CN111718258A - Bexarotene and polyvinylpyrrolidone co-amorphous product and preparation method and its composition and use - Google Patents

Abstract

The invention discloses a co-amorphous product of bexarotene and polyvinylpyrrolidone, a preparation method, and a composition and application thereof. Specifically, the invention discloses a new co-amorphous form formed by bexarotene and polyvinylpyrrolidone; a preparation method of bexarotene and polyvinylpyrrolidone co-amorphous; bexarotene and polyvinylpyrrolidone co-amorphous The application of amorphous form as a medicinal active ingredient in the preparation of medicines for preventing and treating glioma, skin T-cell lymphoma, breast cancer, psoriasis, Kaposi's sarcoma, lung cancer and Cushing's disease.

Description

Bexarotene and polyvinylpyrrolidone co-amorphous product and preparation method and combination thereof objects and uses

technical field

The invention discloses a co-amorphous product of bexarotene and polyvinylpyrrolidone, a preparation method, and a composition and application thereof. Specifically, the invention discloses a co-amorphous product formed by bexarotene and polyvinylpyrrolidone; a preparation method of a co-amorphous product of bexarotene and polyvinylpyrrolidone; bexarotene and polyvinylpyrrolidone co-amorphous The application of the amorphous substance as a medicinal active ingredient in the preparation of medicines for preventing and treating glioma, skin T-cell lymphoma, breast cancer, psoriasis, Kaposi's sarcoma, lung cancer and Cushing's disease.

Background technique

Co-amorphous drug refers to the amorphous substance formed by the non-covalent interaction between the molecules of active drug molecules and co-amorphous ligands in a certain proportion. By forming a co-amorphous form, on the one hand, the drug can improve its physicochemical properties and improve its clinical therapeutic effect, and on the other hand, the co-amorphous form can enrich its crystalline form. For chemical generic drugs, the study of co-amorphous substances can break the patent protection of original drug companies and improve the innovation and market competitiveness of drugs.

The present invention adopts bexarotene as active substance, and its chemical name is 4-[1-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthyl ) vinyl] benzoic acid, the molecular formula is C ₂₄ H ₂₈ O ₂ , and the structural formula is shown in a. The co-amorphous ligand (cocrystal former) used in the invention is polyvinylpyrrolidone, and the structural formula is shown in Figure b.

Daiss et al. used 1,2-bis(chlorodimethylsilyl)ethane as the starting material to synthesize bexarotene analogs by a multi-step synthesis method. The properties of the products were confirmed by elemental analysis and multi-nuclear magnetic resonance studies. , and the structure of the product was characterized by single crystal X-ray diffraction. Bexarotene is identified in the literature as crystal form I ^[1] .

Wei Wei et al. used 2,5-dimethyl-2,5-hexanediol as raw material, and prepared the antitumor drug Besa through seven-step reactions including chlorination, FC alkylation, FC acylation, Wittig reaction, and hydrolysis reaction. Luoding, and its synthesis process was optimized, and the obtained product was crystal I ^[2] .

There is one crystalline form of Bexarotene reported. There are no reports of Bexarotene co-crystals so far.

The present invention finds a co-amorphous solid state and preparation method of bexarotene which are different from the above-mentioned patents or literature research reports.

The research purpose of the present invention is to start with the study of the existence state of bexarotene solid matter, and to search for and discover the co-crystal/co-amorphous form on the active ingredient raw material level of the drug through co-crystal/co-amorphous screening technology and biological activity evaluation technology. There are types and state characteristics of solid substances, and the combination of co-crystal/co-amorphous substances and pharmacodynamics research is to find, discover and develop the superior medicinal co-crystal/co-amorphous of bexarotene with the best clinical efficacy. Solid substances provide basic scientific data; at the same time, it also provides scientific basis for applying for national or international intellectual property invention patent protection based on bexarotene solid pharmaceutical raw materials.

SUMMARY OF THE INVENTION

One of the objectives of the present invention is to provide a co-amorphous state of bexarotene and polyvinylpyrrolidone and a characterization method.

The second objective of the present invention is to provide a method for preparing a co-amorphous product of bexarotene and polyvinylpyrrolidone.

The third object of the present invention: to provide a mixed solid substance containing bexarotene and polyvinylpyrrolidone co-amorphous pure product, or containing any non-zero ratio bexarotene and polyvinylpyrrolidone co-amorphous substance and its pharmaceutical composition .

The fourth object of the present invention is to provide a pharmaceutical composition using bexarotene and polyvinylpyrrolidone co-amorphous as a pharmaceutical active ingredient, and the daily dose of bexarotene for human administration through the digestive tract is in the range of 5-1000 mg , the dosage of injection administration is in the range of 1 to 100 mg. . The pharmaceutical compositions include tablets, capsules, pills, injection preparations, sustained-release or controlled-release preparations.

The fifth object of the present invention is to provide a co-amorphous substance of bexarotene and polyvinylpyrrolidone, which has the advantage of better solubility compared with bexarotene.

The sixth purpose of the present invention is to provide the co-amorphous substance of bexarotene and polyvinylpyrrolidone in the process of treating diseases because the co-amorphous substance increases the blood drug concentration in the living body and exerts an effective drug treatment effect.

The seventh purpose of the present invention is to provide the co-amorphous form of bexarotene and polyvinylpyrrolidone as the active ingredients of medicine in the preparation and prevention of glioma, skin T-cell lymphoma, breast cancer, psoriasis, Kaposi's sarcoma, lung cancer and Use in Cushing's Disease Medications.

In order to solve the above-mentioned technical problems, the present invention adopts the following technical solutions:

1. Morphological characteristics of co-amorphous samples of bexarotene and polyvinylpyrrolidone:

1.1 Bexarotene and polyvinylpyrrolidone co-amorphous substance related to the present invention is the co-amorphous substance formed by bexarotene and polyvinylpyrrolidone in a certain mass ratio, when using powder X-ray diffraction analysis using CuKα radiation experimental conditions , its powder X-ray diffraction pattern shows diffuse diffraction peaks, and the diffraction peak positions are at 2-Theta values of 14.6 ± 0.3° and 18.7 ± 0.3 (Figure 1); the powder X of the physical mixture of bexarotene and polyvinylpyrrolidone The ray diffraction patterns and data are shown in Table 1 and Figure 2. Figure 3 shows a comparison chart of powder X-ray diffraction patterns of bexarotene, polyvinylpyrrolidone, a physical mixture of bexarotene and polyvinylpyrrolidone, and co-amorphous bexarotene and polyvinylpyrrolidone.

As can be seen from Figure 3, the raw material of Bexarotene is in a crystalline state, which is crystal I, and the polyvinylpyrrolidone is in an amorphous state. Its 2Theta has two diffuse diffraction peaks in the range of 3-40°, and the positions are 2 -Theta value is 11.7±0.3° and 19.9±0.3°, the physical mixture of bexarotene and polyvinylpyrrolidone in proportion is a mixture of crystalline and amorphous, bexarotene and polyvinylpyrrolidone co-amorphous There are obvious differences with the above three in terms of the number of diffraction peaks, the positions of diffraction peaks, the intensity of diffraction peaks, and the topological patterns of diffraction peaks, which fully indicates that bexarotene and polyvinylpyrrolidone form a molecular interaction with non-covalent bonds or van der Waals. A co-amorph of force, neither identical nor equivalent to a physical mixture of bexarotene and polyvinylpyrrolidone.

Table 1 Powder X-ray diffraction peaks of physical mixing of bexarotene and polyvinylpyrrolidone

1.2 In the co-amorphous product of bexarotene and polyvinylpyrrolidone involved in the present invention, the mass ratio of bexarotene and polyvinylpyrrolidone is 1:5-5:1, preferably 1:3-3:1.

1.3 The co-amorphous substance of bexarotene and polyvinylpyrrolidone involved in the present invention was analyzed by attenuated total reflection Fourier transform infrared spectroscopy at 3356, 3138, 3075, 3026, 2985, 2967, 2932, 2895, 2625, 2570 ,2602,2494,2480,2423,2223,2112,1970,1909,1860,1776,1680,1606,1588,1532,1488,1462,1406,1363,1326,1287,1260,1219,1180,1129,10 , 1075, 1038, 1016, 988, 979, 965, 899, 880, 865, 850, 804, 746, 733, 684, 681, 671, 658cm ^-1 there are infrared spectral characteristic peaks, among which the infrared spectral characteristic peaks allow The deviation was ±2 cm ^-1 (Figure 4). It can be seen from the infrared spectrum comparison chart of the physical mixture of bexarotene and polyvinylpyrrolidone co-amorphous with bexarotene and polyvinylpyrrolidone (Fig. 5) that bexarotene and polyvinylpyrrolidone co-amorphous There are obvious differences in the number, position and intensity of infrared absorption peaks of the physical mixture of bexarotene and polyvinylpyrrolidone, indicating that the co-amorphous bexarotene and polyvinylpyrrolidone co-amorphous is similar to bexarotene and polyvinylpyrrolidone. Physical mixtures of pyrrolidones are neither identical nor equivalent.

1.4 Bexarotene of the present invention and polyvinylpyrrolidone are co-amorphous, and the polyvinylpyrrolidone used is pharmaceutical grade, and its K value is usually between 10 and 120, preferably PVPK15, PVPK17, PVPK25 and PVPK30.

2. Characteristics of the preparation method of bexarotene and polyvinylpyrrolidone co-amorphous and mixed solid matter:

2.1 The preparation method of the co-amorphous bexarotene and polyvinylpyrrolidone that the present invention relates to, feed bexarotene and polyvinylpyrrolidone in a certain mass ratio, adopt the mechanochemical method of controlling pressure and temperature to prepare bexarotene Co-amorphous with polyvinylpyrrolidone. Wherein, the mass ratio of feeding materials is 1:5 to 5:1, preferably 1:3 to 3:1; the ball-to-material ratio of the liquid addition ball milling method is 1:1 to 10:1, preferably 6:1 to 10:1; The ball milling speed is 20r/min～400r/min; the grinding time is 0.1～10 hours.

2.2 The mixed solid substance of bexarotene and polyvinylpyrrolidone co-amorphous substance of the present invention is the co-amorphous substance component of bexarotene and polyvinylpyrrolidone prepared by the above method, and other chemical substances according to any non-zero Proportions and conventional methods are mixed.

3. The pharmaceutical preparation composition containing bexarotene and polyvinylpyrrolidone co-amorphous components, dosage characteristics and pharmaceutical use:

3.1 The pharmaceutical composition involved in the present invention comprises a co-amorphous substance of bexarotene and polyvinylpyrrolidone and a pharmaceutically acceptable carrier.

3.2 The pharmaceutical composition involved in the present invention comprises a mixed solid substance of co-amorphous bexarotene and polyvinylpyrrolidone and a pharmaceutically acceptable carrier.

3.3 For the pharmaceutical composition of the present invention, the daily dose of bexarotene for human administration through the digestive tract is in the range of 5-1000 mg, and the dose of bexarotene for injection is in the range of 1-100 mg. .

3.4 The pharmaceutical composition according to the present invention is characterized in that, the pharmaceutical composition is various tablets, capsules, pills, injection preparations, sustained-release preparations or controlled-release preparations.

3.5 The present invention relates to bexarotene and polyvinylpyrrolidone co-amorphous, bexarotene and polyvinylpyrrolidone co-amorphous mixed solid substance or pharmaceutical composition in the preparation of prevention and treatment of glioma, skin T-cell lymphoma Cancer, breast cancer, psoriasis, Kaposi's sarcoma, lung cancer, and Cushing's disease drugs.

The present invention relates to a pharmaceutical composition comprising the co-amorphous bexarotene and polyvinylpyrrolidone of the present invention as active ingredients. The pharmaceutical composition can be prepared according to methods known in the art. Bexarotene and polyvinylpyrrolidone co-amorphous components of the present invention can be prepared for human or animal use by combining with one or more pharmaceutically acceptable solid or liquid excipients and/or adjuvants. any dosage form. The content of the co-amorphous substance of bexarotene and polyvinylpyrrolidone in the pharmaceutical composition of the present invention is in the range of 10% to 90% by weight.

The co-amorphous product of bexarotene and polyvinylpyrrolidone of the present invention can be administered in the form of a unit dosage, and the route of administration can be enteral or parenteral, such as oral, intravenous, intramuscular, subcutaneous, nasal, oral mucosa, Eyes, lungs and respiratory tract, skin, vagina, rectum, etc.

The dosage form for administration of the present invention is preferably a solid dosage form. Solid dosage forms can be tablets (including ordinary tablets, enteric-coated tablets, buccal tablets, dispersible tablets, chewable tablets, effervescent tablets, orally disintegrating tablets), capsules (including hard capsules, soft capsules, enteric-coated capsules), granules medicines, powders, pellets, drop pills, suppositories, films, patches, gas (powder) aerosols, sprays, etc.

The co-amorphous product of bexarotene and polyvinylpyrrolidone of the present invention can be made into common preparations, and can also be made into sustained-release preparations, controlled-release preparations, targeted preparations and various microparticle drug delivery systems.

In order to make the co-amorphous product of bexarotene and polyvinylpyrrolidone of the present invention into tablets, various excipients known in the art can be widely used, including diluents, binders, wetting agents, disintegrants, lubricants agent, glidant. The diluent can be starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.; Propanol, etc.; the binder can be starch slurry, dextrin, syrup, honey, glucose solution, microcrystalline cellulose, acacia mucilage, gelatin slurry, sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methylcellulose Base cellulose, ethyl cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, polyethylene glycol, etc.; disintegrants can be dry starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, cross-linked polymer Vinylpyrrolidone, croscarmellose sodium, sodium carboxymethyl starch, sodium bicarbonate and citric acid, polyoxyethylene sorbitan fatty acid ester, sodium lauryl sulfonate, etc.; lubricants and flow aids The agent may be talc, silicon dioxide, stearate, tartaric acid, liquid paraffin, polyethylene glycol and the like.

The tablets can also be further prepared as coated tablets, such as sugar-coated, film-coated, enteric-coated, or bilayer and multi-layer tablets.

In order to make the dosing unit into capsules, the active ingredient bexarotene of the present invention and the co-amorphous polyvinylpyrrolidone can be mixed with a diluent and a glidant, and the mixture can be directly placed in a hard capsule or a soft capsule. The co-amorphous product of bexarotene and polyvinylpyrrolidone of the present invention can also be made into granules or pellets with diluents, binders and disintegrating agents, and then placed in hard capsules or soft capsules. Various diluents, binders, wetting agents, disintegrants, and glidants used for the preparation of the bexarotene and polyvinylpyrrolidone co-amorphous tablets of the present invention can also be used for the preparation of the bexarotene of the present invention Capsules co-amorphous with polyvinylpyrrolidone.

In addition, colorants, preservatives, fragrances, flavors, or other additives can also be added to the pharmaceutical preparations, if desired.

In order to achieve the purpose of medication and enhance the therapeutic effect, the medicament of the present invention can be administered by any known administration method.

The dosage of the co-amorphous pharmaceutical composition of bexarotene and polyvinylpyrrolidone of the present invention can vary in a wide range according to the nature and severity of the disease to be prevented or treated, the individual conditions of the patient or animal, the route of administration and the dosage form. Variety. The above doses may be administered in a single dosage unit or divided into several dosage units, depending on the clinical experience of the physician and the dosing regimen including the use of other therapeutic means.

The co-amorphous substance or composition of bexarotene and polyvinylpyrrolidone of the present invention can be taken alone, or used in combination with other therapeutic drugs or symptomatic drugs. When the co-amorphous bexarotene and polyvinylpyrrolidone of the present invention has a synergistic effect with other therapeutic drugs, its dosage should be adjusted according to the actual situation.

4. Beneficial technical effects of the present invention: the advantages of safety, solubility and biological activity of co-amorphous bexarotene and polyvinylpyrrolidone.

4.1 The co-amorphous product of bexarotene and polyvinylpyrrolidone of the present invention does not contain any crystallization solvent, and has the advantages of good safety as a medicine.

4.2 The co-amorph of bexarotene and polyvinylpyrrolidone of the present invention exhibits a solubility advantage over bexarotene in an aqueous system, especially in the significant improvement in the dissolution rate (Fig. 6).

4.3 Bexarotene of the present invention and polyvinylpyrrolidone co-amorphous as active ingredient development and the biological absorption effect of pharmaceutical composition after oral administration, it is characterized in that using the bexarotene containing as described in claim 1 Sarodine and polyvinylpyrrolidone co-amorphous substances as active ingredients, through the gastrointestinal tract or blood to quickly reach the maximum concentration value and play an advantageous role and application in the prevention and treatment of diseases (Figure 7). The bexarotene and polyvinylpyrrolidone co-amorphous solid matter of the present invention increases the blood concentration of the drug in the living body, thereby exerting a more effective therapeutic effect of the drug.

Description of drawings

Fig.1 Powder X-ray diffraction pattern of bexarotene and polyvinylpyrrolidone co-amorphous

Fig.2 Powder X-ray diffraction pattern of the physical mixture of bexarotene and polyvinylpyrrolidone

Fig. 3 Comparison of powder X-ray diffraction patterns of bexarotene, polyvinylpyrrolidone, physical mixture of bexarotene and polyvinylpyrrolidone, and co-amorphous bexarotene and polyvinylpyrrolidone

Fig.4 Infrared absorption spectrum of co-amorphous bexarotene and polyvinylpyrrolidone

Fig.5 Comparison of infrared absorption spectra of bexarotene and polyvinylpyrrolidone co-amorphous and physical mixture of bexarotene and polyvinylpyrrolidone

Fig.6 Solubility curves of co-amorphous bexarotene, bexarotene and polyvinylpyrrolidone

Fig.7 The time curve of bexarotene, bexarotene and polyvinylpyrrolidone co-amorphous in rats orally absorbed for 0-24h

Fig. 8 Powder X-ray diffraction patterns of co-amorphous bexarotene and polyvinylpyrrolidone in different proportions

Detailed ways

In order to better illustrate the technical solutions of the present invention, the following examples are given, but the present invention is not limited thereto.

Example 1

Preparation method of bexarotene and polyvinylpyrrolidone co-amorphous product 1:

According to the table below, take an appropriate amount of bexarotene and polyvinylpyrrolidone in a mass ratio of 1:1 and put them in a ball mill. The powder X-ray diffraction analysis was carried out, and the diffraction pattern was consistent with Fig. 1, indicating that the obtained sample was a co-amorphous product of bexarotene and polyvinylpyrrolidone.

Table 3 Preparation method parameters of bexarotene and polyvinylpyrrolidone co-amorphous

Preparation method 2 of co-amorphous substance of bexarotene and polyvinylpyrrolidone:

Take 3 parts of Bexarotene 20g, and weigh 4g, 20g, 100g of polyvinylpyrrolidone respectively according to the mass ratio of 5:1, 1:1, 1:5, put them into the ball mill respectively, and select the ball-to-material ratio of 6: 1. The rotation speed is 400 r/min, the grinding is stopped for 2 minutes every 15 minutes, and the ball is milled for 10 hours, 2 hours, and 0.5 hours, respectively, to obtain the co-amorphous samples of bexarotene and polyvinylpyrrolidone, and the obtained samples are analyzed by powder X-ray diffraction , and its diffraction pattern is shown in Figure 8.

Example 2

The solubility characteristics of bexarotene and polyvinylpyrrolidone co-amorphous and bexarotene bulk drug in pure water system were investigated. Referring to the "Technical Guidelines for Dissolution Testing of Ordinary Oral Solid Preparations", the dissolution curves were compared using the model-independent similarity factor (f2) method. When the f2 value is higher than 50, the two curves are considered to be similar, and when the f2 value is lower than 50, the two curves are considered to be different. In the experiment, the Bexarotene sample was used as a reference, and the model-independent similarity factor f2 value was calculated. The dissolved percentage was measured by high performance liquid phase method at a wavelength of 259 nm, and the dissolved percentage was calculated by the external standard method. Taking the time as the abscissa and the dissolution percentage as the ordinate, the dissolution curves were drawn respectively (Fig. 6). The data are shown in the following table: Table 3 Dissolution curve data of bexarotene and polyvinylpyrrolidone co-amorphous and bexarotene in pure water

It can be seen from the experimental data that the dissolution behavior of bexarotene and polyvinylpyrrolidone co-amorphous in pure water system is obviously better than that of bexarotene, which is embodied in the bexarotene and polyvinylpyrrolidone co-amorphous has Faster dissolution rate and higher dissolution amount, easier to absorb more quickly to reach effective blood drug concentration, and its total absorption is also significantly increased, which is 4 times higher than that of bexarotene, which can better achieve the drug The solubility curve of bexarotene and polyvinylpyrrolidone co-amorphous has a stable release platform, which can ensure a stable blood drug concentration during disease treatment.

Example 3

Absorption characteristics and plasma concentration characteristics of bexarotene and polyvinylpyrrolidone co-amorphous in rats:

Twelve SD rats were randomly divided into 2 groups, 6 rats in each group, fasting and drinking 12 hours before administration. The body weight of the rats was weighed, and the bexarotene dosage was calculated according to the bexarotene dosage of 30 mg·kg ^-1 . The bexarotene and the co-amorphous samples of bexarotene and polyvinylpyrrolidone were loaded into the solid drug dispenser, and the samples were injected into the solid drug dispenser. The powder was placed directly into the rat stomach. 5min, 15min, 30min, 45min, 1h, 1.5h, 2h, 4h, 8h, 12h, 24h after administration, blood was collected from the intraocular canthus, placed in a heparinized tube, centrifuged at 4°C, 4000rpm for 10min, and frozen in - 40 ℃ refrigerator to be tested. Precisely draw 100 μL of plasma from experimental animals at different times, put it in a 1.5 mL centrifuge tube, add 10 μL (10ug/ml) of internal standard (ursolic acid) working solution, vortex for 5 min, add 300 uL of acetonitrile to precipitate protein, and 500 uL of ethyl acetate for extraction , vortexed for 5min, centrifuged at 1.34×10 ⁴ rpm for 10min, took 880uL of supernatant in another empty centrifuge tube, dried with nitrogen, and reconstituted with 100μL of reconstituted solution (methanol:water (ammonia 0.1%)=1:1), Vortex for 5 min, centrifuge at 1.34×10 ⁴ rpm for 5 min, and take 90 μL of the supernatant for injection detection.

Detection conditions: Eclipse plus C18 (2.1×100mm, 3.5μm, USA); mobile phase is acetonitrile:water (containing 0.1% ammonia water)=30:70 (v:v); flow rate 0.3mL/min; column temperature 30℃; Injection volume: 10 μL; running time: 8 min; mass spectrum signal: ESI source (positive ion detection mode), ions for quantitative analysis m/z=455 (ursolic acid), m/z=347 (bexarotene) ), the fragmentation voltages are 130V (bexarotene), 130V (ursolic acid), the gain factor is 1.5, the drying airflow is 11.0L/min, the spray chamber voltage is 35psig, the dryer temperature is 350°C, and the capillary voltage 3000V (positive), 3000V (negative).

Table 4 shows the blood concentrations of bexarotene and bexarotene and polyvinylpyrrolidone co-amorphous samples in the blood of rats after oral administration; Table 5 shows the oral bexarotene and bexarotene in rats The pharmacokinetic parameters of co-amorphous samples with polyvinylpyrrolidone from 0 to 24 hours indicate that bexarotene and polyvinylpyrrolidone co-amorphous have the advantages of fast absorption, high blood concentration and prolonged action platform. .

)Table 4 Plasma concentrations at each time point (n=3,

)

Table 5 Pharmacokinetic parameters of bexarotene and co-amorphous bexarotene and polyvinylpyrrolidone after oral administration in SD rats

Example 4

Preparation method 1 (tablet) of combined pharmaceutical preparation:

A preparation method of a combination drug tablet, which is characterized by using bexarotene and polyvinylpyrrolidone co-amorphous, using several excipients as auxiliary components for preparing the combination drug tablet, and preparing according to a certain proportion. Each tablet contains tablet samples with a total amorphous form of 5 to 500 mg. Table 6 gives the tablet formulation ratio:

Table 6 Preparation formula of bexarotene and polyvinylpyrrolidone co-amorphous combination drug tablet

The method for preparing tablet preparations with bexarotene and polyvinylpyrrolidone co-amorphous as raw materials is as follows: mixing several excipients and raw materials uniformly, directly compressing; After the medicine is mixed evenly, it is pressed into tablets.

Preparation method 2 (tablet) of combined pharmaceutical preparation:

A preparation method of a combination drug tablet, which is characterized by using bexarotene and polyvinylpyrrolidone co-amorphous, using several excipients as auxiliary components for preparing the combination drug tablet, and preparing according to a certain proportion. Each tablet contains tablet samples with a total amorphous form of 5 to 500 mg. Table 7 gives the tablet formulation ratio:

Table 7 Preparation formula of bexarotene and polyvinylpyrrolidone co-amorphous combination drug tablet

The method for preparing tablet preparations by co-amorphous bexarotene and polyvinylpyrrolidone as raw materials is as follows: mixing several excipients and raw materials evenly, adding an appropriate amount of 1% sodium hydroxymethyl cellulose solution to prepare The soft material is sieved and granulated, the wet granules are dried, sieved and granulated, and magnesium stearate and talc are added to mix evenly, and press into tablets.

Preparation method 3 (capsule) of combined pharmaceutical preparation:

A preparation method of a combined medicine capsule, which is characterized in that a co-amorphous substance of bexarotene and polyvinylpyrrolidone is used as a raw material drug, several excipients are used as auxiliary components for preparing a combined medicine capsule, and the preparation is made according to a certain proportion. Each tablet contains a capsule sample with a drug content of 5-500 mg, and Table 8 gives the capsule formula ratio:

Table 8 Bexarotene and polyvinylpyrrolidone co-amorphous compound drug capsule formulations of APIs and excipients

The method for preparing capsules with bexarotene and polyvinylpyrrolidone co-amorphous as raw materials is: mixing several excipients and raw materials evenly, adding an appropriate amount of 1% sodium hydroxymethyl cellulose solution to prepare a wet The granules are dried, sieved and granulated, added with magnesium stearate, mixed evenly, and inserted into capsules; , after sieving, directly into capsules.

Example 5

Dosage 1 (tablet) of bexarotene and polyvinylpyrrolidone co-amorphous combination drug:

A pharmaceutical composition prepared and developed using co-amorphous bexarotene and polyvinylpyrrolidone as active ingredients of medicine, characterized in that co-amorphous bexarotene and polyvinylpyrrolidone are used as active ingredients of medicine, and the daily dosage For 900mg, it can be prepared as 3 times a day/3 100mg ordinary tablets each time, or 3 times a day/1 300mg tablet each time.

Dosage of bexarotene and polyvinylpyrrolidone co-amorphous combination drug 2 (capsule):

A pharmaceutical composition prepared and developed using the co-amorphous substance of bexarotene and polyvinylpyrrolidone as the active ingredient of the medicine, characterized in that the co-amorphous substance of bexarotene and polyvinylpyrrolidone is used as the active ingredient of the medicine, and is administered daily The dosage is: 300mg, which can be prepared as 2 50mg capsules 3 times a day / each time, or 1 150mg capsule twice a day / each time.

Problems that need to be explained: the bexarotene and polyvinylpyrrolidone co-amorphous pharmaceutical composition involved in the present invention is affected by many factors on the administration dosage of the active ingredients, for example: the age of the patient, the difference in body surface area, the administration Different routes, times of administration, and different therapeutic purposes result in different dosages for each administration; different absorption and blood drug concentrations exist between samples, etc., which also cause the present invention to use bexarotene and polyvinylpyrrolidone co-amorphous components. Each suitable dosage range is 0.1-20 mg/kg body weight, preferably 2-10 mg/kg body weight. During use, different total dosage regimens of bexarotene and polyvinylpyrrolidone co-amorphous active ingredients should be formulated according to the actual needs of treatment, and can be divided into multiple or one-time administration methods.

references

[1]Daiss, Jürgen O, Burschka C, Mills J S, et al. Synthesis, CrystalStructure Analysis, and Pharmacological Characterization of Disila-bexarotene, a Disila-Analogue of the RXR-Selective Retinoid Agonist Bexarotene [J].Organometallics, 2005, 24(13):3192-3199.

[2] Wei Wei, Ma Shuai. Synthesis and optimization of Bexarotene [J]. Chemical Research and Applications, March 2013, No. 3, Vol. 25.

Claims (11)

1. a bexarotene and polyvinylpyrrolidone co-amorphous, it is characterized in that, bexarotene and polyvinylpyrrolidone form co-amorphous with a certain mass ratio, when using powder X-ray diffraction analysis to adopt Under the experimental conditions of CuK _α radiation, its powder X-ray diffraction pattern showed diffuse diffraction peaks, and the positions of the diffraction peaks were at 2-Theta values of 14.6±0.3° and 18.7±0.3. 2. bexarotene according to claim 1 and polyvinylpyrrolidone co-amorphous, it is characterized in that, the mass ratio of bexarotene and polyvinylpyrrolidone is 1:5～5:1, is preferably 1: 3 to 3:1. 3. The co-amorphous substance of bexarotene and polyvinylpyrrolidone according to claim 1, is characterized in that, when using attenuated total reflection Fourier transform infrared spectroscopy to analyze, at 3356, 3138, 3075, 3026, 2985, 2967 ,2932,2895,2625,2570,2602,2494,2480,2423,2223,2112,1970,1909,1860,1776,1680,1606,1588,1532,1488,1462,1406,1363,1326,1287,1260 , 1219, 1180, 1129, 1099, 1075, 1038, 1016, 988, 979, 965, 899, 880, 865, 850, 804, 746, 733, 684, 681, 671, ^658cm , where the allowable deviation of the characteristic peaks of the infrared spectrum is ±2cm ^-1 . 4. the preparation method of the co-amorphous bexarotene and polyvinylpyrrolidone described in any one of claim 1-3, it is characterized in that, bexarotene and polyvinylpyrrolidone are fed by a certain mass ratio, using Bexarotene and polyvinylpyrrolidone co-amorphous prepared by mechanochemical method with controlled pressure and temperature. 5. The preparation method according to claim 4, wherein the mass ratio of bexarotene and polyvinylpyrrolidone is 1:5 to 5:1, preferably 1:3 to 3:1; the mechanical The chemical method is selected from the ball milling method, wherein the ball-to-material ratio of the ball milling method is 1:1～10:1, preferably 6:1～10:1; the ball milling speed is 20r/min～400r/min; the grinding time is 0.1～10 hours . 6. A mixed solid substance containing bexarotene and polyvinylpyrrolidone co-amorphous, characterized in that, containing bexarotene and polyvinylpyrrolidone co-amorphous according to any one of claims 1-3 The amount is 1-99.9%, preferably 10-99.9%, more preferably 50-99.9%, most preferably 85-99.9%. 7. A pharmaceutical composition, characterized in that it comprises an effective dose of the co-amorphous substance of bexarotene and polyvinylpyrrolidone according to any one of claims 1 to 3 and a pharmaceutically acceptable carrier. 8 . A pharmaceutical composition, characterized in that, it comprises an effective dose of the co-amorphous mixture of bexarotene and polyvinylpyrrolidone as claimed in claim 6 as a mixed solid substance and a pharmaceutically acceptable carrier. 9. The pharmaceutical composition according to any one of claims 7 or 8, wherein the daily dose of bexarotene for human administration through the digestive tract is in the range of 5 to 1000 mg, and the dose of bexarotene for injection is in the range of 1 to 1000 mg. 100mg range. 10. The pharmaceutical composition according to any one of claims 7 or 8, wherein the dosage form of the pharmaceutical composition is a tablet, a capsule, a pill, an injection preparation, a sustained-release preparation or a controlled-release preparation. 11. Bexarotene and polyvinylpyrrolidone co-amorphous matter according to any one of claims 1-3 or bexarotene and polyvinylpyrrolidone co-amorphous matter mixed solid matter according to claim 6 or claim Application of the pharmaceutical composition according to any one of requirements 7 or 8 in the preparation of medicines for preventing and treating glioma, cutaneous T-cell lymphoma, breast cancer, psoriasis, Kaposi's sarcoma, lung cancer and Cushing's disease.

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