.填充剂，其占所述固体药物组合物总重量的约10％至约50％；
    b.粘合剂，其占所述固体药物组合物总重量的约2％至约6％；
    c.崩解剂，其占所述固体药物组合物总重量的约0.1％至约25％；
    d.润滑剂，其占所述固体药物组合物总重量的约0.5％至约8％；
    e.助流剂，其占所述固体药物组合物总重量的约0％至约3％。
  6. 如前述任一权利要求所述的固体药物组合物，其中，所述药学上可接受的载体包括：
    a.填充剂，其占所述固体药物组合物总重量的约20％至约40％；
    b.粘合剂，其占所述固体药物组合物总重量的约3％至约5％；
    c.崩解剂，其占所述固体药物组合物总重量的约1％至约25％；
    d.润滑剂，其占所述固体药物组合物总重量的约1％至约6％；
    e.助流剂，其占所述固体药物组合物总重量的约0％至约1％。
  7. 如前述任一权利要求所述的固体药物组合物，其中，
    所述填充剂选自包含以下的组：微晶纤维素、磷酸钙、磷酸氢钙、淀粉、糊精、预胶化淀粉、甘露醇、山梨醇、乳糖、葡聚糖、蔗糖、右旋糖及其组合；
    所述粘合剂选自包含以下的组：纤维素醚类、聚维酮、共聚维酮、淀粉、玉米糖浆及其组合；其中，所述纤维素醚类包括但不限于羟丙甲纤维素、羟丙基纤维素、甲基纤维素、羟乙基纤维素；
    所述崩解剂选自包含以下的组：交联羧甲基纤维素钠、交联聚维酮、羧甲基淀粉钠、羧甲基纤维素钙、低取代羟丙基纤维素及其组合；
    所述润滑剂选自包含以下的组：硬脂酸镁、硬脂富马酸钠、聚乙二醇、甘油、山嵛酸酯、滑石粉及其组合。
  8. 如前述任一权利要求所述的固体药物组合物，其中，
    所述填充剂选自微晶纤维素、乳糖、甘露醇、山梨醇及其组合；
    所述粘合剂选自羟丙基纤维素、羟丙甲纤维素、聚维酮、共聚维酮及其组合；
    所述崩解剂选自交联羧甲基纤维素钠、交联聚维酮、羧甲基淀粉钠、羧甲基纤维素钙、低取代羟丙基纤维素及其组合；
    所述润滑剂选自硬脂酸镁、硬脂富马酸钠及其组合。
  9. 如前述任一权利要求所述的固体药物组合物，包括具有内相的颗粒。
  10. 如权利要求9所述的固体药物组合物，还包括与所述具有内相的颗粒相邻的外相。
  11. 如权利要求9或10所述的固体药物组合物，其中，所述具有内相的颗粒通过干法制备工艺来制备。
  12. 如权利要求9或10所述的固体药物组合物，其中，所述具有内相的颗粒通过湿法制备工艺来制备。
  13. 如前述任一权利要求所述的固体药物组合物，其中，式1化合物的粒度为D90小于约200微米。
  14. 如前述任一权利要求所述的固体药物组合物，其中，式1化合物的粒度为D90小于约100微米。
  15. 如前述任一权利要求所述的固体药物组合物，还包括包衣。
  16. 如前述任一权利要求所述的固体药物组合物，含有约50mg至约500mg所述式1化合物。
  17. 如前述任一权利要求所述的固体药物组合物，含有约100mg至约300mg所述式1化合物。
  18. 如前述任一权利要求所述的固体药物组合物用于制备治疗多发性硬化、类风湿性关节炎、或者癌症的药物中用途。
  19. 如权利要求18所述的用途，其中，所述癌症包括：皮肤癌、乳腺癌、结直肠癌、前列腺癌、肾癌、卵巢癌、子宫颈癌、子宫内膜癌、胶质母细胞瘤、肺癌、头颈癌、髓母细胞瘤和尿道癌。
PCT/CN2022/143030 2021-12-30 2022-12-28 一种固体药物组合物 Ceased WO2023125724A1 (zh)

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IL313976A IL313976A (en) 2021-12-30 2022-12-28 Solid pharmaceutical preparation
CA3242313A CA3242313A1 (en) 2021-12-30 2022-12-28 SOLID PHARMACEUTICAL COMPOSITION
CN202280013622.0A CN116887817A (zh) 2021-12-30 2022-12-28 一种固体药物组合物
AU2022426506A AU2022426506B2 (en) 2021-12-30 2022-12-28 A solid pharmaceutical composition
MX2024008180A MX2024008180A (es) 2021-12-30 2022-12-28 Una composicion farmaceutica solida.
JP2024538350A JP2024544423A (ja) 2021-12-30 2022-12-28 固体医薬組成物
EP22914974.5A EP4438036A4 (en) 2021-12-30 2022-12-28 SOLID PHARMACEUTICAL COMPOSITION
KR1020247021645A KR20240110883A (ko) 2021-12-30 2022-12-28 고형 약학적 조성물
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CA (1) CA3242313A1 (zh)
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ZA202404874B (en) 2025-02-26
AU2022426506A1 (en) 2024-07-18
JP2024544423A (ja) 2024-11-29
TW202339723A (zh) 2023-10-16
CA3242313A1 (en) 2023-06-07
EP4438036A4 (en) 2025-03-19
IL313976A (en) 2024-08-01
MX2024008180A (es) 2024-07-19
CN116887817A (zh) 2023-10-13
EP4438036A1 (en) 2024-10-02
KR20240110883A (ko) 2024-07-16
AU2022426506B2 (en) 2026-04-02

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