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

Abstract

Puerarin and theophylline co-crystal, preparation method thereof, and composition and use thereof. The present application discloses a co-crystal formed by combining puerarin (English name: Puerarin) and theophylline (English name: Theophylline) through non-covalent bonds, and a preparation method and use thereof. Specifically, the present application discloses a co-crystal formed by puerarin and theophylline, the molecular formula of the co-crystal is C 21 H 20 O9·C7H8N4O2; a preparation method of the puerarin and theophylline co-crystal; and application of the puerarin and theophylline co-crystal in preparation of a drug having effects of preventing and treating cardiovascular diseases, antioxidation, anticancer, antihypertension, blood sugar reduction, anti-inflammation, antipyretic analgesia, anti-Alzheimer's disease, anti-osteoporosis, cardiotonic, diuresis, coronary artery expansion, bronchial smooth muscle relaxation, and central nervous system excitation.

Description

Technical Field

[0001] This invention discloses a cocrystal of puerarin and theophylline, its preparation method, its composition, and its uses. Specifically, this invention discloses a cocrystal formed by puerarin and theophylline; a method for preparing the cocrystal of puerarin and theophylline; and the use of the cocrystal of puerarin and theophylline 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, anti-osteoporosis, cardiotonic, diuretic, coronary artery dilation, bronchial smooth muscle relaxation, and central nervous system stimulation, 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 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]. Puerarin is a product listed in the pharmacopoeia, but due to its poor stability, slow absorption rate and onset of action, it is only used in clinical treatment in the form of injection. At present, it is necessary to improve the stability, absorption rate and onset of action of puerarin.

[0003] Theophylline is a naturally occurring methylpurine alkaloid found in tea leaves. Its chemical name is 2,6-dioxo-1,3-dimethylpurine, with the molecular formula C7H8N4O2 and structural formula shown in Figure b. It has cardiotonic, diuretic, coronary artery dilating, bronchial smooth muscle relaxant, and central nervous system stimulant effects. It is mainly used to treat bronchial asthma, emphysema, bronchitis, and cardiac dyspnea.

[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 terms of 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, and applications. [2-4] .

[0006] The present invention studies the preparation of puerarin and theophylline into a cocrystalline solid substance with specific non-covalent interactions, thereby forming a novel substance distinct from puerarin, theophylline, and simple physical mixtures thereof. Furthermore, the novel cocrystalline solid substance of the present invention has 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, anti-osteoporosis, cardiotonic, diuretic, coronary artery dilation, bronchial smooth muscle relaxation, and central nervous system stimulation. Summary of the Invention

[0007] The technical problem to be solved by this invention:

[0008] One of the technical problems to be solved by the present invention is to provide a state of existence and a characterization method for puerarin-theophylline cocrystal.

[0009] The second technical problem to be solved by this invention is to provide a method for preparing a eutectic of puerarin and theophylline.

[0010] The third technical problem to be solved by the present invention is to provide a pure product containing puerarin and theophylline cocrystals, or a mixed solid substance containing any non-zero proportion of puerarin and theophylline cocrystals, and a pharmaceutical composition thereof.

[0011] The fourth technical problem to be solved by this invention is to provide a pharmaceutical composition using a eutectic of puerarin and theophylline 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.

[0012] The fifth technical problem to be solved by this invention is to provide a puerarin-theophylline cocrystal with better solubility compared to puerarin.

[0013] The sixth technical problem to be solved by this invention is to provide a therapeutic effect by increasing the blood drug concentration in organisms due to the formation of co-crystals of puerarin and theophylline during the treatment of diseases.

[0014] The seventh technical problem to be solved by this invention is to provide the application of using puerarin and theophylline cocrystals and their mixed crystalline solid substances as active pharmaceutical ingredients in the preparation of drugs with the following effects: prevention and treatment of cardiovascular diseases, anti-oxidation, anti-cancer, antihypertensive, hypoglycemic, anti-inflammatory, antipyretic and analgesic, anti-Alzheimer's disease, anti-osteoporosis, cardiotonic, diuretic, coronary artery dilation, bronchial smooth muscle relaxation and central nervous system stimulation.

[0015] To solve the above-mentioned technical problems, the present invention adopts the following technical solution:

[0016] 1. Morphological characteristics of puerarin-theophylline eutectic samples

[0017] 1.1 The puerarin-theophylline eutectic of the present invention is a eutectic substance formed by non-covalent bonding of puerarin and theophylline in a molar ratio of 1:2.

[0018] 1.2 The puerarin-theophylline eutectic 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 theophylline are shown in Table 2. Figure 2 The powder X-ray diffraction patterns of the puerarin-theophylline eutectic and the physical mixture of puerarin and theophylline show significant differences in the number, position, intensity, and topology of diffraction peaks, indicating that the puerarin-theophylline eutectic and the physical mixture of puerarin and theophylline are neither the same nor equivalent.

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

[0020]

[0021]

[0022] Table 2. Powder X-ray diffraction peaks of puerarin and theophylline in physical mixtures

[0023]

[0024] 1.3 The puerarin-theophylline cocrystal of the present invention, when analyzed using attenuated total reflectance Fourier transform infrared spectroscopy, exhibits the following values ​​at 3355, 3243, 3132, 2949, 2888, 2719, 2647, 1693, 1630, 1558, 1516, 1484, 1439, 1386, 1304, 1263, 1247, 1206, 1173, 1132, 1116, 1096, 1053, 1037, 983, 954, 925, 883, 829, 811, 790, 762, 744, 716, 691, 657, 640, 611, 573, 539, 501, 452, 431, and 419 cm⁻¹. 1 There is an infrared spectral characteristic peak at this location, with an allowable deviation of ±2cm. 1 ( Figure 3 ).

[0025] 1.4 The puerarin-theophylline eutectic of the present invention, when analyzed using differential scanning calorimetry (DSC), exhibits an endothermic peak at 196.83℃±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-theophylline eutectic differ significantly from those of puerarin and theophylline in terms of the number and position of endothermic / exothermic peaks, indicating that puerarin and theophylline have formed a new phase, namely the puerarin-theophylline eutectic. Figure 5 ).

[0026] 2. Characteristics of the preparation methods for puerarin-theophylline eutectics and mixed solid substances:

[0027] 2.1 The preparation method of the puerarin-theophylline cocrystal involved in this invention employs a solvent suspension method. Puerarin and theophylline are mixed in a molar ratio of 1:2, an organic solvent is added, and the mixture is stirred at room temperature at a 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-theophylline 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-theophylline and the solid-liquid ratio of the organic solvent are maintained within the range of 1 mg / ml to 500 mg / ml.

[0028] 2.2 The mixed solid substance containing puerarin and theophylline cocrystals that is involved in this invention is prepared by the above method and then mixed with other chemical substances in any non-zero proportion and by conventional methods.

[0029] 3. Pharmaceutical formulations containing puerarin and theophylline co-crystals, dosage characteristics, and pharmaceutical uses:

[0030] 3.1 The pharmaceutical composition of the present invention contains a puerarin-theophylline cocrystal and a pharmaceutically acceptable carrier.

[0031] 3.2 The pharmaceutical composition of the present invention comprises a mixed solid substance of puerarin and theophylline cocrystal and a pharmaceutically acceptable carrier.

[0032] 3.3 The daily dosage of the pharmaceutical composition of the present invention, which is a cocrystal of puerarin and theophylline, is in the range of 10 to 3000 mg.

[0033] 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.

[0034] 3.5 The application of the puerarin-theophylline 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 analgesic, anti-Alzheimer's disease, and anti-osteoporosis.

[0035] This invention relates to pharmaceutical compositions using puerarin and theophylline 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 theophylline cocrystals of this invention with one or more pharmaceutically acceptable solid or liquid excipients and / or adjuvants. The content of the puerarin and theophylline cocrystals and mixed solids of puerarin and theophylline cocrystals of this invention in their pharmaceutical compositions ranges from 10% to 90% by weight.

[0036] The cocrystal of puerarin and theophylline 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.

[0037] 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.

[0038] The puerarin-theophylline cocrystal and the mixed solid material of the puerarin-theophylline cocrystal of the present invention can be made into ordinary preparations, as well as sustained-release preparations, controlled-release preparations, targeted preparations and various microparticle delivery systems.

[0039] In order to form the puerarin-theophylline 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.

[0040] 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.

[0041] To formulate the drug delivery unit into capsules, the active ingredient puerarin and theophylline 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 theophylline 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 theophylline cocrystal tablets can also be used to prepare capsules of the puerarin and theophylline cocrystal of this invention.

[0042] In addition, colorants, preservatives, flavorings, tasters or other additives may be added to pharmaceutical preparations if necessary.

[0043] 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.

[0044] The dosage of the puerarin-theophylline 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.

[0045] The puerarin and theophylline cocrystal or composition of the present invention can be taken alone or in combination with other therapeutic or symptomatic drugs. When the puerarin and theophylline cocrystal of the present invention has a synergistic effect with other therapeutic drugs, its dosage should be adjusted according to the actual situation.

[0046] 4. Beneficial technical effects of the present invention:

[0047] Safety, solubility, stability, and bioavailability of puerarin-theophylline cocrystals.

[0048] 4.1 The puerarin-theophylline cocrystal of the present invention contains no crystallization solvent, thus possessing excellent safety advantages in pharmaceutical preparation. 4.2 The puerarin-theophylline cocrystal of the present invention exhibits superior solubility compared to puerarin raw material. In a buffer solution at pH 6.8, it shows a dissolution rate essentially the same as that of puerarin raw material, but its solubility is higher than that of puerarin raw material (…). Figure 6 ).

[0049] 4.3 The puerarin-theophylline cocrystal of this invention is stable under high temperature (60℃), high humidity (25℃, relative humidity 90% ± 5%), and light (4500 lx ± 500 lx) conditions, exhibiting excellent stability for pharmaceutical preparation. Figure 7 ).

[0050] 4.4 The puerarin and theophylline 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 theophylline 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-theophylline cocrystal

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

[0053] Figure 3 Infrared absorption spectrum of puerarin-theophylline cocrystal

[0054] Figure 4 Differential scanning calorimetry of puerarin-theophylline cocrystal

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

[0056] Figure 6 Solubility curve of puerarin-theophylline cocrystal in pH 6.8 buffer solution

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

[0058] Figure 8 Blood concentration-time curves of puerarin in the cocrystal of puerarin and theophylline (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-theophylline cocrystal:

[0062] Take appropriate amounts of puerarin and theophylline, with a molar ratio of 1:2, and prepare the solution using a solvent suspension method at room temperature. Add the sample to a suitable container, add an appropriate amount of organic solvent, and stir for a suitable 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 condition parameters. Perform powder X-ray diffraction analysis on the solution; the diffraction patterns are all consistent with... Figure 1 The consistency indicates that the obtained sample is a eutectic of puerarin and theophylline.

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

[0064]

[0065]

[0066] Example 2

[0067] In vitro dissolution and release characteristics of puerarin and theophylline cocrystals

[0068] The solubility characteristics of puerarin-theophylline cocrystal and puerarin raw material in water were investigated. The experiments were conducted according to the "Technical Guidelines for Dissolution Testing of Common Oral Solid Dosage Forms". Using puerarin raw material as a reference, the puerarin content was determined by high-performance liquid chromatography (HPLC) at a wavelength of 250 nm, and the amount dissolved was calculated using the external standard method. Dissolution curves were plotted with time on the x-axis and amount dissolved on the y-axis. Figure 6 Specific data are shown in Table 4:

[0069] Table 4 Dissolution curve data

[0070]

[0071] Solubility data show that the cocrystal of puerarin and theophylline exhibits better solubility in a pH 6.8 buffer solution than the raw puerarin. The dissolution rate of the puerarin-theophylline cocrystal is basically the same as that of the raw puerarin, but the amount dissolved is significantly higher, and both solubility curves show a stable release plateau.

[0072] Example 3

[0073] Stability advantages of puerarin-theophylline cocrystals

[0074] High-temperature test: The puerarin-theophylline 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-theophylline cocrystal was stable under the high-temperature influence factor test.

[0075] High humidity test: The puerarin-theophylline 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-theophylline cocrystal was stable under high humidity conditions.

[0076] Light exposure test: The puerarin-theophylline 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-theophylline cocrystal was stable under light exposure conditions.

[0077] Stability studies of the puerarin-theophylline 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 pharmaceutical properties. Figure 7 ).

[0078] Example 4

[0079] In vivo bioabsorption advantages of puerarin-theophylline cocrystals

[0080] 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.

[0081] 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-theophylline 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 stored at -80 °C for analysis.

[0082] 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, and calculate the blood concentrations of puerarin and theophylline 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.

[0083] Detection conditions: Column: ACQUITY BEHC 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:

[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] Pharmacokinetic parameters were calculated based on the measured blood concentration data of puerarin and its cocrystal containing puerarin-theophylline. The main pharmacokinetic parameters are shown in Table 5, and the 0-12 hour blood concentration-time curves are shown in the figure. Figure 8 As shown.

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

[0088]

[0089]

[0090] (mean ± standard error)

[0091] The experimental data above show that, compared with puerarin, the peak time (T) of puerarin in the cocrystal of puerarin and theophylline is shorter. max The half-life (t) was shortened by half. 1 / 2 The time to release the drug is also shortened, allowing it to reach higher therapeutic concentrations faster than puerarin raw materials, making it more suitable for diseases that require rapid release and faster onset of action, such as ischemic angina.

[0092] Example 5

[0093] Preparation method 1 of combination drug formulation (tablets):

[0094] A method for preparing a combination drug tablet, characterized by using pure puerarin and theophylline 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 6 shows the tablet formulation ratio:

[0095] Table 6. Formulation for preparing tablets of puerarin and theophylline cocrystal combination drugs.

[0096]

[0097] The method for preparing tablet formulations using pure puerarin-theophylline cocrystals as raw materials is as follows: mix several excipients with the raw material evenly and compress directly into tablets; or mix the excipients together by dry granulation and then mix evenly with the raw material before compressing into tablets.

[0098] Preparation method 2 for combination drug formulations (tablets):

[0099] A method for preparing a combination drug tablet, characterized by using pure puerarin and theophylline 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:

[0100] Table 7. Formulation for preparing tablets of puerarin and theophylline cocrystal combination drugs.

[0101]

[0102] The method for preparing tablet formulations using pure puerarin and theophylline co-crystals 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 theophylline 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 capsule formulations of puerarin and theophylline cocrystals.

[0106]

[0107]

[0108] The method for preparing puerarin and theophylline co-crystal 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 theophylline co-crystal raw material is directly mixed evenly with several excipients and excipients, sieved, and directly filled into capsules.

[0109] Example 6

[0110] Dosage of the puerarin and theophylline cocrystal combination drug 1 (tablets):

[0111] The pharmaceutical composition developed using puerarin and theophylline cocrystal samples as the active pharmaceutical ingredient is characterized by using puerarin and theophylline cocrystals as the active pharmaceutical ingredient, with a daily dosage of 0.5-300 mg, and can be prepared into ordinary tablets containing 10, 100, 200, 300, and 500 mg of active ingredient per dose of 1-6 tablets.

[0112] Dosage of the puerarin and theophylline cocrystal combination drug 2 (capsules):

[0113] The pharmaceutical composition developed using puerarin and theophylline cocrystal samples as the active pharmaceutical ingredient is characterized by using puerarin and theophylline cocrystals as the active pharmaceutical ingredient, with a daily dosage of 10-3000 mg, and can be prepared into 1-6 capsules containing 10, 100, 200, 300, and 500 mg of active ingredient per dose.

[0114] Issues that need to be explained:

[0115] The dosage of the active ingredient in the puerarin and theophylline 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 result in the appropriate daily dosage range of puerarin and theophylline cocrystal components in this invention being 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 theophylline cocrystal should be formulated according to the actual needs of prevention and treatment, and it can be administered in multiple doses or as a single dose.

[0116] References

[0117] [1]Zhou YX, Zhang H, Peng C. Puerarin: a review of pharmacological effects[J]. Phytotherapy Research, 2014, 28(7): 961-975.

[0118] [2] Inam M, Liu L, Wang JW, et al. Enhancing the physiochemical properties of puerarin via 1-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.

[0119] [3] 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.

[0120] [4]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 puerarin-theophylline cocrystal, characterized in that, Puerarin and theophylline form a eutectic in a molar ratio of 1:

2.

2. The puerarin-theophylline 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-theophylline cocrystal according to claim 1, characterized in that, When analyzed using attenuated total reflectance Fourier transform infrared spectroscopy, the values ​​at 3355, 3243, 3132, 2949, 2888, 2719, 2647, 1693, 1630, 1558, 1516, 1484, 1439, 1386, 1304, 1263, 1247, 1206, 1173, 1132, 1116, 1096, 1053, 1037, 983, 954, 925, 883, 829, 811, 790, 762, 744, 716, 691, 657, 640, 611, 573, 539, 501, 452, 431, and 419 cm⁻¹ were... -1 There is an infrared spectral characteristic peak at this location, with an allowable deviation of ±2cm. -1 .

4. The puerarin-theophylline cocrystal according to claim 1, characterized in that, When analyzed using differential scanning calorimetry, an endothermic peak was observed in the DSC spectrum at 196.83℃±3℃ within the range of 30 to 300℃ at a heating rate of 10℃ / min.

5. The method for preparing the puerarin-theophylline cocrystal as described in any one of claims 1-4, characterized in that, Puerarin and theophylline were fed in a 1:2 molar ratio and a chemical method of suspension in an organic solvent was used to prepare a puerarin-theophylline 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 theophylline 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 h to 96 h; and the obtained suspension is dried by solvent evaporation, natural drying by filtration, or vacuum drying by filtration to prepare puerarin and theophylline eutectic.

7. A mixed solid substance containing a eutectic of puerarin and theophylline, characterized in that, The amount of the puerarin-theophylline eutectic 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-theophylline 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-theophylline 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-theophylline 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-theophylline cocrystal of any one of claims 1-4, or the mixed solid substance of the puerarin-theophylline cocrystal of claim 7, or the pharmaceutical composition of any one of claims 8 or 9, in the preparation of medicaments for the prevention and treatment of cardiovascular diseases, anti-oxidation, anti-cancer, antihypertensive, hypoglycemic, anti-inflammatory, antipyretic and analgesic, anti-Alzheimer's disease, anti-osteoporosis, cardiotonic, diuretic, coronary artery dilation, bronchial smooth muscle relaxation, and central nervous system stimulation.

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