Pharmaceutical compositions, their preparation and use

Abstract

The present invention relates to a pharmaceutical composition, its preparation method and use, the pharmaceutical composition comprising a spirocyclic aryl phosphate or a pharma- ceutically acceptable salt thereof as an active ingredient and a pharma- ceutically acceptable carrier. The D90 of the spirocyclic aryl phosphate or a pharma- ceutically acceptable salt thereof is in the range of 40.3 μm to 79.6 μm. The pharmaceutical composition has high content uniformity, fast dissolution rate, high bioavailability in vivo, and is used for the treatment of cancer.

Description

[Technical field]

[0001] This application claims priority to a Chinese patent application filed on July 5, 2021 with the State Intellectual Property Office of China, bearing application number 202110757316.5 and titled "Pharmaceutical composition of spirocyclic aryl phosphate and preparation method thereof," and a Chinese patent application filed on June 13, 2022 with the State Intellectual Property Office of China, bearing application number 202210660192.3 and titled "Pharmaceutical composition, preparation method and use thereof," each of which is incorporated herein by reference in its entirety.

[0002] <Technical field> The present invention is in the field of medicinal chemistry and relates to pharmaceutical compositions, their preparation and uses. [Background technology]

[0003] Spirocyclic aryl phosphate has the structure shown in the formula below, the 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, and the molecular weight is 569.08. Spirocyclic aryl phosphate is a highly selective inhibitor of anaplastic lymphoma kinase (ALK). At the molecular level, it inhibits the main kinase targets ALK wild type, ALK mutant (ALK L1196M , ALK C1156Y ) and EGFR mutant EGFR T790M / L858RIts inhibitory effect on enzyme activity was measured. Spirocyclic aryl phosphate has similar or slightly better inhibitory activity against four major kinase targets than AP26113. For other related serine, threonine and tyrosine proteases except EGFR wild type, spirocyclic aryl phosphate has lower inhibitory activity in the detectable concentration range, indicating high kinase selectivity. According to the mechanism of action and preclinical results, spirocyclic aryl phosphate can be applied to treat ALK-positive non-small cell lung cancer patients whose disease progresses after crizotinib treatment or who cannot tolerate crizotinib, or patients with ALK-positive non-small cell lung cancer who have not been treated with ALK inhibitors. [ka]

[0004] Spirocyclic aryl phosphate is a white or off-white powder, almost non-hygroscopic, easily soluble in dichloromethane, slightly soluble in ethanol, slightly soluble in water, ethanol or acetonitrile, and almost insoluble or insoluble in 1 mol / L sodium hydroxide solution. However, spirocyclic aryl phosphate is easily soluble in 1 mol / L hydrochloric acid solution, and is a highly soluble compound. Meanwhile, the solubility of a drug directly affects the dissolution rate of a composition containing the drug, and further affects the bioavailability of the pharmaceutical composition. Therefore, how to increase the dissolution rate of a pharmaceutical composition containing spirocyclic aryl phosphate in a solvent other than hydrochloric acid has become an urgent issue. Summary of the Invention [Means for solving the problem]

[0005] It is known in the art that the particle size of a general drug does not significantly affect the dissolution behavior of the drug. However, the present inventor has found that although the particle size of spirocyclic aryl phosphate has a significant effect on the dissolution of the drug in vitro, the dissolution of spirocyclic aryl phosphate is reduced when the particle size is too large or too small. By controlling the particle size of spirocyclic aryl phosphate within a certain range, it is possible to ensure that the dissolution of the drug meets the requirements. Therefore, in order to increase the dissolution rate of spirocyclic aryl phosphate or its pharma- ceutical acceptable salt, it is necessary to appropriately control the particle size range, so that the dissolution rate of spirocyclic aryl phosphate in the preparation containing spirocyclic aryl phosphate can be effectively controlled, and the bioavailability of spirocyclic aryl phosphate in vivo can be further improved.

[0006] In view of this, the present invention aims to provide a pharmaceutical composition, its preparation method and use. The present invention can increase the dissolution rate of the pharmaceutical composition and further increase the bioavailability by controlling the particle size of the spirocyclic aryl phosphate or its pharma- ceutical acceptable salt within a specific range.

[0007] A first aspect of the present invention provides a spirocyclic aryl phosphate or a pharma- ceutical acceptable salt thereof having a particle size distribution satisfying that D90 is within the range of 40.3 μm to 79.6 μm, and the spirocyclic aryl phosphate has the following structure: [ka]

[0008] A second aspect of the present invention provides a spirocyclic aryl phosphate or a pharma- ceutically acceptable salt thereof having a particle size distribution in which D50 is within the range of 13.0 μm to 23.8 μm, or a spirocyclic aryl phosphate or a pharma- ceutically acceptable salt thereof having a particle size distribution in which D50 is within the range of 13.0 μm to 18.2 μm.

[0009] A third aspect of the present invention provides a pharmaceutical composition comprising a spirocyclic aryl phosphate or a pharma- ceutically acceptable salt thereof having a specific particle size and a pharma- ceutically acceptable carrier, wherein the spirocyclic aryl phosphate or a pharma- ceutically acceptable salt thereof is used as an active ingredient, and the specific particle size satisfies that D90 is in the range of 40.3 μm to 79.6 μm, and the spirocyclic aryl phosphate has the following structure: [ka]

[0010] In some embodiments of the present invention, the D50 of the spirocyclic aryl phosphate or a pharma- ceutically acceptable salt thereof is in the range of 13.0 μm to 23.8 μm.

[0011] In some embodiments of the present invention, the D50 of the spirocyclic aryl phosphate or its pharma- ceutically acceptable salt is in the range of 13.0 μm to 18.2 μm. In some embodiments, the crystalline form of the spirocyclic aryl phosphate in the pharmaceutical composition of the present invention is crystalline form A.

[0012] In some preferred embodiments, the crystalline form A of the spirocyclic aryl phosphate in the pharmaceutical composition of the present invention has characteristic peaks at 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°, and 21.2±0.20° in X-ray powder diffraction measured at 2θ angles using Cu-Kα radiation.

[0013] In some preferred embodiments, the crystalline form A of the spirocyclic aryl phosphate in the pharmaceutical composition of the present invention has characteristic peaks 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°, 20.4±0.20°, 21.2±0.20°, 23.6±0.20°, 25.1±0.20°, and 25.6±0.20° in X-ray powder diffraction measured at 2θ angles using Cu-Kα radiation.

[0014] In some more preferred embodiments, the crystalline form A of the spirocyclic aryl phosphate in the pharmaceutical composition of the present invention has an X-ray powder diffraction pattern substantially as shown in FIG.

[0015] In some embodiments, the pharma- ceutically acceptable carrier comprises a filler, a disintegrant, a binder, a glidant, and a lubricant.

[0016] In some preferred embodiments, the filler is one or more selected from the group consisting of starch, mannitol, sorbitol, microcrystalline cellulose, lactose, pregelatinized starch, and inorganic salts, with microcrystalline cellulose and pregelatinized starch compositions being preferred. The inorganic salts may include, but are not limited to, calcium sulfate (containing two molecules of water of crystallization), calcium hydrogen phosphate, calcium carbonate, and the like.

[0017] In some preferred embodiments, the disintegrant is one or more selected from the group consisting of dry starch, sodium carboxymethyl starch, hydroxypropyl starch, low-substituted hydroxypropyl cellulose, crospovidone, and croscarmellose sodium, with sodium carboxymethyl starch being preferred.

[0018] In some preferred embodiments, the binder is one or more selected from the group consisting of distilled water, ethanol, starch slurry, powdered sugar and syrup, hydroxypropyl methylcellulose, povidone, hydroxypropyl cellulose, methylcellulose, ethylcellulose, and sodium carboxymethylcellulose, with hydroxypropyl methylcellulose being preferred.

[0019] In some preferred embodiments, the flow agent is one or more selected from the group consisting of micropowdered silica gel and talcum powder, with micropowdered silica gel being preferred.

[0020] In some preferred embodiments, the lubricant is one or more selected from the group consisting of magnesium stearate, hydrogenated vegetable oil, polyethylene glycol, magnesium lauryl sulfate, and sodium stearyl fumarate, with magnesium stearate being preferred.

[0021] In some embodiments, the pharmaceutical composition of the spirocyclic aryl phosphorus oxide or a pharma- ceutically acceptable salt thereof of the present invention having a particular particle size is an oral administration formulation, and is absorbed from the gastrointestinal tract upon oral administration.

[0022] In some preferred embodiments, the pharmaceutical compositions of the present invention are in the form of a tablet.

[0023] In some preferred embodiments, the pharmaceutical compositions of the present invention are film-coated tablets.

[0024] In some embodiments, the pharmaceutical composition of the present invention contains the spirocyclic aryl phosphate or a pharma- ceutically acceptable salt thereof in an amount of 1.0% to 50.0% by weight of the composition.

[0025] In some preferred embodiments, the pharmaceutical composition of the present invention comprises, by weight percentage, 1%-50% spirocyclic aryl phosphate or a pharma- ceutically acceptable salt thereof, 1%-90% filler, 1%-10% disintegrant, 0.1%-1% flow agent, and 0.5%-5% lubricant.

[0026] In some more preferred embodiments, the pharmaceutical compositions of the present invention contain, by weight, 5.0% spirocyclic aryl phosphate or a pharma- ceutically acceptable salt thereof, 26.0% microcrystalline cellulose, 59.5% pregelatinized starch, 5% sodium carboxymethyl starch, 3.0% hydroxypropyl methylcellulose, 0.5% finely powdered silica gel, and 1% magnesium stearate.

[0027] A fourth aspect of the present invention is 1) thoroughly mixing the spirocyclic aryl phosphate or a pharma- ceutically acceptable salt thereof with internal excipients, including a filler, a binder and a disintegrant as part of the excipients, followed by granulation; 2) adding final additives including fillers, disintegrants and lubricants as other parts of the additives, and then mixing thoroughly; 3) compressing and coating the tablet. A method for producing the pharmaceutical composition in any of the above forms is provided.

[0028] In some aspects of the present invention, a pharmaceutical composition is provided that contains an effective amount of a spirocyclic aryl phosphorus oxide or a pharma- ceutically acceptable salt thereof, a pharma- ceutically acceptable carrier, a diluent, and an excipient. The pharmaceutical composition can be formulated for a particular route of administration, such as oral, parenteral, and rectal. Oral administration includes, but is not limited to, oral, sublingual, and buccal administration. Oral administration may be via, but is not limited to, tablets (film-coated tablets), capsules (including sustained 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, injections, infusions, and nasal or other topical administration. Specifically, parenteral administration may be performed via, but is not limited to, subcutaneous, intravenous, intramuscular or intrasternal injection; infusion techniques, such as sterile injectable aqueous or non-aqueous solutions or suspensions; intranasal administration, such as administration to the nasal mucosa by inhalation spray; topical administration, such as administration in the form of a cream or ointment. Rectal administration, for example, is in the form of a suppository. The above administration modes can be administered alone, but are usually administered with a pharmaceutical carrier selected based on the selected route of administration and standard pharmaceutical practice.

[0029] A fifth aspect of the invention provides the use of a pharmaceutical composition according to any of the above aspects or prepared by the method according to any of the above aspects for treating cancer, including 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), cholangiocarcinoma, renal cancer, thyroid cancer, anaplastic large cell lymphoma, mesothelioma, multiple myeloma, melanoma.

[0030] In some embodiments, the cancer is non-small cell lung cancer.

[0031] In some embodiments, the use is in patients with ALK-positive non-small cell lung cancer whose disease has progressed following treatment with crizotinib or who are intolerant to crizotinib.

[0032] In some embodiments, the use is in patients with ALK-positive non-small cell lung cancer who have not previously been treated with an ALK inhibitor.

[0033] A sixth aspect of the present invention provides a method for treating cancer, comprising administering to a patient a therapeutically effective amount of any of the above pharmaceutical compositions, including 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, and melanoma.

[0034] In some embodiments, the cancer is non-small cell lung cancer.

[0035] In some embodiments, the methods are used in patients with ALK-positive non-small cell lung cancer whose disease progresses after treatment with crizotinib or who are intolerant to crizotinib.

[0036] In some embodiments, the methods described above are used in patients with ALK inhibitor naive ALK positive non-small cell lung cancer.

[0037] In the present invention, D50 means the particle size at which the cumulative volume distribution percentage of the spirocyclic aryl phosphate or its pharma- ceutically acceptable salt, measured from the small diameter side, is 50%, and D90 means the particle size at which the cumulative volume distribution percentage of the spirocyclic aryl phosphate or its pharma- ceutically acceptable salt, measured from the small particle diameter, is 90%.

[0038] Beneficial technical effects: The present invention provides a pharmaceutical composition comprising a spirocyclic aryl phosphate having a specific particle size range or a pharma- ceutical salt thereof, which can increase the dissolution rate of the pharmaceutical composition and improve its bioavailability.

[0039] Unless otherwise specified, the following terms and phrases used in this specification have the following meanings: A particular term or phrase, unless specifically defined, should not be considered indefinite or unclear, but should be understood according to its general meaning.

[0040] The term "pharmacologically acceptable" refers to compounds, materials, compositions, and / or dosage forms that are, within the scope of reasonable medical judgment, suitable for use in contact with the tissues of human beings and animals and that have a reasonable benefit / risk ratio without undue toxicity, irritation, allergic response, or other problem or complication.

[0041] The term "pharmaceutically acceptable salts" refers to derivatives made from the compounds of the present invention and relatively non-toxic acids or bases. These salts may be made during the synthesis, isolation, or purification of the compounds, or may be made by reacting the free form of the purified compounds with an appropriate acid or base. When the compounds contain relatively acidic functional groups, they can be reacted with alkali metal or alkaline earth metal hydroxides or organic amines to give base addition salts, including alkali metal and alkaline earth metal cations such as sodium, lithium, potassium, calcium, magnesium, and non-toxic ammonium, quaternary ammonium, and amine cations. The toxic ammonium, quaternary ammonium, and amine cations specifically include, but are not limited to, ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. The base addition salts also include salts of amino acids such as arginine salts, gluconates, and galacturonates. When the compounds contain relatively basic functional groups, they can be reacted with organic or inorganic acids to give acid addition salts, including inorganic or organic acid salts. Examples of inorganic acid salts include hydrochloride, hydrobromide, nitrate, carbonate, bicarbonate, phosphate, monohydrogenphosphate, dihydrogenphosphate, sulfate, hydrogensulfate, hydroiodide, hydrobromide, metaphosphate, and pyrophosphate. Examples of organic acid salts include acetate, propionate, octanoate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, naphthoate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, maleate, tartrate, and methanesulfonate.

[0042] The term "pharmaceutically acceptable carrier" refers to a vehicle generally accepted in the art for delivering a bioactive agent to an animal, particularly a mammal, and includes, for example, additives, excipients or vehicles, such as fillers, disintegrants, binders, flow agents, lubricants, diluents, preservatives, flow regulators, wetting agents, emulsifiers, suspending agents, sweeteners, flavorings, flavorings, antibacterial agents, antifungal agents, lubricants and dispersing agents, depending on the method of administration and the nature of the dosage form. Pharmaceutically acceptable carriers are formulated according to many factors within the purview of those skilled in the art. Such factors include, but are not limited to, the type and nature of the active agent produced, the subject to whom the composition containing the agent will be administered, the intended route of administration of the composition, and the intended target therapeutic indication. Pharmaceutically acceptable carriers include both aqueous and non-aqueous vehicles and a number of solid and semi-solid dosage forms. Such carriers contain many different components and additives in addition to the active agent, and it is well known to those skilled in the art that such additional components are included in the formulation for various reasons (e.g., stabilization of the active agent, binders, etc.) The term "excipient" generally refers to a carrier, diluent and / or vehicle necessary to formulate an effective pharmaceutical composition.

[0043] The term "therapeutically effective amount" refers to that amount of the pharmaceutical composition of the present invention sufficient to treat a disorder at a reasonable benefit / risk ratio applicable to any medical treatment. It should be recognized, however, that the total daily dosage of the composition of the present invention must be determined by the attending physician within the scope of sound medical judgment. For any particular patient, the specific therapeutically effective amount level must be determined by a variety of factors, including the disorder being treated and the severity of the disorder, the activity of the specific compound used, the specific composition used, the age, weight, general health, sex and diet of the patient, the administration time, route of administration and excretion rate of the specific compound used, the duration of treatment, medications used in conjunction with or simultaneously with the specific compound used, and similar factors well known in the medical art.

[0044] In order to more clearly describe the embodiments of the present invention and the technical solutions of the prior art, the drawings required in the embodiments and the prior art are briefly described below. Obviously, the drawings described below are only some embodiments of the present invention, and those skilled in the art can still obtain other drawings from these drawings without creative labor. [Brief description of the drawings]

[0045] [Figure 1] FIG. 1 shows X-ray powder diffraction patterns of the solid spirocyclic aryl phosphates remaining in the suspensions of Samples 1 to 8 in Table 2 in the solubility test. [Diagram 2] FIG. 2 is a diagram showing a comparison of the dissolution profiles of Examples 1 to 4 and Comparative Examples 1 to 4 in a phosphate buffer solution of pH 6.8. [Diagram 3] FIG. 3 is a diagram showing a comparison of the dissolution profiles of Examples 1 to 4 and Comparative Examples 1 to 4 in purified water+0.5% Tween 20. [Figure 4] FIG. 4 is an X-ray powder diffraction pattern of crystalline form A of spirocyclic aryl phosphate. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0046] In order to make the objectives, technical solutions and advantages of the present invention more clear, the present invention will be described in more detail below with reference to the drawings and examples. Obviously, the described examples are only some embodiments of the present invention, not all examples. Based on the embodiments described in the present invention, all other examples obtained by those skilled in the art without creative labor are also within the scope of the protection claims of the present invention.

[0047] In an embodiment of the present invention, the crystal form of the spirocyclic aryl phosphate is crystal form A, and the raw material is known and commercially available, or can be synthesized by adopting or following a method known in the art.

[0048] Solubility Testing of Spirocyclic Aryl Phosphate The solubility of spirocyclic aryl phosphate in buffer solutions with different pH values ​​was measured. 9 portions of 4 mg sample were weighed and added to a 1.5 mL sample bottle, and then 1 mL of different solvents (0.1 mol / L HCl, 0.01 mol / L HCl, acetate buffer pH 3.5, acetate buffer pH 4.5, phosphate buffer pH 5.5, phosphate buffer pH 6.5, phosphate buffer pH 6.8, phosphate buffer pH 7.5, water) were added, and the raw material compounds were added successively to form saturated solutions according to the dissolution conditions. After placing a magnetic rotor in the above saturated solution, it was placed on a magnetic stirrer (temperature 37°C, avoiding light) and stirred. After stirring for 24 hours, a sample was taken and centrifuged, and the solid sample remaining in the lower layer was subjected to X-ray powder diffraction (XRPD) measurement. The upper layer sample was filtered through a filter membrane, the final pH value of the filtrate was measured, and the saturated solubility of the compound was measured by high performance liquid chromatography (HPLC). The measurement results are shown in Table 1, and the results of the XRPD measurement are shown in FIG.

[0049] [Table 1]

[0050] Note: In Table 1, "soluble", "slightly soluble", "slightly soluble", "slightly soluble", "slightly soluble", and "extremely soluble" mean that 1 g of spirocyclic aryl phosphate can be dissolved in 1 ml to less than 10 ml, 10 ml to less than 30 ml, 30 ml to less than 100 ml, 100 ml to less than 1000 ml, and 1000 ml to less than 10,000 ml, respectively, and "practically insoluble" means that 1 g of spirocyclic aryl phosphate cannot be completely dissolved in 10,000 ml of solvent.

[0051] As can be seen from Table 1, the solubility of spirocyclic aryl phosphate in different pH buffer solutions is related to pH. Spirocyclic aryl phosphate is slightly soluble in 0.1mol / L hydrochloric acid solution, easily soluble in pH3.5 buffer solution, pH4.5 buffer solution, poorly soluble in 0.01mol / L hydrochloric acid solution, pH5.5 buffer solution and pH6.8 buffer solution, slightly soluble in pH6.5 buffer solution, extremely poorly soluble in pH7.5 buffer solution, and practically insoluble in water. As can be seen from Figure 1, the crystal form of spirocyclic aryl phosphate does not change with different solvents.

[0052] Manufacturing and process for pharmaceutical compositions containing spirocyclic aryl phosphates with different particle sizes The content uniformity and in vitro dissolution rate of pharmaceutical compositions containing spirocyclic aryl phosphates with different particle sizes were measured.

[0053] [Table 2]

[0054] [Table 3]

[0055] Examples 1 to 4 Manufacturing Process: The spirocyclic aryl phosphates having different particle sizes, which are Samples 3 to 6 in Table 2, were prepared according to the formulations in Table 3 and the following manufacturing steps to obtain different pharmaceutical compositions, Samples 3A, 4A, 5A, and 6A, respectively.

[0056] Spirocyclic aryl phosphate oxide with different particle sizes, microcrystalline cellulose, pregelatinized starch, hydroxypropyl methylcellulose, and sodium carboxymethyl starch in half the prescribed amount were added to a high shear mixer and mixed for 5 minutes, then purified water was added to granulate and stirred for 8 minutes.

[0057] The mixture was wet sized using a sieve, dried in a fluidized bed, and sieved using a sieve.

[0058] The remaining sodium carboxymethyl starch and silica were sieved and then added to the granules and mixed, and magnesium stearate was sieved and mixed, followed by tableting.

[0059] Comparative Example 1 to Comparative Example 4 The same procedure as in Example 1 was repeated, except that the spirocyclic aryl phosphate was successively replaced with Sample 1, Sample 2, Sample 7, and Sample 8 shown in Table 2.

[0060] Measurement of content uniformity and dissolution rate of pharmaceutical compositions of each Example and Comparative Example 1) Content uniformity detection The content uniformity of the pharmaceutical compositions in each Example and Comparative Example was detected in accordance with the Chinese Pharmacopoeia 2015 Edition "Appendix XE Content Uniformity Test Method," and the results are shown in Table 4.

[0061] [Table 4]

[0062] As can be seen from the results of content uniformity, when the particle size of the drug substance is in the range of 10 μm or more and 200 μm or less, the content uniformity of the pharmaceutical composition all meets the quality standard requirements.

[0063] 2) Dissolution detection The dissolution characteristics of the pharmaceutical compositions of each Example and Comparative Example were measured according to the method for measuring dissolution degree (Chinese Pharmacopoeia, 2015, Part IV, 0512). Specifically, the rotation speed was set to 50 rpm and the temperature was maintained at 37±0.5° C., and the dissolution profile of the pharmaceutical composition was examined. The dissolution data are shown in Tables 5 and 6.

[0064] [Table 5]

[0065] [Table 6]

[0066] As can be seen from the dissolution results in Table 5 and Figure 2, in the phosphate buffer solution of pH 6.8, when the spirocyclic aryl phosphate has D90 in the range of 40.3μm-79.6μm and D50 in the range of 13.0μm-23.8μm, the dissolution results are basically the same and there is no significant difference. Compared with the dissolution data of other particle sizes, the spirocyclic aryl phosphate with D90 in the range of 40.3μm-79.6μm and D50 in the range of 13.0μm-23.8μm was dissolved the fastest in the pharmaceutical composition. When the particle size D90 of the drug substance of the spirocyclic aryl phosphate is less than 40.3μm or D50 is less than 13.0μm, the dissolution gradually slows down. When the particle size D90 of the drug substance of the spirocyclic aryl phosphate is more than 79.6μm or D50 is more than 23.8μm, the dissolution also slows down.

[0067] As can be seen from the dissolution results in Table 6 and Figure 3, in the purified water + 0.5% Tween 20 medium, when the spiro ring aryl phosphate had a D90 in the range of 11.6 μm to 79.6 μm and a D50 in the range of 5.4 μm to 23.8 μm, the dissolution was basically the same. When the particle size D90 of the drug substance exceeded 100 μm and the D50 exceeded 40 μm, the dissolution rate decreased. Referring to Tables 5 and 6, when the spiro ring aryl phosphate had a D90 in the range of 40.3 μm to 79.6 μm and a D50 in the range of 13.0 μm to 23.8 μm, both the pH 6.8 phosphate buffer and the purified water + 0.5% Tween 20 medium showed good dissolution characteristics.

[0068] Stability considerations for pharmaceutical compositions 1) Influence factor experiment The pharmaceutical composition prepared in Example 2 of the present invention was selected and used to study the formation of total impurities in the sample under each of the conditions of light irradiation, high temperature (60°C or 40°C), and high humidity (RH90%±5% or RH75%±5%). The total impurities (%) were calculated by calculating the peak area ratio of the sample and the standard measured by liquid chromatography.

[0069] [Table 7]

[0070] As can be seen from the results in the table, the related substances in the pharmaceutical composition of Example 2 increased slightly under light irradiation and high temperature conditions, but the content was relatively low. Under high humidity conditions, the moisture content increased significantly, but the related substances basically did not change. This indicates that the pharmaceutical composition provided by the present application has good stability under high temperature and high humidity conditions.

[0071] 2) Accelerated stability test Pharmaceutical composition samples 1A, 3A, and 4A prepared in Comparative Example 1, Examples 1 and 2 of the present invention were selected and used to examine the formation of related substances (single impurities and total impurities) in the samples under conditions of 40°C and 75% RH, respectively.

[0072] [Table 8]

[0073] Note: In Table 8, " / " indicates that there is no corresponding parameter.

[0074] Sample 1A (with desiccant), Sample 3A (with desiccant), and Sample 4A (with desiccant) all added desiccant during the product stability standing, but the stability was basically the same, and the increase trend of related substances was also basically the same. Sample 1A (without desiccant) did not add desiccant during standing, and the related substances were relatively high on day 0, but the change thereafter was not significant. Comparing the stability data of Sample 1A with and without desiccant, the content of total impurities was obviously reduced when desiccant was added during standing.

[0075] Clinical Trials 1) Prescription

[0076] [Table A]

[0077] 2) The manufacturing processes of pharmaceutical composition samples 9A and 10A are shown in Example 1.

[0078] 3) Sample 9A and Sample 10A were taken and subjected to clinical trials according to the following dosages, and the data were shown in Table 9:

[0079] [Table 9]

[0080] Analysis of the clinical data shows that as the dose increases from 60 mg to 120 mg, the AUC 0~∞ increased essentially linearly, and as the dose increased 1.5-fold from 60 mg to 90 mg, AUC 0~∞ The increase in bioavailability was less than 1.5 times, and relatively speaking, the bioavailability of the 60mg dose was slightly higher in vivo. Meanwhile, the difference in bioavailability between the 60mg and 120mg doses was not large and was not statistically significant. Meanwhile, 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 increasing dose.

[0081] The method of the present invention has been described through preferred embodiments. It is clear that those skilled in the art can realize and apply the present invention by modifying or appropriately modifying or combining the methods and uses described herein within the content, spirit and scope of the present invention. In particular, although specific embodiments have been illustrated and described, all similar replacements and modifications are obvious to those skilled in the art, and all of these are considered to be included in the present invention.

Claims

1. comprising a spirocyclic aryl phosphate or a pharma- ceutically acceptable salt thereof as an active ingredient and a pharma- ceutically acceptable carrier; The spirocyclic aryl phosphate has a structure represented by the formula: 【Chemistry 1】 The D90 of the spirocyclic aryl phosphate or a pharma- ceutically acceptable salt thereof is in the range of 40.3 μm to 79.6 μm; The D50 of the spirocyclic aryl phosphate or a pharma- ceutically acceptable salt thereof is in the range of 13.0 μm to 23.8 μm; The crystal form of the spirocyclic aryl phosphate is crystal form A; The crystalline form A has characteristic peaks at 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°, and 21.2±0.20° in X-ray powder diffraction at 2θ angles using Cu-Kα radiation; The pharma- ceutically acceptable carriers include fillers, disintegrants, binders, glidants and lubricants; the filler is at least one selected from the group consisting of starch, mannitol, sorbitol, microcrystalline cellulose, lactose, pregelatinized starch, and inorganic salts; The disintegrant is at least one selected from the group consisting of dry starch, sodium carboxymethyl starch, hydroxypropyl starch, low-substituted hydroxypropyl cellulose, crospovidone, and croscarmellose sodium; The binder is at least one selected from the group consisting of distilled water, ethanol, starch slurry, powdered sugar and syrup, hydroxypropyl methylcellulose, povidone, hydroxypropyl cellulose, methylcellulose, ethylcellulose, and sodium carboxymethylcellulose; The fluidizing agent is at least one selected from the group consisting of finely powdered silica gel and talcum powder; The pharmaceutical composition, wherein the lubricant is one or more selected from the group consisting of magnesium stearate, hydrogenated vegetable oil, polyethylene glycol, magnesium lauryl sulfate, and sodium stearyl fumarate.

2. 2. The pharmaceutical composition of claim 1, wherein the D50 of the spirocyclic aryl phosphate or its pharma- ceutically acceptable salt is in the range of 13.0 μm to 18.2 μm.

3. 2. The pharmaceutical composition of claim 1, wherein the filler comprises a composition of microcrystalline cellulose and pregelatinized starch.

4. The pharmaceutical composition according to claim 1, characterized in that the disintegrant comprises sodium carboxymethyl starch.

5. 2. The pharmaceutical composition of claim 1, wherein the binder comprises hydroxypropyl methylcellulose.

6. 2. The pharmaceutical composition of claim 1, wherein the fluidizing agent comprises finely powdered silica gel.

7. 2. The pharmaceutical composition of claim 1, wherein the lubricant comprises magnesium stearate.

8. The pharmaceutical composition according to claim 1 or 2, characterized in that it is in the form of a tablet.

9. The pharmaceutical composition according to claim 8, characterized in that it is a film-coated tablet.

10. The pharmaceutical composition according to claim 1 or 2, characterized in that the components are, in weight percentage, 1% to 50% of the spirocyclic aryl phosphate or its pharma- ceutically acceptable salt, 1% to 90% of the filler, 1% to 10% of the disintegrant, 0.1% to 1% of the glidant, and 0.5% to 5% of the lubricant.

11. The pharmaceutical composition according to claim 10, characterized in that the components, by weight percentage, are 5.0% spirocyclic aryl phosphate or a pharma- ceutically acceptable salt thereof, 26.0% microcrystalline cellulose, 59.5% pregelatinized starch, 5% sodium carboxymethyl starch, 3.0% hydroxypropyl methylcellulose, 0.5% finely powdered silica gel, and 1% magnesium stearate.

12. 1) thoroughly mixing a spirocyclic aryl phosphate or a pharma- ceutically acceptable salt thereof with an internal excipient including a filler, a binder and a disintegrant as part of the excipient, followed by granulation; 2) adding final additives including filler, disintegrant and lubricant as other parts of the additives, and then mixing thoroughly; 3) compressing and coating the tablet. A method for producing the pharmaceutical composition of claim 1.

13. 13. Use of a pharmaceutical composition according to claim 1 or 2 or a pharmaceutical composition prepared by the method according to claim 12 in the manufacture of a medicament for treating cancer.

14. 14. The use of claim 13, wherein the cancer comprises 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, gastrointestinal stromal tumor, acute myeloid leukemia, cholangiocarcinoma, renal cancer, thyroid cancer, anaplastic large cell lymphoma, mesothelioma, multiple myeloma.

15. 15. The use according to claim 14, wherein the cancer is non-small cell lung cancer.

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