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

Abstract

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

Description

Technical Field

[0001] The present invention relates to a phenylbutazone metformin salt, a preparation method, and a composition and use thereof. Specifically, the present invention discloses a salt formed by phenylbutazone and metformin: a phenylbutazone metformin salt; a preparation method of the phenylbutazone metformin salt; and the use of the phenylbutazone metformin salt as a pharmaceutical active ingredient in the preparation of non-steroidal anti-inflammatory analgesic 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 maleic acid, fumaric acid, ligustrazine, betaine, and piperazine. Salt formation can improve the physicochemical properties of drugs, such as stability, solubility, and permeability, thereby enhancing their drugability.

[0003] The present invention uses phenylbutazone as the active substance, the chemical name of which is 4-butyl-1,2-diphenyl-3,5-pyrazolidinedione, and the molecular formula is C 19 H 20 N2O2, the structural formula is shown in a. In the present invention, metformin is used as another active substance, its chemical name is 1,1-dimethylbiguanidine, and its molecular formula is C4H 11 N5, the structural formula is shown in b.

[0004]

[0005] Phenylbutazone is a pyrazolidinedione derivative. Its physical and chemical properties show that it is a white or off-white crystalline powder, odorless, and slightly bitter. It is soluble in acetone or chloroform, soluble in ethanol or ether, and is almost insoluble in water. It is a drug that acts on the central nervous system and is a nonsteroidal anti-inflammatory drug. It has a strong anti-inflammatory effect and is also effective in treating inflammatory pain such as inflammation and ankylosing spondylitis. [1] Currently, the main commercially available phenylbutazone dosage form is phenylbutazone tablets. However, due to its poor water solubility, phenylbutazone dissolves and absorbs poorly in the stomach, resulting in poor oral efficacy, low bioavailability, and limiting its effect in the body. Therefore, it is of great significance to take effective measures to improve the water solubility of phenylbutazone to better exert its therapeutic effect.

[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. [2,3] .

[0007] Research on the polymorphs and salt forms of phenylbutazone: Currently, 6 polymorphs of phenylbutazone have been found, namely α, β, γ, δ, ε, and ζ. [4-6] , and 6 solvates, namely phenylbutazone-benzene solvate, phenylbutazone-cyclohexane solvate, phenylbutazone-1,4-dioxane solvate, phenylbutazone-tetrahydrofuran solvate, phenylbutazone-tetrachloromethane solvate and phenylbutazone-chloroform solvate [7] This patent uses α-type phenylbutazone crystals. There are two reports on phenylbutazone salts, namely phenylbutazone-piperazine salt [8] , and phenylbutazone-N-methylpiperazine salt [9] .

[0008] Due to its poor solubility, phenylbutazone dissolves and absorbs poorly in the stomach, resulting in poor oral efficacy and limited bioavailability. This invention, through crystal engineering technology, has discovered a new solid form of phenylbutazone metformin salt, which is completely different from the aforementioned research reports. While improving the solubility of phenylbutazone, in vivo pharmacokinetic studies in rats have revealed that phenylbutazone metformin salt achieves unexpected technical benefits in terms of increasing the bioabsorption rate of phenylbutazone.

[0009] In order to solve the problems of the prior art, the present invention proposes the salt formation of phenylbutazone and metformin, a preparation method and 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 phenylbutazone and metformin.

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

[0013] The third technical problem to be solved by the present invention is to provide a pure product containing phenylbutazone metformin salt, or a mixed solid material containing phenylbutazone 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 phenylbutazone metformin salt as the active ingredient, wherein the daily dosage of phenylbutazone 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 metformin salt of phenylbutazone, which exhibits a better solubility advantage in phosphate buffer (pH 6.8) than phenylbutazone.

[0016] The sixth technical problem to be solved by the present invention is to provide phenylbutazone 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 phenylbutazone metformin salt as an active pharmaceutical ingredient in the preparation of non-steroidal anti-inflammatory analgesic drugs.

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

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

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

[0021] 1.2 The metformin salt of phenylbutazone involved in the present invention, when analyzed by single crystal X-ray diffraction, exhibits trigonal symmetry, space group R-3, and unit cell parameters: γ=120°. Unit cell volume The molecular formula is C 19 H 20 N2O2·C4H 11 N5. Attached Figure 1 The molecular stereostructure projection diagram of metformin salt of phenylbutazone is given, Figure 2 The unit cell packing diagram of the phenylbutazone metformin salt molecule is given, and Table 1 gives the coordinate parameters of the non-hydrogen atoms of the phenylbutazone metformin salt.

[0022] Table 1 Coordinate parameters of non-hydrogen atoms of metformin salt of phenylbutazone

[0023]

[0024]

[0025] 1.3 The metformin salt of phenylbutazone of the present invention is analyzed by powder X-ray diffraction 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 (Table 2, Figure 3 The X-ray diffraction pattern and data of the physical mixture of phenylbutazone and metformin are shown in Table 3. Figure 4The X-ray diffraction patterns of the powders of phenylbutazone metformin salt and the physical mixture of phenylbutazone and metformin showed obvious differences in the number of diffraction peaks, the positions of the diffraction peaks, the intensities of the diffraction peaks, the topological patterns of the diffraction peaks, etc., indicating that the powders of phenylbutazone metformin salt and the physical mixture of phenylbutazone and metformin are neither the same nor identical.

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

[0027]

[0028]

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

[0030]

[0031] 1.4 The present invention relates to phenylbutazone metformin salt, characterized in that when analyzed by attenuated total reflection Fourier transform infrared spectroscopy, the results are as follows: 3442, 3370, 3308, 3095, 2958, 2928, 2868, 2324, 2104, 1952, 1802, 1735, 1666, 1632, 1594, 1521, 1495, 1455, 14 41, 1419, 1373, 1329, 1284, 1273, 1240, 1199, 1146, 1091, 1071, 1040, 998, 988, 929 ,899,859,835,816,777,758,742,706,689,650,625,613,558,506,476,460,414cm -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 phenylbutazone 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 155±3°C in the DSC spectrum ( Figure 6 The DSC superposition patterns of phenylbutazone, metformin and phenylbutazone metformin salt are shown in Figure 7 The DSC spectra of phenylbutazone, metformin, and phenylbutazone metformin salt showed significant differences in the number and position of endothermic / exothermic peaks, indicating that phenylbutazone metformin salt was a new phase different from phenylbutazone and metformin APIs.

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

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

[0035] 2.1 The suspension stirring method for producing a metformin salt of phenylbutazone according to the present invention comprises using a single solvent system of methanol, ethanol, n-propanol, isopropanol, acetonitrile, acetone, dioxane, or tetrahydrofuran, or a mixed solvent prepared by mixing the above solvents in different ratios. Metformin and phenylbutazone are weighed at a 1:1 molar ratio, and a certain volume of an organic solvent is added thereto, wherein the amount of the 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 the phenylbutazone and metformin salt.

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

[0037] (1) Phenylbutazone 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 a certain volume of organic solvent every 15 minutes, the amount of solvent added is 0.5mL / g to 10mL / 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 the salt of phenylbutazone and metformin.

[0040] 2.3 The mechanochemical preparation method of phenylbutazone metformin salt involved in the present invention is selected from the mechanical ball milling method, the molar ratio of phenylbutazone 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 the phenylbutazone metformin salt involved in the present invention uses isopropyl alcohol as a single solvent or isopropyl alcohol / water (v / v, 3:1) mixed solvent, stirs a 1:1 molar ratio of phenylbutazone and metformin sample at a temperature of 15°C to 60°C for 1h to 12h, and places the sample 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 phenylbutazone metformin salt crystals that meet the requirements of single crystal X-ray diffraction.

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

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

[0044] 3.3 In the pharmaceutical composition of the present invention, the daily dosage of phenylbutazone metformin salt is 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 phenylbutazone metformin salt, a mixed solid substance containing phenylbutazone metformin salt or a pharmaceutical composition in the preparation of non-steroidal anti-inflammatory analgesic drugs.

[0047] The present invention relates to a pharmaceutical composition comprising the present invention's phenylbutazone metformin salt as an active ingredient. The pharmaceutical composition can be prepared according to methods known in the art. The present invention's phenylbutazone metformin salt component 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 present invention's phenylbutazone metformin salt in the pharmaceutical composition ranges from 10% to 90% by weight.

[0048] The phenylbutazone 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 phenylbutazone 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 phenylbutazone 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] To prepare the dosing unit as a capsule, the active ingredient, the phenylbutazone metformin salt of the present invention, can be mixed with a diluent and a glidant, and the mixture can be placed directly into a hard or soft capsule. Alternatively, the active ingredient, the phenylbutazone metformin salt of the present invention, can be first prepared into granules or pellets with a diluent, a binder, and a disintegrant, and then placed into a hard or soft capsule. The various diluents, binders, wetting agents, disintegrants, and glidants used to prepare the phenylbutazone metformin salt tablets of the present invention can also be used to prepare the phenylbutazone metformin salt capsules 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 phenylbutazone 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 physician's clinical experience and the dosage regimen including the use of other therapeutic modalities.

[0057] The phenylbutazone metformin salt or composition of the present invention can be taken alone or in combination with other therapeutic drugs or symptomatic drugs. When the phenylbutazone 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 phenylbutazone metformin salt.

[0059] 4.1 The DSC spectrum of the metformin salt of phenylbutazone of the present invention ( 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 phenylbutazone metformin salt does not contain any crystallization solvent and has good safety advantages in drug development.

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

[0061] 4.4 The metformin salt of phenylbutazone involved in the present invention has a significant advantage in terms of biological absorption rate compared with the phenylbutazone raw material. ( Figure 11 ) BRIEF DESCRIPTION OF THE DRAWINGS

[0062] Figure 1 Molecular 3D structure projection diagram of metformin salt of phenylbutazone

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

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

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

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

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

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

[0069] Figure 8 Thermogravimetric spectrum of phenylbutazone metformin salt

[0070] Figure 9Stability Study of Phenylbutazone Metformin Salt

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

[0072] Figure 11 Pharmacokinetic curves of metformin salt of phenylbutazone and phenylbutazone 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 phenylbutazone metformin salt:

[0076] Take metformin hydrochloride and sodium hydroxide or sodium carbonate or other suitable base, put them into a clean container at a molar ratio of 1:1, add a certain volume of organic solvent, dissolve and add 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 phenylbutazone, stir for a suitable time (1h~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 phenylbutazone metformin salt.

[0077] Table 4 Specific examples of preparation method 1

[0078]

[0079]

[0080] Preparation method 2 of phenylbutazone metformin salt:

[0081] According to the 1:1 molar ratio, weigh appropriate amounts of phenylbutazone and metformin into a clean mortar and grind them evenly to obtain a physical mixture of phenylbutazone and metformin. Every 15 minutes, a certain volume of organic solvent is added dropwise, and the amount of solvent added is 0.5mL / g~10mL / g. Grind the obtained mixture in a clockwise direction for 30min~4h, and dry the obtained product. Powder X-ray diffraction analysis is performed on it, and its diffraction pattern is consistent with Figure 3 The results were consistent, indicating that the obtained sample was phenylbutazone metformin salt.

[0082] Table 5 Specific examples of preparation method 2

[0083]

[0084] Preparation method 3 of phenylbutazone metformin salt:

[0085] Phenylbutazone and metformin 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 phenylbutazone metformin salt.

[0086] Table 6 Specific examples of preparation method 1

[0087]

[0088]

[0089] Preparation method 4 of phenylbutazone metformin salt:

[0090] Weigh 0.5 mmol of metformin and 0.5 mmol of phenylbutazone into a 50 mL beaker, add 15 mL of isopropanol, 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 a relative humidity of 10% to 90% to slowly evaporate the solvent to obtain phenylbutazone metformin salt crystals that meet the requirements of single crystal X-ray diffraction.

[0091] Example 2

[0092] Stability characteristics of phenylbutazone metformin salt:

[0093] Light test: 50 mg of metformin salt of phenylbutazone was placed under light 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 phenylbutazone metformin salt, which was stable under light conditions.

[0094] High temperature test: 50 mg of metformin salt of phenylbutazone 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 phenylbutazone metformin salt, which was stable under high temperature conditions.

[0095] High humidity test: 50 mg of metformin salt of phenylbutazone was placed in high humidity 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 phenylbutazone metformin salt, which was stable under high humidity conditions.

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

[0097] Example 3

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

[0099] The dissolution concentration of phenylbutazone was used as the evaluation index. The content was determined by high performance liquid chromatography at a wavelength of 254 nm, and 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 phenylbutazone metformin salt and phenylbutazone

[0101]

[0102] It can be seen from the experimental data that the dissolution rate of the phenylbutazone metformin salt of the present application in pH 6.8 phosphate buffer is significantly improved compared with phenylbutazone itself. Specifically, the phenylbutazone metformin salt has a faster dissolution rate, and its intrinsic dissolution rate is about 3.7 times higher than that of phenylbutazone itself, which is of great significance for the subsequent improvement of the speed and degree of biological absorption of phenylbutazone.

[0103] Example 4

[0104] The bioabsorption advantages of phenylbutazone metformin salt in vivo

[0105] Based on the SD rat animal model, the pharmacokinetic behavior of phenylbutazone API and phenylbutazone 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 phenylbutazone API and phenylbutazone 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 phenylbutazone API and phenylbutazone metformin salt, it can be seen that the peak time of phenylbutazone after salt formation is T maxThe duration of the drug cycle was extended from 8.0 hours to 9.6 hours. The plasma concentration-time plot shows that some of the salt, which remains undestroyed by the acidic environment of the stomach, exhibits rapid bioabsorption and high plasma concentrations, while the remaining destroyed salt exhibits bioabsorption characteristics roughly similar to those of the phenylbutazone API. This suggests that salt formation accelerates the absorption rate of phenylbutazone, which is crucial for the long-term and stable efficacy of phenylbutazone's rapid anti-inflammatory and analgesic effects.

[0109] Example 5

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

[0111] A method for preparing a combination drug tablet comprises using phenylbutazone 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 phenylbutazone metformin salt combination drug tablets

[0113]

[0114] The method for preparing a tablet preparation using phenylbutazone metformin salt as a raw material 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 phenylbutazone 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 phenylbutazone metformin salt combination drug tablets

[0118]

[0119] The method for preparing a tablet preparation using phenylbutazone metformin salt as a raw material is as follows: several excipients are mixed evenly 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 evenly, and press into tablets.

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

[0121] A method for preparing a combination drug capsule is characterized by using phenylbutazone metformin salt as the API and several excipients as auxiliary ingredients for preparing the combination drug capsule. The ingredients 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 proportions:

[0122] Table 11. Formulation of APIs and excipients for the phenylbutazone metformin salt combination capsule preparation

[0123]

[0124] The method for preparing capsules using phenylbutazone 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 phenylbutazone metformin salt raw material drug is directly uniformly mixed with several excipients and auxiliary materials, the mixture is sieved, and the mixture is directly inserted into capsules.

[0125] Example 6

[0126] Dosage of phenylbutazone metformin salt combination drug 1 (tablet):

[0127] A pharmaceutical composition developed using phenylbutazone metformin salt as a pharmaceutical active ingredient is characterized in that phenylbutazone 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 twice a day / one tablet each time, or 200 mg tablets once a day / one tablet each time.

[0128] Dosage of phenylbutazone metformin salt combination drug 2 (capsule):

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

[0130] Issues requiring clarification: The dosage of the active ingredient in the phenylbutazone metformin salt pharmaceutical composition of the present invention is affected by many factors, such as differences in patient age, body surface area, route of administration, number of doses, and therapeutic objectives, resulting in different dosages per dose. Variations in absorption and blood concentrations between samples also result in the suitable dosage range for each dose of the phenylbutazone metformin salt component of the present invention being 0.005 to 20 mg / kg body weight, preferably 0.01 to 10 mg / kg body weight. Different total dosage regimens for the phenylbutazone metformin salt active ingredient should be formulated based on the actual treatment needs, and can be administered in multiple doses or a single dose.

[0131] References

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Claims

1. A phenylbutazone metformin salt, characterized in that Phenylbutazone and metformin form a salt in a 1:1 molar ratio.

2. The phenylbutazone metformin salt according to claim 1, characterized in that When analyzed using single crystal X-ray diffraction, it exhibits trigonal symmetry with a space group of The unit cell parameters are: γ=120°. Unit cell volume 3. The phenylbutazone metformin salt according to claim 1, characterized in that 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 phenylbutazone metformin salt according to claim 1, characterized in that When analyzed by attenuated total reflection Fourier transform infrared spectroscopy, the peaks were 3442, 3370, 3308, 3095, 2958, 2928, 2868, 2324, 2104, 1952, 1802, 1735, 1666, 1632, 1594, 1521, 1495, 1455, 1441, 1419, 1373, 1329, 1284, 1273, 1240, 1199, 1146, 1091, 1071, 1040, 998, 988, 929, 899, 859, 835, 816, 777, 758, 742, 706, 689, 650, 625, 613, 558, 506, 476, 460, 414 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 phenylbutazone metformin salt according to claim 1, characterized in that 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 155±3°C in the DSC spectrum.

6. The method for preparing phenylbutazone 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, and tetrahydrofuran, or mixed solvents prepared from these solvents in varying ratios. Phenylbutazone 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 phenylbutazone and metformin salt.

7. The method for preparing phenylbutazone metformin salt according to any one of claims 1 to 5, characterized in that: The following steps are involved: (1) Phenylbutazone and metformin raw materials were placed in a mortar at a molar ratio of 1:1 and ground evenly 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 the salt of phenylbutazone and metformin.

8. The mechanochemical method according to claim 7, wherein the molar ratio of phenylbutazone to metformin 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 r / min to 400 r / min.

9. The method for preparing phenylbutazone metformin salt according to any one of claims 1 to 5, characterized in that: The solvent evaporation method was adopted, using isopropanol as a single solvent or isopropanol / water (v / v, 3:1) mixed solvent, stirring a 1:1 molar ratio of phenylbutazone 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 phenylbutazone metformin salt crystals that met the requirements of single crystal X-ray diffraction.

10. A mixed solid material containing phenylbutazone metformin salt, characterized in that: The amount of the phenylbutazone 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 phenylbutazone 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 phenylbutazone 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 phenylbutazone 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 phenylbutazone metformin salt according to any one of claims 1 to 5, the mixed solid material containing phenylbutazone 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 anti-inflammatory analgesics.

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