CN111718258A - Bexarotene and polyvinylpyrrolidone co-amorphous substance, preparation method, composition and application thereof - Google Patents
Bexarotene and polyvinylpyrrolidone co-amorphous substance, preparation method, composition and application thereof Download PDFInfo
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Abstract
The invention discloses a Bexarotene and polyvinylpyrrolidone co-amorphous substance, a preparation method, a composition and application thereof. Specifically, the invention discloses a novel co-amorphous form formed by Bexarotene and polyvinylpyrrolidone; a preparation method of Bexarotene and polyvinylpyrrolidone in a co-amorphous form; the Bexarotene and polyvinylpyrrolidone are used together in an amorphous form as active pharmaceutical ingredients for preparing drugs for preventing and treating glioma, cutaneous T-cell lymphoma, breast cancer, psoriasis, Kaposi's sarcoma, lung cancer and Cushing's disease.
Description
Technical Field
The invention discloses a Bexarotene and polyvinylpyrrolidone co-amorphous substance, a preparation method, a composition and application thereof. Specifically, the invention discloses a co-amorphous substance formed by Bexarotene and polyvinylpyrrolidone; a preparation method of Bexarotene and polyvinylpyrrolidone co-amorphous substance; the application of the Bexarotene and polyvinylpyrrolidone co-amorphous substance as a medicinal active ingredient in preparing medicaments for preventing and treating glioma, cutaneous T-cell lymphoma, breast cancer, psoriasis, Kaposi sarcoma, lung cancer and Cushing's disease.
Background
Drug co-amorphous refers to an amorphous substance formed by non-covalent intermolecular interaction of active drug molecules with co-amorphous ligands in a certain ratio. The medicine can improve the physicochemical property and the clinical treatment effect on one hand by forming the co-amorphous form, and the co-amorphous form can enrich the crystal form on the other hand. For chemical imitation drugs, the patent protection of the original drug research enterprises can be broken through the research of the co-amorphous substance, and the innovativeness and market competitiveness of the drugs are improved.
The invention adopts Bexarotene as an active substance, and the chemical name of the Bexarotene is 4- [1- (5,6,7, 8-tetrahydro-3, 5,5,8, 8-pentamethyl-2-naphthyl) vinyl]Benzoic acid of formula C24H28O2The structural formula is shown as a. The co-amorphous ligand (crystal former) adopted in the invention is polyvinylpyrrolidone, and the structural formula is shown in a figure b.
Daiss et al synthesized bexarotene analogs using 1, 2-bis (chlorodimethylsilyl) ethane as the starting material using a multi-step synthesis, determined product properties by elemental analysis and multinuclear nuclear magnetic resonance studies, and structurally characterized the product by single crystal X-ray diffraction. Bexarotene is determined to be crystal I form in the literature[1]。
The anti-tumor drug Bexarotene is prepared by using 2, 5-dimethyl-2, 5-hexanediol as a raw material through seven steps of reactions such as chlorination, F-C alkylation, F-C acylation, Wittig reaction, hydrolysis and the like, and the synthesis process is optimized, wherein the obtained product is crystal I type[2]。
There are 1 total of reported crystal forms of bexarotene. There is currently no report on the besartan co-crystal.
The invention discloses a Bexarotene co-amorphous solid substance state and a preparation method which are different from the contents reported in the patent or literature research.
The research purpose of the invention is to start from the research on the existence state of the Bexarotene solid matter, search and discover the existence type and state characteristics of the eutectic/co-amorphous solid matter on the level of the raw materials of the active ingredients of the medicament through an eutectic/co-amorphous screening technology and a bioactivity evaluation technology, combine the eutectic/co-amorphous solid matter with pharmacodynamic research, and provide basic scientific data for searching, discovering and developing the superior medicinal eutectic/co-amorphous solid matter of Bexarotene with the optimal clinical curative effect; meanwhile, a scientific basis is provided for applying for national or international intellectual property patent protection on the basis of the Bexarotene solid drug raw material.
Disclosure of Invention
One of the objects of the present invention is: provides the existence state and the representation mode of the Bexarotene and polyvinylpyrrolidone co-amorphous substance.
The second object of the present invention is: provides a preparation method of Bexarotene and polyvinylpyrrolidone co-amorphous substance.
The third object of the present invention is: provides a pure Bexarotene and polyvinylpyrrolidone co-amorphous substance or a mixed solid substance containing Bexarotene and polyvinylpyrrolidone co-amorphous substance in any non-zero proportion and a pharmaceutical composition thereof.
The fourth purpose of the invention is that: provided is a pharmaceutical composition comprising a Bexarotene and polyvinylpyrrolidone together as active pharmaceutical ingredients, wherein the daily dose of Bexarotene for administration through the digestive tract is 5-1000 mg, and the dose for injection is 1-100 mg. . The pharmaceutical composition comprises tablets, capsules, pills, injection preparations and sustained-release or controlled-release preparation medicaments.
The fifth purpose of the invention is: the Bexarotene and polyvinylpyrrolidone co-amorphous substance is provided, and has better solubility advantage compared with Bexarotene.
The sixth purpose of the invention is: provides a Bexarotene and polyvinylpyrrolidone co-amorphous substance which can improve the blood concentration in organisms due to the co-amorphous substance in the process of treating diseases so as to play an effective treatment role of the medicine.
The seventh of the purposes of the present invention: the application of the Bexarotene and polyvinylpyrrolidone in preparing the medicines for preventing and treating glioma, cutaneous T-cell lymphoma, breast cancer, psoriasis, Kaposi sarcoma, lung cancer and Cushing's disease as the active ingredients of the medicines is provided.
In order to solve the technical problems, the invention adopts the following technical scheme:
1. bexarotene and polyvinylpyrrolidone are combined to form amorphous sample morphological characteristics:
1.1 the Bexarotene and polyvinylpyrrolidone co-amorphous substance related by the invention is a co-amorphous substance formed by Bexarotene and polyvinylpyrrolidone according to a certain mass ratio, when CuK alpha radiation experiment conditions are adopted in powder X-ray diffraction analysis, a powder X-ray diffraction spectrum of the Bexarotene and polyvinylpyrrolidone co-amorphous substance presents dispersed 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 (figure 1); the powder X-ray diffraction pattern and data for the physical mixture of beaxarotene and polyvinylpyrrolidone are shown in table 1 and figure 2. Figure 3 shows a powder X-ray diffraction pattern contrast for beasalosin, polyvinylpyrrolidone, a physical mixture of beasalosin and polyvinylpyrrolidone, and a co-amorphous beasalosin and polyvinylpyrrolidone.
As can be seen from fig. 3, the bexarotene raw material is crystalline and is crystalline form I, the polyvinylpyrrolidone is amorphous, 2Theta of the bexarotene raw material has 2 dispersion diffraction peaks in the range of 3-40 °, the positions of the 2Theta values are 11.7 ± 0.3 ° and 19.9 ± 0.3 °, the spectrum of the mixture of the bexarotene and the polyvinylpyrrolidone in proportion is a mixture of crystalline and amorphous, and the cosmophilic compound of the bexarotene and the polyvinylpyrrolidone has obvious differences from the three in the aspects of diffraction peak number, diffraction peak position, diffraction peak intensity, diffraction peak topological pattern and the like, which fully shows that the bexarotene and the polyvinylpyrrolidone form a co-amorphous compound with non-covalent bond or van der waals molecular acting force and is neither the same as nor the same as the physical mixture of the bexarotene and the polyvinylpyrrolidone.
TABLE 1 powder X-ray diffraction Peak of Bexarotene physically blended with polyvinylpyrrolidone
1.2 the Bexarotene and polyvinylpyrrolidone co-amorphous substance provided by the invention, wherein the mass ratio of Bexarotene and polyvinylpyrrolidone is 1: 5-5: 1, and preferably 1: 3-3: 1.
1.3 Bexarotene and polyvinylpyrrolidone co-amorphous form of the invention, when analyzed by attenuated total reflectance Fourier Infrared Spectroscopy, is characterized by 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, 1219, 1180, 1129, 1099, 1075, 1038, 1016, 988, 979, 965, 899, 880, 865, 850, 804, 746, 733, 684, 681, 671, 658cm-1Has characteristic peaks of infrared spectrum, wherein the allowable deviation of the characteristic peaks of the infrared spectrum is +/-2 cm-1(FIG. 4). Bexarotene and polyvinylpyrrolidoneAs can be seen from the comparison graph (fig. 5) of the infrared spectra of the co-amorphous substance and the physical mixture of beasalosin and polyvinylpyrrolidone, the numbers, positions, intensities and other aspects of the infrared absorption peaks of the beasalosin and polyvinylpyrrolidone co-amorphous substance and the physical mixture of beasalosin and polyvinylpyrrolidone are all obviously different, which indicates that the beasalosin and polyvinylpyrrolidone co-amorphous substance and the physical mixture of beasalosin and polyvinylpyrrolidone are neither the same nor the same.
1.4 the Bexarotene and polyvinylpyrrolidone co-amorphous substance of the invention, the polyvinylpyrrolidone used is of pharmaceutical grade, the K value is usually between 10 and 120, and preferably PVPK15, PVPK17, PVPK25 and PVPK30.
2. The preparation method of the Bexarotene and polyvinylpyrrolidone co-amorphous substance and mixed solid substance is characterized by comprising the following steps:
2.1 the invention relates to a preparation method of a Bexarotene and polyvinylpyrrolidone co-amorphous substance, which comprises the steps of feeding Bexarotene and polyvinylpyrrolidone according to a certain mass ratio, and preparing the Bexarotene and polyvinylpyrrolidone co-amorphous substance by a mechanochemical method with controlled pressure and temperature. Wherein the feeding mass ratio is 1: 5-5: 1, preferably 1: 3-3: 1; the ball-material ratio of the liquid adding ball milling method is 1: 1-10: 1, preferably 6: 1-10: 1; the ball milling speed is 20r/min to 400 r/min; the grinding time is 0.1 to 10 hours.
2.2 the solid substance mixture of Bexarotene and polyvinylpyrrolidone of the invention is prepared by mixing Bexarotene and polyvinylpyrrolidone with other chemical substances in any non-zero ratio and by conventional method.
3. The pharmaceutical preparation composition containing Bexarotene and polyvinylpyrrolidone has the following characteristics of administration dosage and pharmaceutical application:
3.1 the pharmaceutical composition contains Bexarotene and polyvinylpyrrolidone co-amorphous substance and a pharmaceutically acceptable carrier.
3.2 the pharmaceutical composition comprises a mixed solid substance of Bexarotene and polyvinylpyrrolidone co-amorphous substance and a pharmaceutically acceptable carrier.
3.3 the pharmaceutical composition of the invention, wherein the dose of the drug for the daily administration of Bexarotene through the alimentary canal is within the range of 5-1000 mg, and the dose of the drug for the injection is within the range of 1-100 mg. .
3.4 the pharmaceutical composition of the present invention is characterized in that the pharmaceutical composition is various tablets, capsules, pills, preparations for injection, sustained release preparations or controlled release preparations.
3.5 the invention relates to the use of a mixed solid substance or a pharmaceutical composition of Bexarotene and polyvinylpyrrolidone co-amorphous substance, Bexarotene and polyvinylpyrrolidone co-amorphous substance in the preparation of medicaments for preventing and treating glioma, cutaneous T-cell lymphoma, breast cancer, psoriasis, Kaposi's sarcoma, lung cancer and Cushing's disease.
The invention relates to a pharmaceutical composition which takes the Bexarotene and polyvinylpyrrolidone together amorphous substance as active ingredients. The pharmaceutical composition may be prepared according to methods well known in the art. Any dosage form suitable for human or animal use can be made by combining the co-amorphous component of bexarotene and polyvinylpyrrolidone of the invention with one or more pharmaceutically acceptable solid or liquid excipients and/or adjuvants. The content of the Bexarotene and polyvinylpyrrolidone co-amorphous substance in the pharmaceutical composition is within the range of 10-90% by weight.
The Bexarotene and polyvinylpyrrolidone co-amorphous substance can be administrated in a unit dosage form, and the administration route can be intestinal tract or parenteral tract, such as oral administration, intravenous injection, intramuscular injection, subcutaneous injection, nasal cavity, oral mucosa, eyes, lungs, respiratory tract, skin, vagina, rectum and the like.
The administration form according to the invention is preferably a solid form. The solid dosage form can be tablet (including common tablet, enteric coated tablet, buccal tablet, dispersible tablet, chewable tablet, effervescent tablet, orally disintegrating tablet), capsule (including hard capsule, soft capsule, and enteric coated capsule), granule, powder, pellet, dripping pill, suppository, pellicle, patch, aerosol (powder), spray, etc.
The Bexarotene and polyvinylpyrrolidone co-amorphous substance can be prepared into common preparations, sustained release preparations, controlled release preparations, targeting preparations and various particle delivery systems.
For the preparation of the inventive bexarotene and polyvinylpyrrolidone co-amorphous form into tablets, a wide variety of excipients known in the art may be used, including diluents, binders, wetting agents, disintegrants, lubricants, glidants. The diluent can be starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.; the humectant can be water, ethanol, isopropanol, etc.; the binder can be starch slurry, dextrin, syrup, Mel, glucose solution, microcrystalline cellulose, acacia slurry, gelatin slurry, sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, ethyl cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, polyethylene glycol, etc.; the disintegrant may be dry starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, crosslinked polyvinylpyrrolidone, crosslinked sodium carboxymethylcellulose, sodium carboxymethyl starch, sodium bicarbonate and citric acid, polyoxyethylene sorbitol fatty acid ester, sodium dodecyl sulfate, etc.; the lubricant and glidant may be talc, silicon dioxide, stearate, tartaric acid, liquid paraffin, polyethylene glycol, and the like.
The tablets may be further formulated into coated tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or double-layer and multi-layer tablets.
In order to prepare the administration unit into a capsule, the active ingredients of the beaxarotene and polyvinylpyrrolidone co-amorphous substance of the invention can be mixed with a diluent and a glidant, and the mixture is directly placed into a hard capsule or a soft capsule. Or the effective components of the Bexarotene and polyvinylpyrrolidone together amorphous matter of the invention are firstly prepared into granules or pellets with diluent, adhesive and disintegrant and then placed into hard capsules or soft capsules. Various diluents, adhesives, wetting agents, disintegrating agents and glidants for preparing the Bexarotene and polyvinylpyrrolidone co-amorphous substance tablet can also be used for preparing the Bexarotene and polyvinylpyrrolidone co-amorphous substance capsule.
In addition, colorants, preservatives, flavors, or other additives may also be added to the pharmaceutical preparation, if desired.
For the purpose of administration and enhancing the therapeutic effect, the drug of the present invention can be administered by any known administration method.
The dosage of the Bexarotene and polyvinylpyrrolidone co-amorphous pharmaceutical composition of the invention can vary widely depending on the nature and severity of the disease to be prevented or treated, the individual condition of the patient or animal, the route of administration and the dosage form, etc. The above-described dosage may be administered in one dosage unit or divided into several dosage units, depending on the clinical experience of the physician and the dosage regimen including the use of other therapeutic means.
The Bexarotene and polyvinylpyrrolidone co-amorphous substance or the composition can be independently taken or used together with other treatment medicines or symptomatic medicines. When the Bexarotene and polyvinylpyrrolidone co-amorphous compound of the invention has synergistic effect with other therapeutic drugs, the dosage of the Bexarotene and polyvinylpyrrolidone co-amorphous compound is adjusted according to actual conditions.
4. The invention has the beneficial technical effects that: the Bexarotene and polyvinylpyrrolidone co-amorphous substance has the advantages of safety, solubility and biological activity.
4.1 the Bexarotene and polyvinylpyrrolidone co-amorphous substance does not contain any crystallization solvent, and has good safety and patent medicine advantages.
4.2 the Bexarotene and polyvinylpyrrolidone co-amorphous form of the invention showed a solubility advantage over Bexarotene in aqueous systems, especially as a significant improvement in dissolution rate (FIG. 6).
4.3 biological absorption effect of the drug developed by using the Bexarotene and polyvinylpyrrolidone co-amorphous form as active ingredients and the pharmaceutical composition thereof of the invention after oral administration, characterized by using the drug containing the Bexarotene and polyvinylpyrrolidone co-amorphous form as active ingredients, which rapidly reaches the maximum concentration value in the gastrointestinal tract or blood to exert the advantageous effect and application in preventing and treating diseases (fig. 7). The Bexarotene and polyvinylpyrrolidone amorphous solid matter improves the blood concentration of the medicine in organisms, thereby playing a more effective treatment role of the medicine.
Drawings
FIG. 1 powder X-ray diffraction pattern of Bexarotene and polyvinylpyrrolidone co-amorphous
FIG. 2 powder X-ray diffraction Pattern of a physical mixture of Bexarotene and polyvinylpyrrolidone
FIG. 3 is a powder X-ray diffraction pattern contrast chart of Bexarotene, polyvinylpyrrolidone, a physical mixture of Bexarotene and polyvinylpyrrolidone, and a co-amorphous blend of Bexarotene and polyvinylpyrrolidone
FIG. 4 is an infrared absorption spectrum of a Bexarotene and polyvinylpyrrolidone co-amorphous substance
FIG. 5 comparative infrared absorption spectra of Bexarotene and polyvinylpyrrolidone co-amorphous and Bexarotene and polyvinylpyrrolidone physical mixtures
FIG. 6 solubility curves for Bexarotene, Bexarotene and polyvinylpyrrolidone co-amorphous
FIG. 7 is a graph showing the oral absorption curves of 0-24h of the co-amorphous Bexarotene, Bexarotene and polyvinylpyrrolidone in rats
FIG. 8 powder X-ray diffraction patterns of Bexarotene and polyvinylpyrrolidone co-amorphous substance at different ratios
Detailed Description
The following examples are given to better illustrate the technical aspects of the present invention, but the present invention is not limited thereto.
Example 1
according to the table shown below, a proper amount of Bexarotene and polyvinylpyrrolidone are put into a ball milling tank according to the mass ratio of 1:1, a proper ball-material ratio is selected, a proper rotating speed is set, and grinding is carried out for a proper time. Powder X-ray diffraction analysis is carried out on the N-acetylsalicylic acid, the diffraction pattern of the N-acetylsalicylic acid is consistent with that of figure 1, and the obtained sample is a Bexarotene and polyvinylpyrrolidone co-amorphous substance.
TABLE 3 preparation method parameters of Bexarotene and polyvinylpyrrolidone co-amorphous
taking 20g of 3 parts of Bexarotene, weighing 4g, 20g and 100g of polyvinylpyrrolidone according to the mass ratio of 5:1, 1:1 and 1:5 respectively, putting the weighed materials into a ball milling tank respectively, selecting the ball-material ratio of 6:1, rotating speed of 400r/min, stopping grinding for 2min every 15min, ball milling for 10 hours, 2 hours and 0.5 hour respectively to obtain Bexarotene and polyvinylpyrrolidone co-amorphous substance samples, and carrying out powder X-ray diffraction analysis on the obtained samples, wherein the diffraction pattern of the obtained samples is shown in figure 8.
Example 2
The solubility characteristics of the Bexarotene and polyvinylpyrrolidone co-amorphous substance and Bexarotene bulk drug in a pure water system are investigated. According to the determination of the general oral solid preparation dissolution test technical guideline, a model independent similarity factor (f2) method is adopted for dissolution curve comparison, the similarity of dissolution curves of the Bexarotene and polyvinylpyrrolidone co-amorphous substance samples in 2 solvent systems is compared through calculation of f2 values, 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. The experiment used a beaxarotene sample as a reference and calculated a model independent similarity factor f2 value. Percent dissolution the percent dissolution was calculated using the HPLC method by measuring the Bexarotene content at 259nm wavelength and using an external standard method. Dissolution curves were respectively plotted with time as abscissa and% dissolution as ordinate (fig. 6). The data are shown in the following table: TABLE 3 dissolution Curve data of Bexarotene with polyvinylpyrrolidone co-amorphous and Bexarotene in pure Water
The experimental data show that the dissolution behavior of the Bexarotene and polyvinylpyrrolidone co-amorphous substance in a pure water system is obviously better than that of Bexarotene, and the Bexarotene and polyvinylpyrrolidone co-amorphous substance has faster dissolution rate and higher dissolution amount, is easy to be absorbed more quickly to reach effective blood concentration, has obviously increased total absorption amount, is improved by 4 times compared with Bexarotene, and can better realize the disease treatment effect of the medicament; the solubility curve of the Bexarotene and polyvinylpyrrolidone co-amorphous substance has a stable release platform, and can ensure that the blood concentration is kept stable in the disease treatment process.
Example 3
The Bexarotene and polyvinylpyrrolidone co-amorphous substance has the absorption characteristics and blood concentration characteristics in a rat body:
12 SD rats were randomly divided into 2 groups of 6 rats each, and fasted without water deprivation for 12h prior to dosing. Weighing the weight of the rat according to 30mg kg-1The method comprises the steps of putting a Bexarotene sample, a Bexarotene sample and a polyvinylpyrrolidone-co-amorphous substance sample into a solid drug delivery device, directly putting the drug powder into a rat stomach through an oral cavity, taking blood at an intraocular canthus for 5min, 15min,30min, 45min, 1h, 1.5h, 2h, 4h, 8h, 12h and 24h, placing the blood in a heparinization tube, centrifuging the blood at 4 ℃ and 4000rpm for 10min, freezing the blood in a refrigerator at-40 ℃ to be detected, precisely sucking 100 mu L of blood plasma of an experimental animal at different time, placing the blood plasma in a 1.5mL centrifuge tube, adding 10 mu L (10ug/mL) of an internal standard (ursolic acid) working solution, vortexing the blood for 5min, adding 300uL of acetonitrile for precipitating protein agent and 500uL of ethyl acetate for extraction, vortexing the blood for 5min, and 1.34 × 10 for 10min4Centrifuging at rpm for 10min, collecting 880uL supernatant, blowing with nitrogen gas, dissolving in 100 μ L complex solution (methanol: water (0.1% ammonia water): 1), vortex oscillating for 5min, and mixing with 1.34 × 104Centrifuging at rpm for 5min, and sampling 90 μ L of supernatant.
Detection conditions are as follows: eclipse plus C18 (2.1X 100mm,3.5 μm, USA); the mobile phase is acetonitrile: water (containing 0.1% ammonia) 30:70(v: v); the flow rate is 0.3 mL/min; the column temperature is 30 ℃; sample introduction amount: 10 mu L of the solution; operating 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), fragmentation voltages 130V (bexarotene), 130V (ursolic acid), gain factor 1.5, drying air flow 11.0L/min, spray chamber voltage 35psig, dryer temperature 350 ℃, capillary voltage 3000V (positive), 3000V (negative).
Table 4 shows the blood concentration of rats at various time points after oral administration of bexarotene and a sample of a co-amorphous substance of bexarotene and polyvinylpyrrolidone; table 5 shows the pharmacokinetic parameters of the oral betasol and the betasol-polyvinylpyrrolidone co-amorphous sample of rats for 0-24h, which indicates that the betasol-polyvinylpyrrolidone co-amorphous sample has the advantageous biological characteristics of fast absorption, high blood concentration and prolonged action platform.
Table 4 blood concentration at each time point (n-3,
)
TABLE 5 pharmacokinetic parameters of SD rats after oral administration of Bexarotene and Bexarotene together with polyvinylpyrrolidone
Example 4
Method for the preparation of a combined pharmaceutical preparation 1 (tablet):
a preparation method of a combined medicine tablet is characterized in that a Bexarotene and polyvinylpyrrolidone co-amorphous substance and a plurality of excipients are used as auxiliary material components for preparing the combined medicine tablet, each tablet containing 5-500 mg of co-amorphous substance is prepared according to a certain proportion, and the formula proportion of the tablet is given in Table 6:
TABLE 6 preparation formulation of Bexarotene and polyvinylpyrrolidone co-amorphous combination pharmaceutical tablet
The method for preparing the tablet preparation by taking the Bexarotene and polyvinylpyrrolidone as the amorphous substances comprises the following steps: mixing several excipients with the raw materials, and directly tabletting; or mixing the auxiliary materials, granulating by a dry method, uniformly mixing with the raw material medicines, and tabletting to obtain the traditional Chinese medicine.
Method for the preparation of a combined pharmaceutical preparation 2 (tablet):
a preparation method of a combined medicine tablet is characterized in that a Bexarotene and polyvinylpyrrolidone co-amorphous substance and a plurality of excipients are used as auxiliary material components for preparing the combined medicine tablet, each tablet containing 5-500 mg of co-amorphous substance is prepared according to a certain proportion, and the formula proportion of the tablet is given in Table 7:
TABLE 7 preparation formulation of Bexarotene and polyvinylpyrrolidone co-amorphous combination pharmaceutical tablet
The method for preparing the tablet preparation by taking Bexarotene and polyvinylpyrrolidone as the amorphous bulk drugs comprises the following steps: mixing several excipients with the raw materials, adding appropriate amount of 1% sodium carboxymethylcellulose solution, making into soft material, sieving, granulating, oven drying, sieving, grading, adding magnesium stearate and pulvis Talci, mixing, and tabletting.
Method for preparing a combined pharmaceutical preparation 3 (capsule):
a preparation method of a combined medicine capsule is characterized in that a Bexarotene and polyvinylpyrrolidone co-amorphous substance is used as a raw material medicine, a plurality of excipients are used as auxiliary material components for preparing the combined medicine capsule, a capsule sample with the medicine content of 5-500 mg is prepared according to a certain proportion, and the formula proportion of the capsule is given in a table 8:
bulk drug and auxiliary material formula of Bexarotene and polyvinylpyrrolidone co-amorphous combined drug capsule preparation in Table 8
The method for preparing the capsules by taking the Bexarotene and polyvinylpyrrolidone as the amorphous substances comprises the following steps: mixing several excipients with the raw materials, adding appropriate amount of 1% sodium carboxymethylcellulose solution, making into wet granules, oven drying, sieving, grading, adding magnesium stearate, mixing, and making into capsule; or directly mixing the Bexarotene and polyvinylpyrrolidone with several excipient adjuvants without granulating, sieving, and directly encapsulating.
Example 5
Administration dose 1 (tablet) of bexarotene and polyvinylpyrrolidone co-amorphous combination drug:
the pharmaceutical composition is characterized in that the Bexarotene and polyvinylpyrrolidone co-amorphous substance is used as the active ingredient of the medicine, the daily administration dose is 900mg, and the Bexarotene and polyvinylpyrrolidone co-amorphous substance can be respectively prepared into 3 tablets each time 3 times a day, 100mg common tablets each time, or 1 tablet each time 3 times a day, 300mg tablets each time.
Administration dose 2 (capsule) of the Bexarotene and polyvinylpyrrolidone co-amorphous compound combination medicament:
the pharmaceutical composition prepared and developed by using the Bexarotene and polyvinylpyrrolidone co-amorphous substance as the active pharmaceutical ingredients is characterized in that the Bexarotene and polyvinylpyrrolidone co-amorphous substance is used as the active pharmaceutical ingredients, the daily administration dose is 300mg, and 50mg capsules of 2 capsules 3 times a day or 150mg capsules of 1 capsule 2 times a day can be prepared respectively.
Problems to be explained are: the Bexarotene and polyvinylpyrrolidone co-amorphous substance pharmaceutical composition has many factors on the administration dosage of the effective components, such as: the age and the body surface area of patients are different, and the administration route, the administration frequency and the treatment purpose are different, so that the dosage of each administration is different; the differences in absorption and blood levels between samples also result in the invention using the Bexarotene and polyvinylpyrrolidone co-amorphous form of the present invention in a suitable dosage range of 0.1-20mg/kg body weight, preferably 2-10mg/kg body weight per dose. When in use, different total dosage schemes of the effective components of the Bexarotene and polyvinylpyrrolidone co-amorphous substance are prepared according to different actual requirements of treatment conditions, and the total dosage schemes can be completed in a multi-time or one-time administration mode.
Reference to the literature
[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] Synthesis and optimization of weiwei, marshal, bexarotene [ J ] chemical research and application, vol 25, 3 rd month, 2013.
Claims (11)
1. A Bexarotene and polyvinylpyrrolidone co-amorphous substance is characterized in that Bexarotene and polyvinylpyrrolidone form a co-amorphous substance according to a certain mass ratio, and CuK is adopted when powder X-ray diffraction analysis is usedαWhen 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.
2. The Bexarotene and polyvinylpyrrolidone co-amorphous form according to claim 1, wherein the weight ratio of Bexarotene to polyvinylpyrrolidone is 1: 5-5: 1, preferably 1: 3-3: 1.
3. The Bexarotene and polyvinylpyrrolidone co-amorphous form of claim 1, wherein the analysis is performed using attenuated total reflectance Fourier 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、1099、1075、1038、1016、988、979、965、899、880、865、850、804、746、733、684、681、671、658cm-1Has characteristic peaks of infrared spectrum, wherein the allowable deviation of the characteristic peaks of the infrared spectrum is +/-2 cm-1。
4. The process for preparing the Bexarotene and polyvinylpyrrolidone co-amorphous form according to any one of claims 1 to 3, wherein Bexarotene and polyvinylpyrrolidone co-amorphous form is prepared by feeding Bexarotene and polyvinylpyrrolidone in a certain mass ratio and using a mechanochemical method with controlled pressure and temperature.
5. The preparation method according to claim 4, wherein the mass ratio of the Bexarotene to the polyvinylpyrrolidone is 1: 5-5: 1, preferably 1: 3-3: 1; the mechanochemical method is selected from a 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 to 400 r/min; the grinding time is 0.1 to 10 hours.
6. A mixed solid material comprising a copaimorph of bexarotene and polyvinylpyrrolidone, wherein the copaimorph of bexarotene and polyvinylpyrrolidone of any of claims 1 to 3 is contained in an amount of 1 to 99.9%, preferably 10 to 99.9%, more preferably 50 to 99.9%, most preferably 85 to 99.9%.
7. A pharmaceutical composition comprising an effective amount of the co-amorphous bexarotene of any one of claims 1 to 3 and polyvinylpyrrolidone and a pharmaceutically acceptable carrier.
8. A pharmaceutical composition comprising an effective amount of the copaimorph of claim 6 in a solid admixture with polyvinylpyrrolidone and a pharmaceutically acceptable carrier.
9. The pharmaceutical composition according to any of claims 7 or 8, wherein the amount of the drug administered by the alimentary tract of a daily human of Bexarotene is in the range of 5 to 1000mg and the amount of the drug administered by injection is in the range of 1 to 100 mg.
10. Pharmaceutical composition according to any one of claims 7 or 8, characterized in that the pharmaceutical composition is in the form of a tablet, capsule, pill, injectable preparation, sustained release preparation or controlled release preparation.
11. Use of the bexarotene co-amorphous form of bexarotene with polyvinylpyrrolidone according to any one of claims 1 to 3 or the mixed solid form of bexarotene with polyvinylpyrrolidone according to claim 6 or the pharmaceutical composition according to any one of claims 7 or 8 for the preparation of a medicament for the prophylaxis and treatment of glioma, cutaneous T-cell lymphoma, breast cancer, psoriasis, kaposi's sarcoma, lung cancer and cushing's disease.
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| CN112999213A (en) * | 2019-12-19 | 2021-06-22 | 中国医学科学院药物研究所 | Application of Bexarotene in preparation of anti-pituitary adrenocorticotropic hormone adenoma medicine |
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| US20100272815A1 (en) * | 2009-04-28 | 2010-10-28 | Actavis Group Ptc Ehf | Amorphous form of tapentadol hydrochloride |
| WO2018227179A1 (en) * | 2017-06-09 | 2018-12-13 | Isp Investments Llc | Small-molecule lactams in coamorphous pharmaceutical phases |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20100272815A1 (en) * | 2009-04-28 | 2010-10-28 | Actavis Group Ptc Ehf | Amorphous form of tapentadol hydrochloride |
| WO2018227179A1 (en) * | 2017-06-09 | 2018-12-13 | Isp Investments Llc | Small-molecule lactams in coamorphous pharmaceutical phases |
Non-Patent Citations (1)
| Title |
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| GOODWIN, MELISSA J.等: "Small-Molecule Povidone Analogues in Coamorphous Pharmaceutical Phases", 《CRYSTAL GROWTH & DESIGN》 * |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN112999213A (en) * | 2019-12-19 | 2021-06-22 | 中国医学科学院药物研究所 | Application of Bexarotene in preparation of anti-pituitary adrenocorticotropic hormone adenoma medicine |
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