CN111714479A - A pharmaceutical composition containing bexarotene - Google Patents

Abstract

The invention discloses a pharmaceutical composition containing bexarotene, a preparation method and application. Specifically, the present invention discloses a pharmaceutical composition containing bexarotene and a preparation method; the pharmaceutical composition containing bexarotene is used as a pharmaceutical active ingredient in the preparation and prevention of glioma and cutaneous T-cell lymphoma , breast cancer, psoriasis, Kaposi's sarcoma, lung cancer and Cushing's disease drugs.

Description

A pharmaceutical composition containing bexarotene

technical field

The invention discloses a pharmaceutical composition containing bexarotene, a preparation method and application. Specifically, the present invention discloses a pharmaceutical composition containing bexarotene and a preparation method; the pharmaceutical composition containing bexarotene is used as a pharmaceutical active ingredient in the preparation and prevention of glioma and cutaneous T-cell lymphoma , breast cancer, psoriasis, Kaposi's sarcoma, lung cancer and Cushing's disease drugs.

Background technique

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 cocrystal former used in the invention is polyvinylpyrrolidone, and the structural formula is shown in the following formula 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 crystalline form I ^[1] .

Wei Wei et al. used 2,5-dimethyl-2,5-hexanediol as raw material, and obtained the antitumor drug Besa through seven steps of 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.

Based on the discovery of the co-crystal of bexarotene and ligustrazine, and the co-amorphous substance of bexarotene and polyvinylpyrrolidone, the present invention finds that the combination of the above two solid substances and bexarotene in a specific ratio can It achieves the advantageous biological characteristics of fast absorption, high blood concentration and prolonged action platform. Provide basic scientific data for finding, discovering, and developing the superior medicinal co-crystal/co-amorphous solid substance of Bexarotene with the best clinical efficacy; at the same time, it also provides a basis for applying for national applications based on Bexarotene solid pharmaceutical raw material substances Or provide scientific basis for international intellectual property invention patent protection.

SUMMARY OF THE INVENTION

One of the objectives of the present invention is to provide a pharmaceutical composition containing bexarotene and a preparation method thereof.

The second object of the present invention is to provide a pharmaceutical preparation using a pharmaceutical composition containing bexarotene as a pharmaceutical active ingredient. The daily dose of bexarotene administered to humans through the digestive tract is in the range of 5 to 1000 mg, and is administered by injection. The dosage is in the range of 1 to 100 mg. . The pharmaceutical preparations include tablets, capsules, pills, injection preparations, sustained-release or controlled-release preparations.

The third purpose of the present invention is to provide the pharmaceutical composition containing bexarotene to better exert the effective therapeutic effect of the medicine due to the biological absorption advantages such as fast absorption rate, high blood drug concentration and prolonged action platform during the treatment of diseases.

The fourth object of the present invention: the pharmaceutical composition containing bexarotene is used as an active ingredient in the preparation and prevention of glioma, cutaneous T-cell lymphoma, breast cancer, psoriasis, Kaposi's sarcoma, lung cancer and Cushing's disease application in medicine.

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 The pharmaceutical composition containing bexarotene according to the present invention contains bexarotene, bexarotene and ligustrazine co-crystal and bexarotene and polyvinylpyrrolidone co-amorphous.

1.2 The pharmaceutical composition involved in the present invention is characterized in that, calculated according to the mole fraction of bexarotene, it contains 10 parts of bexarotene, 10-50 parts of bexarotene and ligustrazine cocrystal, bexarotene Butyl and polyvinylpyrrolidone have a total of 10-50 parts of amorphous.

衍射峰相对强度：峰高值(Height％)或峰面积值(Area％)具有如下特征(表1，图1)：1.3 The pharmaceutical composition involved in the present invention, the bexarotene and ligustrazine co-crystals are co-crystals formed by bexarotene and ligustrazine in a molar ratio of 2:1, when using powder X-ray diffraction analysis using CuK Diffraction peak position: 2-Theta value (°) or d value under _α radiation experimental conditions

Diffraction peak relative intensity: peak height value (Height %) or peak area value (Area %) has the following characteristics (Table 1, Figure 1):

Table 1 Powder X-ray diffraction peaks of co-crystal of bexarotene and ligustrazine

；使用衰减全反射傅立叶红外光谱法进行分析时，在3094、3040、3015、2954、2855、2775、2602、2491、1936、1889、1835、1701、1606、1563、1495、1467、1453、1415、1394、1361、1337、1311、1252、1237、1190、1178、1135、1113、1083、1074、1046、1015、986、970、916、901、891、868、850、811、789、781、763、736、718、704、684cm^-1处存在红外光谱特征峰，其中红外光谱特征峰的允许偏差为±2cm^-1(图2)；

; when analyzed using ATR-FTIR, at 3094, 3040, 3015, 2954, 2855, 2775, 2602, 2491, 1936, 1889, 1835, 1701, 1606, 1563, 1495, 1467, 1453, 1415, 1394, 1361, 1337, 1311, 1252, 1237, 1190, 1178, 1135, 1113, 1083, 1074, 1046, 1015, 986, 970, 916, 901, 891, 868, 850, 811, 789, 781, 763, At 736, 718, 704, and 684 cm ^-1 , there are characteristic infrared spectrum peaks, and the allowable deviation of infrared spectrum characteristic peaks is ±2 cm ^-1 (Fig. 2);

When analyzed by differential scanning calorimetry, when the heating rate was 10°C per minute, there were two endothermic peaks at 133°C±3°C and 223°C±3°C in the DSC spectrum (Figure 3).

1.4 The pharmaceutical composition involved in the present invention, the described bexarotene and polyvinylpyrrolidone co-amorphous, wherein the mass ratio of bexarotene and polyvinylpyrrolidone is 5:1 to 1:5, preferably It is 3:1 to 1:3; when using powder X-ray diffraction analysis using CuK _α radiation experimental conditions, its powder X-ray diffraction pattern shows diffuse diffraction peaks, and the diffraction peak positions are at 2-Theta value of 14.6 ± 0.3° and 18.7±0.3° (Figure 4);

Attenuated total reflection FTIR analysis 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, 658 cm ^-1 there are infrared spectral characteristic peaks, wherein the allowable deviation of infrared spectral characteristic peaks is ±2cm ^-1 (Fig. 5).

1.4 The pharmaceutical composition involved in the present invention, the bexarotene and polyvinylpyrrolidone co-amorphous, the polyvinylpyrrolidone used is pharmaceutical grade, and its K value is usually between 10 and 120, preferably PVPK15, PVPK17 , PVPK25 and PVPK30.

衍射峰相对强度：峰高值(Height％)或峰面积值(Area％)具有如下特征(表2，图6)：1.5 The pharmaceutical composition involved in the present invention, the bexarotene, is bexarotene crystal form I, when the powder X-ray diffraction analysis adopts CuK _α radiation experimental conditions, the position of the diffraction peak: 2-Theta value (°) or d value

Diffraction peak relative intensity: peak height value (Height %) or peak area value (Area %) has the following characteristics (Table 2, Figure 6):

Table 2 Powder X-ray diffraction peaks of bexarotene

2. Characteristics of the preparation method of the pharmaceutical composition:

2.1 The bexarotene pharmaceutical composition of the present invention is to combine bexarotene, bexarotene and ligustrazine co-crystal, bexarotene and polyvinyl pyrrolidone co-amorphous in a certain proportion with a conventional method. Mix.

2.2 the preparation method of bexarotene of the present invention and ligustrazine eutectic is to feed bexarotene and ligustrazine by a certain molar ratio, and adopt the mechanochemical method of controlling pressure and temperature to prepare bexarotene and ligustrazine. Ligustrazine cocrystal, obtained by drying at high temperature; the molar ratio is that the mole number of ligustrazine is higher than 1/2 of the mole number of bexarotene, and the preferred molar ratio of bexarotene and ligustrazine is 3:2～1 : 5, and the more preferred molar ratio of bexarotene and ligustrazine is 1:1 to 1:3. Among them, the mechanochemical method is preferably liquid ball milling method, and the ball-to-material ratio of liquid addition ball milling method is 1:1～10:1, preferably 6:1～10:1; the ball milling speed is 20r/min～400r/min The kind of organic solvent that adds liquid is any one or more mixed solvents made through different proportioning combinations; Described organic solvent is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butyl alcohol Alcohol, amyl alcohol, isoamyl alcohol, n-hexanol, ethylene glycol, acetonitrile, acetone, ethyl acetate, dioxane, tetrahydrofuran, n-hexane and/or cyclohexane; the amount of liquid added is 0.01～1 gram per gram of sample 100ml; grinding time is 0.05-10 hours; high temperature drying temperature is 40-80°C; drying time is 0.1-10 hours.

2.3 The preparation method of bexarotene and polyvinylpyrrolidone co-amorphous substance of the present invention is to feed bexarotene and polyvinylpyrrolidone in a certain mass ratio, and adopt the mechanochemical method of controlling pressure and temperature to prepare bexarotene. Rodin and polyvinylpyrrolidone co-amorphous. Wherein, the mass ratio of bexarotene to polyvinylpyrrolidone is 1:5 to 5:1, preferably 1:3 to 3:1; the mechanochemical method is selected from the ball milling method, wherein the ball material of the ball milling method The ratio 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.

3. Pharmaceutical preparations, dosage characteristics and pharmaceutical uses of the pharmaceutical composition:

3.1 The pharmaceutical composition involved in the present invention further contains a pharmaceutically acceptable carrier.

3.2 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 for injection is in the range of 1-100 mg. .

3.3 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.

3.4 The present invention relates to the application of the pharmaceutical composition in the preparation of medicines for the prevention and treatment of glioma, cutaneous T-cell lymphoma, breast cancer, psoriasis, Kaposi's sarcoma, lung cancer and Cushing's disease.

The pharmaceutical composition involved in the present invention, its pharmaceutical preparation can be prepared according to methods known in the art, by mixing the pharmaceutical composition containing bexarotene of the present invention with one or more pharmaceutically acceptable solid or liquid excipients Agents and/or adjuvants are combined into any dosage form suitable for human or animal use. The content of the pharmaceutical composition containing bexarotene of the present invention in the pharmaceutical preparation is in the range of 10% to 90% by weight.

The pharmaceutical composition containing bexarotene of the present invention can be administered in unit dosage form, and the route of administration can be enteral or parenteral, such as oral, intravenous, intramuscular, subcutaneous, nasal, oral mucosa, eye, lung 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 pharmaceutical preparation of the bexarotene-containing pharmaceutical composition of the present invention can be made into common preparations, sustained-release preparations, controlled-release preparations, targeted preparations and various microparticle drug delivery systems.

In order to make the bexarotene-containing pharmaceutical composition of the present invention into tablets, various excipients known in the art can be widely used, including diluents, binders, wetting agents, disintegrating agents, lubricants, adjuvants flow agent. 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 dosage unit into a capsule, the pharmaceutical composition containing bexarotene can be mixed with a diluent, a glidant, and the mixture can be directly placed in a hard capsule or a soft capsule. The pharmaceutical composition containing bexarotene can also be prepared 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 in the preparation of bexarotene-containing pharmaceutical composition tablets can also be used in the preparation of bexarotene-containing pharmaceutical composition capsules agent.

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 pharmaceutical preparation of the pharmaceutical composition containing bexarotene of the present invention can vary widely according to the nature and severity of the disease to be prevented or treated, individual conditions of patients or animals, administration routes and dosage forms. 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 pharmaceutical composition containing bexarotene of the present invention can be taken alone, or used in combination with other therapeutic drugs or symptomatic drugs. When the pharmaceutical composition containing bexarotene 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 biological activity of the pharmaceutical composition containing bexarotene.

The biological absorption effect of the pharmaceutical composition containing bexarotene of the present invention after oral administration is characterized in that, through bexarotene, bexarotene and ligustrazine cocrystal and bexarotene and polyvinylpyridine The dosage ratio of the co-amorphous iodine can achieve the advantageous biological characteristics of fast absorption in the gastrointestinal tract or blood, high blood concentration and prolonged action platform, so as to play an advantageous role and application in the prevention and treatment of diseases ( Figure 7).

Description of drawings

Fig.1 Powder X-ray diffraction pattern of co-crystal of bexarotene and ligustrazine

Fig.2 Infrared absorption spectrum of bexarotene and ligustrazine co-crystal

Fig.3 Differential scanning calorimetry of co-crystal of bexarotene and ligustrazine

Fig.4 Powder X-ray diffraction pattern of bexarotene and polyvinylpyrrolidone co-amorphous

Fig.5 Infrared absorption spectrum of bexarotene and polyvinylpyrrolidone co-amorphous

Fig.6 Powder X-ray diffraction pattern of Bexarotene

Fig. 7 The drug time curve of bexarotene and the pharmaceutical composition containing bexarotene in rats orally absorbed 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 pharmaceutical composition containing bexarotene 1

Weigh 50 mg of bexarotene crystal type I, 88 mg of bexarotene and ligustrazine eutectic, and 100 mg of co-amorphous bexarotene and polyvinylpyrrolidone 1:1, and physically mix them uniformly according to conventional methods. get.

Preparation method of pharmaceutical composition containing bexarotene 2

Weigh 50 mg of bexarotene crystal type I, 440 mg of bexarotene and ligustrazine eutectic, and 500 mg of co-amorphous bexarotene and polyvinylpyrrolidone 1:1, and physically mix them uniformly according to conventional methods. get.

Example 2

Preparation method of bexarotene and ligustrazine cocrystal 1:

According to the table below, take appropriate amounts of bexarotene and ligustrazine into a mortar, add an appropriate amount of organic solvent, manually grind for an appropriate time, and dry at high temperature. 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-crystal of bexarotene and ligustrazine.

Preparation method 2 of bexarotene and ligustrazine cocrystal:

As shown in the table below, take an appropriate amount of bexarotene and ligustrazine into a ball mill jar, add an appropriate amount of organic solvent, select an appropriate ball-to-material ratio, set an appropriate rotation speed, grind for an appropriate time, and dry at high temperature. 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-crystal of bexarotene and ligustrazine.

Preparation method 3 of bexarotene and ligustrazine cocrystal:

According to the table below, take an appropriate amount of bexarotene and ligustrazine into a clean container, add an appropriate amount of organic solvent, stir at room temperature for an appropriate time, the obtained suspension is filtered, and the solid material is dried at high temperature. 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-crystal of bexarotene and ligustrazine.

Example 3

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. 4, indicating that the obtained sample was a co-amorphous product of bexarotene and polyvinylpyrrolidone.

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 4

Absorption characteristics and plasma concentration characteristics of pharmaceutical compositions containing bexarotene in rats:

18 SD rats were randomly divided into 3 groups with 6 rats in each group. They were fasted for 12 hours before administration. The body weight of the rats was weighed and calculated by the Bexarotene dosage of 30 mg·kg ^-1 . The molar ratio of azine co-crystal, bexarotene and polyvinylpyrrolidone co-amorphous is 1:1:1), pharmaceutical composition 2 (bexarotene, bexarotene and chuanxiong) containing bexarotene The molar ratio of oxazine co-crystal, bexarotene and polyvinylpyrrolidone co-amorphous is 1:5:5) The sample is loaded into a solid drug dispenser, and the medicinal powder is directly placed into the rat stomach through the oral cavity. 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 5 min, centrifuged at 1.34×10 ⁴ rpm for 10 min, took 880 μL of supernatant into another empty centrifuge tube, dried with nitrogen, and reconstituted with 100 μL 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 3 provides the blood concentration of each time point in the blood of rats after oral administration of bexarotene and the pharmaceutical composition samples containing bexarotene, and the experimental results show that the two pharmaceutical compositions containing bexarotene have The advantages of fast absorption speed, high blood drug concentration and prolonged action platform.

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

)

Example 5

Preparation method 1 (tablet) of pharmaceutical preparation:

A preparation method of a combined drug tablet, which is characterized in that a pharmaceutical composition containing bexarotene and several excipients are used as auxiliary ingredients for preparing the combined drug tablet, and each tablet containing bexarotene is formulated according to a certain proportion. Table 4 gives the tablet formulation ratio of sarotin in 5-500mg tablet samples:

Table 4 The preparation formula of the pharmaceutical composition tablet containing bexarotene

The method for preparing a tablet preparation with a pharmaceutical composition containing bexarotene as a raw material drug is as follows: mixing several excipients with the raw material drug uniformly, and directly compressing the tablet; After pressing, you can get it.

Preparation method 2 (tablet) of combined pharmaceutical preparation:

A preparation method of a combination drug tablet, which is characterized in that a pharmaceutical composition containing bexarotene is used, several excipients are used as auxiliary ingredients for preparing the combination drug tablet, and each tablet is prepared according to a certain proportion and proportion. Table 5 gives the tablet formulation ratio:

Table 5 contains the preparation formula of the pharmaceutical composition combination medicine tablet of bexarotene

The method for preparing a tablet preparation containing a pharmaceutical composition containing bexarotene as a raw material drug is as follows: mixing several excipients and the raw material drug uniformly, adding an appropriate amount of 1% sodium hydroxymethyl cellulose solution to prepare a soft material , sieving and granulating, drying the wet granules, sieving and granulating, adding magnesium stearate and talc, mixing evenly, and pressing into tablets.

Preparation method 3 (capsule) of combined pharmaceutical preparation:

A preparation method of a combined medicine capsule, which is characterized in that a pharmaceutical composition containing bexarotene is used, several excipients are used as auxiliary ingredients for preparing the combined medicine capsule, and each tablet is formulated according to a certain proportion to make the medicine content of each tablet. In the capsule samples of 5～500mg, Table 6 gives the capsule formula ratio:

Table 6 contains the pharmaceutical composition of bexarotene, the raw material drug and the auxiliary material formulation of the drug combination drug capsule preparation

The method for preparing a capsule containing a pharmaceutical composition containing bexarotene as a bulk drug is as follows: mixing several excipients and bulk drug uniformly, adding an appropriate amount of 1% sodium hydroxymethyl cellulose solution, making wet granules and drying Sieve and granulate, add magnesium stearate, mix evenly, and insert into capsules; , directly into capsules.

Example 6

Dosage 1 (tablet) of pharmaceutical composition containing bexarotene:

The pharmaceutical preparation developed by using the pharmaceutical composition containing bexarotene as the active pharmaceutical ingredient is characterized in that the pharmaceutical composition containing bexarotene is used as the active ingredient of the medicine, and the daily dosage is 900 mg, which can be prepared into 3 regular 100mg tablets 3 times a day or 1 300mg tablet 3 times a day.

Dosage 2 (capsule) of pharmaceutical composition containing bexarotene:

Use the pharmaceutical composition containing bexarotene as the pharmaceutical active ingredient to prepare and develop the pharmaceutical composition, it is characterized in that using the pharmaceutical composition containing bexarotene as the active ingredient of the medicine, the daily dosage is: 300mg, can It is prepared as 2 50mg capsules 3 times a day / each time, or 1 150mg capsule 2 times a day / each time.

Problems that need to be explained: the pharmaceutical composition containing bexarotene involved in the present invention is affected by many factors on the dosage of the active ingredient, such as: the age of the patient, the difference in body surface area, the route of administration, the number of administrations, Different therapeutic purposes result in different dosages for each administration; different absorption and blood drug concentrations exist between samples, etc., which also causes the present invention to use the bexarotene-containing pharmaceutical composition components in the appropriate dosage range of 0.1-20 mg each time /kg body weight, preferably 2-10 mg/kg body weight. During use, different total dosage regimens of the active ingredients of the pharmaceutical composition containing bexarotene should be formulated according to the actual needs of different treatment situations, which 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 (9)

1. A pharmaceutical composition containing Bexarotene is characterized by containing Bexarotene, a Bexarotene and ligustrazine eutectic compound and Bexarotene and polyvinylpyrrolidone co-amorphous compound.

2. The pharmaceutical composition according to claim 1, which comprises 10 parts of Bexarotene, 10-50 parts of Bexarotene and ligustrazine eutectic compound and 10-50 parts of Bexarotene and polyvinylpyrrolidone co-amorphous compound calculated according to the molar parts of Bexarotene.

3. The pharmaceutical composition of claim 1, wherein the eutectic of bexarotene and ligustrazine is bexarotene and ligustrazine in a 2:1 molar ratio when CuK is used for powder X-ray diffraction analysis_αDiffraction peak position under irradiation test conditions: 2-Theta value (°) or d value

Diffraction peak relative intensity: the peak Height value (Height%) or peak Area value (Area%) has the following characteristics:

4. the pharmaceutical composition according to claim 1 wherein Bexarotene is co-amorphous with polyvinylpyrrolidone and is characterized by CuK when analyzed using powder X-ray diffraction_αWhen the powder X-ray diffraction pattern is radiated under the experimental condition, the powder X-ray diffraction pattern of the powder X-ray diffraction pattern shows scattered diffraction peaks, and the positions of the diffraction peaks are 14.6 +/-0.3 degrees and 18.7 +/-0.3 degrees of 2-Theta values.

5. A process for the preparation of a pharmaceutical composition according to any of claims 1-2, characterized in that beasalutin, a eutectic of beasalutin with ligustrazine and a co-amorphous of beasalutin with polyvinylpyrrolidone are mixed in a specific ratio in a conventional manner.

6. The pharmaceutical composition according to any one of claims 1-2, further comprising a pharmaceutically acceptable carrier.

7. The pharmaceutical composition according to claim 6, wherein the amount of the Bexarotene administered via the digestive tract in a daily human is in the range of 5 to 1000mg and the amount of the Bexarotene administered by injection is in the range of 1 to 100 mg.

8. The pharmaceutical composition of claim 6, wherein the pharmaceutical composition is in the form of a tablet, capsule, pill, injectable, sustained release or controlled release formulation.

9. Use of a pharmaceutical composition according to any one of claims 1-2 for the manufacture of a medicament for the prevention or treatment of glioma, cutaneous T-cell lymphoma, breast cancer, psoriasis, kaposi's sarcoma, lung cancer and cushing's disease.

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