CN115869315B - Solid dispersion and preparation of FGFR inhibitor, preparation method and application thereof - Google Patents
Solid dispersion and preparation of FGFR inhibitor, preparation method and application thereofInfo
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- CN115869315B CN115869315B CN202211538286.XA CN202211538286A CN115869315B CN 115869315 B CN115869315 B CN 115869315B CN 202211538286 A CN202211538286 A CN 202211538286A CN 115869315 B CN115869315 B CN 115869315B
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Abstract
本发明公开了一种FGFR抑制剂的固体分散体、制剂、其制备方法及其应用，所述的固体分散体包含载体和活性成分，所述活性成分为如式(I)所示的化合物和/或其药学上可接受的盐、其晶型和其溶剂合物中的一种或多种；所述载体为聚乙烯吡咯烷酮/聚乙酸乙烯酯的共聚物、聚乙烯吡咯烷酮、HPMCAS、Soluplus、HPMC、PEG、HPMCP、聚甲基丙烯酸酯、聚乙烯醇和羟丙基纤维素中的一种或组合物。本发明固体分散体具有良好的溶出度，有效成分的溶解度显著提高，用所述的固体分散体形成的制剂可以有效改善FGFR抑制剂的生物利用度，具有良好的溶出度和稳定性，可提高用药安全性。 This invention discloses a solid dispersion, formulation, preparation method, and application of an FGFR inhibitor. The solid dispersion comprises a carrier and an active ingredient. The active ingredient is one or more of a compound of formula (I) and/or its pharmaceutically acceptable salt, crystal form, and solvate. The carrier is one or a combination of polyvinylpyrrolidone/polyvinyl acetate copolymer, polyvinylpyrrolidone, HPMCAS, Soluplus, HPMC, PEG, HPMCP, polymethyl methacrylate, polyvinyl alcohol, and hydroxypropyl cellulose. The solid dispersion of this invention exhibits good dissolution, significantly improving the solubility of the active ingredient. Formulations formed using the solid dispersion can effectively improve the bioavailability of FGFR inhibitors, exhibiting good dissolution and stability, and enhancing medication safety.
Description
Technical Field
The invention relates to a solid dispersion and a preparation of an FGFR inhibitor, a preparation method and application thereof.
Background
The receptor tyrosine kinase plays a key role in various links such as tumorigenesis, invasion and metastasis, drug resistance and the like due to abnormal expression activation or gene mutation. Has become an important target for the development of antitumor drugs. Among them, the fibroblast growth factor receptor (fibroblastgrowthfactorreceptors, FGFRs) is an important member of the receptor tyrosine kinase family, mainly comprising four subtypes FGFR1, FGFR2, FGFR3 and FGFR 4. The ligand is fibroblast growth factor (FibroblastGrowthFactors, FGFs). Due to gene amplification, mutation, fusion or ligand induction, each member of FGFR is continuously activated, so that proliferation, invasion and migration of tumor cells are induced, angiogenesis is promoted, and occurrence and development of tumors are promoted. The FGFRs are highly expressed and abnormally activated in various tumors, and are closely related to the bad prognosis of tumor patients, such as non-small cell lung cancer, breast cancer, gastric cancer, bladder cancer, endometrial cancer, prostate cancer, cervical cancer, colon cancer, esophageal cancer, keratectoma, myeloma, rhabdomyosarcoma and the like. Studies show that FGFR1 amplification accounts for 20% of that of non-small cell lung cancer, and by researching in vitro proliferation, signal passage and the like of lung cancer cell strains amplified by FGFR1, FGFR selective inhibitors can effectively inhibit activation of FGFR1 signal passage and proliferation of cells. Among breast cancers, the amplification of the chromosome (8 pl-12) region where FGFR1 is located accounts for about 10% of those of ER-positive patients, and the abnormal activation of FGFR2 signaling pathway caused by the high expression of FGFR mRNA and the amplification or mutation of FGFR2 gene associated with poor prognosis of patients is mainly associated with gastric cancer, triple-negative breast cancer, endometrial cancer, etc. The expansion rate of FGFR2 in gastric cancer tissues is 5% -10%. Analysis of 313 gastric cancer tissues shows that the expansion of FGFR2 is significantly related to tumor size, local infiltration degree, lymph node metastasis and occurrence of distant metastasis, and gastric cancer with FGFR2 expansion is generally a progressive tumor, has a poor prognosis, and has relatively low overall survival rate of patients. FGFR2 amplification accounts for 4% of refractory triple negative breast cancers. Endometrial cancer is a common gynaecological genital tract tumor, and mutations in FGFR2 account for approximately 12% of endometrial cancers. FGFR3 mutations account for 50% -60% in non-invasive bladder cancer and 10% -15% in invasive bladder cancer. FGFR3t (4; 14) (p 16.3; q 32) gene rearrangements account for 15-20% in multiple myeloma. In addition, FGFR and its ligand FGFs of various subtypes have abnormal expression and activation in liver cancer, such as FGFR2, FGFR3, FGFR4, FGF19, FGF2, FGF5, FGF8, FGF9, and the like. Several preclinical and clinical studies have shown the importance of aberrant activation of the FGF/FGFR axis in liver cancer. It is not neglected that aberrant activation of the FGF/FGFR axis is closely related to resistance to EGFR inhibitors, neovascular inhibitors, endocrine therapies, and the like. Therefore, the development of targeted FGFR inhibitors has become a leading-edge hotspot for anti-tumor drug research.
In particular, it has been found that one or more of the compounds of formula I, pharmaceutically acceptable salts thereof, crystalline forms thereof and solvates thereof are good FGFR inhibitors, with significant efficacy in the treatment of diseases areas including those resulting from high expression and abnormal activation of FGFRs, such as non-small cell lung cancer, breast cancer, stomach cancer, bladder cancer, endometrial cancer, prostate cancer, cervical cancer, colon cancer, esophageal cancer, keratoblastoma, myeloma, rhabdomyosarcoma. Thus, one or more of the compounds of formula I, pharmaceutically acceptable salts thereof, crystalline forms thereof and solvates thereof will be useful as a medicament for the treatment of the above-mentioned diseases.
The preferred route of administration is by oral administration. This route of administration provides maximum comfort and convenience of administration. The bioavailability obtained after oral administration is a measure of the effectiveness of the pharmaceutical oral dosage form. Bioavailability after oral administration depends on several factors such as the solubility of the active substance in the aqueous medium, the dose strength, the dissolution of the dosage form, absorption through the gastrointestinal tract and first pass effects. Accordingly, there is a need to develop solid pharmaceutical compositions for oral administration comprising one or more of the compounds of formula I, pharmaceutically acceptable salts thereof, crystalline forms thereof and solvates thereof and formulations thereof to improve the drug dissolution, absorption and exposure characteristics of the drug after administration, thereby improving inter-patient variability and enhancing clinical efficacy.
Disclosure of Invention
The invention provides a solid dispersion, a preparation method and application of FGFR inhibitor of one or more of a compound shown in a formula (I), pharmaceutically acceptable salt, crystal form and solvate thereof. Compared with crystalline API, the solid dispersion has obviously improved solubility and bioavailability in vitro.
In a first aspect of the present invention there is provided a pharmaceutical composition comprising a solid dispersion comprising (a) one or more of a compound of formula (I), a pharmaceutically acceptable salt thereof, a crystalline form thereof and a solvate thereof:
And (b) a pharmaceutically acceptable matrix selected from the group consisting of polyvinylpyrrolidone/polyvinyl acetate copolymers, polyvinylpyrrolidone, HPMCAS, soluplus, HPMC, PEG, HPMCP, polymethacrylates, polyvinyl alcohol and hydroxypropyl cellulose, or combinations thereof, preferably, the matrix is selected from the group consisting of polyvinylpyrrolidone/polyvinyl acetate copolymers, polyvinylpyrrolidone, polymethacrylates, or combinations thereof.
In another preferred embodiment, the compound of formula (I) is present in the pharmaceutical composition in an amount of 0.001 to 99.999% by weight.
In another preferred embodiment, the pharmaceutically acceptable salts include inorganic and organic salts, and preferably, the pharmaceutically acceptable salts are salts of the compounds of the present invention with acids. Suitable salt-forming acids include, but are not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, and acidic amino acids such as aspartic acid, glutamic acid.
In another preferred embodiment, the polyvinylpyrrolidone/polyvinyl acetate copolymer is PVP VA64.
In another preferred embodiment, the weight ratio of one or more of the compound of formula I, its pharmaceutically acceptable salts, its crystalline forms and its solvates to the polyvinylpyrrolidone/polyvinyl acetate copolymer is from 1:0.5 to 1:20 (preferably 1:2-8, more preferably 1:3-5), calculated as the mass of the free base of the compound of formula (I).
In another preferred embodiment, the polyvinylpyrrolidone is selected from the group consisting of PVP K30, PVP K12, PVP K15, PVP K17, PVP K25, PVP K60, PVP K90, or a combination thereof.
In another preferred embodiment, the weight ratio of one or more of the compound of formula I, its pharmaceutically acceptable salts, its crystalline forms and its solvates to polyvinylpyrrolidone is from 1:0.5 to 1:20 (preferably 1:2-8, more preferably 1:3-5), calculated as the mass of the corresponding free base of the compound of formula (I).
In another preferred embodiment, the polymethacrylate is selected from the group consisting of:EPO、L100、S100、RL、 RS and RD100, or a combination thereof.
In another preferred embodiment, the weight ratio of one or more of the compounds of formula I, their pharmaceutically acceptable salts, their crystalline forms and their solvates to polymethacrylate is from 1:0.5 to 1:20 (preferably 1:2-8, more preferably 1:3-5), calculated as the mass of the free base of the compound of formula (I).
In a second aspect of the present invention, there is provided a method for preparing a solid dispersion according to the first aspect of the present invention, wherein the method is any one of the following method one, method two or method three:
the method one comprises the steps of mixing (a) one or more of the compound of formula I, pharmaceutically acceptable salts thereof, crystalline forms thereof, and solvates thereof with (b) a pharmaceutically acceptable matrix, and (c) a solvent to form a solution or suspension;
mixing one or more of the compound of the formula I, pharmaceutically acceptable salts thereof, crystal forms thereof and solvates thereof with a pharmaceutically acceptable matrix, heating and extruding to obtain the solid dispersion;
the third method comprises the steps of mixing one or more of the compound of the formula I, pharmaceutically acceptable salts thereof, crystal forms thereof and solvates thereof with (b) a pharmaceutically acceptable matrix and (c) a solvent, and then spray drying to obtain the solid dispersion.
In another preferred embodiment, the first process is a process wherein the solvent is selected from the group consisting of water, a C1-C6 alcohol solvent, a C2-C6 ester solvent, a C2-C6 ketone solvent, a C1-C6 halogenated hydrocarbon solvent, a C2-C6 nitrile solvent, and a C2-C6 ether solvent, or a combination thereof, preferably the C1-C6 alcohol solvent is ethanol and/or methanol, the C2-C6 ester solvent is ethyl acetate, the C2-C6 ketone solvent is acetone, the C1-C6 halogenated hydrocarbon solvent is methylene chloride, the C2-C6 nitrile solvent is acetonitrile, the C2-C6 ether solvent is tetrahydrofuran, and more preferably the solvent is selected from the group consisting of acetone, ethanol, water, or a combination thereof;
and/or in the first method, the mass-volume ratio of one or more of the compound shown in the formula I, the pharmaceutically acceptable salt thereof, the crystal form thereof and the solvate thereof to the solvent is 0.1-60 mg/ml, preferably 5-30 mg/ml;
And/or in the second method, the extrusion temperature is 150-250 ℃, preferably 160-220 ℃;
and/or, in the second method, the extrusion operation further comprises a crushing step;
And/or in the third method, the solvent is selected from the group consisting of water, a C1-C6 alcohol solvent, a C2-C6 ester solvent, a C2-C6 ketone solvent, a C1-C6 halogenated hydrocarbon solvent, a C2-C6 nitrile solvent and a C2-C6 ether solvent, or a combination thereof, preferably the C1-C6 alcohol solvent is ethanol and/or methanol, the C2-C6 ester solvent is ethyl acetate, the C2-C6 ketone solvent is acetone, the C1-C6 halogenated hydrocarbon solvent is dichloromethane, the C2-C6 nitrile solvent is acetonitrile, the C2-C6 ether solvent is tetrahydrofuran, more preferably the solvent is a mixed solution of acetone, ethanol and water, and most preferably the solvent is a mixed solvent of acetone, ethanol and water 2-4:6-8:1-3 (v: v);
And/or in the third method, the mass-volume ratio of one or more of the compound shown in the formula I, the pharmaceutically acceptable salt thereof, the crystal form thereof and the solvate thereof to the solvent is 0.1-30 mg/ml;
and/or in the third method, the set temperature of the spray drying equipment is 40-200 ℃, preferably 50-150 ℃.
In a third aspect of the present invention there is provided a formulation comprising a solid dispersion according to the first aspect of the present invention, and a carrier selected from the group consisting of fillers, disintegrants, glidants, lubricants, or combinations thereof.
In another preferred embodiment, the filler is selected from the group consisting of microcrystalline cellulose, lactose, pregelatinized starch, dibasic calcium phosphate, mannitol, calcium phosphate, or a combination thereof, preferably the filler is selected from the group consisting of a combination of microcrystalline cellulose and lactose, a combination of microcrystalline cellulose and pregelatinized starch, a combination of microcrystalline cellulose and mannitol, or a combination of microcrystalline cellulose and calcium phosphate, more preferably the filler is microcrystalline cellulose or a "combination of microcrystalline cellulose and lactose";
And/or 0.2 to 8 parts by mass of the filler, preferably 0.2 to 2 parts (e.g., 0.25 parts, 0.40 parts, 0.43 parts, 0.72 parts, 0.84 parts, 0.85 parts, 0.86 parts or 0.90 parts) based on 1 part by mass of the solid dispersion;
And/or the disintegrant is selected from the group consisting of croscarmellose sodium, low substituted hydroxypropyl cellulose sodium, sodium carboxymethyl starch, or a combination thereof, preferably the disintegrant is croscarmellose sodium;
and/or the mass part of the disintegrating agent is 0.03-0.4 part (for example, 0.075 part, 0.09 part, 0.1 part, 0.14 part) preferably 0.05-0.3 part based on 1 part by mass of the solid dispersion;
and/or, the preparation further comprises a capsule shell;
and/or the preparation further comprises a coating agent.
In another preferred example, when the filler is a combination of microcrystalline cellulose and lactose, the mass ratio of microcrystalline cellulose to lactose is 1 (0.5-2) (e.g. 1:0.5, 1:1 or 1:2), preferably 1 (1-2), and more preferably 1:1;
and/or the microcrystalline cellulose is selected from the group consisting of microcrystalline cellulose PH102, silicified microcrystalline cellulose 90, silicified microcrystalline cellulose HD 90, microcrystalline cellulose PH105, microcrystalline cellulose KG802, microcrystalline cellulosePreferably, the microcrystalline cellulose is microcrystalline cellulose PH102 and/or microcrystalline cellulose KG802;
and/or, the lactose is anhydrous lactose and lactose monohydrate;
And/or, the glidant is silicon dioxide;
And/or, when the preparation further comprises a glidant, the glidant is 0.006-0.2 part by weight, preferably 0.01-0.06 part by weight, for example 0.01 part by weight, 0.02 part by weight, 0.03 part by weight or 0.04 part by weight, based on 1 part by weight of the solid dispersion;
And/or the lubricant is magnesium stearate and/or sodium stearyl fumarate;
And/or, when the preparation further comprises a lubricant, the lubricant is 0.004 to 0.1 parts by mass, preferably 0.004 to 0.04 parts by mass, for example 0.006 parts, 0.007 parts, 0.01 parts or 0.02 parts by mass, based on 1 part by mass of the solid dispersion;
and/or, when the preparation further comprises a capsule shell, the capsule shell is made of gelatin or hydroxypropyl methylcellulose;
And/or, when the formulation further comprises a coating agent, the coating agent is a gastric-soluble film coating premix, e.g II;
And/or, when the preparation further comprises a coating agent, the coating agent is 0.01-0.2 part by weight, and preferably 0.04-0.1 part by weight (for example, 0.06 part by weight) based on 1 part by weight of the solid dispersion.
In another preferred embodiment, the formulation comprises:
A solid dispersion in which the weight ratio of the compound of formula (I) to the matrix is 1:3-5, and
A carrier, wherein the carrier is one or more selected from the following groups (1) - (6):
(1) 25-35wt% of microcrystalline cellulose, 10-20wt% of lactose and 4-6wt% of croscarmellose sodium (the balance being solid dispersion);
(2) 20-35wt% of microcrystalline cellulose, 5-20wt% of lactose, 4-6wt% of croscarmellose sodium, 0.1-5% of silicon dioxide and 0.1-5% of magnesium stearate (the balance being solid dispersion);
(3) 20-35wt% of microcrystalline cellulose, 5-20wt% of lactose, 4-6wt% of croscarmellose sodium, 0.1-5% of silicon dioxide and 0.1-5% of magnesium stearate (the balance being solid dispersion);
(4) 5-60wt% of microcrystalline cellulose, 4-6wt% of croscarmellose sodium and 0.1-5% of magnesium stearate (the balance being solid dispersion);
(5) 5-60wt% lactose, 4-6wt% croscarmellose sodium, 0.1-5% silicon dioxide and 0.1-5% magnesium stearate (the balance being solid dispersion);
(6) And a capsule shell.
In another preferred embodiment, the carrier is a combination of the plurality of the carriers (1) to (6), for example, the solid dispersion is dispersed in the carrier of any one of the carriers (1) to (5) and then filled into the capsule shell, or the solid dispersion is dispersed in the combination of the plurality of the carriers (1) to (5).
In a fourth aspect, the present invention provides the use of a formulation according to the first aspect of the invention in the manufacture of a medicament for the treatment of hyperproliferative diseases.
In another preferred embodiment, the hyperproliferative disease is a cancer, preferably the cancer is selected from the group consisting of non-small cell lung cancer, breast cancer, stomach cancer, bladder cancer, endometrial cancer, prostate cancer, cervical cancer, colon cancer, esophageal cancer, keratoblastoma, myeloma, rhabdomyosarcoma.
It is understood that within the scope of the present invention, the above-described technical features of the present invention and technical features specifically described below (e.g., in the examples) may be combined with each other to constitute new or preferred technical solutions. And are limited to a space, and are not described in detail herein.
Drawings
FIG. 1 is a graph of dissolution trend of API crystals, API amorphous, and solid dispersions in FaSSIF;
FIG. 2 is a polarization microscope spectrum of API crystals and solid dispersions (example 10, example 11 and example 12);
FIG. 3 is an XRPD overlay of a solid dispersion prepared from API crystals and a different carrier;
FIG. 4 is a graph showing the dissolution trend of API crystals and solid dispersions of different drug loading rates in SGF+FaSSIF;
FIG. 5 is a polarization microscope spectrum of a 20% -50% drug loading solid dispersion (examples 12,13,14 and 15);
FIG. 6 is an XRPD pattern for an API crystal with a 20% -50% drug loading solid dispersion.
Detailed Description
The invention provides a solid dispersion, a preparation method and application of FGFR inhibitor aiming at one or more of a compound shown in a formula (I), pharmaceutically acceptable salt, crystal form and solvate thereof. The solid dispersion effectively improves the medicine solubility and the dissolution rate thereof, obviously improves the bioavailability of the FGFR inhibitor, has good stability, improves the medication safety, and solves the defects of lower solubility and difficult preparation of the existing FGFR inhibitor.
Terminology
As used herein, PVP VA is a copolymer of polyvinylpyrrolidone and polyvinyl acetate polymerized, meaning that polyvinylpyrrolidone and polyvinyl acetate are polymerized in the corresponding proportions when PVP VA is identified by a number (e.g., PVP VA64 refers to a copolymer of polyvinylpyrrolidone and polyvinyl acetate polymerized at 60:40).
As used herein, PVP in PVP K30 refers to polyvinylpyrrolidone, the K value being the model of PVP, here referring to polyvinylpyrrolidone with a K value of 30.
As used herein, HPMCAS refers to hydroxypropyl methylcellulose acetate succinate (e.g., HPMCAS LG, etc. refer to hydroxypropyl methylcellulose acetate succinate of varying degrees of substitution, where HPMCAS LG refers to hydroxypropyl methylcellulose acetate succinate of low degree of substitution (degree of substitution of acetyl), in particulate form.
As used herein, soluplus refers to a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer.
As used herein, HPMC (e.g., HPMC E3LV, etc.) refers to hydroxypropyl methylcellulose, where HPMC E3LV refers to low viscosity hydroxypropyl methylcellulose, model E3.
As used herein, PEG refers to polyethylene glycol.
As used herein, HPMCP refers to phthaloyl hydroxypropyl methyl cellulose ester.
As used in the specificationEPO refers to a copolymer of butyl methacrylate, dimethylaminoethyl methacrylate and methyl methacrylate (1:2:1).L100 refers to a copolymer of methacrylic acid and ethyl acrylate (1:1).S100 refers to methacrylic acid and methyl methacrylate (1:2) copolymers.RL refers to a copolymer of ethyl acrylate, methyl methacrylate and trimethylaminoethyl methacrylate chloride (1:2:0.2).RS refers to copolymers of ethyl acrylate, methyl methacrylate and trimethylaminoethyl methacrylate chloride (1:2:0.1).RD100 refers toRL and sodium hydroxymethyl cellulose (9:1) mixture. The above products are all from the winning industry group.
Solid dispersion containing a compound of formula (I)
The invention provides a solid dispersion which comprises a carrier and an active ingredient, wherein the active ingredient is one or more of a compound shown as a formula (I) and/or pharmaceutically acceptable salts, crystal forms and solvates thereof, wherein the pharmaceutically acceptable salts comprise inorganic and organic salts, and one preferable salt is a salt formed by the compound and acid. Suitable salt-forming acids include, but are not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, and acidic amino acids such as aspartic acid, glutamic acid;
The carrier comprises a component selected from the group consisting of polyvinylpyrrolidone/polyvinyl acetate copolymer (e.g. PVP VA 64), polyvinylpyrrolidone (e.g. PVP K30), HPMCAS (e.g. HPMCAS LG), soluplus, HPMC (e.g. HPMC E3 LV), PEG, HPMCP, polymethacrylate (e.g. PVP VA 64) EPO), polyvinyl alcohol, and hydroxypropyl cellulose, or any combination of one or more thereof.
The compounds of formula (I), pharmaceutically acceptable salts and solvates thereof are generally crystalline forms having very low solubility in aqueous medium at 37 ℃ for 24 hours at pH 1-10 in acidic to basic medium in the range of 0.0004-0.0198mg/mL. The applicant has unexpectedly found that by combining a compound of formula (I), a pharmaceutically acceptable salt thereof and a solvate thereof with a suitable carrier, the compound of formula (I), a pharmaceutically acceptable salt thereof and a solvate thereof can be highly dispersed in the carrier in an amorphous state, the solubility and bioavailability of the compound of formula (I), a pharmaceutically acceptable salt thereof and a solvate thereof can be greatly improved on the basis of maintaining a high drug loading, and the solid dispersion of the present invention does not convert or degrade even after being allowed to stand for 2 months.
The carrier is preferably a copolymer of polyvinylpyrrolidone/polyvinyl acetate (e.g. PVP VA 64), polyvinylpyrrolidone (e.g. PVP K30)、HPMCAS 716G、HPMCAS LG、HPMCAS 126G、HPMCAS MG、HPMC AS HG、HPMCAS 912G、Soluplus、HPMC E3LV、HPMC E5、HPMC K4M、PEG4000、PEG6000、HPMCP、 polyvinyl acetate (e.g. polyvinyl acetateEPO), polyvinyl alcohol and hydroxypropyl cellulose, more preferably one or more of a polyvinylpyrrolidone/polyvinyl acetate copolymer, polyvinylpyrrolidone and polymethacrylate.
In a preferred embodiment, the carrier is a copolymer of polyvinylpyrrolidone and polyvinyl acetate (PVP-VA series, such as PVP VA64, i.e., a copolymer of polyvinylpyrrolidone and polyvinyl acetate polymerized at a 60:40 ratio).
In another preferred embodiment, the carrier is a polymethacrylate, including but not limited toEPO。
In another preferred embodiment, the carrier is polyvinylpyrrolidone (PVP), including but not limited to PVP K30.
In another preferred embodiment, the carrier may be a combination of one or more of the foregoing.
The amount of carrier may be that which is conventional in the art, for example, by selecting an appropriate amount depending on the dosage form or amount to be administered. The mass ratio of the active ingredient to the carrier is preferably (0.5-10) of the composition 1 of one or two of the carriers, the composition ratio is further preferably (1-7) (for example, 1:1, 1:1.5, 3:7, 1:3, 1:4 or 1:6.7), and most preferably (3-5). When the mass ratio of the active ingredient to the carrier is within the range of 1 (1-7), at least one of the equilibrium solubility, moldability, dissolution rate and the like of the solid dispersion has a good effect, for example, the dissolution rate is superior to that of the individual active ingredient. When the mass ratio of the active ingredient to the carrier is in the range of 1 (3-5), at least one of the equilibrium solubility, moldability and dissolution of the solid dispersion is more effective.
In one embodiment of the invention, the solid dispersion is an amorphous solid dispersion.
As a preferred embodiment of the present invention, the solid dispersion contains 1 part by mass of the component of the solid dispersion prepared by the active ingredient, and in this composition, the preferred preparation method of the solid dispersion is a solvent evaporation method.
As a preferred embodiment of the present invention, the solid dispersion contains 1 part by mass of the active ingredient and 4 parts by mass of PVP K30, and the preferred preparation method of the solid dispersion is solvent evaporation.
As a preferred embodiment of the present invention, the solid dispersion contains 1 part by mass of the active ingredient and 4 parts by mass of PVP VA64, and the preferred preparation method of the solid dispersion is solvent evaporation.
As a preferred embodiment of the present invention, the solid dispersion contains 1 part by mass of the active ingredient and 4 parts by mass of Soluplus, and at this composition, the solid dispersion is preferably prepared by a solvent evaporation method.
As a preferred embodiment of the present invention, the solid dispersion comprises 1 part by mass of the active ingredient and 4 parts by mass of HPMC E3LV, and the preferred preparation method of the solid dispersion is solvent evaporation method.
As a preferred embodiment of the present invention, the solid dispersion comprises 1 part by mass of the active ingredient and 4 parts by mass of HPMC AS MG, and the preferred preparation method of the solid dispersion is solvent evaporation method.
As a preferred embodiment of the present invention, the solid dispersion comprises 1 part by mass of the active ingredient and 4 parts by mass of HPMCP, and the preferred preparation method of the solid dispersion is solvent evaporation method.
As a preferred embodiment of the present invention, the solid dispersion contains 1 part by mass of the active ingredient and 4 parts by mass of the componentsAt this composition, the preferred method of preparing the solid dispersion is solvent evaporation.
As a preferred embodiment of the present invention, the solid dispersion contains 1 part by mass of the active ingredient and 4 parts by mass of the componentsL100, under this composition, the preferred method of preparation of the solid dispersion is solvent evaporation.
As a preferred embodiment of the present invention, the solid dispersion contains 1 part by mass of the active ingredient and 4 parts by mass of the componentsIn this composition, the preferred method of preparing the solid dispersion is spray drying.
As a preferred embodiment of the present invention, the solid dispersion contains 1 part by mass of the active ingredient and 4 parts by mass of PVP K30, and the preferred preparation method of the solid dispersion is a spray drying method.
As a preferred embodiment of the present invention, the solid dispersion contains 1 part by mass of the active ingredient and 4 parts by mass of PVP VA64, and the preferred preparation method of the solid dispersion is a spray drying method.
As a preferred embodiment of the present invention, the solid dispersion contains 3 parts by mass of the active ingredient and 7 parts by mass of PVP VA64, and the preferred preparation method of the solid dispersion is a spray drying method.
As a preferred embodiment of the present invention, the solid dispersion contains 1 part by mass of the active ingredient and 1.5 parts by mass of PVP VA64, and the preferred preparation method of the solid dispersion is a spray drying method.
As a preferred embodiment of the present invention, the solid dispersion contains 1 part by mass of the active ingredient and 1 part by mass of PVP VA64, and the preferred preparation method of the solid dispersion is a spray drying method.
Preparation of solid Dispersion
The invention also provides a preparation method of the solid dispersion, which comprises the following method one, method two or method three:
The method I comprises the steps of mixing one or more of the compound shown as the formula I, pharmaceutically acceptable salt thereof, crystal forms thereof and solvates thereof and other components with a solvent to form a solution or suspension;
mixing one or more of the compound shown in the formula I, pharmaceutically acceptable salt thereof, crystal forms thereof and solvates thereof and other components, heating and extruding to obtain the solid dispersion;
The third method comprises the steps of mixing one or more of the compound shown as the formula I, pharmaceutically acceptable salt thereof, crystal forms thereof and solvates thereof and other components with a solvent, and performing spray drying to obtain the solid dispersion.
In the first method, the solvent may be any solvent used in a conventional solvent evaporation method in the art, and preferably, the solvent is one or more of water, an alcohol solvent, an ester solvent, a ketone solvent, a halogenated hydrocarbon solvent, a nitrile solvent and an ether solvent. The alcohol solvent can be ethanol and/or methanol, the ester solvent can be ethyl acetate, the ketone solvent can be acetone, the halogenated hydrocarbon solvent can be dichloromethane, the nitrile solvent can be acetonitrile, and the ether solvent can be tetrahydrofuran. Preferably, the solvent is tetrahydrofuran and/or acetone and/or ethanol and/or water.
In the first method, the solvent may be used in an amount conventional in the art, and preferably, the mass-volume ratio of "one or more of the compound represented by the formula I, its pharmaceutically acceptable salt, its crystal form and its solvate" to the solvent is 0.1 to 60mg/ml, and may be 5 to 30mg/ml.
In the second method, the extrusion temperature may be conventional in the art, preferably, the extrusion temperature is 150 to 250 ℃, and more preferably, the extrusion temperature is 160 to 220 ℃.
In the second method, the extrusion operation preferably further comprises a pulverizing step.
In the third method, the solvent may be any solvent as is conventional in the art, and preferably, the solvent is one or more of water, an alcohol solvent, an ester solvent, a ketone solvent, a halogenated hydrocarbon solvent, a nitrile solvent and an ether solvent. The alcohol solvent can be ethanol and/or methanol, the ester solvent can be ethyl acetate, the ketone solvent can be acetone, the halogenated hydrocarbon solvent can be dichloromethane, the nitrile solvent can be acetonitrile, and the ether solvent can be tetrahydrofuran. Preferably, the solvent is tetrahydrofuran and/or acetone and/or ethanol and/or water. Preferably, the solvent is any one or more of acetone, ethanol and water, and most preferably, the volume ratio of acetone, ethanol and water is 3:7:2.
In the third method, the solvent may be used in an amount conventional in the art, and preferably, the mass-volume ratio of "one or more of the compound shown in the formula I, its pharmaceutically acceptable salt, its crystal form and its solvate" to the solvent is 0.1-30 mg/ml.
In the third method, preferably, the spray drying temperature may be set to 40 ℃ to 200 ℃, preferably 50 ℃ to 150 ℃.
Formulations comprising solid dispersions
The invention also provides a preparation containing the solid dispersion, which comprises the solid dispersion, a filler, a disintegrating agent, a glidant and a lubricant.
The type of filler in the formulation may be conventional in the art, preferably the filler is one or more of microcrystalline cellulose, lactose, pregelatinized starch, dibasic calcium phosphate, mannitol and calcium phosphate, for example, a combination of microcrystalline cellulose and lactose, a combination of microcrystalline cellulose and pregelatinized starch, a combination of microcrystalline cellulose and mannitol, or a combination of microcrystalline cellulose and calcium phosphate, preferably the filler is microcrystalline cellulose or a "combination of microcrystalline cellulose and lactose";
When the filler is a combination of microcrystalline cellulose and lactose, preferably, the mass ratio of microcrystalline cellulose to lactose is 1 (0.5-2) (e.g., 1:0.5, 1:1, or 1:2), more preferably 1 (1-2), and most preferably 1:1.
Wherein, when the filler contains microcrystalline cellulose, the microcrystalline cellulose may be of a type conventional in the art, preferably microcrystalline cellulosePH102, silicified microcrystalline cellulose 90, silicified microcrystalline cellulose HD90, microcrystalline cellulose PH105, microcrystalline cellulose KG802, and microcrystalline celluloseOne or more of the pH101, more preferably, the microcrystalline cellulose is microcrystalline cellulosePH102 and/or microcrystalline cellulose KG802.
Wherein when the filler contains lactose, the lactose may be of a kind conventional in the art, preferably the lactose is anhydrous lactose and/or lactose monohydrate.
The amount of the filler in the preparation may be conventional in the art, and preferably, the filler is 0.2 to 8 parts by mass, and more preferably, the filler is 0.2 to 2 parts by mass, for example, 0.25 parts, 0.40 parts, 0.43 parts, 0.72 parts, 0.84 parts, 0.85 parts, 0.86 parts or 0.90 parts, based on 1 part by mass of the solid dispersion.
In the preparation, the type of the disintegrating agent can be conventional in the art, preferably the disintegrating agent is one or more of croscarmellose sodium, low substituted hydroxypropyl cellulose sodium and sodium carboxymethyl starch, and more preferably the disintegrating agent is croscarmellose sodium.
In the preparation, the amount of the disintegrating agent may be conventional in the art, preferably, the mass part of the disintegrating agent is 0.03 to 0.4 part, more preferably, the mass part of the disintegrating agent is 0.05 to 0.3 part, for example, 0.075 part, 0.09 part, 0.1 part, and 0.14 part, based on 1 part by mass of the solid dispersion.
The formulation preferably further comprises a glidant, and when the formulation further comprises a glidant, the glidant may be of a type conventional in the art, preferably the glidant is silicon dioxide.
When the formulation further comprises a glidant, the glidant may be used in an amount conventional in the art, preferably, the glidant is 0.006 to 0.2 part by mass, more preferably, the glidant is 0.01 to 0.06 part by mass, for example, 0.01 part by mass, 0.02 part by mass, 0.03 part by mass, or 0.04 part by mass, based on 1 part by mass of the solid dispersion.
The formulation preferably further comprises a lubricant. When the formulation further comprises a lubricant, the type of lubricant may be conventional in the art, preferably the lubricant is magnesium stearate and/or sodium stearyl fumarate.
When the formulation further comprises a lubricant, the lubricant may be used in an amount conventional in the art, preferably, the lubricant is 0.004 to 0.1 parts by mass, more preferably, the lubricant is 0.004 to 0.04 parts by mass, for example, 0.006 parts, 0.007 parts, 0.01 parts or 0.02 parts by mass, based on 1 part by mass of the solid dispersion.
The preparation preferably further comprises a capsule shell, and when the preparation is a capsule, the capsule shell is made of gelatin or hydroxypropyl methylcellulose.
The formulation preferably further comprises a coating agent, and when the formulation further comprises a coating agent, the type of coating agent may be conventional in the art, preferably the coating agent is a gastric-soluble film coating premix, such asII。
When the formulation further comprises a coating agent, the coating agent may be used in an amount conventional in the art, preferably, the coating agent is 0.01 to 0.2 parts by mass, more preferably, the coating agent is 0.04 to 0.1 parts by mass, for example, 0.06 parts by mass, based on 1 part by mass of the solid dispersion.
The invention also provides application of the preparation containing the solid dispersion in preparing medicines for treating hyperproliferative diseases.
Preferably, the hyperproliferative disease is cancer.
Preferably, the cancer is selected from the group consisting of non-small cell lung cancer, breast cancer, gastric cancer, bladder cancer, endometrial cancer, prostate cancer, cervical cancer, colon cancer, esophageal cancer, keratoblastoma, myeloma, rhabdomyosarcoma, and the like.
The above preferred conditions can be arbitrarily combined on the basis of not deviating from the common knowledge in the art, and thus, each preferred embodiment of the present invention can be obtained.
The solid dispersion provided by the invention can enable the active ingredient to be highly dispersed in the carrier in an amorphous state, and on the basis of keeping higher drug loading, the solubility of the compound in the formula (I), pharmaceutically acceptable salt and solvate thereof in gastrointestinal fluid is improved, and the dissolution rate and bioavailability of the compound are improved. The preparation of the invention has good dissolution and low impurity content (the total impurity content is lower than 2 percent and the maximum single impurity content is lower than 0.5 percent).
The invention will be further illustrated with reference to specific examples. It is to be understood that these examples are illustrative of the present invention and are not intended to limit the scope of the present invention. The experimental methods, in which specific conditions are not noted in the following examples, are generally conducted under conventional conditions or under conditions recommended by the manufacturer. Percentages and parts are by weight unless otherwise indicated.
EXAMPLE 1 preparation of solid Dispersion
The solid dispersion was prepared by solvent evaporation method by precisely weighing 10mg of the crystalline form of the hydrochloride of the compound of formula (I) (hereinafter referred to as "API" or "drug substance") in a 40mL vial, adding 1mL of solvent (tetrahydrofuran: water=6:1, v: v) for dissolution, and heating at 80 ℃ to rapidly evaporate the solvent to dryness, thereby obtaining the amorphous API.
In this example, the crystalline form of the hydrochloride salt of the compound of formula (I) produced a solid dispersion, i.e. with a drug loading of 100%.
Drug solubility tests were performed on API, API amorphous and solid dispersions (taking a certain amount of API, API amorphous of example 1 and solid dispersions of examples 2-9, respectively, in 40ml vials, respectively, 10ml of 37 ℃ FaSSIF solution was added, stirred at 500rpm, respectively, samples were sampled at different time points to examine the solubility) and the results are shown in table 1 and fig. 1.
EXAMPLE 2 preparation of solid Dispersion
The solid dispersion was prepared by solvent evaporation method comprising precisely weighing 10mg of the crystalline form of the hydrochloride of the compound of formula (I) (hereinafter referred to as "API" or "drug substance") and 40mg of the copolymer of polyvinylpyrrolidone and polyvinyl acetate (PVP VA 64), placing in a 40mL vial, adding 1mL of solvent (tetrahydrofuran: water=6:1, v: v) for dissolution, and heating at 80 ℃ to rapidly evaporate the solvent to dryness, thereby obtaining a solid dispersion with a drug loading of 20%.
In this example, the mass ratio of the crystalline form of the hydrochloride salt of the compound of formula (I) to PVP VA64 is 1:4, i.e. the drug loading is 20%.
Drug solubility tests were performed on API, API amorphous and solid dispersions (taking a certain amount of API, API amorphous of example 1 and solid dispersions of examples 2-9, respectively, in 40ml vials, respectively, 10ml of 37 ℃ FaSSIF solution was added, stirred at 500rpm, respectively, samples were sampled at different time points to examine the solubility) and the results are shown in table 1 and fig. 1.
EXAMPLE 3 preparation of solid Dispersion
The solid dispersion was prepared by solvent evaporation method comprising precisely weighing 10mg of the hydrochloride salt of the compound of formula (I) (hereinafter referred to as "API" or "drug substance") and 40mg of polyvinylpyrrolidone K30 (PVP K30), placing in a 40mL vial, adding 1mL of solvent (tetrahydrofuran: water=6:1, v:v) for dissolution, and heating at 80 ℃ to rapidly evaporate the solvent to dryness, thereby obtaining a solid dispersion with a drug loading of 20%.
In this example, the mass ratio of the crystalline form of the hydrochloride salt of the compound of formula (I) to PVP K30 was 1:4, i.e. the drug loading was 20%. Drug solubility tests were performed on API, API amorphous and solid dispersions (taking a certain amount of API, API amorphous of example 1 and solid dispersions of examples 2-9, respectively, in 40ml vials, respectively, 10ml of 37 ℃ FaSSIF solution was added, stirred at 500rpm, respectively, samples were sampled at different time points to examine the solubility) and the results are shown in table 1 and fig. 1.
EXAMPLE 4 preparation of solid Dispersion
The solid dispersion was prepared by solvent evaporation method by precisely weighing 10mg and 40mg of Soluplus in a 40mL vial in which 1mL of solvent (tetrahydrofuran: water=6:1, v: v) was added for dissolution, and heating at 80 ℃ to rapidly evaporate the solvent to dryness, thereby obtaining a solid dispersion having a drug loading of 20%.
In this example, the mass ratio of the crystalline form of the hydrochloride salt of the compound of formula (I) to the Soluplus is 1:4, i.e. the drug loading is 20%. Drug solubility tests were performed on API, API amorphous and solid dispersions (taking a certain amount of API, API amorphous of example 1 and solid dispersions of examples 2-9, respectively, in 40ml vials, respectively, 10ml of 37 ℃ FaSSIF solution was added, stirred at 500rpm, respectively, samples were sampled at different time points to examine the solubility) and the results are shown in table 1 and fig. 1.
EXAMPLE 5 preparation of solid Dispersion
The solid dispersion was prepared by solvent evaporation method comprising precisely weighing 10mg of the crystalline form of the hydrochloride of the compound of formula (I) (hereinafter referred to as "API" or "drug substance") and 40mg of HPMC e3lv, placing in a 40mL vial, adding 1mL of solvent (tetrahydrofuran: water=6:1, v:v) for dissolution, and heating at 80 ℃ to rapidly evaporate the solvent to dryness, thereby obtaining a solid dispersion with a drug loading of 20%.
In this example, the mass ratio of the crystalline form of the hydrochloride salt of the compound of formula (I) to HPMC E3LV was 1:4, i.e. the drug loading was 20%.
Drug solubility tests were performed on API, API amorphous and solid dispersions (taking a certain amount of API, API amorphous of example 1 and solid dispersions of examples 2-9, respectively, in 40ml vials, respectively, 10ml of 37 ℃ FaSSIF solution was added, stirred at 500rpm, respectively, samples were sampled at different time points to examine the solubility) and the results are shown in table 1 and fig. 1.
EXAMPLE 6 preparation of solid Dispersion
The solid dispersion was prepared by solvent evaporation method by precisely weighing 10MG and 40MG of HPMCAS MG in a 40mL vial, adding 1mL of solvent (tetrahydrofuran: water=6:1, V: V) for dissolution, and heating at 80℃to rapidly evaporate the solvent to dryness, thereby obtaining a solid dispersion with a drug loading of 20%.
In this example, the mass ratio of the crystalline form of the hydrochloride salt of the compound of formula (I) to HPMCAS MG is 1:4, i.e. the drug loading is 20%.
Drug solubility tests were performed on API, API amorphous and solid dispersions (taking a certain amount of API, API amorphous of example 1 and solid dispersions of examples 2-9, respectively, in 40ml vials, respectively, 10ml of 37 ℃ FaSSIF solution was added, stirred at 500rpm, respectively, samples were sampled at different time points to examine the solubility) and the results are shown in table 1 and fig. 1.
EXAMPLE 7 preparation of solid Dispersion
The solid dispersion was prepared by solvent evaporation method comprising precisely weighing 10mg of the hydrochloride salt of the compound of formula (I) (hereinafter referred to as "API" or "drug substance") and 40mg of HPMCP, placing in a 40mL vial, adding 1mL of solvent (tetrahydrofuran: water=6:1, v: v) for dissolution, and heating at 80 ℃ to rapidly evaporate the solvent to dryness, thereby obtaining a solid dispersion with a drug loading of 20%.
In this example, the mass ratio of the crystalline form of the hydrochloride salt of the compound of formula (I) to HPMCP is 1:4, i.e. the drug loading is 20%.
Drug solubility tests were performed on API, API amorphous and solid dispersions (taking a certain amount of API, API amorphous of example 1 and solid dispersions of examples 2-9, respectively, in 40ml vials, respectively, 10ml of 37 ℃ FaSSIF solution was added, stirred at 500rpm, respectively, samples were sampled at different time points to examine the solubility) and the results are shown in table 1 and fig. 1.
EXAMPLE 8 preparation of solid Dispersion
The solid dispersion is prepared by solvent evaporation method by precisely weighing 10mg and 40mg of the crystalline form of hydrochloride of the compound of formula (I) (hereinafter referred to as "API" or "drug substance")EPO was placed in a 40mL vial, dissolved in 1mL of solvent (tetrahydrofuran: water=6:1, V: V), and heated at 80℃to rapidly evaporate the solvent to give a solid dispersion with a drug loading of 20%.
In this example, the hydrochloride salt of the compound of formula (I) is in crystalline form andThe mass ratio of EPO is 1:4, namely the drug loading is 20%. Drug solubility tests were performed on API, API amorphous and solid dispersions (taking a certain amount of API, API amorphous of example 1 and solid dispersions of examples 2-9, respectively, in 40ml vials, respectively, 10ml of 37 ℃ FaSSIF solution was added, stirred at 500rpm, respectively, samples were sampled at different time points to examine the solubility) and the results are shown in table 1 and fig. 1.
EXAMPLE 9 preparation of solid Dispersion
The solid dispersion is prepared by solvent evaporation method by precisely weighing 10mg and 40mg of the crystalline form of hydrochloride of the compound of formula (I) (hereinafter referred to as "API" or "drug substance")L100, put in a 40mL vial, dissolved by adding 1mL of solvent (tetrahydrofuran: water=6:1, V: V), heated at 80 ℃ to evaporate the solvent rapidly, thus obtaining a solid dispersion with a drug loading of 20%.
In this example, the hydrochloride salt of the compound of formula (I) is in crystalline form andThe mass ratio of L100 is 1:4, namely the drug loading is 20%.
Drug solubility tests were performed on API, API amorphous and solid dispersions (taking a certain amount of API, API amorphous of example 1 and solid dispersions of examples 2-9, respectively, in 40ml vials, respectively, 10ml of 37 ℃ FaSSIF solution was added, stirred at 500rpm, respectively, samples were sampled at different time points to examine the solubility) and the results are shown in table 1 and fig. 1.
TABLE 1 solvent evaporation method to prepare solubility of 20% drug loading solid dispersion in FaSSIF
The results show that the solubility of the solid dispersion is significantly improved in the case of the hydrochloride of the compound of formula I according to the present invention combined with a carrier such as polyvinylpyrrolidone/polyvinyl acetate copolymer, polyvinylpyrrolidone, polymethacrylate and the like, while the solubility improvement degree is limited in the case of using other carriers such as HMPC, and therefore, it is preferable to prepare the solid dispersion using the polyvinylpyrrolidone/polyvinyl acetate copolymer, polyvinylpyrrolidone, polymethacrylate as a carrier.
EXAMPLE 10 preparation of solid Dispersion
The solid dispersion was prepared by spray-drying by precisely weighing 2g and 8g of the crystalline form of the hydrochloride of the compound of formula (I) (hereinafter referred to as "API" or "drug substance")EPO is placed in a 100mL bottle, 80mL of solvent (tetrahydrofuran: water=6:1, V: V) is added into the 100mL bottle to prepare a clear solution containing 25mg/mL of API concentration, relevant parameters of spray drying equipment are set, the equipment is started, and a solid dispersion is prepared in a spray drying mode, so that the solid dispersion with the drug loading of 20% is obtained.
In this example, the hydrochloride salt of the compound of formula (I) is in crystalline form andThe mass ratio of EPO is 1:4, namely the drug loading is 20%.
The API and solid dispersion were subjected to a drug solubility test by a two-step method (30 mg and 6mg of the solid dispersion prepared above were placed in a 40mL vial, then 3mL of SGF solution was added to prepare a solution having a target concentration of 2mg/mL, after stirring at 37℃and 600rpm for 0.5hr, 200. Mu.L of the sample was sampled to examine the solubility in SGF, then 2 times the amount of the FaSSIF solution was added to the remaining sample, stirring was continued at 37℃and 600rpm for 0.5hr, 1.5hr and 3.5hr, 200. Mu.L of each was sampled, and the sample was examined for its solubility in SGF+FaSSIF solution, the results of which are shown in Table 2.
A certain amount of solid dispersion samples were taken for respectively carrying out a polarizing microscope, XRPD and stability study. The results of the polarized light microscope are shown in FIG. 2, the superimposed XRPD pattern is shown in FIG. 3 (sample name of example 10 in pattern: ASD_Eudragit EPO; API in pattern represents XRPD pattern of API), and the prepared solid dispersion has good stability after being placed for one week under the condition of 40 ℃ and 75% RH.
EXAMPLE 11 preparation of solid Dispersion
The solid dispersion is prepared by precisely weighing 2g and 8g PVP K30 in a crystal form (hereinafter referred to as "API" or "bulk drug") of the hydrochloride of the compound of formula (I), placing the crystal form and 8g PVP K30 in a 100mL bottle, adding a proper amount of solvent (acetone: ethanol: water=3:7:2, V: V) into the 100mL bottle to prepare a clear solution containing 25mg/mL of API concentration, setting relevant parameters of spray drying equipment, starting the equipment, and preparing the solid dispersion by adopting a spray drying mode, thereby obtaining the solid dispersion with the drug loading of 20%.
In this example, the mass ratio of the crystalline form of the hydrochloride salt of the compound of formula (I) to PVP K30 was 1:4, i.e. the drug loading was 20%.
Drug solubility tests were performed on the API and solid dispersion (30 mg and 6mg of the solid dispersion prepared above were placed in a 40mL vial, then 3mL of SGF solution was added to prepare a solution having a target concentration of 2mg/mL, after stirring at 37℃and 600rpm for 0.5hr, 200. Mu.L of the test sample was sampled for the solubility in SGF, then 2 times the amount of FaSSIF solution was added to the remaining sample, stirring was continued at 37℃and 600rpm for 0.5hr, 1.5hr and 3.5hr, 200. Mu.L of each was sampled, and the sample was tested for the solubility in SGF+FaSSIF solution, the results of which are shown in Table 2.
A certain amount of solid dispersion samples were taken for respectively carrying out a polarizing microscope, XRPD and stability study. The results of the polarized light microscope are shown in FIG. 2, the XRPD stacked graph is shown in FIG. 3 (sample name of example 11 in the graph: ASD_PVPK30; sample graph name of dried 48 hours: ASD_PVPK30_Dry 48 hours), and the prepared solid dispersion has good stability after being placed for one week under the condition of 40 ℃ and 75% RH.
EXAMPLE 12 preparation of solid Dispersion
The solid dispersion is prepared by precisely weighing 2g and 8g of copolymer of polyvinylpyrrolidone and polyvinyl acetate (PVP VA 64) in a crystal form of hydrochloride of the compound of formula (I) (hereinafter referred to as "API" or "bulk drug"), placing the crystal form and the copolymer in a 100mL bottle, adding a proper amount of solvent (acetone: ethanol: water=3:7:2, V: V) into the 100mL bottle, preparing a clear solution containing 25mg/mL of API concentration, setting relevant parameters of spray drying equipment, starting equipment, and preparing the solid dispersion by adopting a spray drying mode, thereby obtaining the solid dispersion with 20% of drug loading rate.
In this example, the mass ratio of the crystalline form of the hydrochloride salt of the compound of formula (I) to the copolymer of polyvinylpyrrolidone and polyvinyl acetate (PVP VA 64) was 1:4, i.e. the drug loading was 20%.
Drug solubility tests were performed on the API and solid dispersion (30 mg and 6mg of the solid dispersion prepared above were placed in a 40mL vial, then 3mL of SGF solution was added to prepare a solution having a target concentration of 2mg/mL, after stirring at 37℃and 600rpm for 0.5hr, 200. Mu.L of the test sample was sampled for the solubility in SGF, then 2 times the amount of FaSSIF solution was added to the remaining sample, stirring was continued at 37℃and 600rpm for 0.5hr, 1.5hr and 3.5hr, 200. Mu.L of each was sampled, and the sample was tested for the solubility in SGF+FaSSIF solution, the results of which are shown in Table 2.
A certain amount of solid dispersion samples were taken for respectively carrying out a polarizing microscope, XRPD and stability study. The results of the polarized light microscope are shown in FIG. 2, the XRPD stacked graph is shown in FIG. 3 (sample name of an example 12 in the graph: ASD_PVPVA 64; sample graph name of a dried 48-hour sample: ASD_PVPVA 64_Dry 48 h), and the prepared solid dispersion has good stability after being placed for one week under the condition of 40 ℃ and 75% RH.
TABLE 2 solubility of solid dispersions prepared by spray drying in SGF+FaSSIF
The results show that the prepared solid dispersion has good solubility, wherein the solubility is improved by about 69 times compared with the API crystal in the condition of gastric juice with stomach, and the solubility is also improved by tens of times in the condition of gastric juice with stomach. Thus, the solid dispersion of the present invention greatly improves the solubility of API crystals.
EXAMPLE 13 preparation of solid Dispersion
The solid dispersion was prepared by precisely weighing 1g and 4g of a copolymer of polyvinylpyrrolidone and polyvinyl acetate (PVP VA 64) in the form of a hydrochloride of the compound of formula (I) (hereinafter referred to as "API" or "drug substance"), placing in a 100mL bottle, adding 40mL of a solvent (acetone: ethanol: water=3:7:2, V: V) into the 100mL bottle to prepare a clear solution containing 25mg/mL of API concentration, setting relevant parameters of a spray drying apparatus, opening the apparatus, and preparing the solid dispersion by spray drying, thereby obtaining a solid dispersion with a drug loading of 20%.
In this example, the mass ratio of the crystalline form of the hydrochloride salt of the compound of formula (I) to the copolymer of polyvinylpyrrolidone and polyvinyl acetate (PVP VA 64) was 1:4, i.e. the drug loading was 20%.
Drug solubility tests were performed on the API and the solid dispersion (weighing the above-mentioned amount of solid dispersion, which was converted to 6mg after API, weighing 6mg of API for comparison, respectively placing in 40mL vials, then adding 3mL of SGF solution to prepare a solution with a target concentration of 2mg/mL, stirring at 37 ℃ for 0.5hr at 600rpm, sampling 200. Mu.L of the sample to detect the solubility in SGF, then adding 2 times the amount of FaSSIF solution to the remaining sample, continuing stirring at 37 ℃ for 0.5hr, 1.5hr and 3.5hr, sampling 200. Mu.L of each sample, respectively, detecting the solubility of the sample in SGF+FaSSIF solution, the solubility results being shown in Table 3, the solubility trend being shown in FIG. 4 (sample name of example 13 in the map: FR 00895-6-ASD-VA 64-20% -0805; the solubility trend graph of API crystals in the map represents API).
A certain amount of solid dispersion samples were taken for respectively carrying out a polarizing microscope, XRPD and stability study. The results of the polarized light microscope are shown in figure 5;0-day XRPD stack of figure 6 (sample name of example 13 in the pattern: FR00895-6-ASD-PVP VA64-20% -0805), and the prepared samples are respectively placed at 25 ℃ per 60RH, 40 ℃ per 75% RH and 40 ℃ for 2 weeks, 4 weeks and 2 months, and the results show that the prepared solid dispersion has good stability.
EXAMPLE 14 preparation of solid Dispersion
The solid dispersion was prepared by precisely weighing 1g and 2.33g of a copolymer of polyvinylpyrrolidone and polyvinyl acetate (PVP VA 64) in the form of a hydrochloride of the compound of formula (I) (hereinafter referred to as "API" or "drug substance"), placing in a 100mL bottle, adding 40mL of a solvent (acetone: ethanol: water=3:7:2, V: V) into the 100mL bottle, preparing a clear solution containing 25mg/mL of API concentration, setting parameters related to spray drying equipment, starting equipment, and preparing the solid dispersion by spray drying, thereby obtaining a solid dispersion with a drug loading of 30%.
In this example, the mass ratio of the crystalline form of the hydrochloride salt of the compound of formula (I) to the copolymer of polyvinylpyrrolidone and polyvinyl acetate (PVP VA 64) was 3:7, i.e. the drug loading was 30%.
Drug solubility tests were performed on the API and the solid dispersion (weighing the above-mentioned amount of solid dispersion, converting it into 6mg after API, placing it in a 40mL vial, then adding 3mL of SGF solution to prepare a solution with a target concentration of 2mg/mL, stirring at 37 ℃ for 0.5hr at 600rpm, sampling 200. Mu.L of the sample to test the solubility in SGF, then adding 2 times the amount of FaSSIF solution to the remaining sample, continuing stirring at 37 ℃ for 600rpm for 0.5hr, 1.5hr and 3.5hr, sampling 200. Mu.L of each, and measuring the solubility of the sample in SGF+FaSSIF solution, the solubility results are shown in Table 3, and the solubility trend is shown in FIG. 4 (sample name of example 14 in the graph: FR00895-6-ASD-PVP VA64-30% -0805).
A certain amount of solid dispersion samples were taken for respectively carrying out a polarizing microscope, XRPD and stability study. The results of the polarized light microscope are shown in figure 5;0-day XRPD stack of figure 6 (sample name of example 14 in the pattern: FR00895-6-ASD-PVP VA64-30% -0805), and the prepared samples are respectively placed at 25 ℃ per 60RH, 40 ℃ per 75% RH and 40 ℃ for 2 weeks, 4 weeks and 2 months, and the results show that the prepared solid dispersion has good stability.
EXAMPLE 15 preparation of solid Dispersion
The solid dispersion was prepared by precisely weighing 1g of a crystalline form of the hydrochloride of the compound of formula (I) (hereinafter referred to as "API" or "drug substance") and 1.5g of a copolymer of polyvinylpyrrolidone and polyvinyl acetate (PVP VA 64), placing in a 100mL bottle, adding 40mL of a solvent (acetone: ethanol: water=3:7:2, v: v) to the above 100mL bottle, preparing a clear solution containing 25mg/mL of API concentration, setting parameters related to spray drying equipment, starting equipment, and preparing the solid dispersion by spray drying to obtain a solid dispersion with a drug loading of 40%.
In this example, the mass ratio of the crystalline form of the hydrochloride salt of the compound of formula (I) to the copolymer of polyvinylpyrrolidone and polyvinyl acetate (PVP VA 64) was 2:3, i.e. the drug loading was 40%.
Drug solubility tests were performed on the API and the solid dispersion (weighing the above-mentioned amount of solid dispersion, converting it into 6mg after API, placing it in a 40mL vial, then adding 3mL of SGF solution to prepare a solution with a target concentration of 2mg/mL, stirring at 37 ℃ for 0.5hr at 600rpm, sampling 200. Mu.L of the sample to test the solubility in SGF, then adding 2 times the amount of FaSSIF solution to the remaining sample, continuing stirring at 37 ℃ for 600rpm for 0.5hr, 1.5hr and 3.5hr, sampling 200. Mu.L of each, and measuring the solubility of the sample in SGF+FaSSIF solution, the solubility results are shown in Table 3, and the solubility trend is shown in FIG. 4 (sample name of example 15 in the graph: FR00895-6-ASD-PVP VA64-40% -0805).
A certain amount of solid dispersion samples were taken for respectively carrying out a polarizing microscope, XRPD and stability study. The results of the polarized light microscope are shown in figure 5;0-day XRPD stack of figure 6 (sample name of example 15 in the pattern: FR00895-6-ASD-PVP VA64-40% -0805), and the prepared samples are respectively placed at 25 ℃ per 60RH, 40 ℃ per 75% RH and 40 ℃ for 2 weeks, 4 weeks and 2 months, and the results show that the prepared solid dispersion has good stability.
EXAMPLE 16 preparation of solid Dispersion
The solid dispersion was prepared by precisely weighing 1g of a crystalline form of the hydrochloride of the compound of formula (I) (hereinafter referred to as "API" or "drug substance") and 1g of a copolymer of polyvinylpyrrolidone and polyvinyl acetate (PVP VA 64), placing in a 100mL bottle, adding 40mL of a solvent (acetone: ethanol: water=3:7:2, v: v) to the 100mL bottle to prepare a clear solution containing 25mg/mL of API concentration, setting parameters related to spray drying equipment, opening the equipment, and preparing the solid dispersion by spray drying to obtain a solid dispersion with a drug loading of 50%.
In this example, the mass ratio of the crystalline form of the hydrochloride salt of the compound of formula (I) to the copolymer of polyvinylpyrrolidone and polyvinyl acetate (PVP VA 64) was 1:1, i.e. the drug loading was 50%.
Drug solubility tests were performed on the API and solid dispersion (weighing the above-mentioned amounts of solid dispersion, converting them into 6mg and 6mg of API, placing them in a 40mL vial, then adding 3mL of SGF solution to prepare a solution with a target concentration of 2mg/mL, stirring at 37℃and 600rpm for 0.5hr, sampling 200. Mu.L of the test sample for the solubility in SGF, then adding 2 times the amount of the FaSSIF solution to the remaining sample, continuing stirring at 37℃and 600rpm for 0.5hr, 1.5hr and 3.5hr, and sampling 200. Mu.L of each of them, respectively, to examine the solubility of the sample in SGF+FaSSIF solution, the solubility results being shown in Table 3, and the solubility trends being shown in FIG. 4 (sample name of example 16 in the graph: FR 00895-6-ASD-VA 64-50% -0805).
A certain amount of solid dispersion samples were taken for respectively carrying out a polarizing microscope, XRPD and stability study. The results of the polarized light microscope are shown in figure 5;0-day XRPD stack of figure 6 (sample name of example 16 in the pattern: FR00895-6-ASD-PVP VA64-50% -0805), and the prepared samples are respectively placed at 25 ℃ per 60RH, 40 ℃ per 75% RH and 40 ℃ for 2 weeks, 4 weeks and 2 months, and the results show that the prepared solid dispersion has good stability.
TABLE 3 solubility of solid dispersions prepared by spray drying in SGF+FaSSIF
The results show that the prepared solid dispersion has good solubility, wherein the solubility is improved by about 42 times compared with the API crystal in the condition of gastric juice with stomach, and the solubility is also improved by tens of times in the condition of gastric juice with stomach. Thus, the solid dispersion of the present invention greatly improves the solubility of API crystals.
EXAMPLE 17 preparation of solid dispersion capsules
According to the preparation method of example 12, 5g of a crystalline form of hydrochloride of the compound of formula (I) (hereinafter referred to as "API" or "drug substance") and 20g of a copolymer of polyvinylpyrrolidone and polyvinyl acetate (PVP VA 64) were weighed, placed in a beaker, 200ml of a solvent (acetone: ethanol: water=3:7:2, v: v) was added to the beaker to prepare a clear solution containing 25mg/ml of API concentration, parameters related to spray drying equipment were set, the equipment was turned on, a solid dispersion was prepared by spray drying, the obtained sample was placed in a vacuum oven at 40 ℃, and dried for about 20 hours to obtain a solid dispersion having a drug loading of 20%.
125Mg of the solid dispersion (batch No. FR01146-9-20% ASD-0909) with the drug loading rate of 20% is weighed and put into a white opaque 0-size Gelatin Capsule shell to prepare capsules with the specification of 25 mg/granule, and the batch No. of the capsules is FR01146-9-20% ASD-Gelatin Capsule-0914.
EXAMPLE 18 preparation of solid dispersion tablets
Weighing solid dispersion and microcrystalline cellulose according to the preparation method of example 12PH 102), lactose and croscarmellose sodium (wherein, solid dispersion, microcrystalline cellulose @, arePH 102), lactose and croscarmellose sodium with the mass ratio of 50%, 30%, 15% and 3% in the total material respectively, and mixing the solid dispersion and microcrystalline cellulosePH 102), lactose and croscarmellose sodium are sieved and mixed uniformly, granulated by a dry granulator, added with 1% of silicon dioxide and 1% of magnesium stearate according to a proportion, and mixed uniformly.
Tablets were made on an experimental tablet press (ZP 14) with a 10mm round die to give plain tablets with a tablet weight of 400 mg. The tablet was tested for each parameter, wherein the average hardness was 100N, the average thickness was 5.87mm, and the disintegration time was 5 minutes 30 seconds. Example 19 bioavailability test of the solid Dispersion prepared in example 12 in rats test animals
Test drug
API (hydrochloride salt of the compound of formula I)
EXAMPLE 20 solid Dispersion (ASD 1)
EXAMPLE 21 solid Dispersion (ASD 2)
1. Study outline
SD rats are a suitable rodent species for evaluation of test drug PK. The test article was administered orally (lavage) because the oral route is the intended route of administration to the human body. Animal use was reviewed and approved by the Institutional Animal Care and Use Committee (IACUC). PK sample collection blood samples were collected 0.083, 0.5, 1, 2, 4, 8 and 24 hours before, after injection for intravenous treatment. For other administrations, blood samples were collected before, 0.5, 1, 2, 4, 8, 12 and 24 hours after administration. PK sample analysis all plasma samples collected were analyzed.
2. Results of the study
Table 8 summary of plasma pharmacokinetic parameters of rats in each dose group of test drug
In all oral administrations, the absolute bioavailability of ASD1 of example 10 was 5.63% and the relative bioavailability was 840% at the same dose, and the absolute bioavailability of ASD2 of example 12 was 7.74% and the relative bioavailability was 1155% at the same dose. The solid dispersion of the examples has significantly improved bioavailability in rats.
Example 22 bioavailability test of the solid Dispersion capsules prepared in example 17 in beagle dogs
1. Test animals
2. Test drug
API preparation (hydrochloride tablets of the compound of formula I)
Solid dispersion Capsule prepared in example 23
3. Study outline
Beagle dogs are suitable non-rodent species for evaluation of the test drug PK. The test article was administered orally (tablet/capsule) because the oral route is the intended route of administration to the human body. Animal use was reviewed and approved by the Institutional Animal Care and Use Committee (IACUC). PK sample collection blood samples were collected before, 0.5, 1, 2, 4, 8, 12 and 24 hours after dosing. PK sample analysis all plasma samples collected were analyzed.
4. Results of the study
Table 9 summary of plasma pharmacokinetic parameters for each dose group of test drug beagle
The solid dispersion capsule ASD capsule prepared in example 17 at the same dose had a relative bioavailability of 308% in all oral administrations. The example solid dispersion has significantly improved bioavailability in beagle dogs.
All documents mentioned in this disclosure are incorporated by reference in this disclosure as if each were individually incorporated by reference. Further, it will be appreciated that various changes and modifications may be made by those skilled in the art after reading the above teachings, and such equivalents are intended to fall within the scope of the application as defined in the appended claims.
Claims (22)
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