Puerarin co-crystal with valine, process for its preparation and compositions and uses thereof

Abstract

The application discloses a co-crystal of puerarin (English name: Puerarin) and valine (English name: Valine) combined by non-covalent bond, a preparation method and application thereof. 21 H 20 O9·C5H 10 NO2; a preparation method of the co-crystal of puerarin and valine; and application of the co-crystal of puerarin and valine in preparation of a drug with effects of preventing and treating cardiovascular diseases, antioxidation, anticancer, anti-hypertension, blood sugar reduction, anti-inflammation, antipyretic analgesia, anti-Alzheimer's disease and anti-osteoporosis.

Description

Technical Field

[0001] This invention discloses a cocrystal of puerarin and valine, its preparation method, its composition, and its uses. Specifically, this invention discloses a cocrystal formed by puerarin and valine; a method for preparing the cocrystal of puerarin and valine; and the use of the cocrystal of puerarin and valine as an active pharmaceutical ingredient in the preparation of drugs for the prevention and treatment of cardiovascular diseases, anti-oxidation, anti-cancer, antihypertensive, hypoglycemic, anti-inflammatory, antipyretic analgesic, anti-Alzheimer's disease, and anti-osteoporosis, belonging to the field of pharmaceutical technology. Background Technology

[0002] Puerarin is an isoflavone derivative with crown-expanding effects extracted from the dried root of Pueraria lobata (Willd.) Ohwi, a legume. Its chemical name is 8-β-D-glucopyranose-4',7-dihydroxyisoflavone, and its molecular formula is C0. 21 H 20 O9, with the structural formula shown in Figure a, can play a role in preventing and treating cardiovascular diseases, anti-oxidation, anti-cancer, antihypertensive, hypoglycemic, anti-inflammatory, antipyretic and analgesic, anti-Alzheimer's disease, and anti-osteoporosis. [1] .

[0003] Valine is a five-carbon branched, nonpolar α-amino acid, chemically named 2-amino-3-methylbutyric acid, with the molecular formula C5H12O. 10 NO2, with the structural formula shown in b, is one of the eight essential amino acids and a glucogenic amino acid. It works with two other high-concentration amino acids (isoleucine and leucine) to promote normal growth, repair tissues, regulate blood sugar, and provide the necessary energy.

[0004]

[0005] Currently, four types of puerarin cocrystals have been discovered, including puerarin-L-proline cocrystal, puerarin-L-proline cocrystal ethanol dihydrate, puerarin-lornoxicam cocrystal, and puerarin-4,4'-bipyridine cocrystal. These four cocrystals differ fundamentally from the present invention in their composition. In summary, no research content similar to or conflicting with the present invention has been found in terms of material morphology, composition ratio, preparation method, or application. [2-4] .

[0006] The present invention studies the preparation of a cocrystalline solid substance with specific non-covalent interactions between puerarin and valine, thereby forming a novel substance distinct from puerarin, valine, and simple physical mixtures thereof. Furthermore, the novel cocrystalline solid substance of the present invention reveals unexpected technical advantages in the preparation of drugs with effects such as prevention and treatment of cardiovascular diseases, anti-oxidation, anti-cancer, antihypertensive, hypoglycemic, anti-inflammatory, antipyretic and analgesic, anti-Alzheimer's disease, and anti-osteoporosis.

[0007] Currently, there is a need to improve the stability, absorption rate, and onset of action of puerarin. Summary of the Invention

[0008] The technical problem to be solved by this invention:

[0009] One of the technical problems to be solved by the present invention is to provide a state of existence and a characterization method for a puerarin-valine cocrystal.

[0010] The second technical problem to be solved by the present invention is to provide a method for preparing a cocrystal of puerarin and valine.

[0011] The third technical problem to be solved by the present invention is to provide a pure product containing puerarin and valine cocrystals, or a mixed solid substance containing any non-zero proportion of puerarin and valine cocrystals, and a pharmaceutical composition thereof.

[0012] The fourth technical problem to be solved by this invention is to provide a pharmaceutical composition using a co-crystal of puerarin and valine as the active pharmaceutical ingredient, wherein the dosage for each administration is in the range of 10–3000 mg. The pharmaceutical composition includes tablets, capsules, pills, injectable formulations, sustained-release or controlled-release formulations.

[0013] The fifth technical problem to be solved by this invention is to provide a cocrystal of puerarin and valine with better solubility compared to puerarin.

[0014] The sixth technical problem to be solved by this invention is to provide a method in which puerarin and valine cocrystals increase the blood drug concentration in the body and exert a therapeutic effect during the treatment of diseases by forming cocrystals.

[0015] The seventh technical problem this invention aims to solve is to provide the application of using puerarin and valine cocrystals and their mixed crystalline solids as active pharmaceutical ingredients in the preparation of drugs with effects such as prevention and treatment of cardiovascular diseases, anti-oxidation, anti-cancer, antihypertensive, hypoglycemic, anti-inflammatory, antipyretic and analgesic, anti-Alzheimer's disease, and anti-osteoporosis. To solve the above technical problem, this invention adopts the following technical solution:

[0016] 1. Morphological characteristics of puerarin-valine cocrystal samples

[0017] 1.1 The puerarin-valine cocrystal of the present invention is a cocrystal formed by puerarin and valine in a 1:1 molar ratio bonded by non-covalent bonds.

[0018] 1.2 The puerarin-valine cocrystal of the present invention, when analyzed by powder X-ray diffraction using CuK... α Under radiation experimental conditions, the diffraction peak positions are: 2-Theta (°) or The relative intensity of diffraction peaks: peak height (Height%) or peak area (Area%) has the following characteristics (Table 1, Figure 1 The powder X-ray diffraction pattern and data of the physical mixture of puerarin and valine are shown in Table 2. Figure 2 The powder X-ray diffraction patterns of the puerarin-valine cocrystal and the physical mixture of puerarin and valine show significant differences in the number, position, intensity, and topology of diffraction peaks, indicating that the puerarin-valine cocrystal and the physical mixture of puerarin and valine are neither the same nor equivalent.

[0019] Table 1. Powder X-ray diffraction peak values ​​of the puerarin-valine cocrystal.

[0020]

[0021]

[0022] Table 2. Powder X-ray diffraction peaks of puerarin and valine physically mixed.

[0023]

[0024]

[0025] 1.3 The puerarin-valine cocrystal of the present invention, when analyzed using attenuated total reflectance Fourier transform infrared spectroscopy, showed the following values ​​at 3486, 3352, 3169, 2905, 2629, 2111, 1621, 1588, 1515, 1456, 1393, 1369, 1328, 1294, 1257, 1216, 1179, 1130, 1113, 1068, 1052, 1037, 1014, 1002, 991, 949, 901, 889, 878, 833, 824, 802, 790, 776, 743, 716, 661, 632, 608, 569, 540, 507, 489, 446, 428, and 404 cm⁻¹. -1 cm -1 There is an infrared spectral characteristic peak at this location, with an allowable deviation of ±2cm. -1 ( Figure 3 ).

[0026] 1.4 The puerarin-valine cocrystal of the present invention, when analyzed using differential scanning calorimetry (DSC), exhibits an endothermic peak at 238.84℃±3℃ in its DSC spectrum within the temperature range of 30–300℃ at a heating rate of 10℃ / min. Figure 4 The melting point peak of the eutectic is shown. The DSC spectra of the puerarin-valine eutectic and puerarin / valine cocrystal show significant differences in the number and position of endothermic / exothermic peaks, indicating that puerarin and valine have formed a new phase, namely the puerarin-valine eutectic. Figure 5 ).

[0027] 2. Characteristics of the preparation methods for puerarin-valine cocrystals and mixed solid substances:

[0028] 2.1 The preparation method of the puerarin-valine cocrystal involved in this invention employs a solvent suspension method. Puerarin and valine are mixed in a molar ratio of 1:1, an organic solvent is added, and the mixture is stirred at room temperature at a stirring speed of 100 r / min to 1000 r / min for 0.1 hours to 96 hours. The resulting suspension is dried by solvent evaporation, filtration and natural drying, or filtration and vacuum drying to obtain the puerarin-valine cocrystal. The organic solvent is preferably a mixture of methanol, ethanol, acetonitrile, acetone, tetrahydrofuran, dioxane, n-hexane, and cyclohexane prepared in different proportions; the total mass of puerarin-valine and the solid-liquid ratio of the organic solvent are maintained within the range of 1 mg / ml to 500 mg / ml.

[0029] 2.2 The mixed solid material containing puerarin and valine cocrystals of the present invention is prepared by the above method and then mixed with other chemical substances in any non-zero proportion and by conventional methods.

[0030] 3. Pharmaceutical formulations containing puerarin and valine cocrystals, dosage characteristics, and pharmaceutical uses: 3.1 The pharmaceutical composition of the present invention contains puerarin and valine cocrystals and a pharmaceutically acceptable carrier. 3.2 The pharmaceutical composition of the present invention contains a mixed solid substance of puerarin and valine cocrystals and a pharmaceutically acceptable carrier.

[0031] 3.3 The daily dosage of the pharmaceutical composition of the present invention, which is a cocrystal of puerarin and valine, is in the range of 10 to 3000 mg.

[0032] 3.4 The pharmaceutical composition of the present invention is characterized in that the dosage form of the pharmaceutical composition is various tablets, capsules, pills, injectable preparations, sustained-release preparations or controlled-release preparations.

[0033] 3.5 The application of the puerarin-valine cocrystal of the present invention in the preparation of drugs with the functions of preventing and treating cardiovascular diseases, anti-oxidation, anti-cancer, antihypertensive, hypoglycemic, anti-inflammatory, antipyretic and analgesic, anti-Alzheimer's disease, and anti-osteoporosis.

[0034] This invention relates to pharmaceutical compositions using puerarin and valine cocrystals as active ingredients. These pharmaceutical compositions can be prepared according to methods known in the art. Any dosage form suitable for human or animal use can be formulated by combining the puerarin and valine cocrystals of this invention with one or more pharmaceutically acceptable solid or liquid excipients and / or adjuvants. The content of the puerarin and valine cocrystals and mixed solids of puerarin and valine cocrystals of this invention in their pharmaceutical compositions ranges from 10% to 90% by weight.

[0035] The puerarin-valine cocrystal of the present invention can be administered in unit dose form, and the route of administration can be enteric or non-enteric, such as oral, intravenous, intramuscular, subcutaneous, nasal, oral mucosa, eye, lung and respiratory tract, skin, vagina, rectum, etc.

[0036] The preferred dosage form for administration in this invention is a solid dosage form. Solid dosage forms can be tablets (including regular tablets, enteric-coated tablets, lozenges, dispersible tablets, chewable tablets, effervescent tablets, orally disintegrating tablets), capsules (including hard capsules, soft capsules, and enteric-coated capsules), granules, powders, microcapsules, droplets, suppositories, films, patches, aerosols, sprays, etc.

[0037] The cocrystals of puerarin and valine, and the mixed solid substances of puerarin and valine cocrystals of the present invention, can be formulated into ordinary preparations, as well as into sustained-release preparations, controlled-release preparations, targeted preparations, and various microparticle delivery systems.

[0038] To form the puerarin-valine cocrystal of the present invention into tablets, a wide variety of excipients known in the art can be used, including diluents, binders, wetting agents, disintegrants, lubricants, and flow aids. Diluents can be starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, dicalcium phosphate, calcium carbonate, etc.; wetting agents can be water, ethanol, isopropanol, etc.; binders can be starch paste, dextrin, syrup, honey, glucose solution, microcrystalline cellulose, gum arabic paste, gelatin paste, sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, polyethylene glycol, etc.; disintegrants can be dry starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch, sodium bicarbonate and citric acid, polyoxyethylene sorbitol fatty acid ester, sodium dodecyl sulfonate, etc.; lubricants and flow aids can be talc, silica, stearate, tartaric acid, liquid paraffin, polyethylene glycol, etc.

[0039] Tablets can also be further processed into coated tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or bilayer and multilayer tablets.

[0040] To formulate the drug delivery unit into capsules, the active ingredient puerarin and valine cocrystal can be mixed with a diluent and a flow aid, and the mixture can be directly placed into hard or soft capsules. Alternatively, the active ingredient puerarin and valine cocrystal can be first formed into granules or microspheres with a diluent, binder, and disintegrant, and then placed into hard or soft capsules. Various diluents, binders, wetting agents, disintegrants, and flow aids used to prepare puerarin and valine cocrystal tablets can also be used to prepare capsules of the puerarin and valine cocrystal of this invention.

[0041] In addition, colorants, preservatives, flavorings, tasters or other additives may be added to pharmaceutical preparations if necessary.

[0042] To achieve the intended therapeutic purpose and enhance the therapeutic effect, the drug of the present invention can be administered using any known method of drug administration.

[0043] The dosage of the puerarin and valine cocrystal pharmaceutical composition of the present 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. The above dosage can be administered as a single unit or divided into several units, depending on the physician's clinical experience and the administration regimen, including the use of other treatment methods.

[0044] The puerarin and valine cocrystal or composition of the present invention can be taken alone or in combination with other therapeutic or symptomatic drugs. When the puerarin and valine cocrystal of the present invention has a synergistic effect with other therapeutic drugs, its dosage should be adjusted according to the actual situation.

[0045] 4. Beneficial technical effects of the present invention:

[0046] Safety, hygroscopicity, stability and bioabsorption advantages of puerarin-valine cocrystals.

[0047] 4.1 The puerarin-valine cocrystal of the present invention does not contain any crystallization solvent, and has good advantages in terms of safety in drug preparation.

[0048] 4.2 The puerarin-valine cocrystal of the present invention has a lower hygroscopic rate compared to the active pharmaceutical ingredient. Figure 6 )

[0049] 4.3 The puerarin-valine cocrystal of the present invention is stable under conditions of high temperature (60℃), high humidity (25℃, relative humidity 90% ± 5%), and light exposure (4500 lx ± 500 lx), exhibiting excellent drug-grade stability. Figure 7 ).

[0050] 4.4 The puerarin and valine cocrystal of the present invention, as an active ingredient, and the resulting drug and pharmaceutical composition, exhibit superior biological absorption after oral administration, rapidly reaching maximum concentrations in the gastrointestinal tract or blood, thus exerting an advantageous effect in the prevention and treatment of diseases. The puerarin and valine cocrystal of the present invention has a significant advantage over raw puerarin in increasing its in vivo blood drug concentration, thereby better exerting the drug's effective therapeutic effect. Figure 8 ). Attached Figure Description

[0051] Figure 1 Powder X-ray diffraction pattern of puerarin and valine cocrystal

[0052] Figure 2 Powder X-ray diffraction pattern of a physical mixture of puerarin and valine

[0053] Figure 3 Infrared absorption spectrum of puerarin and valine cocrystal

[0054] Figure 4 Differential scanning calorimetry spectrum of puerarin and valine cocrystal

[0055] Figure 5 Differential scanning calorimetry (DSC) spectra of puerarin and valine cocrystals and puerarin and valine raw materials

[0056] Figure 6 Hygroscopicity curves of puerarin-valine cocrystal and puerarin raw material

[0057] Figure 7 Stability spectrum of puerarin-valine cocrystal

[0058] Figure 8 Blood concentration-time curves of puerarin in the cocrystal of puerarin and valine (0-12h). Detailed Implementation

[0059] To better illustrate the technical solution of the present invention, the following embodiments are provided, but the present invention is not limited thereto.

[0060] Example 1

[0061] Preparation method of puerarin and valine cocrystal:

[0062] Take appropriate amounts of puerarin and valine, with a molar ratio of 1:1. Add the sample to a suitable container using a solvent suspension method at room temperature, add an appropriate amount of organic solvent, and stir for an appropriate time at room temperature. Then, evaporate the solvent in the resulting suspension, filter and allow it to air dry, or filter and vacuum dry. See Table 3 for the conditions and parameters. Perform powder X-ray diffraction analysis on the sample; the diffraction patterns are all consistent with... Figure 1 The consistency indicates that the obtained sample is a cocrystal of puerarin and valine.

[0063] Table 3. Specific examples of methods for preparing puerarin-valine cocrystals

[0064]

[0065] Example 2

[0066] Hygroscopic characteristics of puerarin-valine cocrystal

[0067] The hygroscopicity of puerarin raw material and puerarin-valine cocrystal was evaluated using dynamic steam adsorption (DVS). The mass change with humidity and the adsorption / desorption were investigated at a temperature of 25℃ and a relative humidity range of 0%-90%. Specific data are shown in Table 4.

[0068] Table 4. DVS data (percentage change in mass) of puerarin raw material and puerarin-valine cocrystal.

[0069]

[0070] The DVS experiment results show that the cocrystal of puerarin and valine has a smaller maximum hygroscopic weight gain and lower hygroscopicity compared to the raw puerarin, indicating that the cocrystal of puerarin and valine has superior drug-like properties. Figure 6 )

[0071] Example 3

[0072] Stability advantages of puerarin and valine cocrystals

[0073] High-temperature test: The puerarin-valine cocrystal sample was placed in an open, clean petri dish and placed at 60°C for 10 days. Samples were taken on days 0, 5, and 10. Powder X-ray diffraction analysis of the samples obtained at the above sampling points showed that the puerarin-valine cocrystal was stable under the high-temperature influence factor test.

[0074] High humidity test: The puerarin-valine cocrystal sample was placed in an open, clean petri dish and stored at 25°C and 90% ± 5% relative humidity for 10 days. Samples were taken on days 0, 5, and 10. Powder X-ray diffraction analysis of the samples obtained at the above sampling points showed that the puerarin-valine cocrystal was stable under high humidity conditions.

[0075] Illumination test: The puerarin-valine cocrystal sample was placed in an open, clean petri dish and then placed in an illumination box equipped with a fluorescent lamp at an illuminance of 4500 lx ± 500 lx for 10 days. Samples were taken on days 0, 5, and 10. Powder X-ray diffraction analysis of the samples obtained at the above sampling points showed that the puerarin-valine cocrystal was stable under illumination conditions.

[0076] Stability studies of the puerarin-valine cocrystal demonstrated that the cocrystal remained stable for 10 days under high temperature, high humidity, and light conditions, improving upon the instability of puerarin raw material in high humidity environments and exhibiting stable drug-like properties. Figure 7 ).

[0077] Example 4

[0078] In vivo bioabsorption advantages of puerarin and valine cocrystal

[0079] Standard solution: Accurately weigh 5.00 mg of puerarin standard, add 50 mL of methanol to dissolve and mix thoroughly, and prepare a 100 μg / mL puerarin stock solution. Store at -20℃. Dilute with methanol to prepare standard solutions of different concentrations before use. Internal standard solution: Accurately weigh 5.00 mg of apigenin, add 50 mL of methanol to dissolve and mix thoroughly, and prepare a 100 μg / mL apigenin stock solution. Store at -20℃. Dilute with methanol to prepare a 100 ng / mL internal standard working solution before use.

[0080] SD rats were randomly divided into two groups of six each. They were raised under standard feeding conditions with free access to water. After fasting for 12 hours, puerarin and puerarin-valine cocrystal samples were administered via gavage at a dose of 100 mg / kg. At 5 min, 15 min, 30 min, 1 h, 1.5 h, 2 h, 4 h, 6 h, 8 h, and 12 h post-administration, approximately 0.3 mL of blood was collected from the posterior ocular venous plexus and placed into heparinized anticoagulant tubes. The tubes were centrifuged at 5000 rpm for 10 min at 4 °C, and 100 μL of the supernatant was collected and stored at -80 °C for analysis.

[0081] For the assay, accurately pipette 100 μL of plasma, add 10 μL of internal standard puerarin working solution, then add 300 μL of acetonitrile, shake thoroughly for 3 min, centrifuge (13000 rpm, 10 min), collect 380 μL of the supernatant and blow dry with nitrogen until dry, then add 100 μL of 50% methanol to reconstitute, shake thoroughly for 3 min, centrifuge (13000 rpm, 3 min), collect 90 μL of the supernatant in an inner liner tube, and inject 3 μL. Detect the standard curve using the same method. Calculate the blood concentrations of puerarin and valine by substituting the ratio of the drug peak area to the internal standard peak area into the standard curve, and plot the blood concentration-time curve.

[0082] Detection conditions: Column: ACQUITY BEH C 18 (2.1×50mm, 1.7μm); Mobile phase A was 0.1% formic acid, and mobile phase B was acetonitrile. Column temperature was 40℃; injection volume: 3μL; run time: 7min. Gradient elution conditions were as follows:

[0083]

[0084]

[0085] Mass spectrometry conditions: negative ion mode, kudzu mass-to-charge ratio of 415.2, and poplar mass-to-charge ratio of 253.1.

[0086] The pharmacokinetic parameters of puerarin and its cocrystal containing puerarin and valine were calculated. The main pharmacokinetic parameters are shown in Table 5, and the 0-24 hour plasma concentration-time curves are shown below. Figure 8 As shown.

[0087] Table 5. Main pharmacokinetic parameters of puerarin in physical mixtures and puerarin-valine cocrystals.

[0088]

[0089] (mean ± standard error)

[0090] The experimental data above show that, compared with puerarin, the peak time (T) of puerarin in the cocrystal of puerarin and valine is shorter. max The half-life (t) is shortened by half. 1 / 2 The duration of action allows it to reach higher therapeutic concentrations faster than the raw material puerarin, and the maximum plasma concentration C of the puerarin / valine cocrystal is also extended. max Its AUC is about twice that of puerarin raw material, giving it advantages in terms of faster onset of action, longer duration of action, and better bioabsorption.

[0091] Example 5

[0092] Preparation method 1 of combination drug formulation (tablets):

[0093] A method for preparing a combination drug tablet, characterized by using pure puerarin and valine cocrystal as the active pharmaceutical ingredient (API) of the combination drug, and using several excipients as excipients for preparing the combination drug tablet, and preparing tablet samples with a drug content of 10-500 mg per tablet according to a certain ratio. Table 6 shows the tablet formulation ratio:

[0094] Table 6. Formulation for preparing tablets of puerarin and valine cocrystal combination drugs.

[0095]

[0096] The method for preparing tablet formulations using pure puerarin and valine cocrystals as raw materials is as follows: mix several excipients with the raw material evenly and compress directly into tablets; or mix the excipients by dry granulation and then mix evenly with the raw material before compressing into tablets.

[0097] Preparation method 2 for combination drug formulations (tablets):

[0098] A method for preparing a combination drug tablet, characterized by using pure puerarin and valine cocrystal as the active pharmaceutical ingredient (API) and several excipients as excipients for preparing the combination drug tablet, and preparing tablet samples with a drug content of 10-500 mg per tablet according to a certain ratio. Table 7 shows the tablet formulation ratios:

[0099] Table 7. Formulation for preparing tablets of puerarin and valine cocrystal combination drugs.

[0100]

[0101]

[0102] The method for preparing tablet formulations using pure puerarin and valine cocrystals as raw materials is as follows: several excipients are mixed evenly with the raw materials, an appropriate amount of 1% sodium hydroxymethyl cellulose solution is added to form a soft material, which is then granulated by sieving, the wet granules are dried, sieved and sized, magnesium stearate and talc are added and mixed evenly, and then tableted to obtain the final product.

[0103] Preparation method 3 of combination drug formulation (capsule):

[0104] A method for preparing a combination drug capsule, characterized by using pure puerarin and valine cocrystal as the active pharmaceutical ingredient (API) and several excipients as excipients for preparing the combination drug capsule, and preparing capsule samples with a drug content of 10-500 mg per tablet according to a certain ratio. Table 8 shows the capsule formulation ratio:

[0105] Table 8. Active pharmaceutical ingredients and excipients for puerarin and valine cocrystal combination drug capsules.

[0106]

[0107] The method for preparing puerarin and valine cocrystal raw materials into tablet formulations is as follows: several excipients are mixed evenly with the raw material, an appropriate amount of 1% sodium carboxymethyl cellulose solution is added, wet granules are prepared, dried, sieved and granulated, magnesium stearate is added and mixed evenly, and then inserted into capsules; or, without using the granulation step, the puerarin and valine cocrystal raw material is directly mixed evenly with several excipients and excipients, sieved, and directly filled into capsules.

[0108] Example 6

[0109] Dosage of the puerarin and valine cocrystal combination drug 1 (tablet):

[0110] A pharmaceutical composition developed using puerarin and valine cocrystal samples as the active pharmaceutical ingredient is characterized by the use of puerarin and valine cocrystal as the active pharmaceutical ingredient, with a daily dosage of 0.5-300 mg. It can be prepared into conventional tablets containing 10, 100, 200, 300, and 500 mg of the active ingredient per dose of 1-6 tablets. Dosage of the puerarin and valine cocrystal combination drug 2 (capsules):

[0111] Pharmaceutical compositions developed using puerarin and valine cocrystals as the active pharmaceutical ingredient (API) are characterized by the use of the puerarin and valine cocrystal as the API, with a daily dosage of 10-3000 mg. These compositions can be prepared into capsules containing 10, 100, 200, 300, or 500 mg of the API per dose, ranging from 1 to 6 capsules. Points requiring clarification:

[0112] The dosage of the active ingredient in the puerarin and valine cocrystal pharmaceutical composition involved in this invention is influenced by many factors, such as: different uses for prevention and treatment resulting in different daily dosages; different nature and severity of the disease resulting in different daily dosages; differences in patient gender, age, body surface area, route of administration, frequency of administration, and treatment purpose resulting in different daily dosages; in addition, differences in absorption and blood drug concentration between crystal forms also contribute to the fact that the appropriate daily dosage range for the puerarin and valine cocrystal component in this invention is 0.002-60 mg / kg body weight, preferably 0.01-30 mg / kg body weight. When using it, different total dosage schemes of the active ingredient in the puerarin and valine cocrystal should be formulated according to the actual needs of prevention and treatment, and it can be administered in multiple or single doses.

[0113] References

[0114] [1]Zhou YX, Zhang H, Peng C. Puerarin: a review of pharmacological effects[J]. Phytotherapy Research, 2014, 28(7):961-975.

[0115] [2] Inam M, Liu L, Wang JW, et al. Enhancing the physicochemical properties of puerarin via l-proline co-crystallization: synthesis, characterization, and dissolution studies of two phases of pharmaceutical co-crystals[J]. International Journal of Molecular Sciences, 2021, 22(2):928.

[0116] [3] Jin Yang, Lu Xiang, Jiang Chengjun. Preparation and characterization of puerarin-pyridine cocrystal [J]. Journal of Zhejiang University of Science and Technology, 2019, 31(1):30-35.

[0117] [4] Hua Yun, Wu Yushen, Zheng Daoyi, et al. Study on the improvement of lornoxicam dissolution behavior and tablet compressibility by eutectic technology [J]. Acta Pharmaceutica Sinica, 2022, 57(4):1163-1171.

[0118] [5]Cao W, Zhou Y, Yan T, et al. Solubility, Dissolution Rate and LD50Studies on Cocrystals of Bipyridine with Puerarin and Quercetin[J]. Available at SSRN 4384288.

Claims

1. A cocrystal of puerarin and valine, characterized in that, Puerarin and valine form a eutectic in a 1:1 molar ratio.

2. The puerarin-valine cocrystal according to claim 1, characterized in that, When using powder X-ray diffraction analysis with CuK α Under radiation experimental conditions, the diffraction peak position is: 2-Theta (°) or The relative intensity of diffraction peaks: peak height (Height%) or peak area (Area%) has the following characteristics:

3. The puerarin-valine cocrystal according to claim 1, characterized in that, When analyzed using attenuated total reflectance Fourier transform infrared spectroscopy, the values ​​at 3486, 3352, 3169, 2905, 2629, 2111, 1621, 1588, 1515, 1456, 1393, 1369, 1328, 1294, 1257, 1216, 1179, 1130, 1113, 1068, 1052, 1037, 1014, 1002, 991, 949, 901, 889, 878, 833, 824, 802, 790, 776, 743, 716, 661, 632, 608, 569, 540, 507, 489, 446, 428, and 404 ccm were obtained. -1 There is an infrared spectral characteristic peak at this location, with an allowable deviation of ±2cm. -1 .

4. The puerarin-valine cocrystal according to claim 1, characterized in that, When analyzed using differential scanning calorimetry, an endothermic peak was observed at 238.84℃±3℃ in the DSC spectrum within the range of 30 to 300℃ at a heating rate of 10℃ / min.

5. The method for preparing the puerarin-valine cocrystal according to any one of claims 1-4, characterized in that, Puerarin and valine were fed in a 1:1 molar ratio and a chemical method of suspension in an organic solvent was used to prepare a puerarin-valine cocrystal.

6. According to the preparation method of claim 5, the organic solvent in the solvent suspension method is selected from any one or more of methanol, ethanol, tetrahydrofuran, acetone, acetonitrile, dioxane, n-hexane, and cyclohexane, and is prepared by combining them in different proportions; the total mass of puerarin and valine to the solid-liquid ratio of the organic solvent is 1 mg / mL to 500 mg / mL; the stirring speed is 100 r / min to 1000 r / min; the stirring time is 0.1 hours to 96 hours; and the obtained suspension is dried by solvent evaporation, natural drying by filtration, or vacuum drying by filtration to prepare puerarin and valine cocrystals.

7. A mixed solid substance containing a co-crystal of puerarin and valine, characterized in that, The amount of the puerarin and valine cocrystal as described in any one of claims 1-4 is 1-99.9%, preferably 10-99.9%, more preferably 50-99.9%, and most preferably 85-99.9%.

8. A pharmaceutical composition, characterized in that, The product contains an effective dose of the puerarin-valine cocrystal of any one of claims 1-4 and a pharmaceutically acceptable carrier.

9. A pharmaceutical composition, characterized in that, A mixed solid substance containing an effective dose of the puerarin and valine cocrystal as described in claim 7 and a pharmaceutically acceptable carrier.

10. The pharmaceutical composition according to any one of claims 8 or 9, characterized in that, The daily dosage of puerarin and valine cocrystals ranges from 10 mg to 3000 mg.

11. The pharmaceutical composition according to any one of claims 8 or 9, characterized in that, The dosage form of the pharmaceutical composition is tablets, capsules, pills, powder for injection, sustained-release preparations, or controlled-release preparations.

12. Use of the puerarin and valine cocrystal of any one of claims 1-4, or the mixed solid substance of the puerarin and valine cocrystal of claim 7, or the pharmaceutical composition of any one of claims 8 or 9, in the preparation of a medicament for the prevention and treatment of cardiovascular diseases, anti-oxidation, anti-cancer, antihypertensive, hypoglycemic, anti-inflammatory, antipyretic analgesic, anti-Alzheimer's disease, and anti-osteoporosis.

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