Nitrendipine and polyvinylpyrrolidone co-amorphous substance and application thereof

Abstract

The invention discloses a nitrendipine and polyvinylpyrrolidone co-amorphous substance, the weight ratio of nitrendipine to polyvinylpyrrolidone is 1: 1, and compared with nitrendipine, the nitrendipine and polyvinylpyrrolidone co-amorphous substance has higher solubility, dissolution rate and stability.

Description

Technical Field

[0001] The present invention belongs to the field of medical technology, and in particular, relates to a co-amorphous substance of nitrendipine and polyvinyl pyrrolidone, a preparation method, a composition and use thereof. Background Art

[0002] Nitrendipine, chemical name is 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydro-3,5-pyridinedicarboxylic acid methyl ester ethyl ester, molecular formula is C 18 H 20 N2O6, with the structural formula shown in formula a below. It is a dihydropyridine derivative, and its antihypertensive effect is similar to that of nifedipine, but it is more effective and lasts longer, up to 15 hours. As a second-generation dihydropyridine calcium antagonist, it can selectively act on the calcium channels of vascular smooth muscle, inhibit the transmembrane calcium ion influx of vascular smooth muscle and myocardium, has a greater affinity for blood vessels than for myocardium, and has a stronger selective effect on coronary arteries. It can reduce myocardial oxygen consumption and has a protective effect on ischemic myocardium. Nitrendipine can cause systemic vasodilation (including coronary arteries and renal arterioles), producing an effect mainly to reduce diastolic blood pressure. Nitrendipine can also reduce myocardial oxygen consumption and has a protective effect on ischemic myocardium. Unlike diltiazem, verapamil and nifedipine, nitrendipine has no effect on the conduction of the sinoatrial node or atrioventricular node. After use, adverse reactions may occur such as headache, dizziness, palpitations, facial flushing, dry mouth, nausea, ankle edema, and mild reflex heart rate acceleration (Stoepel K, Heise A, Kazeda S., Pharmacological studies of the antihypertensive effect of nitrendipine [J], Arzneimittelforsch, 1981, 31: 2056; National Pharmacopoeia Commission "Pharmacopoeia of the People's Republic of China" Part II, [M], Beijing, China Medical Science and Technology Press, 2020).

[0003] Polyvinylpyrrolidone (PVP), referred to as PVP, is a non-ionic polymer compound with the molecular formula (C6H9NO) n , the structural formula is shown in b.

[0004]

[0005] There is a need to improve the bioavailability and stability of nitrendipine. Summary of the invention

[0006] One or more embodiments of the present application provide a co-amorphous compound of nitrendipine and polyvinyl pyrrolidone, wherein the weight ratio of nitrendipine to polyvinyl pyrrolidone is 1:1.

[0007] In one or more embodiments, the polyvinyl pyrrolidone is PVPK-30, PVPK-60, or PVPK-90.

[0008] In one or more embodiments, wherein CuK is used α The powder X-ray diffraction pattern of the co-amorphous material exhibits diffuse diffraction peaks when irradiated and expressed in 2θ angles, wherein the peak values ​​of the diffuse diffraction peaks are located at 11.34±0.3° and 21.28±0.3°.

[0009] In one or more embodiments, CuK α Radiation and expressed in 2θ angles, the powder X-ray diffraction pattern of the co-amorphous material is as follows Figure 1 shown.

[0010] In one or more embodiments, when analyzed using attenuated total reflection Fourier transform infrared spectroscopy, the infrared spectrum of the co-amorphous compound is 3313±2 cm -1 、3091±2cm -1 、2951±2cm -1 、1651±2cm -1 、1526±2cm -1 、1491±2cm -1 、1460±2cm -1 、1434±2cm -1 、1423±2cm -1 、1381±2cm -1 、1347±2cm -1 、1309±2cm -1 、1287±2cm -1 、1273±2cm -1 、1209±2cm -1 、1118±2cm -1 、1094±2cm -1 、1050±2cm -1 、1020±2cm -1 、957±2cm -1 、924±2cm -1 、901±2cm -1 、840±2cm -1 、827±2cm -1 、806±2cm -1 、780±2cm -1、743±2cm -1 、704±2cm -1 、679±2cm -1 、646±2cm -1 、573±2cm -1 、472±2cm -1 There are characteristic peaks in the infrared spectrum.

[0011] In one or more embodiments, the infrared spectrum of the co-amorphous compound is as follows: Figure 3 shown.

[0012] In one or more embodiments, the differential scanning calorimetry spectrum of the co-amorphous compound is as follows: Figure 4 shown.

[0013] In one or more embodiments, within the range of 30-170° C., the heating rate is 10° C. / min.

[0014] One or more embodiments of the present application provide a method for preparing the co-amorphous substance of the present application, which comprises mixing nitrendipine and polyvinyl pyrrolidone in a weight ratio of 1:1, and preparing the co-amorphous substance by a mechanochemical method.

[0015] In one or more embodiments, the mechanochemical method is selected from liquid grinding and liquid ball milling, wherein the liquid organic solvent is selected from one or more of methanol, ethanol, tetrahydrofuran, acetone, acetonitrile, dioxane, n-hexane, and cyclohexane.

[0016] In one or more embodiments, the volume ratio or weight ratio between any two of the organic solvents is 1:10 to 10:1 (e.g., 1:10, 1:9, 1:8, 1:7, 1:6, 1:5, 1:4, 1:3, 1:2, 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1).

[0017] In one or more embodiments, the amount of the organic solvent added is 5 to 100 mL of organic solvent per gram of the mixed sample of nitrendipine and polyvinyl pyrrolidone; the grinding time of the liquid addition grinding method is 0.1 hour to 10 hours (for example, 5 hours), the drying temperature is 25-60°C (for example, 40°C), and the drying time is 2 to 10 hours (for example, 6 hours); the bowl filling rate is 10% to 50% (for example, 30%), and the reciprocating speed is 20 to 70 m / min (meters per minute) (for example, 45 m / min); the shear impact energy of the ball mill is 10kw to 800kw; the ball-to-material ratio is 6:1 to 10:1; and the ball mill speed is 300r / min to 400r / min.

[0018] One or more embodiments of the present application provide a solid mixture comprising the co-amorphous material of the present application.

[0019] In one or more embodiments, the amount of the co-amorphous material is 1-99.9 wt % (e.g., 10 wt %, 20 wt %, 30 wt %, 40 wt %, 50 wt %, 60 wt %, 70 wt %, 80 wt %, 90 wt %) based on the weight of the solid mixture.

[0020] In one or more embodiments, the amount of the co-amorphous material is 10-99.9 wt %, 50-99.9 wt %, 85-99.9 wt % based on the weight of the solid mixture.

[0021] One or more embodiments of the present application provide a pharmaceutical composition comprising a therapeutically effective amount of the co-amorphous substance of the present application or the solid mixture of the present application and a pharmaceutically acceptable carrier.

[0022] In one or more embodiments, the daily dosage of the pharmaceutical composition is 10 to 1000 mg (eg, 100 mg, 500 mg, 900 mg).

[0023] In one or more embodiments, the pharmaceutical composition is prepared as tablets, capsules, pills, or powder injections.

[0024] In one or more embodiments, the pharmaceutical composition is prepared as a sustained-release formulation or a controlled-release formulation.

[0025] One or more embodiments of the present application provide use of the co-amorphous substance of the present application, the solid mixture of the present application, or the pharmaceutical composition of the present application in the preparation of a drug for preventing and / or treating coronary heart disease and congestive heart failure.

[0026] In one or more embodiments, the co-amorphous material does not contain a crystallization solvent or a crystallization water component.

[0027] In one or more embodiments, there are no obvious endothermic peaks and exothermic peaks in the differential scanning calorimetry spectrum of the co-amorphous compound.

[0028] In one or more embodiments, the amount of the co-amorphous material is 10-99.9 wt %, 50-99.9 wt %, or 85-99.9 wt % based on the weight of the solid mixture.

[0029] In one or more embodiments, there is provided a co-amorphous compound formed by non-covalent bonding of nitrendipine and polyvinyl pyrrolidone, wherein the molecular formula of the co-amorphous compound is C 18 H 20 N2O6·(C6H9NO)n .

[0030] In one or more embodiments, nitrendipine and polyvinylpyrrolidone (PVP) are prepared into a co-amorphous solid material with non-covalent interaction, thereby forming a new substance different from nitrendipine, PVP and a simple physical mixture of the two.

[0031] In one or more embodiments, the co-amorphous solid material of the present application has achieved unexpected technical advantages in the preparation of drugs for treating coronary heart disease, congestive heart failure and other diseases.

[0032] In one or more embodiments, a mixed solid material or pharmaceutical composition comprising a co-amorphous mixture of nitrendipine and PVP in any non-zero ratio is provided.

[0033] In one or more embodiments, a pharmaceutical composition using a co-amorphous product of nitrendipine and PVP as a pharmaceutically active ingredient is provided, wherein the dosage per administration is 10 to 1000 mg. The pharmaceutical composition can be prepared as tablets, capsules, pills, injection preparations, sustained-release or controlled-release preparations.

[0034] In one or more embodiments, the co-amorphous compound of nitrendipine and PVP of the present application has better solubility than nitrendipine.

[0035] In one or more embodiments, the co-amorphous compound of nitrendipine and PVP of the present application is advantageously released during the treatment of diseases due to the formation of a co-amorphous substance, resulting in unexpected clinical effects.

[0036] In one or more embodiments, provided is the use of a co-amorphous substance of nitrendipine and PVP and a mixed crystalline solid substance thereof as a pharmaceutical active ingredient in the preparation of a drug for treating coronary heart disease and congestive heart failure.

[0037] Morphological characteristics of amorphous samples of nitrendipine and PVP

[0038] The co-amorphous substance of nitrendipine and PVP of the present application is a co-amorphous substance formed by combining nitrendipine and PVP in a weight ratio of 1:1 through non-covalent bonds.

[0039] The powder X-ray diffraction patterns of the co-amorphous substance of nitrendipine and PVP and the physical mixture of nitrendipine and PVP in the present application are significantly different in terms of the number of diffraction peaks, the position of the diffraction peaks, the intensity of the diffraction peaks, the topological pattern of the diffraction peaks, etc., indicating that nitrendipine and PVP form a co-amorphous substance, and the physical mixture of nitrendipine and PVP is a different substance (see Figure 1 and Figure 2 ).

[0040] Table 1 Powder X-ray diffraction peak data of physical mixture of nitrendipine and PVP

[0041]

[0042] The co-amorphous product of nitrendipine and PVP of the present application is analyzed by attenuated total reflection Fourier transform infrared spectroscopy at 3313, 3091, 2951, 1651, 1526, 1491, 1460, 1434, 1423, 1381, 1347, 1309, 1287, 1273, 1209, 1118, 1094, 1050, 1020, 957, 924, 901, 846, 827, 806, 780, 743, 704, 679, 646, 573, 472 cm -1 There is a characteristic peak of infrared spectrum at the position, and the allowable deviation of the characteristic peak of infrared spectrum is ±2cm -1 (See Figure 3 ).

[0043] The nitrendipine and PVP co-amorphous product of the present application, when analyzed by differential scanning calorimetry, has no obvious endothermic peaks and exothermic peaks in its DSC spectrum within the range of 30 to 170°C and at a heating rate of 10°C / min (see Figure 4 ), which is the melting point peak of the co-amorphous product. The DSC spectra of the co-amorphous product of nitrendipine and PVP are significantly different from those of nitrendipine and PVP in terms of the number and position of endothermic / exothermic peaks, indicating that nitrendipine and PVP form a new phase, namely, the co-amorphous product of nitrendipine and PVP (see Figure 5 ).

[0044] Preparation method of co-amorphous substance and mixed solid substance of nitrendipine and PVP

[0045] The preparation method of the co-amorphous substance of nitrendipine and PVP of the present application adopts a mechanochemical grinding method to mix nitrendipine and PVP in a weight ratio of 1:1, add an organic solvent, and grind for 0.1 to 10 hours and dry for 2 to 10 hours under room temperature; the bowl filling rate of the liquid grinding method is 10% to 50%, and the reciprocating motion speed is 20 to 70 m / min; the shear impact energy of the ball mill is 10kw to 800kw; the ball-to-material ratio is 6:1 to 10:1; the ball mill speed is 300r / min to 400r / min, and the co-amorphous substance of nitrendipine and PVP is obtained. The organic solvent is selected from any one of methanol, ethanol, acetonitrile, acetone, tetrahydrofuran, dioxane, n-hexane, and cyclohexane, or a mixed solvent prepared by combining multiple solvents in different proportions.

[0046] The mixed solid material containing the co-amorphous product of nitrendipine and PVP of the present application is prepared by mixing the co-amorphous product of nitrendipine and PVP obtained by the above method with other chemical substances in any non-zero ratio and in a conventional manner.

[0047] Pharmaceutical preparation composition containing a co-amorphous substance of nitrendipine and PVP, dosage characteristics and pharmaceutical use

[0048] The pharmaceutical composition of the present application comprises a co-amorphous substance of nitrendipine and PVP and a pharmaceutically acceptable carrier.

[0049] The pharmaceutical composition of the present application comprises a mixed solid of a co-amorphous substance of nitrendipine and PVP and a pharmaceutically acceptable carrier.

[0050] The pharmaceutical composition of the present application comprises a co-amorphous product of nitrendipine and PVP, and the daily dosage is within the range of 10 to 1000 mg.

[0051] The dosage form of the pharmaceutical composition of the present application can be various tablets, capsules, pills, injection preparations, sustained-release preparations or controlled-release preparations.

[0052] The co-amorphous product of nitrendipine and PVP of the present application has application in treating diseases such as duodenal ulcer, gastric ulcer, reflux esophagitis, Zollinger-Ellison syndrome and the like.

[0053] The pharmaceutical composition of the present application with the co-amorphous substance of nitrendipine and PVP as the active ingredient can be prepared according to methods known in the art. The co-amorphous substance of nitrendipine and PVP of the present application can be combined with one or more pharmaceutically acceptable solid or liquid excipients and / or adjuvants to prepare any dosage form suitable for human or animal use. The co-amorphous substance of nitrendipine and PVP of the present application, and the mixed solid containing the co-amorphous substance of nitrendipine and PVP in the pharmaceutical composition thereof are contained in an amount of 10% to 90% by weight.

[0054] The co-amorphous product of nitrendipine and PVP of the present application can be administered in a unit dosage form, and the administration route can be enteral or parenteral, such as oral, intravenous, intramuscular, subcutaneous, nasal, oral mucosa, eyes, lungs and respiratory tract, skin, vagina, rectum, etc.

[0055] The dosage form of the present application may be a solid dosage form. The solid dosage form may be tablets (including ordinary tablets, enteric-coated tablets, lozenges, dispersible tablets, chewable tablets, effervescent tablets, orally disintegrating tablets), capsules (including hard capsules, soft capsules, enteric-coated capsules), granules, powders, pellets, dripping pills, suppositories, films, patches, aerosols (powders), sprays, etc.

[0056] The co-amorphous product of nitrendipine and PVP and the mixed solid material containing the co-amorphous product of nitrendipine and PVP of the present application can be made into ordinary preparations, and can also be made into sustained-release preparations, controlled-release preparations, targeted preparations and various microparticle drug delivery systems.

[0057] In order to form the co-amorphous product of nitrendipine and PVP of the present application into tablets, various excipients known in the art can be widely used, including diluents, binders, wetting agents, disintegrants, lubricants, and glidants. The diluent may be starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.; the wetting agent may be water, ethanol, isopropanol, etc.; the binder may be starch slurry, dextrin, syrup, honey, glucose solution, microcrystalline cellulose, acacia slurry, gelatin slurry, sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose, acrylic resin, carbomer, polyvinyl pyrrolidone, polyethylene glycol, etc.; the disintegrant may be dry starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, cross-linked polyvinyl pyrrolidone, cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch, sodium bicarbonate and citric acid, polyoxyethylene sorbitan fatty acid ester, sodium dodecyl sulfate, etc.; the lubricant and glidant may be talc, silicon dioxide, stearate, tartaric acid, liquid paraffin, polyethylene glycol, etc.

[0058] Tablets can be further made into coated tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or double-layer tablets and multi-layer tablets.

[0059] The dosing unit can be made into a capsule, and the co-amorphous substance of the active ingredient nitrendipine and PVP 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 substance of the active ingredient nitrendipine and PVP can also be first made into granules or pellets with a diluent, a binder, and a disintegrant, and then placed in a hard capsule or a soft capsule. Various diluents, binders, wetting agents, disintegrants, and glidants used to prepare tablets of the co-amorphous substance of nitrendipine and PVP can also be used to prepare capsules of the co-amorphous substance of nitrendipine and PVP of the present invention.

[0060] Furthermore, if necessary, colorants, preservatives, perfumes, flavoring agents or other additives may be added to the pharmaceutical preparations.

[0061] In order to achieve the purpose of medication and enhance the therapeutic effect, the drug of the present invention can be administered by any known administration method.

[0062] The dosage of the pharmaceutical composition of the co-amorphous product of nitrendipine and PVP of the present application can vary widely 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, etc. The above dosage can be administered in one dosage unit or divided into several dosage units, depending on the clinical experience of the doctor and the dosage regimen including the use of other treatment means.

[0063] The co-amorphous compound or composition of nitrendipine and PVP of the present application can be taken alone or used in combination with other therapeutic drugs or symptomatic drugs. When the co-amorphous compound of nitrendipine and PVP of the present invention has a synergistic effect with other therapeutic drugs, its dosage should be adjusted according to the actual situation.

[0064] Beneficial technical effects of the present invention:

[0065] The co-amorphous product of nitrendipine and PVP of the present application has advantages in terms of safety, solubility, dissolution rate, stability, bioavailability, in vivo absorption rate and absorbability.

[0066] The co-amorphous product of nitrendipine and PVP of the present application does not contain any crystallization solvent and has the advantage of good safety in drug formulation.

[0067] The co-amorphous product of nitrendipine and PVP of the present application shows a higher concentration in the duodenum, which is specifically reflected in the simulated duodenal fluid (pH 4.5) dissolution system. After the drug dissolution reaches equilibrium, the dissolution amount increases, which is about 1.5 times higher than that of nitrendipine (see Figure 6 ).

[0068] The co-amorphous product of nitrendipine and PVP of the present application can be stably present under high temperature (60°C) and light (45001x±5001x) conditions (see Figure 7 ).

[0069] In one or more embodiments, there are many factors affecting the dosage of the active ingredient of the pharmaceutical composition of the co-amorphous substance of nitrendipine and PVP of the present application, such as: different daily dosages due to different uses for prevention and treatment; different daily dosages due to different natures of the disease and severity of the disease; different daily dosages due to different genders, ages, and body surface areas of patients, different routes of administration, number of administrations, and different treatment purposes; in addition, the absorption and blood drug concentrations between crystalline samples are different, which also cause the daily suitable dosage range of the co-amorphous substance component of nitrendipine and PVP to be 0.002-20 mg / kg body weight, such as 0.01-10 mg / kg body weight. When used, different total dosage plans of the active ingredients of the co-amorphous substance of nitrendipine and PVP should be formulated according to the actual prevention and treatment requirements, and can be completed in multiple or one-time administration. BRIEF DESCRIPTION OF THE DRAWINGS

[0070] Figure 1 This is the powder X-ray diffraction pattern of the co-amorphous product of nitrendipine and PVP.

[0071] Figure 2 The figure is the powder X-ray diffraction pattern of the physical mixture of nitrendipine and PVP.

[0072] Figure 3 This is the infrared absorption spectrum of the co-amorphous product of nitrendipine and PVP.

[0073] Figure 4 This is the differential scanning calorimetry spectrum of the co-amorphous product of nitrendipine and PVP.

[0074] Figure 5 It is the differential scanning calorimetry superposition spectrum of the co-amorphous product of nitrendipine and PVP and the raw materials of nitrendipine and PVP.

[0075] Figure 6 This is the solubility curve of the co-amorphous product of nitrendipine and PVP in duodenal fluid (pH = 4.5).

[0076] Figure 7 This is the stability spectrum of the co-amorphous product of nitrendipine and PVP. DETAILED DESCRIPTION

[0077] In order to better illustrate the technical solution of the present invention, the following embodiments are given, but the present invention is not limited thereto.

[0078] Example 1

[0079] Preparation of co-amorphous product of nitrendipine and PVP

[0080] Take appropriate amount of nitrendipine and PVP in a weight ratio of 1:1, add the sample to a bowl of suitable capacity at room temperature by liquid grinding or liquid ball milling, add appropriate amount of organic solvent, grind at room temperature at appropriate speed for appropriate time, and dry the obtained powder or paste sample naturally or under reduced pressure. The condition parameters of the preparation method are shown in Table 2 and Table 3. Powder X-ray diffraction analysis was performed on it, and the diffraction patterns were consistent with Figure 1 The results showed that the obtained sample was a co-amorphous product of nitrendipine and PVP.

[0081] Table 2 Specific examples of the preparation method of the co-amorphous product of nitrendipine and PVP by adding liquid and grinding

[0082]

[0083] Table 3 Specific examples of the preparation method of the co-amorphous product of nitrendipine and PVP by liquid ball milling

[0084]

[0085] Example 2

[0086] In vitro solubility characteristics of co-amorphous mixture of nitrendipine and PVP

[0087] The solubility characteristics of the co-amorphous product of nitrendipine and PVP and the nitrendipine API in water were investigated. The experiment was conducted in accordance with the Technical Guidelines for Dissolution Tests of Ordinary Oral Solid Preparations. The nitrendipine content was determined at a wavelength of 237 nm using high performance liquid chromatography, and the amount of dissolution was calculated using the external standard method. Dissolution curves were drawn with time as the horizontal axis and the amount of dissolution as the vertical axis (see Figure 6 ). The specific data are shown in Table 4.

[0088] Table 4 Dissolution curve data

[0089]

[0090] It can be seen from the solubility data that the dissolution behavior of the co-amorphous compound of nitrendipine and PVP in pH = 4.5 is better than that of the nitrendipine raw material. Specifically, the dissolution rate of the co-amorphous compound of nitrendipine and PVP is increased. After about 6 hours, the dissolution rate of the co-amorphous compound of nitrendipine and PVP is increased by 1.5 times compared with the nitrendipine raw material, and higher blood drug concentrations can be obtained faster during disease treatment.

[0091] Example 3

[0092] Stability of the co-amorphous product of nitrendipine and PVP

[0093] High temperature test: The sample of the co-amorphous product of nitrendipine and PVP was placed in an open clean surface dish at 60°C for 10 days, and samples were taken on the 0th day, the 5th day and the 10th day. The samples obtained from the above sampling points were subjected to powder X-ray diffraction analysis, and the results showed that the co-amorphous product of nitrendipine and PVP was stable under the high temperature influence factor test.

[0094] Light test: Place the sample of the co-amorphous product of nitrendipine and PVP in an open clean surface dish, place it in a light box equipped with a fluorescent lamp, and place it for 10 days under the condition of illumination of 4500lx±500lx, and take samples on the 0th day, the 5th day and the 10th day. The samples obtained from the above sampling points were subjected to powder X-ray diffraction analysis, and the results showed that the co-amorphous product of nitrendipine and PVP was stable under light conditions.

[0095] The stability study of the co-amorphous product of nitrendipine and PVP proved that the co-amorphous product remained stable in a high temperature and light environment for 10 days and had stable drug-forming properties (see Figure 7 ).

[0096] Example 4

[0097] Preparation method 1 of amorphous drug preparation (tablets):

[0098] Preparation method: Use the pure amorphous product of nitrendipine and PVP as the raw material, use several excipients as the auxiliary ingredients of the tablets, and prepare tablet samples with a drug content of 10 to 500 mg per tablet in a certain ratio. Table 5 gives the tablet formula ratio.

[0099] Table 5 Preparation formula of co-amorphous tablets of nitrendipine and PVP

[0100]

[0101] The method of preparing a tablet preparation using the pure co-amorphous product of nitrendipine and PVP as a raw material is as follows: several excipients are mixed evenly with the raw material and directly tableted; or the auxiliary materials are mixed and dry granulated, and then mixed evenly with the raw material and then tableted.

[0102] Preparation method 2 of amorphous drug preparation (tablets):

[0103] Preparation method: Use the pure amorphous product of nitrendipine and PVP as the raw material, use several excipients as the auxiliary ingredients of the tablets, and prepare tablet samples with a drug content of 10 to 500 mg per tablet in a certain proportion. Table 6 gives the tablet formula ratio.

[0104] Table 6 Preparation formula of co-amorphous tablets of nitrendipine and PVP

[0105]

[0106] The method for preparing a tablet preparation using a pure co-amorphous product of nitrendipine and PVP as a raw material is as follows: uniformly mixing several excipients with the raw material, adding an appropriate amount of 1% sodium hydroxymethylcellulose solution to prepare a soft material, sieving granules, drying the wet granules, sieving whole granules, adding magnesium stearate and talcum powder, mixing uniformly, and tableting to obtain the tablet preparation.

[0107] Preparation method 3 of amorphous drug preparation (capsules):

[0108] Preparation method: Use the pure amorphous product of nitrendipine and PVP as the raw material of the combination drug, use several excipients as auxiliary ingredients for preparing the combination drug capsules, and prepare capsule samples with a drug content of 10 to 500 mg per tablet according to a certain ratio. Table 7 gives the capsule formula ratio.

[0109] Table 7 API and excipient formula of the co-amorphous capsule preparation of nitrendipine and PVP

[0110]

[0111] The method for preparing a tablet preparation from a co-amorphous bulk drug of nitrendipine and PVP is as follows: uniformly mixing several excipients with the bulk drug, adding an appropriate amount of 1% sodium hydroxymethylcellulose solution to prepare wet granules, drying and sieving the whole granules, adding magnesium stearate and mixing uniformly, and inserting into capsules; or without using the granulation step, directly mixing the co-amorphous bulk drug of nitrendipine and PVP with several excipients and auxiliary materials uniformly, sieving, and directly filling into capsules to prepare the tablet preparation.

[0112] Example 5

[0113] Dosage of the co-amorphous compound of nitrendipine and PVP 1 (tablet):

[0114] The pharmaceutical composition developed by using the co-amorphous sample of nitrendipine and PVP as the active ingredient of the drug, using the co-amorphous sample of nitrendipine and PVP as the active ingredient of the drug, has a daily dosage of 0.5-300 mg, and can be prepared into ordinary tablet types of 1-6 tablets each time, containing 10, 100, 200, 300, and 500 mg of active ingredients.

[0115] Dosage of the co-amorphous compound of nitrendipine and PVP 2 (capsules):

[0116] A pharmaceutical composition is developed using a sample of a co-amorphous product of nitrendipine and PVP as the active ingredient of the drug. The co-amorphous product of nitrendipine and PVP is used as the active ingredient of the drug. The daily dosage is 10-3000 mg, and the drug can be prepared into capsules of 1-6 capsules each time, containing 10, 100, 200, 300, and 500 mg of the active ingredient.

Claims

1. A co-amorphous product of nitrendipine and polyvinyl pyrrolidone, wherein the weight ratio of nitrendipine to polyvinyl pyrrolidone is 1:1; preferably, the polyvinyl pyrrolidone is PVPK-30, PVPK-60, or PVPK-90.

2. The co-amorphous material according to claim 1, wherein CuK α The powder X-ray diffraction pattern of the co-amorphous material is expressed as diffuse diffraction peaks, wherein the peak values ​​of the diffuse diffraction peaks are located at 11.34±0.3° and 21.28±0.3°; preferably, CuK α The powder X-ray diffraction pattern of the co-amorphous material is shown in FIG1 .

3. The co-amorphous material according to claim 1, wherein when analyzed by attenuated total reflection Fourier transform infrared spectroscopy, the infrared spectrum of the co-amorphous material is 3313±2cm- 1 、3091±2cm- 1 、2951±2cm- 1 、1651±2cm- 1 、1526±2cm- 1 、1491±2cm- 1 、1460±2cm- 1 、1434±2cm- 1 、1423±2cm- 1 、1381±2cm- 1 、1347±2cm- 1 、1309±2cm- 1 、1287±2cm- 1 、1273±2cm- 1 、1209±2cm- 1 、1118±2cm- 1 、1094±2cm- 1 、1050±2cm- 1 、1020±2cm- 1 、957±2cm- 1 、924±2cm- 1 、901±2cm- 1 、840±2cm- 1 、827±2cm- 1 、806±2cm- 1 、780±2cm- 1 、743±2cm- 1 、704±2cm- 1 、679±2cm- 1 、646±2cm- 1 、573±2cm- 1 、472±2cm- 1 There is a characteristic peak of infrared spectrum at; preferably, the infrared spectrum of the co-amorphous material is shown in Figure 3.

4. The co-amorphous material according to claim 1, wherein the differential scanning calorimetry spectrum of the co-amorphous material is shown in Figure 4; preferably, within the range of 30 to 170°C, the heating rate is 10°C / min.

5. The method for preparing the co-amorphous substance according to any one of claims 1 to 4, comprising mixing nitrendipine and polyvinyl pyrrolidone in a weight ratio of 1:1, and preparing the co-amorphous substance by a mechanochemical method; Preferably, the mechanochemical method is selected from liquid grinding method and liquid ball milling method, wherein the liquid organic solvent is selected from one or more of methanol, ethanol, tetrahydrofuran, acetone, acetonitrile, dioxane, n-hexane, and cyclohexane; Preferably, the volume ratio or weight ratio between any two of the organic solvents is 1:10 to 10:1; Preferably, the amount of the organic solvent added is 5 to 100 mL of organic solvent per gram of the mixed sample of nitrendipine and polyvinyl pyrrolidone; the grinding time of the liquid addition grinding method is 0.1 hour to 10 hours, the drying temperature is 25-60°C, and the drying time is 2 to 10 hours; the bowl filling rate is 10% to 50%, and the reciprocating motion speed is 20 to 70 m / min; the shear impact energy of the ball mill is 10kw to 800kw; the ball-to-material ratio is 6:1 to 10:1; and the ball mill speed is 300r / min to 400r / min.

6. A solid mixture comprising the co-amorphous material of any one of claims 1 to 4; preferably, based on the weight of the solid mixture, the amount of the co-amorphous material is 1-99.9 wt %, preferably 10-99.9 wt %, more preferably 50-99.9 wt %, and most preferably 85-99.9 wt %.

7. A pharmaceutical composition comprising a therapeutically effective amount of the co-amorphous substance according to any one of claims 1 to 4 or the solid mixture according to claim 6 and a pharmaceutically acceptable carrier.

8. The pharmaceutical composition according to claim 7, wherein the single-day dosage of the pharmaceutical composition is 10 to 1000 mg.

9. The pharmaceutical composition according to claim 7, wherein the pharmaceutical composition is prepared as tablets, capsules, pills, or powder injections; preferably, the pharmaceutical composition is prepared as a sustained-release preparation or a controlled-release preparation.

10. Use of the co-amorphous substance according to any one of claims 1 to 4, the solid mixture according to claim 6, or the pharmaceutical composition according to any one of claims 7 to 9 in the preparation of a medicament for preventing and / or treating coronary heart disease and congestive heart failure.

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