Ketoprofen metformin salt as well as preparation method, composition and application thereof

Abstract

The invention discloses ketoprofen metformin salt as well as a preparation method, a composition and application thereof. Specifically, the invention discloses a novel chemical entity taking ketoprofen metformin salt as a pharmaceutical active ingredient. A process for the preparation of ketoprofen metformin salts; the invention relates to application of ketoprofen metformin salt as an active pharmaceutical ingredient in preparation of non-steroidal antipyretic, analgesic and anti-inflammatory drugs, and belongs to the technical field of medicines.

Description

Technical Field

[0001] The present invention discloses a ketoprofen metformin salt, a preparation method, a composition, and uses thereof. Specifically, the present invention discloses a salt formed by ketoprofen and metformin: a ketoprofen metformin salt; a preparation method of the ketoprofen metformin salt; and the use of the ketoprofen metformin salt as a pharmaceutical active ingredient in the preparation of non-steroidal antipyretic, analgesic, and anti-inflammatory drugs, belonging to the field of pharmaceutical technology. Background Art

[0002] Drug salt formation, the process by which a new chemical entity is formed through electrostatic interaction via proton transfer between a drug molecule and an oppositely charged salt-forming ligand (salt former), is an important approach in drug development. Commonly used salt-forming ligands are small molecule acids or bases, such as malonic acid, fumaric acid, ligustrazine, betaine, and piperazine. Salt formation can improve the physicochemical properties of the API, such as stability and solubility, thereby enhancing its drugability.

[0003] The present invention uses ketoprofen as the active substance, whose chemical name is 2-(3-benzoylphenyl)-propionic acid, and its molecular formula is C 16 H 14 O3, the structural formula is shown in a. In the present invention, metformin is used as another active substance, its chemical name is 1,1-dimethylbiguanide, and its molecular formula is C4H 11 N5, the structural formula is shown in b.

[0004]

[0005] Ketoprofen belongs to the 2-arylpropionic acid class of nonsteroidal anti-inflammatory drugs. Its physical and chemical properties show that it is a white crystalline powder, odorless or almost odorless, highly soluble in methanol, easily soluble in ethanol, acetone or ether, and almost insoluble in water. Ketoprofen mainly inhibits the activity of cyclooxygenase (COXs) proinflammatory peptides and / or lipoxygenase (LOXs), thereby inhibiting the biosynthesis of inflammatory substances prostaglandins (PGs), leukotrienes (LTs) and thromboxanes (TXs), reducing the release of bradykinin, and thus exerting its good antipyretic, analgesic and anti-inflammatory effects, and also has a certain inhibitory effect on platelet adhesion and aggregation reactions. [1] It is widely used in clinical practice to treat various pains such as rheumatoid arthritis, rheumatic arthritis, ankylosing spondylitis, osteoarthritis, rheumatic arthritis, dysmenorrhea, toothache, postoperative pain, cancer pain and acute renal colic. [2,3] Clinical studies have shown that compared with similar drugs, it has significant advantages such as lower dosage, higher efficacy, better tolerability, and milder toxicity and side effects. Currently, ketoprofen preparations available in China mainly include enteric-coated capsules, sustained-release capsules, sustained-release tablets, gels, liniments, suppositories, and patches.

[0006] Metformin is a biguanide derivative and a first-line drug for the treatment of type 2 diabetes. It has multiple biological activities and has no hypoglycemic effect on normal subjects. A large number of studies have shown that the introduction of metformin can improve the thermal stability, solubility, permeability and other physical and chemical properties of the drug, making it an ideal salt-forming ligand. [4,5] .

[0007] Research on the polymorphic form and salt form of ketoprofen: There is currently one crystalline form of ketoprofen [6] The raw material used in this patent is this crystal form. So far, there are 6 reports on ketoprofen salts, namely ketoprofen-L-lysine salt [7] , ketoprofen-cysteine ​​salt [8] , ketoprofen-1-phenylethylamine salt [9] , ketoprofen-tromethamine salt

[10] , ketoprofen glucosamine salt, ketoprofen proline salt and ketoprofen hydroxyproline salt

[11] .

[0008] Due to the poor solubility of ketoprofen, its dissolution and absorption in the stomach are poor, resulting in limited bioavailability. Excessive dosage may cause side effects such as gastrointestinal discomfort, allergic reactions, and neurological symptoms.

[12] Therefore, taking effective measures to improve the solubility of ketoprofen is very important for reducing the dosage and improving its bioavailability. The present invention, through crystal engineering technology, has discovered a new ketoprofen metformin salt solid material that is completely different from the above-mentioned patents or literature research reports. While improving the solubility of ketoprofen, through in vivo pharmacokinetic experiments in rats, it was found that ketoprofen metformin salt has achieved unexpected technical effects in improving ketoprofen bioavailability and bioabsorption rate.

[0009] In order to solve the problems of the prior art, the present invention provides a salt of ketoprofen and metformin, a preparation method and an application. Summary of the Invention

[0010] The technical problems to be solved by the present invention are:

[0011] One of the technical problems to be solved by the present invention is to provide the existence state and characterization method of salt substances of ketoprofen and metformin.

[0012] The second technical problem to be solved by the present invention is to provide a method for preparing ketoprofen metformin salt.

[0013] The third technical problem to be solved by the present invention is to provide a pure product containing ketoprofen metformin salt, or a mixed solid material containing ketoprofen metformin salt in any non-zero ratio and a pharmaceutical composition thereof.

[0014] The fourth technical problem to be solved by the present invention is to provide a pharmaceutical composition using ketoprofen metformin salt as the active pharmaceutical ingredient, wherein the daily dosage of ketoprofen metformin salt is within the range of 5 to 3000 mg. The pharmaceutical composition includes tablets, capsules, pills, injectable preparations, granules, powders, pellets, dropping pills, suppositories, films, patches, aerosols, sprays, sustained-release preparations, or controlled-release preparations.

[0015] The fifth technical problem to be solved by the present invention is to provide a ketoprofen metformin salt that exhibits better solubility and bioavailability advantages compared to ketoprofen.

[0016] The sixth technical problem to be solved by the present invention is to provide a ketoprofen metformin salt which can improve the bioavailability in the body during the treatment of diseases due to the salt-type substance and thus exert an effective therapeutic effect of the drug.

[0017] The seventh technical problem to be solved by the present invention: the use of ketoprofen metformin salt as an active ingredient in the preparation of non-steroidal antipyretic, analgesic and anti-inflammatory drugs.

[0018] In order to solve the above technical problems, the present invention adopts the following technical solutions:

[0019] 1. Morphological characteristics of ketoprofen metformin salt samples:

[0020] 1.1 The ketoprofen metformin salt of the present invention is characterized in that ketoprofen and metformin form a salt in a molar ratio of 1:1.

[0021] 1.2 The ketoprofen metformin salt of the present invention, when analyzed by single crystal X-ray diffraction, exhibits monoclinic symmetry, space group P21 / c, and unit cell parameters: β=93.628°. Unit cell volume The molecular formula is C 16 H 14 O3·C4H 11 N5. Attached Figure 1 The molecular stereostructure projection diagram of ketoprofen metformin salt is given, Figure 2 The unit cell packing diagram of the ketoprofen metformin salt molecule is given, and Table 1 gives the non-hydrogen atom coordinate parameters of the ketoprofen metformin salt.

[0022] Table 1 Non-hydrogen atom coordinate parameters of ketoprofen metformin salt

[0023]

[0024]

[0025] 1.3 The ketoprofen metformin salt of the present invention is analyzed by powder X-ray diffraction using CuKα Under radiation experimental conditions, diffraction peak position: 2-Theta value (°) or d value Diffraction peak relative intensity: peak height value (Height%) or peak area value (Area%) has the following characteristics (Table 2, Figure 3 ). The X-ray diffraction pattern and data of the physical mixture of ketoprofen and metformin are shown in Table 3. Figure 4 The X-ray diffraction patterns of ketoprofen metformin salt and the physical mixture of ketoprofen and metformin showed obvious differences in the number of diffraction peaks, diffraction peak positions, diffraction peak intensities, and diffraction peak topology, indicating that ketoprofen metformin salt and the physical mixture of ketoprofen and metformin are neither the same nor identical.

[0026] Table 2 Powder X-ray diffraction peak values ​​of ketoprofen metformin salt

[0027]

[0028]

[0029] Table 3 Powder X-ray diffraction peaks of metformin and ketoprofen physical mixture

[0030]

[0031] 1.4 The ketoprofen metformin salt of the present invention is characterized in that when analyzed by attenuated total reflection Fourier transform infrared spectroscopy, the 2. 1379, 1353, 1318, 1275, 1240, 1194, 1178, 1170, 1132, 1094, 1051, 1018, 997, 962 ,931,873,849,834,816,780,727,710,696,665,640,605,558,514,483,447,416cm -1 There is an infrared spectrum characteristic peak at the position where the allowable deviation of the infrared spectrum characteristic peak is ±2cm -1 ( Figure 5 ).

[0032] 1.5 The ketoprofen metformin salt of the present invention is characterized in that, when analyzed using differential scanning calorimetry, when the heating rate is 10°C per minute, there is an endothermic peak at 167±3°C in the DSC spectrum ( Figure 6 ). The DSC superposition patterns of ketoprofen, metformin and ketoprofen metformin salt are shown in Figure 7The DSC spectra of ketoprofen, metformin, and ketoprofen metformin salt showed significant differences in the number and position of endothermic / exothermic peaks, indicating that ketoprofen metformin salt was a new phase different from ketoprofen and metformin APIs.

[0033] 2. Characteristics of the preparation method of ketoprofen metformin salt and mixed solid material:

[0034] The preparation method of ketoprofen metformin salt of the present invention comprises the following methods:

[0035] 2.1 The suspension stirring method of the ketoprofen metformin salt of the present invention is to use a single solvent system of methanol, ethanol, n-propanol, isopropanol, acetonitrile, acetone, dioxane, tetrahydrofuran or a mixed solvent prepared by mixing the above solvents in different ratios. Metformin and ketoprofen in a 1:1 molar ratio are weighed, and a certain volume of organic solvent is added thereto. The amount of solvent added is 0.5 mL / g to 20 mL / g. The mixture is stirred at 100 to 400 rpm for 1 to 12 hours at a temperature of 20°C to 45°C. The product is dried to obtain a solid product of ketoprofen and metformin salt.

[0036] 2.2 The liquid-assisted grinding method for preparing ketoprofen metformin salt of the present invention comprises the following steps:

[0037] (1) ketoprofen and metformin were placed in a mortar at a molar ratio of 1:1 and ground evenly to obtain a mixture;

[0038] (2) Grinding the mixture obtained in step (1) in a clockwise direction, and adding an organic solvent dropwise thereto every 15 minutes, with the amount of solvent added being 0.5 mL / g to 10 mL / g, and grinding for 30 minutes to 4 hours. The organic solvent is preferably a mixed solvent prepared by combining any one or more of methanol, ethanol, acetone, acetonitrile, and isopropanol in different proportions;

[0039] (3) drying the product obtained in step (2) to obtain a solid product of metformin and ketoprofen salt.

[0040] 2.3 The mechanochemical preparation method of ketoprofen metformin salt involved in the present invention is selected from the mechanical ball milling method, the molar ratio of ketoprofen to metformin is 1:1.5~1.5:1, preferably 1:1.1~1.1:1, the ball-to-material ratio is 1:1~10:1, preferably 6:1~10:1; the ball milling speed is 20r / min~400r / min; and the grinding time is 1~24h.

[0041] 2.4 The solvent volatilization preparation method of ketoprofen metformin salt involved in the present invention is to use methanol as a single solvent or a methanol / water (v / v, 3:1) mixed solvent, stir a 1:1 molar ratio of ketoprofen and metformin sample at a temperature of 15°C to 60°C for 1h to 12h, place the sample in an ambient temperature of 20°C to 40°C and an ambient relative humidity of 10% to 90%, and slowly evaporate the solvent to obtain ketoprofen metformin salt crystals that meet the requirements of single crystal X-ray diffraction.

[0042] 2.5 The mixed solid material containing ketoprofen metformin salt involved in the present invention is obtained by mixing the ketoprofen metformin salt component obtained by the above method with other chemical substances in any non-zero ratio and in a conventional manner.

[0043] 3. Pharmaceutical compositions containing ketoprofen and metformin salt, dosage characteristics, and pharmaceutical uses: 3.1 The present invention relates to a pharmaceutical composition comprising ketoprofen and metformin salt and a pharmaceutically acceptable carrier. 3.2 The present invention relates to a pharmaceutical composition comprising a mixed solid substance of ketoprofen and metformin salt and a pharmaceutically acceptable carrier.

[0044] 3.3 The pharmaceutical composition of the present invention has a daily dosage of ketoprofen metformin salt in the range of 5 to 3000 mg.

[0045] 3.4 The pharmaceutical composition involved in the present invention is characterized in that the pharmaceutical composition is various tablets, capsules, pills, injection preparations, granules, powders, micropills, dropping pills, suppositories, films, patches, aerosols, sprays, sustained-release preparations or controlled-release preparations.

[0046] 3.5 The present invention relates to the use of ketoprofen metformin salt, a mixed solid substance containing ketoprofen metformin salt or a pharmaceutical composition in the preparation of non-steroidal antipyretic, analgesic and anti-inflammatory drugs.

[0047] The present invention relates to a pharmaceutical composition comprising the ketoprofen metformin salt of the present invention as an active ingredient. The pharmaceutical composition can be prepared according to methods known in the art. The ketoprofen metformin salt of the present invention can be combined with one or more pharmaceutically acceptable solid or liquid excipients and / or adjuvants to form any dosage form suitable for human or animal use. The content of the ketoprofen metformin salt of the present invention in the pharmaceutical composition is in the range of 10% to 90% by weight.

[0048] The ketoprofen metformin salt of the present invention can be administered in a unit dosage form, and the administration route can be enteral or parenteral, mainly oral.

[0049] The dosage form of the present invention is preferably a solid dosage form. The solid dosage form can 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, micropills, dropping pills, suppositories, films, patches, aerosols (powders), sprays, etc.

[0050] The ketoprofen metformin salt of the present invention can be prepared into common preparations, sustained-release preparations, controlled-release preparations, targeted preparations and various microparticle drug delivery systems.

[0051] In order to prepare the ketoprofen metformin salt of the present invention into tablets, various excipients known in the art can be widely used, including diluents, binders, wetting agents, disintegrants, lubricants, and glidants. Diluents can be starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.; wetting agents can be water, ethanol, isopropyl alcohol, etc.; binders can 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.; disintegrants can 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 lauryl sulfate, etc.; lubricants and glidants can be talc, silicon dioxide, stearate, tartaric acid, liquid paraffin, polyethylene glycol, etc.

[0052] The 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.

[0053] In order that the dosing unit is made into capsule, effective ingredient ketoprofen metformin salt of the present invention can be mixed with diluent, glidant, and mixture is directly placed in hard capsule or soft capsule. Also effective ingredient ketoprofen metformin salt of the present invention can be made into granule or micropill with diluent, adhesive, disintegrant earlier, then be placed in hard capsule or soft capsule. Various diluents, adhesive, wetting agent, disintegrant, glidant kinds that are used to prepare ketoprofen metformin salt tablet of the present invention also can be used for preparing the capsule of ketoprofen metformin salt of the present invention.

[0054] Furthermore, if necessary, colorants, preservatives, perfumes, flavorings or other additives may be added to the pharmaceutical preparations.

[0055] To achieve the purpose of medication and enhance the therapeutic effect, the drug of the present invention can be administered by any known method of administration.

[0056] The dosage of the ketoprofen metformin salt 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 dosage unit or divided into several dosage units, depending on the clinical experience of the physician and the dosage regimen including the use of other therapeutic means.

[0057] The ketoprofen metformin salt or composition of the present invention can be taken alone or in combination with other therapeutic drugs or symptomatic drugs. When the ketoprofen metformin salt of the present invention has a synergistic effect with other therapeutic drugs, its dosage should be adjusted according to the actual situation.

[0058] 4. Beneficial technical effects of the present invention: the safety, stability, solubility and biological activity advantages of ketoprofen metformin salt.

[0059] 4.1 Ketoprofen metformin salt of the present invention, its DSC spectrum ( Figure 6 ) does not have any endothermic peaks due to loss of crystallization solvent or crystal water, and its thermogravimetric analysis diagram ( Figure 8 ) in the sample before decomposition, there is no weight loss peak, indicating that ketoprofen metformin salt does not contain any crystallization solvent and has good safety advantages in drug development.

[0060] 4.2 The ketoprofen metformin salt of the present invention can remain stable under high temperature, high humidity and light conditions compared to metformin which is extremely unstable under high humidity conditions, and has good stability as a medicine ( Figure 9 ). 4.3 The ketoprofen metformin salt of the present invention exhibits a solubility advantage in phosphate buffer (pH 6.8) that is significantly superior to that of ketoprofen itself ( Figure 10 ).

[0061] 4.4 The ketoprofen metformin salt of the present invention has significant advantages in terms of bioabsorption and utilization compared with the ketoprofen raw material, which is specifically reflected in the formation of ketoprofen metformin salt, which makes the maximum blood concentration of ketoprofen C max The area under the curve (AUC) value increased by 1.1 times. BRIEF DESCRIPTION OF THE DRAWINGS

[0062] Figure 1 Molecular stereoscopic structure projection diagram of ketoprofen metformin salt

[0063] Figure 2 Unit cell stacking diagram of ketoprofen metformin salt molecule

[0064] Figure 3 Powder X-ray diffraction pattern of ketoprofen metformin salt

[0065] Figure 4Powder X-ray diffraction pattern of ketoprofen and metformin physical mixture

[0066] Figure 5 Infrared absorption spectrum of ketoprofen metformin salt

[0067] Figure 6 Differential scanning calorimetry of ketoprofen metformin salt

[0068] Figure 7 Differential scanning calorimetry spectra of ketoprofen, metformin and ketoprofen metformin salt

[0069] Figure 8 Thermogravimetric spectrum of ketoprofen metformin salt

[0070] Figure 9 Ketoprofen Metformin Salt Stability Study Graph

[0071] Figure 10 Intrinsic dissolution profiles of ketoprofen metformin salt and ketoprofen

[0072] Figure 11 Ketoprofen metformin salt and pharmacokinetic curves of ketoprofen DETAILED DESCRIPTION

[0073] In order to better illustrate the technical solutions of the present invention, the following examples are given, but the present invention is not limited thereto.

[0074] Example 1

[0075] Preparation method 1 of ketoprofen metformin salt:

[0076] Take metformin hydrochloride and sodium hydroxide or sodium carbonate or other suitable base, put them into a clean container in a molar ratio of 1:1, add a certain volume of organic solvent, the amount of solvent added is 0.5mL / g~20mL / g, stir for a suitable time (4~12h) under suitable temperature conditions (20~50℃), filter, collect all the filtrate, add equimolar ketoprofen, stir for a suitable time (1~12h) at a speed of 100~400r / min under suitable temperature conditions (20~45℃), filter the resulting suspension solvent and vacuum dry, filter and dry naturally or evaporate to dryness. Perform powder X-ray diffraction analysis on it, and its diffraction pattern is the same as Figure 3 The results were consistent, indicating that the obtained sample was ketoprofen metformin salt.

[0077] Table 4 Specific examples of preparation method 1

[0078]

[0079]

[0080] Preparation method 2 of ketoprofen metformin salt:

[0081] According to the molar ratio of 1:1, appropriate amounts of ketoprofen and metformin were weighed and placed in a clean mortar. After grinding evenly, a physical mixture of ketoprofen and metformin was obtained. A certain volume of organic solvent was added dropwise every 15 minutes. The amount of solvent added was 0.5mL / g to 10mL / g. The mixture was ground in a clockwise direction for a certain time and the obtained product was dried. The powder X-ray diffraction analysis was performed on it. The diffraction pattern was the same as Figure 3 The results were consistent, indicating that the obtained sample was ketoprofen metformin salt.

[0082] Table 5 Specific examples of preparation method 2

[0083]

[0084] Preparation method 3 of ketoprofen metformin salt:

[0085] Metformin and ketoprofen in a 1:1 molar ratio were weighed and placed in a clean ball mill. A certain volume of organic solvent was added dropwise every 15 minutes, and the mixture was ground at a certain speed. After grinding for a certain time, the obtained product was dried. The powder X-ray diffraction analysis of the ground sample was performed, and its diffraction pattern was consistent with that of the sample. Figure 3 The results were consistent, indicating that the obtained sample was ketoprofen metformin salt.

[0086] Table 6 Specific examples of preparation method 1

[0087]

[0088]

[0089] Preparation method 4 of ketoprofen metformin salt:

[0090] Weigh 0.5 mmol of metformin and 0.5 mmol of ketoprofen into a 50 mL beaker, add 15 mL of methanol, stir for 4 h at an appropriate temperature (20-50 ° C), filter, and place in an ambient temperature of 20 ° C to 40 ° C and an ambient relative humidity of 10% to 90% to slowly evaporate the solvent to obtain ketoprofen metformin salt crystals that meet the requirements of single crystal X-ray diffraction.

[0091] Example 2

[0092] Stability characteristics of ketoprofen metformin salt:

[0093] Illumination test: 50 mg of ketoprofen metformin salt was placed under illumination for 5 days and 10 days, and then subjected to powder X-ray diffraction analysis. The diffraction patterns were consistent with those of Figure 3The results were consistent, indicating that the sample was ketoprofen metformin salt, which was stable under light conditions.

[0094] High temperature test: 50 mg of ketoprofen metformin salt was placed under high temperature conditions for 5 days and 10 days, and the powder X-ray diffraction analysis was performed on it. The diffraction pattern was the same as Figure 3 The results were consistent, indicating that the sample was ketoprofen metformin salt, which was stable under high temperature conditions.

[0095] High humidity test: 50 mg of ketoprofen metformin salt was placed under high humidity conditions for 5 days and 10 days, and then subjected to powder X-ray diffraction analysis. The diffraction patterns were consistent with those of Figure 3 The results were consistent, indicating that the sample was ketoprofen metformin salt, which was stable under high humidity conditions.

[0096] The stability study of ketoprofen metformin proved that ketoprofen metformin salt remained stable for 10 days in a high temperature, high humidity and light environment, and the introduction of metformin did not cause problems of high hygroscopicity and poor stability.

[0097] Example 3

[0098] The ketoprofen metformin salt of the present invention significantly improves the solubility of the ketoprofen bulk drug in phosphate buffer solution (pH 6.8).

[0099] The ketoprofen dissolution concentration was used as the evaluation index, and the content was determined by high performance liquid chromatography at a wavelength of 254 nm. The sample dissolution concentration was calculated by external standard method. The intrinsic dissolution curves ( Figure 10 ). The data are shown in Table 7:

[0100] Table 7 Intrinsic dissolution curve data of ketoprofen metformin salt and Tongluofen

[0101]

[0102] Since the 150 mg sample used in the experiment was completely dissolved in the first 15 minutes of the ketoprofen metformin salt, only the first 15 minutes of sampling were considered in the calculation. The experimental data show that the solubility of the ketoprofen metformin salt of the present application in pH 6.8 phosphate buffer is significantly improved compared to ketoprofen itself. Specifically, the ketoprofen metformin salt has a faster dissolution rate, which is approximately 24.4 times higher than that of ketoprofen itself, making it easier to quickly absorb and achieve effective blood concentrations.

[0103] Example 4

[0104] Bioabsorption advantages of ketoprofen and metformin in vivo

[0105] Based on the SD rat animal model, the pharmacokinetic behavior of ketoprofen API and ketoprofen metformin salt in rats was investigated by solid oral administration. The relevant pharmacokinetic parameters obtained from the experiment are shown in Table 8. The concentration-time curves of ketoprofen API and ketoprofen metformin salt were plotted with blood collection time (min) as the horizontal axis and blood drug concentration (μg / mL) as the vertical axis ( Figure 11 ).

[0106] Table 8 Pharmacokinetic parameters

[0107]

[0108] By comparing the pharmacokinetic parameters of ketoprofen API and ketoprofen metformin salt, it can be seen that the formation of ketoprofen metformin salt makes the half-life of ketoprofen t 1 / 2z The time was extended from 13.04h to 15.9h, and the maximum blood concentration C max The area under the curve (AUC) value increased by 1.1 times. Furthermore, the blood concentration-time plot showed that some of the salt that was not destroyed by the acidic environment of the stomach exhibited rapid bioabsorption and high blood concentrations, while the remaining destroyed salt exhibited bioabsorption characteristics roughly similar to those of the ketoprofen API. This suggests that salt formation accelerates ketoprofen's absorption rate and improves its bioavailability, which is crucial for achieving ketoprofen's rapid antipyretic, analgesic, and anti-inflammatory effects.

[0109] Example 5

[0110] Preparation method 1 of combined pharmaceutical preparation (tablets):

[0111] A method for preparing a combination drug tablet comprises using ketoprofen metformin salt and several excipients as auxiliary ingredients for preparing the combination drug tablet, and preparing tablet samples containing 5 to 500 mg of cocrystal per tablet according to a certain ratio. Table 9 shows the tablet formulation ratio:

[0112] Table 9 Preparation formula of ketoprofen metformin salt combination drug tablets

[0113]

[0114] The method for preparing ketoprofen metformin salt as a raw material into a tablet preparation is as follows: several excipients are mixed evenly with the raw material and the tablets are directly compressed; or the excipients are mixed and dry granulated and then mixed evenly with the raw material and the tablets are compressed to obtain the tablet preparation.

[0115] Preparation method 2 of combined pharmaceutical preparation (tablets):

[0116] A method for preparing a combination drug tablet comprises using ketoprofen metformin salt and several excipients as auxiliary ingredients for preparing the combination drug tablet, and preparing tablet samples containing 5 to 500 mg of cocrystal per tablet according to a certain ratio. Table 10 shows the tablet formulation ratio:

[0117] Table 10 Preparation formula of ketoprofen metformin salt combination drug tablets

[0118]

[0119] The method for preparing a tablet preparation using ketoprofen metformin salt as a raw material is as follows: several excipients are uniformly mixed with the raw material, an appropriate amount of 1% sodium hydroxymethylcellulose solution is added to prepare a soft material, sieve and granulate the wet granules, dry the wet granules, sieve and refine the granules, add magnesium stearate and talc powder, mix uniformly, and press into tablets to obtain the tablet preparation.

[0120] Preparation method 3 of combined pharmaceutical preparation (capsules):

[0121] A method for preparing a combination drug capsule is characterized by using ketoprofen metformin salt as the API and several excipients as auxiliary ingredients for preparing the combination drug capsule. The excipients are mixed in a certain proportion to produce capsule samples with a drug content of 5 to 500 mg per tablet. Table 11 shows the capsule formulation ratios:

[0122] Table 11: API and excipient formulas for ketoprofen metformin salt combination capsule preparations

[0123]

[0124] The method for preparing capsules using ketoprofen metformin salt as a raw material drug is as follows: several excipients are uniformly mixed with the raw material drug, an appropriate amount of 1% sodium hydroxymethylcellulose solution is added to prepare wet granules, the wet granules are dried and sieved, magnesium stearate is added to mix uniformly, and the granules are inserted into capsules; or the granulation step is omitted, and the ketoprofen metformin salt raw material drug is directly uniformly mixed with several excipients and auxiliary materials, the mixture is sieved, and the mixture is directly filled into capsules.

[0125] Example 6

[0126] Dosage of ketoprofen and metformin combination drug 1 (tablet):

[0127] A pharmaceutical composition developed using ketoprofen metformin salt as a pharmaceutical active ingredient is characterized in that ketoprofen metformin salt is used as the active ingredient of the drug, with a daily dosage of 200 mg, and can be prepared into 100 mg ordinary tablets to be taken twice a day / one tablet each time, or 200 mg tablets to be taken once a day / one tablet each time.

[0128] Dosage of ketoprofen and metformin combination drug 2 (capsules):

[0129] A pharmaceutical composition developed using ketoprofen metformin salt as a pharmaceutical active ingredient is characterized in that ketoprofen metformin salt is used as the pharmaceutical active ingredient, with a daily dosage of 500 mg, which can be prepared into a 250 mg capsule twice a day or a 500 mg capsule once a day.

[0130] Issues that need to be explained: The ketoprofen metformin salt pharmaceutical composition involved in the present invention has many factors affecting the dosage of the active ingredient, such as: differences in patient age, body surface area, route of administration, number of administrations, and therapeutic purposes, resulting in different dosages per dose; differences in absorption and blood concentrations between samples, etc., also cause the present invention to use the ketoprofen metformin salt component in each suitable dosage range of 0.005 to 20 mg / kg body weight, preferably 0.01 to 10 mg / kg body weight. When used, different total dosage plans of the ketoprofen metformin salt active ingredient should be formulated according to the actual treatment needs of different situations, and can be completed in multiple or single administration modes.

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[0143]

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Claims

1. A ketoprofen metformin salt, characterized in that Ketoprofen and metformin form a salt in a 1:1 molar ratio.

2. The ketoprofen metformin salt according to claim 1, characterized in that When analyzed using single crystal X-ray diffraction, it exhibits monoclinic symmetry, space group P21 / c, and unit cell parameters: β=93.628°. Unit cell volume 3. The ketoprofen metformin salt according to claim 1, wherein When using powder X-ray diffraction analysis using CuK α Under radiation experimental conditions, diffraction peak position: 2-Theta value (°) or d value Diffraction peak relative intensity: peak height value (Height%) or peak area value (Area%) has the following characteristics:

4. The ketoprofen metformin salt according to claim 1, wherein When analyzed by attenuated total reflection Fourier transform infrared spectroscopy, the peaks were 3852, 3737, 3429, 3327, 3099, 2981, 2929, 2756, 2284, 1893, 1743, 1656, 1575, 1563, 1557, 1487, 1447, 1417, 1402, 1379, 1353, 1318, 1275, 1240, 1194, 1178, 1170, 1132, 1094, 1051, 1018, 997, 962, 931, 873, 849, 834, 816, 780, 727, 710, 696, 665, 640, 605, 558, 514, 483, 447, 416 cm -1 There is an infrared spectrum characteristic peak at the position where the allowable deviation of the infrared spectrum characteristic peak is ±2cm -1 .

5. The ketoprofen metformin salt according to claim 1, wherein When analyzed using differential scanning calorimetry, it was shown that when the heating rate was 10°C per minute, there was an endothermic peak at 167±3°C in the DSC spectrum.

6. The method for preparing the ketoprofen metformin salt according to any one of claims 1 to 5, characterized in that: A suspension stirring method is employed, using a single solvent system of methanol, ethanol, n-propanol, isopropanol, acetonitrile, acetone, dioxane, or tetrahydrofuran, or a mixed solvent prepared from these solvents in varying ratios. Ketoprofen and metformin are weighed at a 1:1 molar ratio, and a certain volume of organic solvent (0.5 mL / g to 20 mL / g) is added. The mixture is stirred at 100 to 400 rpm for 1 to 12 hours at a temperature of 20°C to 45°C. The product is dried to obtain a solid product of the ketoprofen and metformin salt.

7. The method for preparing the ketoprofen metformin salt according to any one of claims 1 to 5, characterized in that: The following steps are involved: (1) placing ketoprofen and metformin in a mortar at a molar ratio of 1:1 and grinding them uniformly to obtain a mixture; (2) Grind the mixture obtained in step (1) in a clockwise direction, and add an organic solvent dropwise thereto every 15 minutes, with the amount of solvent added being 0.5 mL / g to 10 mL / g, and grind for 30 minutes to 4 hours. The organic solvent is selected from a mixed solvent prepared by combining any one or more of methanol, ethanol, acetone, acetonitrile, and isopropanol in different proportions; (3) drying the product obtained in step (2) to obtain a solid product of ketoprofen and metformin salt.

8. The mechanochemical method according to claim 7, wherein the molar ratio of metformin to ketoprofen is 1:1.5 to 1.5:1, preferably 1:1.1 to 1.1:1; the mechanochemical method is selected from mechanical ball milling, wherein the ball-to-material ratio of the ball milling method is 1:1 to 10:1, preferably 6:1 to 10:1; and the ball milling speed is 20 rpm to 400 rpm.

9. The method for preparing the ketoprofen metformin salt according to any one of claims 1 to 5, characterized in that: The solvent evaporation method was adopted, using methanol as a single solvent or a methanol / water (v / v, 3:1) mixed solvent, stirring a 1:1 molar ratio of ketoprofen and metformin sample at a temperature of 15°C to 60°C for 1h to 12h, and then slowly evaporating the solvent under ambient temperature of 20°C to 40°C and relative humidity of 10% to 90% to obtain ketoprofen metformin salt crystals that met the requirements of single crystal X-ray diffraction.

10. A mixed solid material containing ketoprofen and metformin salt, characterized in that: The amount of the ketoprofen metformin salt according to any one of claims 1 to 5 is 1 to 99.9%, preferably 10 to 99.9%, more preferably 50 to 99.9%, and most preferably 85 to 99.9%.

11. A pharmaceutical composition, characterized in that Contains an effective dose of the ketoprofen metformin salt according to any one of claims 1 to 5 and a pharmaceutically acceptable carrier.

12. A pharmaceutical composition, characterized in that A mixed solid material containing ketoprofen and metformin salt according to claim 10 containing an effective dose and a pharmaceutically acceptable carrier.

13. The pharmaceutical composition according to any one of claims 11 or 12, characterized in that The daily dosage of ketoprofen metformin salt is in the range of 5 to 3000 mg.

14. The pharmaceutical composition according to any one of claims 11 or 12, characterized in that The dosage form of the pharmaceutical composition is tablets, capsules, pills, injection preparations, granules, powders, pellets, dropping pills, suppositories, films, patches, aerosols, sprays, sustained-release preparations or controlled-release preparations.

15. Use of the ketoprofen metformin salt according to any one of claims 1 to 5, the mixed solid material containing ketoprofen metformin salt according to claim 10, or the pharmaceutical composition according to any one of claims 11 or 12 in the preparation of non-steroidal antipyretic, analgesic and anti-inflammatory drugs.

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