WO2023280090A1 - 一种药用组合物及其制备方法和用途 - Google Patents

一种药用组合物及其制备方法和用途 Download PDF

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WO2023280090A1
WO2023280090A1 PCT/CN2022/103576 CN2022103576W WO2023280090A1 WO 2023280090 A1 WO2023280090 A1 WO 2023280090A1 CN 2022103576 W CN2022103576 W CN 2022103576W WO 2023280090 A1 WO2023280090 A1 WO 2023280090A1
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pharmaceutical composition
cancer
composition according
phosphorus oxide
pharmaceutically acceptable
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PCT/CN2022/103576
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English (en)
French (fr)
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郑晓清
程丽珍
耿伟峰
杨清敏
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齐鲁制药有限公司
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Priority to EP22836841.1A priority Critical patent/EP4306115A1/en
Priority to KR1020237033255A priority patent/KR20230152118A/ko
Priority to CN202280013340.0A priority patent/CN116867497A/zh
Priority to AU2022306151A priority patent/AU2022306151A1/en
Priority to JP2023552522A priority patent/JP2024508497A/ja
Priority to BR112023022711A priority patent/BR112023022711A2/pt
Priority to CA3215383A priority patent/CA3215383A1/en
Publication of WO2023280090A1 publication Critical patent/WO2023280090A1/zh

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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
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • A61K9/2009—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—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
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin

Definitions

  • the invention belongs to the field of medicinal chemistry, and relates to a medicinal composition, a preparation method and application thereof.
  • Spiral aryl phosphorus oxide its structure is shown in the following formula, and its chemical name is: (2-((5-chloro-2-((2-methoxy-4-(9-methyl-3,9- Diazaspiro[5.5]undec-3-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide, molecular weight 569.08, is a highly selective anaplastic lymphoma Kinase (ALK) Inhibitors.
  • ALK anaplastic lymphoma Kinase
  • ALK wild type ALK mutant (ALK L1196M , ALK C1156Y ) and EGFR mutant EGFR T790M/L858R enzyme activity was determined.
  • the inhibitory activity of spirocyclic aryl phosphine oxides on the 4 major kinase targets is comparable to or slightly superior to that of AP26113; for other related serine, threonine and tyrosine proteases, except EGFR wild type, within the detection concentration range Has low inhibitory activity and exhibits high kinase selectivity.
  • spirocyclic aryl phosphorus oxides can be used to treat ALK-positive non-small cell lung cancer patients who have progressed after crizotinib treatment or cannot tolerate crizotinib, or have not used ALK Inhibitors in patients with ALK-positive non-small cell lung cancer.
  • Spirocyclic aryl phosphorus oxide is white or off-white powder, almost non-hygroscopic; easily soluble in dichloromethane; slightly soluble in methanol, slightly soluble in water, ethanol or acetonitrile; in 1mol/L sodium hydroxide solution Almost insoluble or insoluble in However, it is easily soluble in 1mol/L hydrochloric acid solution and is a compound with high solubility.
  • the solubility of the drug directly affects the dissolution rate of the composition containing the drug, which in turn affects the bioavailability of the drug composition. Therefore, how to improve the dissolution rate of pharmaceutical compositions containing spirocyclic aryl phosphorus oxides in solvents other than hydrochloric acid has become an urgent problem to be solved.
  • the particle size of a general drug has no significant effect on the drug dissolution behavior.
  • the inventors have found that although the particle size of the spirocyclic aryl phosphorus oxide has a significant impact on the dissolution of the drug in vitro, too large or too small a particle size will lead to a decrease in the dissolution of the spirocyclic aryl phosphorus oxide. Only when the particle size of the spirocyclic aryl phosphorus oxide is within a certain range can the drug dissolution meet the requirements.
  • the particle size range should be properly controlled, so as to effectively control the spirocyclic aryl phosphorus oxide in preparations containing spirocyclic aryl phosphorus oxide.
  • the dissolution rate of the oxide further improves the bioavailability of the spirocyclic aryl phosphorus oxide in vivo.
  • the object of the present invention is to provide a pharmaceutical composition and its preparation method and use, and the spirocyclic aryl phosphorus oxide or its pharmaceutically acceptable salt has a particle size in a specific range, which can improve the pharmaceutical composition. Dissolution rate, thereby improving bioavailability.
  • a spirocyclic aryl phosphorus oxide or a pharmaceutically acceptable salt thereof whose particle size distribution satisfies D90 in the range of 40.3 ⁇ m to 79.6 ⁇ m, and the spirocyclic aryl phosphorus oxide has the following structure :
  • a spirocyclic aryl phosphorus oxide or a pharmaceutically acceptable salt thereof with a particle size distribution satisfying D50 in the range of 13.0 ⁇ m to 23.8 ⁇ m or, providing a particle size distribution satisfying D50 in the range of A spirocyclic aryl phosphorus oxide in the range of 13.0 ⁇ m to 18.2 ⁇ m or a pharmaceutically acceptable salt thereof.
  • the third aspect of the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a spirocyclic aryl phosphorus oxide or a pharmaceutically acceptable salt thereof with a specific particle size and a pharmaceutically acceptable carrier, a spirocyclic aryl phosphorus oxide or a pharmaceutically acceptable carrier thereof
  • a pharmaceutically acceptable salt is used as the active ingredient, and the specific particle size satisfies D90 in the range of 40.3 ⁇ m to 79.6 ⁇ m, and the spirocyclic aryl phosphorus oxide has the following structure:
  • the D50 of the spirocyclic aryl phosphorus oxide or a pharmaceutically acceptable salt thereof is within the range of 13.0 ⁇ m to 23.8 ⁇ m.
  • the D50 of the spirocyclic aryl phosphorus oxide or a pharmaceutically acceptable salt thereof is in the range of 13.0 ⁇ m to 18.2 ⁇ m.
  • the crystal form of the spirocyclic aryl phosphorus oxide in the pharmaceutical composition of the present invention is Form A.
  • the crystal form A of the spirocyclic aryl phosphorus oxide in the pharmaceutical composition of the present invention uses Cu-K ⁇ radiation, and the X-ray powder diffraction represented by the 2 ⁇ angle is at 8.5 ⁇ 0.20°, There are characteristic peaks at 10.1 ⁇ 0.20°, 12.1 ⁇ 0.20°, 14.6 ⁇ 0.20°, 17.7 ⁇ 0.20°, 18.7 ⁇ 0.20°, 20.4 ⁇ 0.20°, 21.2 ⁇ 0.20°.
  • the crystal form A of the spirocyclic aryl phosphorus oxide in the pharmaceutical composition of the present invention uses Cu-K ⁇ radiation, and the X-ray powder diffraction represented by the 2 ⁇ angle is at 8.5 ⁇ 0.20°, 9.3 ⁇ 0.20°, 10.1 ⁇ 0.20°, 12.1 ⁇ 0.20°, 13.7 ⁇ 0.20°, 14.6 ⁇ 0.20°, 15.7 ⁇ 0.20°, 16.5 ⁇ 0.20°, 17.7 ⁇ 0.20°, 18.7 ⁇ 0.20°, 20.0 ⁇ 0.20°, There are characteristic peaks at 20.4 ⁇ 0.20°, 21.2 ⁇ 0.20°, 23.6 ⁇ 0.20°, 25.1 ⁇ 0.20°, 25.6 ⁇ 0.20°.
  • the crystal form A of the spirocyclic aryl phosphorus oxide in the pharmaceutical composition of the present invention has an X-ray powder diffraction pattern substantially as shown in FIG. 4 .
  • pharmaceutically acceptable carriers include fillers, disintegrants, binders, glidants, and lubricants.
  • the filler is selected from one or a combination of starch, mannitol, sorbitol, microcrystalline cellulose, lactose, pregelatinized starch, inorganic salts, preferably microcrystalline cellulose and pregelatinized starch composition.
  • inorganic salts may include, but are not limited to, calcium sulfate (containing two molecules of crystal water), calcium hydrogen phosphate, calcium carbonate, and the like.
  • the disintegrating agent is selected from dry starch, sodium carboxymethyl starch, hydroxypropyl starch, low-substituted hydroxypropyl cellulose, crospovidone, croscarmellose sodium One or a combination of them, preferably sodium starch glycolate.
  • the binder is selected from distilled water, ethanol, starch slurry, powdered sugar and syrup, hypromellose, povidone, hydroxypropyl cellulose, methyl cellulose, ethyl cellulose One or a combination of sodium carboxymethylcellulose and sodium carboxymethylcellulose, preferably hypromellose.
  • the glidant is selected from one or a combination of micropowder silica gel and talc powder, preferably micropowder silica gel.
  • the lubricant is selected from one or a combination of magnesium stearate, hydrogenated vegetable oil, polyethylene glycol, magnesium lauryl sulfate, sodium stearyl fumarate, preferably magnesium stearate .
  • the pharmaceutical composition of the spirocyclic aryl phosphorus oxide with a specific particle size or a pharmaceutically acceptable salt thereof of the present invention is an oral preparation, which is absorbed through the gastrointestinal tract through oral administration.
  • the pharmaceutical compositions of the invention are in tablet form.
  • the pharmaceutical composition of the invention is a film-coated tablet.
  • the spirocyclic aryl phosphorus oxide or a pharmaceutically acceptable salt thereof accounts for 1.0%-50.0% by weight in the composition.
  • each component by weight percentage is: spirocyclic aryl phosphorus oxide or a pharmaceutically acceptable salt thereof accounts for 1% to 50%, and filler 1% ⁇ 90%, disintegrant 1% ⁇ 10%, glidant 0.1% ⁇ 1%, lubricant 0.5%-5%.
  • each component by weight percentage is: spirocyclic aryl phosphorus oxide or its pharmaceutically acceptable salt 5.0%, microcrystalline cellulose 26.0%, pre- Gelatinized starch 59.5%, sodium starch glycolate 5%, hydroxypropyl methylcellulose 3.0%, micronized silica gel 0.5%, magnesium stearate 1%.
  • the fourth aspect of the present invention provides a method for preparing the pharmaceutical composition in any of the above schemes, which includes the following steps:
  • the part of the internal excipients includes fillers, binders and disintegrants;
  • auxiliary materials include fillers, disintegrants and lubricants;
  • a pharmaceutical composition which contains an effective amount of spirocyclic aryl phosphorus oxide or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, diluent and excipient .
  • Pharmaceutical compositions can be formulated for specific routes of administration, such as oral, parenteral, rectal, and the like.
  • Oral administration may include, but is not limited to, oral, sublingual, buccal, oral administration may be through, but is not limited to, tablets (film-coated tablets), capsules (including sustained release or timed release formulations), pills , powders, granules, elixirs, tinctures, suspensions (including nanosuspensions, microsuspensions, spray-dried dispersions), syrups or emulsions; parenteral administration may include, but is not limited to, injection, infusion Injection, and nasal or other topical administration, specifically, may be by, but not limited to, subcutaneous, intravenous, intramuscular, or intrasternal injection; infusion techniques, e.g., as sterile injectable aqueous or non-aqueous solutions or suspensions ; nasally, including to the nasal mucosa, for example by inhalation spray; topically, for example in the form of a cream or ointment. Rectal administration, eg in the form of suppositories.
  • the fifth aspect of the present invention provides a use of the pharmaceutical composition in any of the above schemes or the pharmaceutical composition prepared by the method in any of the above schemes for treating cancer.
  • the above cancers include non-small cell lung cancer, lymphoma, non-Hodgkin's lymphoma, ovarian cancer, cervical cancer, prostate cancer, colorectal cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, melanoma, Leukemia, gastric cancer, endometrial cancer, lung cancer, hepatocellular carcinoma, gastric cancer, gastrointestinal stromal tumor (GIST), acute myeloid leukemia (AML), bile duct cancer, kidney cancer, thyroid cancer, anaplastic large cell lymphoma , mesothelioma, multiple myeloma, melanoma.
  • the cancer is non-small cell lung cancer.
  • the above-mentioned use is for patients with ALK-positive non-small cell lung cancer whose disease has progressed without crizotinib treatment or who cannot tolerate crizotinib.
  • the above use is for ALK-positive non-small cell lung cancer patients who have not used ALK inhibitors.
  • the sixth aspect of the present invention provides a method for treating cancer, which comprises administering to a patient a therapeutically effective amount of the pharmaceutical composition in any of the aforementioned schemes.
  • the above cancers include non-small cell lung cancer, lymphoma, non-Hodgkin's lymphoma, ovarian cancer, cervical cancer, prostate cancer, colorectal cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, melanoma, Leukemia, gastric cancer, endometrial cancer, lung cancer, hepatocellular carcinoma, gastric cancer, gastrointestinal stromal tumor, acute myeloid leukemia, cholangiocarcinoma, renal cancer, thyroid cancer, anaplastic large cell lymphoma, mesothelioma, multiple myeloma, melanoma.
  • the cancer is non-small cell lung cancer.
  • the above approach is used in patients with ALK-positive non-small cell lung cancer whose disease has progressed without crizotinib treatment or who cannot tolerate crizotinib.
  • the methods described above are used in patients with ALK-positive non-small cell lung cancer who are ALK inhibitor-na ⁇ ve.
  • D50 refers to the particle diameter corresponding to when the cumulative volume distribution percentage of spirocyclic aryl phosphorus oxide or its pharmaceutically acceptable salt reaches 50% from the small particle size
  • D90 refers to the particle size corresponding to the small particle size measurement. The particle size corresponding to when the cumulative volume distribution percentage of the spirocyclic aryl phosphorus oxide or its pharmaceutically acceptable salt reaches 90%.
  • the present invention provides a pharmaceutical composition containing spirocyclic aryl phosphorus oxides with a specific particle size range or a pharmaceutically acceptable salt thereof, which can increase the dissolution rate of the pharmaceutical composition and improve bioavailability.
  • pharmaceutically acceptable means, within the scope of sound medical judgment, suitable for use in contact with human and animal tissues without undue toxicity, irritation, allergic reaction or other problems or complications, and with a reasonable benefit/risk ratio Comparable to those compounds, materials, compositions and/or dosage forms.
  • pharmaceutically acceptable salt refers to derivatives prepared from the compounds of the present invention with relatively non-toxic acids or bases. These salts can be prepared during compound synthesis, isolation, purification, or alone by reacting the free form of the purified compound with an appropriate acid or base.
  • the compound contains relatively acidic functional groups, react with alkali metals, alkaline earth metal hydroxides or organic amines to obtain base addition salts, including cations based on alkali metals and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium, etc.
  • non-toxic ammonium, quaternary ammonium and amine cations specifically including but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, etc.
  • salts of amino acids such as arginine salts, gluconate salts, galacturonate salts, and the like.
  • an organic acid or an inorganic acid When the compound contains a relatively basic functional group, it reacts with an organic acid or an inorganic acid to obtain an acid addition salt, including an inorganic acid salt or an organic acid salt, and an inorganic acid salt such as hydrochloride, hydrobromide, nitrate, carbon salt, bicarbonate, phosphate, monohydrogen phosphate, dihydrogen phosphate, sulfate, hydrogen sulfate, hydroiodide, hydrobromide, metaphosphate, pyrophosphate;
  • the organic acid Salts include, for example, acetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, malonate salt, mandelate, benzoate, chlorobenzoate, methyl benzoate, dinitrobenzoate, naphthoate, benzenesulfonate, toluenesulfonate, phenyleth
  • pharmaceutically acceptable carrier refers to a medium generally acceptable in the art for delivering biologically active agents to animals, especially mammals, including, for example, adjuvants, excipients according to the mode of administration and the nature of the dosage form. Or excipients, such as fillers, disintegrants, binders, glidants, lubricants, diluents, preservatives, flow regulators, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring Agents, Fragrances, Antibacterials, Antifungals, Lubricants and Dispersants. Pharmaceutically acceptable carriers are formulated according to a number of factors that are within the purview of those of ordinary skill in the art.
  • compositions containing the agent include, but are not limited to: the type and nature of the active agent being formulated, the subject to whom the composition containing the agent is to be administered, the intended route of administration of the composition, and the intended therapeutic indication.
  • Pharmaceutically acceptable carriers include both aqueous and non-aqueous media and various solid and semisolid dosage forms. Such carriers include many different ingredients and additives in addition to the active agent, such additional ingredients being included in formulations for a variety of reasons (e.g., stabilizing the active agent, binders, etc.) are well known to those of ordinary skill in the art .
  • excipient generally refers to a carrier, diluent and/or medium required to formulate an effective pharmaceutical composition.
  • terapéuticaally effective amount refers to a sufficient amount of a pharmaceutical composition of the invention to treat a disorder at a reasonable effect/risk ratio applicable to any medical treatment. It should be recognized, however, that the total daily usage of the compositions of the present invention must be determined by the attending physician within the scope of sound medical judgment.
  • the particular therapeutically effective dosage level will depend on a number of factors, including the disorder being treated and the severity of the disorder; the activity of the particular compound employed; the particular composition employed; The age, weight, general health, sex and diet of the patient; the timing, route of administration, and rate of excretion of the specific compound employed; the duration of treatment; drugs used in combination or concomitantly with the specific compound employed; and Similar factors are well known in the medical arts.
  • Fig. 1 is the X-ray powder diffraction test figure of the sample 1-sample 8 in table 2 in the suspension liquid remaining solid spirocyclic aryl phosphorus oxide in the solubility test;
  • Fig. 2 is embodiment 1-embodiment 4, comparative example 1-comparative example 4 dissolution curve comparison in pH6.8 phosphate buffer;
  • Fig. 3 is embodiment 1-embodiment 4, comparative example 1-comparative example 4 in the dissolution curve comparison in purified water plus 0.5% Tween 20;
  • Fig. 4 is the X-ray powder diffraction pattern of crystal form A of spirocyclic aryl phosphorus oxide.
  • the crystal form of the spirocyclic aryl phosphorus oxide is the crystal form A
  • the raw material is known and can be purchased in the market, or can be synthesized by adopting or following methods known in the art.
  • solubility changes of spirocyclic aryl phosphorus oxides in different pH buffers are related to pH, and can be dissolved in 0.1mol/L hydrochloric acid solution, in pH3.5 buffer, pH4.5 buffer Soluble in medium, slightly soluble in 0.01mol/L hydrochloric acid solution, pH5.5 buffer and pH6.8 buffer, slightly soluble in pH6.5 buffer, very slightly soluble in pH7.5 buffer, almost soluble in water insoluble. It can be seen from Figure 1 that the crystal form of the spirocyclic aryl phosphorus oxide does not change in different solvents.
  • Example 1 Sample 3A 100.0 4.7
  • Example 2 Sample 4A 100.1 6.1
  • Example 3 Sample 5A 98.8 5.9
  • Example 4 Sample 6A 99.7 4.5 Comparative example 1 Sample 1A 98.9 5.2 Comparative example 2
  • Sample 2A 99.8 4.6 Comparative example 3
  • the content uniformity of the pharmaceutical composition meets the quality standard requirements when the particle size of the raw material medicine is not greater than 200 ⁇ m and not less than 10 ⁇ m.
  • dissolution properties of the pharmaceutical compositions of each example and comparative example were tested according to the dissolution method (Chinese Pharmacopoeia 2015 Edition Four Part 0512), specifically, the rotating speed was 50 revolutions per minute, kept at 37 ⁇ 0.5 ° C, and the pharmaceutical composition was investigated. Dissolution curve, dissolution data are shown in Table 5 and Table 6 below.
  • the dissolution results in Table 5 and Figure 2 show that in pH 6.8 phosphate buffer, when the D90 of the spirocyclic aryl phosphorus oxide is in the range of 40.3 ⁇ m to 79.6 ⁇ m, and the D50 is in the range of 13.0 ⁇ m to 23.8 ⁇ m, the dissolution results Basically the same, no significant difference; compared with other particle size dissolution data, the spirocyclic aryl phosphorus oxides with D90 in the range of 40.3 ⁇ m to 79.6 ⁇ m and D50 in the range of 13.0 ⁇ m to 23.8 ⁇ m were dissolved in the pharmaceutical composition
  • the dissolution results in Table 6 and Figure 3 show that in the medium of purified water + 0.5% Tween 20, the D90 of spirocyclic aryl phosphorus oxides is between 11.6 ⁇ m and 79.6 ⁇ m, and the D50 is in the range of 5.4 ⁇ m to 23.8 ⁇ m.
  • the dissolution is basically the same, the particle size D90 of the bulk drug exceeds 100 ⁇ m, and the D50 exceeds 40 ⁇ m, and the dissolution rate decreases.
  • Example 2 of the present invention Select the pharmaceutical composition prepared in Example 2 of the present invention, and investigate the generation of total impurities in the sample under the conditions of light, high temperature (60°C or 40°C), and high humidity (RH90% ⁇ 5% or RH75% ⁇ 5%) respectively.
  • the calculation of the total impurity (%) is obtained by calculating the ratio of the peak areas of the sample to be tested and the reference substance through liquid phase measurement.
  • Sample 1A (with desiccant), sample 3A (with desiccant), and sample 4A (with desiccant) all added desiccant during the stability placement process of the product, and the stability was basically the same, and the growth trend of related substances was basically the same; sample 1A ( No desiccant) No desiccant was added during the placement process, and the related substances were relatively large at 0 days, but the changes in the later period were not significant. Comparing the stability data of sample 1A with and without desiccant, the results show that the total impurity content is significantly lower after adding desiccant during storage.
  • the AUC 0- ⁇ basically increases linearly.
  • the AUC 0- ⁇ increases by less than 1.5 times, compared to 60mg
  • the in vivo bioavailability of the given dose is slightly higher.
  • the bioavailability of 60mg ⁇ 120mg dose is not much different, and there is no statistically significant difference.
  • the bioavailability of the 180mg dose group was lower than that of the 120mg dose group, indicating that the bioavailability in vivo did not increase with the increase of the administered dose.

Abstract

一种药用组合物及其制备方法和用途，药用组合物包含螺环芳基磷氧化物或其药学上可接受的盐作为活性成分和药学上可接受的载体。所述螺环芳基磷氧化物或其药学上可接受盐的D90在40.3μm至79.6μm范围内。所述药用组合物含量均匀度高且溶出速率快，体内生物利用度高，可用于治疗癌症。

Description

一种药用组合物及其制备方法和用途
本申请要求于2021年7月5日提交中国专利局、申请号为202110757316.5、发明名称为“螺环芳基磷氧化物的药用组合物及其制备方法”的中国专利申请，以及于2022年6月13日提交中国专利局、申请号为202210660192.3、发明名称为“一种药用组合物及其制备方法和用途”的中国专利申请的优先权，其全部内容通过引用结合在本申请中。
技术领域
本发明属于药物化学领域，涉及一种药用组合物及其制备方法和用途。
背景技术
螺环芳基磷氧化物，其结构如下式所示，化学名称为：(2-((5-氯-2-((2-甲氧基-4-(9-甲基-3,9-二氮杂螺[5.5]十一烷-3-基)苯基)氨基)嘧啶-4-基)氨基)苯基)二甲基氧膦，分子量569.08，是一种高选择性间变性淋巴瘤激酶(ALK)抑制剂。在分子水平上测定了其对主要激酶靶点ALK野生型、ALK突变型(ALK L1196M、ALK C1156Y)及EGFR突变型EGFR T790M/L858R酶活性的抑制作用。螺环芳基磷氧化物对4个主要激酶靶点的抑制活性与AP26113相当或略优；对其它相关的丝氨酸，苏氨酸和酪氨酸蛋白酶，除了EGFR野生型外，在检测浓度范围内抑制活性低，显示出具有高的激酶选择性。根据作用机制和临床前试验结果，螺环芳基磷氧化物可用于治疗经克唑替尼治疗后疾病进展或不能耐受克唑替尼的ALK阳性非小细胞肺癌患者，或未使用过ALK抑制剂的ALK阳性非小细胞肺癌患者。
Figure PCTCN2022103576-appb-000001
螺环芳基磷氧化物为白色或类白色粉末，几乎无引湿性；在二氯甲烷中易溶；在甲醇中略溶，在水、乙醇或乙腈中微溶；在1mol/L氢氧化钠溶液中几乎不溶或不溶。但在1mol/L盐酸溶液中易溶，为高溶解度化合物。而药物的溶解性直接影响含有该药物的组合物的溶 出速度，进而影响该药物组合物的生物利用度。因此，如何提高含有螺环芳基磷氧化物的药物组合物在除盐酸以外的溶剂中的溶出速度成为亟待解决的问题。
发明内容
本领域知晓一般药物的粒径大小对药物溶出行为没有显著性影响。但是本发明人研究发现，虽然螺环芳基磷氧化物的粒径大小对药物体外溶出具有显著性影响，但粒径过大或过小都会导致螺环芳基磷氧化物溶出降低，只有控制螺环芳基磷氧化物的粒径在一定范围内才能保证药物溶出符合要求。所以为了提高螺环芳基磷氧化物或其药学上可接受的盐的溶出速度，应适当控制其粒径范围，从而有效地控制含有螺环芳基磷氧化物的制剂中螺环芳基磷氧化物的溶出速度，进一步提高螺环芳基磷氧化物的在体内的生物利用度。
有鉴于此，本发明的目的在于提供一种药用组合物及其制备方法和用途，螺环芳基磷氧化物或其药学上可接受的盐具有特定范围的粒径能够提高药用组合物的溶出速率，进而提高生物利用度。
在本发明的第一方面提供一种粒径分布满足D90在40.3μm至79.6μm范围内的螺环芳基磷氧化物或其药学上可接受的盐，螺环芳基磷氧化物具有如下结构：
Figure PCTCN2022103576-appb-000002
在本发明的第二方面提供一种粒径分布满足D50在13.0μm至23.8μm范围内的螺环芳基磷氧化物或其药学上可接受的盐或者，提供一种粒径分布满足D50在13.0μm至18.2μm范围内的螺环芳基磷氧化物或其药学上可接受的盐。
本发明第三方面提供一种包含特定粒径的螺环芳基磷氧化物或其药学上可接受的盐及药学上可接受的载体的药用组合物，螺环芳基磷氧化物或其药学上可接受的盐作为活性成分，所述特定粒径满足D90在40.3μm至79.6μm范围内，螺环芳基磷氧化物具有如下结构：
Figure PCTCN2022103576-appb-000003
本发明的一些方案中，螺环芳基磷氧化物或其药学上可接受的盐的D50满足在13.0μm至23.8μm范围内。
在本发明的一些方案中，螺环芳基磷氧化物或其药学上可接受的盐D50在13.0μm至18.2μm范围内。在一些实施方案中，本发明的药用组合物中的螺环芳基磷氧化物的晶型为晶型A。
在优选的一些方案中，本发明的药用组合物中的螺环芳基磷氧化物的晶型A，使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在8.5±0.20°、10.1±0.20°、12.1±0.20°、14.6±0.20°、17.7±0.20°、18.7±0.20°、20.4±0.20°、21.2±0.20°处有特征峰。
在优选的一些方案中，本发明的药用组合物中的螺环芳基磷氧化物的晶型A，使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射在8.5±0.20°、9.3±0.20°、10.1±0.20°、12.1±0.20°、13.7±0.20°、14.6±0.20°、15.7±0.20°、16.5±0.20°、17.7±0.20°、18.7±0.20°、20.0±0.20°、20.4±0.20°、21.2±0.20°、23.6±0.20°、25.1±0.20°、25.6±0.20°有特征峰。
在更优选的一些方案中，本发明的药用组合物中的螺环芳基磷氧化物的晶型A，所述晶型A具有基本如图4所示的X-射线粉末衍射图谱。
在一些实施方案中，药学上可接受的载体包含填充剂、崩解剂、粘合剂、助流剂及润滑剂。
在优选的一些方案中，所述填充剂选自淀粉、甘露醇、山梨醇、微晶纤维素、乳糖、预胶化淀粉、无机盐中之一或组合，优选微晶纤维素和预胶化淀粉组合物。上述无机盐可以包括但不限于硫酸钙(含两个分子的结晶水)、磷酸氢钙、碳酸钙等。
在优选的一些方案中，所述崩解剂选自干淀粉、羧甲基淀粉钠、羟丙基淀粉、低取代羟丙基纤维素、交联聚维酮、交联羧甲基纤维素钠中之一或组合，优选羧甲淀粉钠。
在优选的一些方案中，所述粘合剂选自蒸馏水、乙醇、淀粉浆、糖粉和糖浆、羟丙甲 纤维素、聚维酮、羟丙基纤维素、甲基纤维素、乙基纤维素、羧甲基纤维素钠中之一或组合，优选羟丙甲纤维素。
在优选的一些方案中，所述助流剂选自微粉硅胶、滑石粉中之一或组合，优选微粉硅胶。
在优选的一些方案中，所述润滑剂选自硬脂酸镁、氢化植物油、聚乙二醇、十二烷基硫酸镁、硬脂富马酸钠中之一或组合，优选硬脂酸镁。
在一些实施方案中，本发明特定粒径的螺环芳基磷氧化物或其药学上可接受的盐的药用组合物为口服制剂，通过口服给药经胃肠道吸收。
在优选的一些方案中，本发明的药用组合物是片剂形式的。
在优选的一些方案中，本发明的药用组合物是薄膜包衣的片剂。
在一些实施方案中，本发明的药用组合物，所述螺环芳基磷氧化物或其可药用盐在组合物中占比为1.0％～50.0％重量比。
在一些优选的方案中，本发明的药用组合物，各组分按重量百分比为：螺环芳基磷氧化物或其药学上可接受的盐占比1％～50％，填充剂1％～90％，崩解剂1％～10％，助流剂0.1％～1％，润滑剂0.5％-5％。
在更优选的一些方案中，本发明的药用组合物，各组分按重量百分比为：螺环芳基磷氧化物或其药学上可接受的盐5.0％，微晶纤维素26.0％，预胶化淀粉59.5％，羧甲淀粉钠5％，羟丙甲基纤维素3.0％，微粉硅胶0.5％，硬脂酸镁1％。
本发明的第四方面提供一种上述任一方案中的药用组合物的制备方法，其包括如下步骤：
1)将螺环芳基磷氧化物或其药学上可接受的盐和部分内加辅料充分混合后，再制粒，所述部分内加辅料包括填充剂、粘合剂和崩解剂；
2)外加其他辅料后，充分混合，所述其他辅料包括填充剂、崩解剂和润滑剂；
3)压片包衣。
在本发明的一些方案中，提供一种药用组合物，其含有有效量的螺环芳基磷氧化物或其药学上可接受的盐和药学上可接受的载体、稀释剂和赋形剂。药用组合物能配制用于特定给药途径，如口服给药、胃肠外给药和直肠给药等。口服给药可以包括但不限于口服、舌下给药、含服，口服给药可以通过但不限于片剂(薄膜包衣的片剂)、胶囊剂(包括持续释放或定时释放处方)、丸剂、散剂、颗粒剂、酏剂、酊剂、混悬液(包括纳米混悬液、微 米混悬液、喷雾干燥分散剂)、糖浆剂或乳剂；胃肠外给药可以包括但不限于注射、输注，以及经鼻或其它局部给药，具体地，可以通过但不限于皮下、静脉内、肌内或胸骨内的注射；输注技术，例如作为无菌可注射水溶液或非水溶液或混悬液；经鼻，包括对鼻粘膜给药，例如通过吸入喷雾；局部，例如以乳膏或软膏的形式给药。直肠给药，例如以栓剂的形式。上述给药方式可单独给药，但通常会与根据所选择的给药途径和标准药学操作选择的药学载体一起给药。
本发明的第五方面提供一种上述任一方案中的药用组合物或上述任一方案中的方法制备的药用组合物用于治疗癌症的用途。上述癌症包括非小细胞肺癌、淋巴瘤、非霍奇金淋巴瘤、卵巢癌、宫颈癌、前列腺癌、结肠直肠癌、乳腺癌、胰腺癌、胶质瘤、胶质母细胞瘤，黑色素瘤、白血病、胃癌、子宫内膜癌、肺癌、肝细胞癌、胃癌、胃肠道间质瘤(GIST)、急性髓细胞白血病(AML)、胆管癌、肾癌、甲状腺癌、间变性大细胞淋巴瘤、间皮瘤、多发性骨髓瘤、黑色素瘤。
在一些方案中，上述癌症为非小细胞肺癌。
在一些方案中，上述用途为用于未经克唑替尼治疗后疾病进展或不能耐受克唑替尼的ALK阳性非小细胞肺癌患者。
在一些方案中，上述用途为用于未使用过ALK抑制剂的ALK阳性非小细胞肺癌患者。
本发明的第六方面提供一种治疗癌症的方法，其包括向患者施用治疗有效量的前述任一方案中的药用组合物。上述癌症包括非小细胞肺癌、淋巴瘤、非霍奇金淋巴瘤、卵巢癌、宫颈癌、前列腺癌、结肠直肠癌、乳腺癌、胰腺癌、胶质瘤、胶质母细胞瘤，黑色素瘤、白血病、胃癌、子宫内膜癌、肺癌、肝细胞癌、胃癌、胃肠道间质瘤、急性髓细胞白血病、胆管癌、肾癌、甲状腺癌、间变性大细胞淋巴瘤、间皮瘤、多发性骨髓瘤、黑色素瘤。
在一些方案中，上述癌症为非小细胞肺癌。
在一些方案中，上述方法用于未经克唑替尼治疗后疾病进展或不能耐受克唑替尼的ALK阳性非小细胞肺癌患者。
在一些方案中，上述方法用于未使用过ALK抑制剂的ALK阳性非小细胞肺癌患者。
在本发明中，D50是指从小粒径测起，螺环芳基磷氧化物或其药学上可接受的盐累计体积分布百分数达到50％时所对应的粒径；D90是指从小粒径测起，螺环芳基磷氧化物或其药学上可接受的盐累计体积分布百分数达到90％时所对应的粒径。
有益技术效果：
本发明提供包含具有特定粒径范围的螺环芳基磷氧化物或其药学上可接受的盐的药用组合物，能够提高药用组合物的溶出速率，提高生物利用度。
除非另有说明，本文所用的下列术语和短语旨在具有下列含义。一个特定的术语或短语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照普通的含义去理解。
术语“药学上可接受的”指在合理的医学判断范围内适合与人类和动物的组织接触使用而无过度的毒性、刺激、过敏反应或其它的问题或并发症，与合理的收益/风险比相当的那些化合物、材料、组合物和/或剂型。
术语“药学上可接受的盐”是指本发明化合物与相对无毒的酸或碱制备得到的衍生物。这些盐可以在化合物合成、分离、纯化期间就被制备，或者单独使用经过纯化的化合物的游离形式与适合的酸或碱反应。当化合物中含有相对酸性的官能团时，与碱金属、碱土金属氢氧化物或有机胺反应得到碱加成盐，包括基于碱金属与碱土金属的阳离子，例如钠、锂、钾、钙、镁等，以及无毒的铵、季铵和胺阳离子，具体包括但不限于铵、四甲基铵、四乙基铵、甲胺、二甲胺、三甲胺、三乙胺、乙胺等。还涵盖氨基酸的盐，例如精氨酸盐、葡糖酸盐、半乳糖醛酸盐等。当化合物中含有相对碱性的官能团时，与有机酸或无机酸反应得到酸加成盐，包括无机酸盐或有机酸盐，无机酸盐例如盐酸盐、氢溴酸盐、硝酸盐、碳酸盐、碳酸氢根盐、磷酸盐、磷酸一氢盐、磷酸二氢盐、硫酸盐、硫酸氢盐、氢碘酸盐、氢溴酸盐、偏磷酸盐、焦磷酸盐；所述有机酸盐包括如乙酸盐、丙酸盐、辛酸盐、异丁酸盐、草酸盐、丙二酸盐、琥珀酸盐、辛二酸盐、癸二酸盐、富马酸盐、马来酸盐、扁桃酸盐、苯甲酸盐、氯苯甲酸盐、甲基苯甲酸盐、二硝基苯甲酸盐、萘甲酸盐、苯磺酸盐、甲苯磺酸盐、苯乙酸盐、柠檬酸盐、乳酸盐、马来酸盐、酒石酸盐、甲磺酸盐等。
术语“药学上可接受的载体”是指本领域通常可接受的用于将生物活性药剂递送给动物、特别是哺乳动物的介质，根据给药方式和剂型的性质包括例如佐剂、赋形剂或赋形物，例如填充剂、崩解剂、粘合剂、助流剂、润滑剂、稀释剂、防腐剂、流动调节剂、润湿剂、乳化剂、助悬剂、甜味剂、调味剂、芳香剂、抗菌剂、抗真菌剂、润滑剂和分散剂。药学上可接受的载体在本领域普通技术人员的眼界范围内根据大量因素配制。其包括但不限于：配制的活性药剂的类型和性质，要将含有该药剂的组合物给药的对象，组合物的预期给药途径，和目标治疗适应症。药学上可接受的载体包括含水介质和非水介质这两者以及多种固体和半固体剂型。除了活性药剂以外，这样的载体包括许多不同的成分和添加剂，因多 种原因(例如稳定活性药剂、粘合剂等)在处方中包括的这样的另外的成分对于本领域普通技术人员是众所周知的。术语“赋形剂”通常是指配制有效的药用组合物所需要载体、稀释剂和/或介质。
术语“治疗有效量”是指本发明药用组合物以适用于任何医学治疗的合理效果/风险比治疗障碍的足够量的药用组合物。但应认识到，本发明组合物的总日用量须由主诊医师在可靠的医学判断范围内作出决定。对于任何具体的患者，具体的治疗有效剂量水平须根据多种因素而定，所述因素包括所治疗的障碍和该障碍的严重程度；所采用的具体化合物的活性；所采用的具体组合物；患者的年龄、体重、一般健康状况、性别和饮食；所采用的具体化合物的给药时间、给药途径和排泄率；治疗持续时间；与所采用的具体化合物组合使用或同时使用的药物；及医疗领域公知的类似因素。
附图说明
为了更清楚地说明本发明实施例和现有技术的技术方案，下面对实施例和现有技术中所需要使用的附图作简单地介绍，显而易见地，下面描述中的附图仅仅是本发明的一些实施例，对于本领域普通技术人员来讲，在不付出创造性劳动的前提下，还可以根据这些附图获得其他的附图。
图1为表2中的样品1-样品8在溶解度测试中在混悬液中剩余固体螺环芳基磷氧化物的X射线粉末衍射测试图；
图2为实施例1-实施例4、对比例1-对比例4在pH6.8磷酸盐缓冲液中溶出曲线对比；
图3为实施例1-实施例4、对比例1-对比例4在纯化水加0.5％吐温20中溶出曲线对比；
图4为螺环芳基磷氧化物晶型A的X-射线粉末衍射图谱。
具体实施方式
为使本发明的目的、技术方案、及优点更加清楚明白，以下参照附图并举实施例，对本发明进一步详细说明。显然，所描述的实施例仅仅是本发明一部分实施例，而不是全部的实施例。基于本发明中的实施例，本领域普通技术人员在没有作出创造性劳动前提下所获得的所有其他实施例，都属于本发明保护的范围。
在本发明实施例中，螺环芳基磷氧化物的晶型为晶型A，该原料是已知的并且可以在市场上买到，或者可以采用或按照本领域已知的方法来合成。
螺环芳基磷氧化物溶解度测定
测定螺环芳基磷氧化物在不同pH值缓冲液中的溶解度。分别称取4mg供试品9份加入到1.5mL的样品瓶中，然后分别加入1mL不同的溶媒(0.1mol/L HCl，0.01mol/L HCl，pH3.5醋酸盐缓冲液，pH4.5醋酸盐缓冲液，pH5.5磷酸盐缓冲液，pH6.5磷酸盐缓冲液，pH6.8磷酸盐缓冲液，pH7.5磷酸盐缓冲液，水)，根据溶解情况，不断加入原料化合物，使之形成饱和溶液。将磁子加入到上述饱和溶液中，然后置于磁力搅拌器上(温度为37℃，避光)进行搅拌。搅拌24小时后取样离心，下层残留固体样品进行X射线粉末衍射(XRPD)测试。上层样品用滤膜过滤，测定滤液的最终pH值，并用高效液相色谱(HPLC)测定该化合物的饱和溶解度。测定结果见表1，XRPD测试结果见图1。
表1 螺环芳基磷氧化物在不同pH值缓冲液中溶解度测定结果
Figure PCTCN2022103576-appb-000004
注：表1中的易溶、溶解、略溶、微溶、极微溶分别是指1g的螺环芳基磷氧化物分别能在1ml～不到10ml、10ml～不到30ml、30ml～不到100ml、100ml～不到1000ml、1000ml～不到10000ml的溶剂中溶解，几乎不溶是指1g的螺环芳基磷氧化物在10000ml溶剂中不能完全溶解。
从表1可以看出，螺环芳基磷氧化物在不同pH值缓冲液中的溶解度变化与pH相关，能溶解于0.1mol/L盐酸溶液，在pH3.5缓冲液、pH4.5缓冲液中易溶，在0.01mol/L盐酸溶液、pH5.5缓冲液和pH6.8缓冲液中微溶，在pH6.5缓冲液中略溶，在pH7.5缓冲液中 极微溶解，在水中几乎不溶。从图1可以看出，螺环芳基磷氧化物在不同溶媒中，其晶型未发生变化。
含不同粒径螺环芳基磷氧化物的药用组合物的制备及工艺
测试含有不同粒径的螺环芳基磷氧化物的药用组合物的含量均匀度及体外溶出速率。
表2：不同粒径螺环芳基磷氧化物样品
粒径 样品1 样品2 样品3 样品4 样品5 样品6 样品7 样品8
D90(μm) 11.6 27.1 40.3 62 69 79.6 122 193
D50(μm) 5.4 10.1 13.0 23.8 16.1 18.2 47.9 63.1
D10(μm) 0.7 1.3 1.6 5.0 1.8 2.3 6.8 7.8
表3 螺环芳基磷氧化物固体组合物
Figure PCTCN2022103576-appb-000005
实施例1-实施例4
制备工艺：
将表2中的样品3至样品6不同粒径的螺环芳基磷氧化物分别按照表3中的处方和以下制备步骤得到不同的药用组合物样品3A、样品4A、样品5A、样品6A：
将不同粒径的螺环芳基磷氧化物与微晶纤维素、预胶化淀粉、羟丙甲纤维素、一半处方量的羧甲淀粉钠加入到高剪切搅拌机(High shear mixer)中，混合时间5min；加入纯化水制粒，搅拌8min。
采用整粒机进行湿整粒；流化床进行烘干；采用整粒机进行过筛。
将剩余羧甲淀粉钠和二氧化硅过筛加入到颗粒中，混合；外加硬脂酸镁过筛，混合，压片。
对比例1-对比例4
除了将螺环芳基磷氧化物依次替换成表2所示的样品1、样品2、样品7和样品8以外，其余与实施例1相同。
各实施例和对比例的药用组合物含量均匀度及溶出速率测试
1)含量均匀度检测
各实施例和对比例的药用组合物的含量均匀度检测参考中国药典2015版“附录XE含量均匀度检查法”，结果见表4。
表4 含量均匀度
    平均含量(％) 含量均匀度(A+2.20S≤15.0)
实施例1 样品3A 100.0 4.7
实施例2 样品4A 100.1 6.1
实施例3 样品5A 98.8 5.9
实施例4 样品6A 99.7 4.5
对比例1 样品1A 98.9 5.2
对比例2 样品2A 99.8 4.6
对比例3 样品7A 99.4 5.4
对比例4 样品8A 99.0 4.3
根据含量均匀度结果可知，当原料药粒径在不大于200μm且不小于10μm范围内药用组合物的含量均匀度均满足质量标准要求。
2)溶出度检测
各实施例和对比例的药用组合物的溶出性能按照溶出度测定法(中国药典2015年版四部0512)测试，具体地，转速为每分钟50转，保持37±0.5℃，考察药用组合物的溶出曲线，溶出数据见下表5和表6。
表5 螺环芳基磷氧化物固体组合物在pH6.8磷酸盐缓冲液中溶出数据
Figure PCTCN2022103576-appb-000006
Figure PCTCN2022103576-appb-000007
表6 螺环芳基磷氧化物固体组合物在纯化水+0.5％吐温20溶出数据
Figure PCTCN2022103576-appb-000008
表5以及图2的溶出结果表明在pH6.8磷酸盐缓冲液中，当螺环芳基磷氧化物的D90在40.3μm至79.6μm范围内、D50在13.0μm至23.8μm范围内，溶出结果基本一致，无明显差异；与其他粒径溶出数据相比，D90在40.3μm至79.6μm范围内、D50在13.0μm至23.8μm范围内的螺环芳基磷氧化物在药用组合物中溶出最快，当螺环芳基磷氧化物原料药粒径D90小于40.3μm或D50小于13.0μm，溶出逐渐变慢；D90大于79.6μm或D50大于23.8μm时，溶出也变慢。
表6以及图3的溶出结果表明在纯化水+0.5％吐温20的介质中，螺环芳基磷氧化物的D90在11.6μm到79.6μm之间、D50在5.4μm至23.8μm范围内，溶出基本一致，原料药粒径D90超过100μm、D50超过40μm，溶出速率下降。参考表5和表6，当螺环芳基磷氧化物的D90在40.3μm至79.6μm范围内D50在13.0μm至23.8μm范围内，其在pH6.8磷酸盐缓冲液和纯化水+0.5％吐温20的介质中均具有良好的溶出性能。
药用组合物的稳定性考察
1)影响因素实验
选取本发明实施例2制备的药用组合物，分别考察样品在光照、高温(60℃或40℃)、高湿(RH90％±5％或RH75％±5％)条件下的总杂质的生成情况。总杂质(％)的计算，是将待测样品和对照品通过液相测定，求两者峰面积比值所得。
表7 螺环芳基磷氧化物片影响因素数据
Figure PCTCN2022103576-appb-000009
由表中结果可知，实施例2中的药用组合物在光照及高温条件下有关物质略有增长，但含量较低。虽然高湿条件下水分增长很多，但是有关物质基本无变化。从而说明本申请提供的药用组合物在高温、高湿条件下具有良好的稳定性。
2)加速稳定性实验
选取对比例1、本发明实施例1和实施例2制备的药用组合物样品1A、样品3A、样品4A，分别考察样品在40℃RH75％条件下的有关物质(单杂和总杂)的生成情况。
表8 加速稳定性数据
Figure PCTCN2022103576-appb-000010
注：表8中的“/”表示不存在对应的参数。
样品1A(有干燥剂)、样品3A(有干燥剂)、样品4A(有干燥剂)自制品稳定性放置过程中均加入干燥剂，稳定性基本一致，有关物质增长趋势基本一致；样品1A(无干燥剂)放置过程中未加入干燥剂，有关物质0天较大，但是后期变化也不大。对比样品1A加入干燥剂和不加干燥剂的稳定性数据，结果表明放置过程中加入干燥剂后总杂质含量明显更低。
临床试验
1)处方：
Figure PCTCN2022103576-appb-000011
2)药用组合物样品9A和10A的制备工艺见实施例1。
3)取样品9A和样品10A，按照以下剂量进行临床试验，数据见下表9。
表9 螺环芳基磷氧化物片临床试验数据
Figure PCTCN2022103576-appb-000012
Figure PCTCN2022103576-appb-000013
从临床数据分析可得，给药剂量从60mg增加至120mg时，AUC 0-∞基本是按线性增长，剂量从60mg增加1.5倍至90mg时，AUC 0-∞增加小于1.5倍，相对来说60mg给药剂量体内生物利用对略高。但是60mg～120mg剂量的生物利用度相差不大，统计学上无显著性差异。而180mg剂量组生物利用度低于120mg剂量组，表明体内生物利用度并不是随给药剂量增加而提高。
本发明的方法已经通过较佳实施例进行了描述，相关人员明显能在本发明内容、精神和范围内对本文所述的方法和应用进行改动或适当变更与组合，来实现和应用本发明。需要特别指出的是，虽然举例说明和描述了具体实施方案，但所有类似替换和改动对本领域技术人员来说是显而易见的，它们都被视为包括在本发明内。

Claims (25)

  1. 一种药用组合物，其包含螺环芳基磷氧化物或其药学上可接受的盐作为活性成分和药学上可接受的载体，所述螺环芳基磷氧化物具有如下结构：
    Figure PCTCN2022103576-appb-100001
    并且所述螺环芳基磷氧化物或其药学上可接受的盐的D90在40.3μm至79.6μm范围内。
  2. 根据权利要求1所述的药用组合物，其中，所述螺环芳基磷氧化物或其药学上可接受的盐的D50在13.0μm至23.8μm范围内。
  3. 根据权利要求1所述的药用组合物，其中，所述螺环芳基磷氧化物或其药学上可接受的盐的D50在13.0μm至18.2μm范围内。
  4. 根据权利要求1-3中任一项所述的药用组合物，其中，所述螺环芳基磷氧化物的晶型为晶型A。
  5. 根据权利要求1-3中任一项所述的药用组合物，其特征在于，所述药学上可接受的载体包括填充剂、崩解剂、粘合剂、助流剂及润滑剂。
  6. 根据权利要求5所述的药用组合物，其特征在于，所述填充剂选自淀粉、甘露醇、山梨醇、微晶纤维素、乳糖、预胶化淀粉、无机盐之一或它们的组合。
  7. 根据权利要求6所述的药用组合物，其特征在于，所述填充剂包括微晶纤维素和预胶化淀粉的组合物。
  8. 根据权利要求5所述的药用组合物，其特征在于，所述崩解剂选自干淀粉、羧甲基淀粉钠、羟丙基淀粉、低取代羟丙基纤维素、交联聚维酮、交联羧甲基纤维素钠之一或它们的组合。
  9. 根据权利要求8所述的药用组合物，其特征在于，所述崩解剂包括羧甲基淀粉钠。
  10. 根据权利要求5所述的药用组合物，其特征在于，所述粘合剂选自蒸馏水、乙醇、淀粉浆、糖粉和糖浆、羟丙甲纤维素、聚维酮、羟丙基纤维素、甲基纤维素、乙基纤维素、 羧甲基纤维素钠之一或它们的组合。
  11. 根据权利要求10所述的药用组合物，其特征在于，所述粘合剂包括羟丙甲纤维素。
  12. 根据权利要求5所述的药用组合物，其特征在于，所述助流剂选自微粉硅胶、滑石粉之一或它们的组合。
  13. 根据权利要求12所述的药用组合物，其特征在于，所述助流剂包括微粉硅胶。
  14. 根据权利要求5所述的药用组合物，其特征在于，所述润滑剂选自硬脂酸镁、氢化植物油、聚乙二醇、十二烷基硫酸镁、硬脂富马酸钠之一或组合。
  15. 根据权利要求14所述的药用组合物，其特征在于，所述润滑剂包括硬脂酸镁。
  16. 根据权利要求1-3中任一项所述的药用组合物，其特征在于，所述药用组合物是片剂形式的。
  17. 根据权利要求16所述的药用组合物，其特征在于，所述药用组合物是薄膜包衣的片剂。
  18. 根据权利要求1-3中任一项所述的药用组合物，其特征在于，各组分按重量百分比为：螺环芳基磷氧化物或其药学上可接受的盐1％～50％、填充剂1％～90％、崩解剂1％～10％、助流剂0.1～1％、润滑剂0.5％-5％。
  19. 根据权利要求18所述的药用组合物，其特征在于，各组分按重量百分比为：螺环芳基磷氧化物或其药学上可接受的盐5.0％，微晶纤维素26.0％，预胶化淀粉59.5％，羧甲淀粉钠5％，羟丙甲基纤维素3.0％，微粉硅胶0.5％，硬脂酸镁1％。
  20. 一种制备权利要求1所述的药用组合物的方法，其包括以下步骤：
    1)将螺环芳基磷氧化物或其药学上可接受的盐和部分内加辅料充分混合后，再制粒，所述部分内加辅料包括填充剂、粘合剂和崩解剂；
    2)外加其他辅料后，充分混合，所述其他辅料包括填充剂、崩解剂和润滑剂；
    3)压片包衣。
  21. 根据权利要求1-19中任一项所述的药用组合物或根据权利要求20所述的方法制备的药用组合物用于治疗癌症的用途。
  22. 根据权利要求21所述的用途，其中，所述癌症包括非小细胞肺癌、淋巴瘤、非霍奇金淋巴瘤、卵巢癌、宫颈癌、前列腺癌、结肠直肠癌、乳腺癌、胰腺癌、胶质瘤、胶质母细胞瘤，黑色素瘤、白血病、胃癌、子宫内膜癌、肺癌、肝细胞癌、胃癌、胃肠道间质瘤、急性髓细胞白血病、胆管癌、肾癌、甲状腺癌、间变性大细胞淋巴瘤、间皮瘤、多发 性骨髓瘤、黑色素瘤。
  23. 根据权利要求22所述的用途，其中，所述癌症为非小细胞肺癌。
  24. 一种治疗癌症的方法，其包括向患者施用治疗有效量的权利要求1-19中任一项所述的药用组合物，所述癌症包括非小细胞肺癌、淋巴瘤、非霍奇金淋巴瘤、卵巢癌、宫颈癌、前列腺癌、结肠直肠癌、乳腺癌、胰腺癌、胶质瘤、胶质母细胞瘤，黑色素瘤、白血病、胃癌、子宫内膜癌、肺癌、肝细胞癌、胃癌、胃肠道间质瘤、急性髓细胞白血病、胆管癌、肾癌、甲状腺癌、间变性大细胞淋巴瘤、间皮瘤、多发性骨髓瘤、黑色素瘤。
  25. 根据权利要求24所述的方法，所述癌症为非小细胞肺癌。
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