Composition and eutectic mixture of pentoxifylline and non-steroidal anti-inflammatory drug as well as preparation method and application of composition and eutectic mixture

Abstract

The invention provides a composition of pentoxifylline and a non-steroidal anti-inflammatory drug, a eutectic mixture as well as a preparation method and application of the composition and the eutectic mixture. The non-steroidal anti-inflammatory drug is prepared from diclofenac, indometacin, celecoxib, acetylsalicylic acid, ibuprofen and naproxen. According to the invention, the eutectic mixture of pentoxifylline and the non-steroidal anti-inflammatory drug is prepared by a liquid-assisted grinding method or a solvent evaporation method, and the eutectic mixture comprises pentoxifylline and the non-steroidal anti-inflammatory drug in a molar ratio of 0.1: 0.9-0.9: 0.1. Wherein the melting points of the eutectoid pentoxifylline-diclofenac, the pentoxifylline-indometacin and the pentoxifylline-celecoxib are 92.9 DEG C + / -5 DEG C, 91.1 DEG C + / -5 DEG C and 88.2 DEG C + / -3 DEG C respectively, and the melting points of the eutectoid pentoxifylline-diclofenac, the pentoxifylline-indometacin and the pentoxifylline-celecoxib are reduced compared with single pentoxifylline or non-steroidal anti-inflammatory drugs. The solubility of the pentoxifylline-diclofenac and the solubility of the pentoxifylline-indometacin are improved by 6 times and 4 times or above compared with those of single non-steroidal anti-inflammatory drugs. In addition, the pentoxifylline and non-steroidal anti-inflammatory drug eutectic mixture has a synergistic analgesic effect, and the analgesic effect is obviously superior to that of a single drug. The pentoxifylline and non-steroidal anti-inflammatory drug eutectic mixture provided by the invention has good solubility and analgesic activity, and has a wide application prospect.

Description

Technical Field

[0001] The present invention relates to the field of medicine, and in particular to a composition of pentoxifylline and non-steroidal anti-inflammatory drugs, a eutectic, and a preparation method and application thereof Background Art

[0002] Pain is considered the fifth vital sign and has become the third largest health problem for humans after cardiovascular and cerebrovascular diseases and tumors. Currently, chronic pain affects more than 30% of the world's population. Pain has seriously affected the quality of life of patients and caused a huge economic burden. Although there are a large number of effective and widely used analgesics, such as opioids, non-steroidal anti-inflammatory drugs, and some antidepressants, the safety and side effects of these drugs have limited their clinical use.

[0003] Existing single-target analgesics have limitations, and the development of new drugs is difficult and slow, so the current clinical recommendation is to adopt a multimodal analgesic strategy. The multimodal analgesic strategy combines analgesics and analgesic methods with different mechanisms of action to block different phases and targets of the pathophysiological mechanism of pain, reduce peripheral and central sensitization, achieve the best analgesic effect, and reduce the dosage of analgesics and adverse drug reactions.

[0004] Drug-drug eutectics are one of the effective research strategies to achieve multimodal analgesia. Eutectics are a combination of two or more crystalline substances that melt at a single temperature, which is lower than the melting point of a single compound. They can improve the transdermal penetration or oral absorption of drugs, and their performance is better than that of a single component. The compounds in the eutectic mixture still retain their original crystalline state within a short range, but due to the presence of other substances, the crystallization process is inhibited at a specific ratio. The eutectic mixture retains the original crystalline morphology at the microscopic level, and appears ordered within a short distance; at the macroscopic level, it appears disordered over a long range. The specific external manifestations of its disorder are lower melting point, increased solubility, and dissolution rate. Therefore, eutectics can combine two drugs together, which can not only improve the solubility of poorly soluble drugs, but also combine two therapeutically relevant drugs into a fixed-dose delivery system. It is expected to overcome the problems of large solubility differences, incompatibility, and poor stability in traditional combination drugs, and is considered to be a promising drug development strategy.

[0005]

[0006] Pentoxifylline (PEN), whose structural formula is shown in formula (I), is commonly used clinically to treat chest tightness, palpitations and other symptoms caused by diseases such as acute coronary syndrome and myocardial infarction. In recent years, the role of pentoxifylline in neuropathic pain has been widely confirmed. It has a nonspecific phosphodiesterase inhibitor effect similar to that of propentofylline, and may produce analgesic effects by inhibiting glial cell activation. However, there are few studies on the treatment or prevention of acute pain with pentoxifylline. In addition, long-term use may lead to the generation of tolerance, and an increase in dosage is required to maintain the same analgesic effect. There may also be cross-tolerance with other opioids, which may limit its therapeutic effect.

[0007]

[0008] Nonsteroidal anti-inflammatory drugs (NSAIDs), the common structure of which is shown in formula (II), have good analgesic and anti-inflammatory effects, occupy an important position in the World Health Organization's list of essential drugs, and are one of the most commonly used analgesics. NSAIDs mainly exert analgesic, anti-inflammatory and antipyretic effects by inhibiting cyclooxygenase, and are mostly used to treat patients with pain and inflammation, such as chronic pain, osteoarthritis, rheumatoid arthritis, postoperative pain, dysmenorrhea, etc. However, long-term use of NSAIDs will produce a series of side effects, including gastric ulcers and bleeding, cardiovascular risks, kidney damage and other side effects. At the same time, the adverse physical and chemical properties of NSAIDs, especially low solubility, limit the rapid onset and clinical application of NSAIDs.

[0009] Therefore, the development of eutectics of pentoxifylline and nonsteroidal anti-inflammatory drugs is expected to overcome the problems of poor solubility and large fluctuations in bioavailability of NSAIDs, while exerting a synergistic analgesic effect of the two, reducing the effective dose and thus reducing dose-related side effects. Summary of the invention

[0010] The purpose of the present invention is to provide a composition and a eutectic of pentoxifylline and a non-steroidal anti-inflammatory drug in view of the defects of the prior art, and to provide a method for the development or preparation of non-opioid analgesics to overcome the deficiencies of the prior art.

[0011] To achieve the above object, the present invention provides the following technical solution: a composition or eutectic of pentoxifylline and nonsteroidal anti-inflammatory drugs. The nonsteroidal anti-inflammatory drugs (NSAIDs) are a large class of drugs with different chemical structures but the same pharmacological effects, mainly reducing the generation of various prostaglandins and thromboxanes by inhibiting cyclooxygenase, including diclofenac (DIC), indomethacin (IND), celecoxib (CEL), acetylsalicylic acid (Acetylsalicylic acid), ibuprofen (Ibuprofen), naproxen (Naproxen), etc. The applicant recognizes that new NSAIDs may be under development, and the present invention contemplates a composition or eutectic containing these new agents and pentoxifylline.

[0012] The eutectic of the pentoxifylline and non-steroidal anti-inflammatory drug composition is pentoxifylline and diclofenac in a molar ratio of 0.1:0.9 to 0.9:0.1; pentoxifylline and indomethacin in a molar ratio of 0.1:0.9 to 0.9:0.1; and pentoxifylline and celecoxib in a molar ratio of 0.1:0.9 to 0.9:0.1.

[0013] As a preferred technical solution of the present invention, the melting point of the eutectic formed by pentoxifylline and diclofenac is 92.9°C±5°C; the melting point of the eutectic formed by pentoxifylline and indomethacin is 91.1°C±5°C; the melting point of the eutectic formed by pentoxifylline and celecoxib is 88.2°C±3°C.

[0014] As a preferred technical solution of the present invention, the molar ratio of pentoxifylline to diclofenac is 0.4:0.6-0.7:0.3; the molar ratio of pentoxifylline to indomethacin is 0.4:0.6-0.8:0.2; and the molar ratio of pentoxifylline to celecoxib is 0.4:0.6-0.7:0.3.

[0015] The invention discloses a method for preparing a eutectic product of a composition of pentoxifylline and non-steroidal anti-inflammatory drugs, which adopts a grinding method, a solvent evaporation method and a melt cooling method.

[0016] The specific steps of the grinding method are as follows: grinding pentoxifylline and non-steroidal anti-inflammatory drugs (in a molar ratio of 0.1:0.9 to 0.9:0.1) with the assistance of a solvent, and finally drying to obtain a low eutectic mixture.

[0017] The specific steps of the solvent evaporation method are as follows: pentoxifylline and nonsteroidal anti-inflammatory drugs (in a molar ratio of 0.1:0.9 to 0.9:0.1) are stirred and dissolved in a solvent, and then the solvent is removed and dried to obtain the eutectic mixture.

[0018] As a preferred technical solution of the present invention, the solid-liquid ratio of the total mass of the drug in the liquid-assisted grinding method to the solvent is (1-20) g:1 mL; the solid-liquid ratio of the total mass of the drug in the solvent evaporation method to the solvent is (10-400) mg:1 mL.

[0019] As a preferred technical solution of the present invention, the organic solvent is any one or more of benzene, carbon tetrachloride, 1,2-dichloroethane, 1,1-dichloroethylene, 1,1,1-trichloroethane, acetonitrile, aminobenzene, chloroform, cyclohexane, 1,2-dichloroethylene, dichloromethane, 1,2-dimethoxyethane, N,N-dimethylacetamide, dimethylformamide, dioxane, 2-ethoxyethanol, ethylene glycol, formamide, n-hexane, methanol, ethylene glycol methyl ether, methyl butyl ketone, methylcyclohexane, N-methylpyrrolidone, nitromethane, pyridine, sulfolane, 1,2,3,4-tetrahydrophthalate, toluene, 1,1,2-trichloroethylene, xylene, ethanol, ethyl acetate, cyclopentyl methyl ether, acetone, tetrahydrofuran, heptane, isopropanol, and n-propanol.

[0020] To achieve the above-mentioned object of the invention, the present invention also provides a pharmaceutical composition, comprising the eutectic of pentoxifylline and non-steroidal anti-inflammatory drugs as described above and pharmaceutically acceptable excipients.

[0021] As a further improvement of the present invention, the dosage form of the pharmaceutical composition includes powder, tablet, granule, capsule, pill, film, ointment, suppository or paste.

[0022] To achieve the above-mentioned purpose of the invention, the present invention also provides an application of the above-mentioned eutectic of pentoxifylline and non-steroidal anti-inflammatory drugs or the above-mentioned pharmaceutical composition, wherein the eutectic or the pharmaceutical composition is used to prevent, treat or alleviate pain-related symptoms or diseases.

[0023] The beneficial effects of the present invention are:

[0024] (a) The eutectics of pentoxifylline-diclofenac, pentoxifylline-indomethacin and pentoxifylline-celecoxib prepared by the grinding method, solvent evaporation method and melt cooling method of the present invention have significantly improved solubility compared with the solubility of a single non-steroidal anti-inflammatory drug;

[0025] (c) The pentoxifylline and nonsteroidal anti-inflammatory drug composition and eutectic of the present invention overcome the problems of poor solubility and large fluctuation in bioavailability of NSAIDs, while exerting a synergistic analgesic effect of the two, reducing the effective dose, and thus reducing dose-related side effects.

[0026] (b) The preparation method of the present invention is simple and easy to carry out, has good reproducibility, is easy to industrialize and apply, and has good application prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Figure 1 The differential scanning calorimetry (DSC) spectra of the eutectic PEN-DIC at different mole fractions are shown below:

[0028] Figure 2 DSC spectra of eutectic PEN-IND at different mole fractions

[0029] Figure 3 This is the DSC spectrum of the eutectic PEN-CEL mole fraction ratio of 0.5:0.5;

[0030] Figure 4 The infrared spectrum analysis (IR) spectra of DIC, PEN and eutectic PEN-DIC;

[0031] Figure 5 IR spectra of PEN, IND and eutectic PEN-IND;

[0032] Figure 6 Powder X-ray diffraction (PXRD) patterns of PEN, DIC and eutectic PEN-DIC;

[0033] Figure 7 PXRD patterns of PEN, IND and eutectic PEN-IND;

[0034] Figure 8 Schematic diagram of the analgesic effects of PEN, DIC and IND in the acute inflammatory pain model induced by carrageenan ( Figure 8 A: Effects of PEN on mechanical pain threshold of mice; Figure 8 B: Changes in AUC at different doses of PEN; Figure 8 C: Effect of DIC on mechanical pain threshold of mice; Figure 8 D: Changes in AUC of DIC at different doses; Figure 8 E: Effect of IND on mechanical pain threshold of mice; Figure 8 F: Changes in AUC at different doses of IND);

[0035] Fig. 9 Schematic diagram of the analgesic effect of the eutectic PEN-DIC and PEN-IND in the acute inflammatory pain model induced by carrageenan ( Fig. 9 A: Effect of eutectic PEN-DIC on mechanical pain threshold of mice; Fig. 9 B: Changes in AUC of eutectic PEN-DIC at different doses; Fig. 9 C: Effect of eutectic PEN-IND on mechanical pain threshold of mice; Fig. 9 D: AUC changes of eutectic PEN-IND at different doses);

[0036] Fig.10 The isoradiometric analysis diagrams of the eutectic PEN-DIC and PEN-IND in the acute inflammatory pain model induced by carrageenan ( Fig.10 A: PEN-DIC isoradiative analysis diagram of eutectic; Fig.10 B: Isoradiative analysis diagram of low eutectic PEN-IND). DETAILED DESCRIPTION

[0037] The preferred embodiments of the present invention are described in detail below in conjunction with the accompanying drawings so that the advantages and features of the present invention can be more easily understood by those skilled in the art, thereby making a clearer and more explicit definition of the protection scope of the present invention. It should be understood that these embodiments are only used to illustrate the present invention and are not used to limit the scope of the present invention.

[0038] The invention provides a pentoxifylline and non-steroidal anti-inflammatory drug composition and a eutectic for preventing or treating pain; the non-steroidal anti-inflammatory drugs include diclofenac, indomethacin, celecoxib, acetylsalicylic acid, ibuprofen, and naproxen; the pentoxifylline and non-steroidal anti-inflammatory drug composition and the eutectic include a eutectic PEN-DIC of pentoxifylline and diclofenac in a molar ratio of 0.1:0.9 to 0.9:0.1, and a pentoxifylline and a eutectic PEN-DIC in a molar ratio of 0.1:0.9 to 0.9:0.1. The invention relates to a low eutectic product PEN-IND of ketothecine and indomethacin and a low eutectic product PEN-CEL of pentoxifylline and celecoxib with a molar ratio of 0.1:0.9 to 0.9:0.1. Compared with a single non-steroidal anti-inflammatory drug, the low eutectics PEN-DIC, PEN-IND and PEN-CEL have significantly lower melting points and significantly higher solubility, and have good analgesic effects in an inflammatory pain model, with analgesic activity superior to that of a single drug, and have good clinical application prospects.

[0039] Example 1: Preparation of eutectics of pentoxifylline-diclofenac (PEN-DIC), pentoxifylline-indomethacin (PEN-IND) and pentoxifylline-celecoxib (PEN-CEL)

[0040] The reagents for preparing the eutectic mixture of pentoxifylline and nonsteroidal anti-inflammatory drugs are shown in Table 1.

[0041] Table 1 Experimental reagents used in the preparation of eutectic mixtures of pentoxifylline and nonsteroidal anti-inflammatory drugs

[0042]

[0043] The eutectic PEN-DIC was prepared using a liquid-assisted grinding method. A total of 1 mmol of PEN and DIC with molar ratios of 0.9:0.1, 0.8:0.2, 0.7:0.3, 0.6:0.4, 0.5:0.5, 0.4:0.6, 0.3:0.7, 0.2:0.8 and 0.1:0.9 was weighed into an agate mortar, and methanol (50 μL) was added to assist grinding for 15 minutes to obtain the eutectic PEN-DIC.

[0044] The low eutectic PEN-DIC was prepared by solvent evaporation method. A total of 10 mmol of PEN and DIC with molar ratios of 0.9:0.1, 0.8:0.2, 0.7:0.3, 0.6:0.4, 0.5:0.5, 0.4:0.6, 0.3:0.7, 0.2:0.8 and 0.1:0.9 were placed in a 250 mL flask, 100 mL of ethanol was added, and magnetic stirring was performed for 15 minutes. After the solution was clarified, the solvent was removed by rotary evaporation under reduced pressure, and then the obtained product was dried in a vacuum oven at 50 ° C for 3 hours to obtain the low eutectic PEN-DIC.

[0045] The eutectic PEN-IND was prepared using a liquid-assisted grinding method. A total of 1 mmol of PEN and IND with molar ratios of 0.9:0.1, 0.8:0.2, 0.7:0.3, 0.6:0.4, 0.5:0.5, 0.4:0.6, 0.3:0.7, 0.2:0.8 and 0.1:0.9 was weighed into an agate mortar, and methanol (50 μL) was added to assist grinding for 15 minutes to obtain the eutectic PEN-IND.

[0046] The low eutectic PEN-IND was prepared by solvent evaporation. A total of 10 mmol of PEN and IND with molar ratios of 0.9:0.1, 0.8:0.2, 0.7:0.3, 0.6:0.4, 0.5:0.5, 0.4:0.6, 0.3:0.7, 0.2:0.8 and 0.1:0.9 were placed in a 250 mL flask, 100 mL of ethanol was added, and magnetic stirring was performed for 15 minutes. After the solution was clarified, the solvent was removed by rotary evaporation under reduced pressure, and the resulting product was dried in a vacuum oven at 50 ° C for 3 hours to obtain the low eutectic PEN-IND.

[0047] The eutectic PEN-CEL was prepared using a liquid-assisted grinding method. A total of 1 mmol of PEN and CEL with molar ratios of 0.9:0.1, 0.8:0.2, 0.7:0.3, 0.6:0.4, 0.5:0.5, 0.4:0.6, 0.3:0.7, 0.2:0.8 and 0.1:0.9 was weighed into an agate mortar, and methanol (50 μL) was added to assist grinding for 15 minutes to obtain the eutectic PEN-CEL.

[0048] The low eutectic PEN-CEL was prepared by solvent evaporation. A total of 10 mmol of PEN and CEL with molar ratios of 0.9:0.1, 0.8:0.2, 0.7:0.3, 0.6:0.4, 0.5:0.5, 0.4:0.6, 0.3:0.7, 0.2:0.8 and 0.1:0.9 were placed in a 250 mL flask, 100 mL of ethanol was added, and magnetic stirring was performed for 15 minutes. After the solution was clarified, the solvent was removed by rotary evaporation under reduced pressure, and then the obtained product was dried in a vacuum oven at 50 ° C for 3 hours to obtain the low eutectic PEN-CEL.

[0049] Example 2: Differential Scanning Calorimetry (DSC) Analysis of Eutectics Pentoxifylline-Diclofenac (PEN-DIC), Pentoxifylline-Indomethacin (PEN-IND) and Pentoxifylline-Celecoxib (PEN-CEL)

[0050] Eutectics PEN-DIC, PEN-IND and PEN-CEL were prepared by referring to the method described in Example 1. Differential scanning calorimetry (DSC) analysis was performed using a differential scanning calorimeter (Netzsch DSC 200F3), and about 5 mg of the sample was heated from room temperature to 300°C at a temperature gradient of 10°C / min under the protection of dry nitrogen (40 mL / min).

[0051] The experimental results are as follows Figure 1 As shown in the figure, PEN has an endothermic peak at 105.4℃, and DIC has an endothermic peak at 180.7℃. The eutectic PEN-DIC with a molar ratio in the range of 0.1:0.9 to 0.9:0.1 has an endothermic peak near 92.9℃±5℃ in the DSC spectrum. Compared with the single drugs PEN and DIC, the melting point of the eutectic PEN-DIC has decreased. The eutectic PEN-DIC shows a single endothermic peak at a molar fraction ratio of 0.4:0.6, while the DSC curve of the PEN-DIC eutectic shows a second endothermic peak near 170℃ in the molar ratio range of 0.1:0.9 to 0.3:0.7, indicating that the mixing effect of the PEN-DIC eutectic is slightly poor at this ratio.

[0052] like Figure 2As shown, IND has an endothermic peak at 160.6℃. The eutectic PEN-IND with a molar ratio in the range of 0.1:0.9 to 0.9:0.1 has an endothermic peak near 91.1℃±5℃ in the DSC spectrum. Compared with PEN and IND alone, the melting point of the eutectic PEN-IND has decreased. The eutectic PEN-IND shows a single endothermic peak at a molar fraction ratio of 0.5:0.5, while the DSC curve of the PEN-IND eutectic shows a second endothermic peak near 157℃ in the molar ratio range of 0.1:0.9 to 0.3:0.7, indicating that the mixing effect of the PEN-IND eutectic is slightly poor at this ratio.

[0053] like Figure 3 As shown in the figure, CEL has an endothermic peak at 161.6℃. The eutectic PEN-CEL with a molar ratio in the range of 0.1:0.9 to 0.9:0.1 has an endothermic peak near 88.2℃±3℃ in the DSC spectrum. Compared with PEN and CEL alone, the melting point of the eutectic PEN-CEL has decreased.

[0054] Example 3: Infrared spectral analysis of eutectics of pentoxifylline-diclofenac (PEN-DIC), pentoxifylline-indomethacin (PEN-IND) and pentoxifylline-celecoxib (PEN-CEL)

[0055] Referring to the method described in Example 1, the prepared eutectic PEN-DIC, PEN-IND and PEN-CEL were ground with potassium bromide and pressed into tablets at 500-4000 cm -1 The spectral range is 4cm -1 Resolution The samples were examined using infrared spectroscopy.

[0056] The infrared spectra of the eutectic PEN-DIC and its API are as follows: Figure 4 As shown in the figure, compared with the characteristic peaks of PEN or DIC single components, the absorption peaks of the eutectic PEN-DIC in the infrared spectrum have no obvious changes, which is the superposition of the characteristic peaks of PEN and DIC. These results indicate that the parent compound exists in its original crystalline state in the eutectic system without forming new molecules or intermolecular interactions.

[0057] The infrared spectra of the eutectic PEN-IND and its API are as follows: Figure 5 As shown in the figure, compared with the characteristic peaks of PEN or IND single components, the absorption peaks of the eutectic PEN-IND in the infrared spectrum have no obvious changes, which is the superposition of the characteristic peaks of PEN and IND. These results indicate that the parent compound exists in its original crystalline state in the eutectic system without forming new molecules or intermolecular interactions.

[0058] Compared with the characteristic peaks of PEN or CEL single components, the absorption peaks of the eutectic PEN-CEL in the infrared spectrum have no obvious changes, which is the superposition of the characteristic peaks of PEN and CEL. These results show that the parent compound exists in its original crystalline state in the eutectic system without forming new molecules or intermolecular interactions.

[0059] Example 4: Powder X-ray Diffraction (PXRD) Analysis of Eutectics Pentoxifylline-Diclofenac (PEN-DIC), Pentoxifylline-Indomethacin (PEN-IND) and Pentoxifylline-Celecoxib (PEN-CEL)

[0060] Eutectic PEN-DIC, PEN-IND and PEN-CEL were prepared by referring to the method described in Example 1. The prepared eutectic powder was tested using a powder X-ray diffractometer (PANalytical X′PERT), using Cu-Ka radiation (wavelength λ=1.540598A), the set voltage and current were 40 kV and 30 mA respectively, the 2θ scanning range was 3° to 60°, and the scanning speed was 2° / min.

[0061] The powder X-ray diffraction patterns of the eutectic PEN-DIC and its API are shown in Figure 6 As shown, the compound in the eutectic still retains the crystalline state of its original parent drug within a short distance. Compared with the single components of PEN or DIC, the eutectic PEN-DIC has no new characteristic diffraction peaks in PXRD, which is a superposition of the characteristic peaks of PEN and DIC.

[0062] The powder X-ray diffraction patterns of the eutectic PEN-IND and its API are shown in Figure 7 As shown, the compound in the eutectic still retains the crystalline state of its original parent drug within a short distance. Compared with the single components of PEN or IND, the eutectic PEN-IND has no new characteristic diffraction peaks in PXRD, which is the superposition of the characteristic peaks of PEN and IND.

[0063] The compound in the eutectic PEN-CEL still retains the crystalline state of its original parent drug within a short distance. Compared with the single components of PEN or CEL, the eutectic PEN-CEL has no new characteristic diffraction peaks in PXRD, which is the superposition of the characteristic peaks of PEN and CEL.

[0064] Example 5: Equilibrium Solubility Analysis of Eutectics Pentoxifylline-Diclofenac (PEN-DIC) and Pentoxifylline-Indomethacin (PEN-IND)

[0065] The reagents and chemicals for the equilibrium solubility analysis experiment of the low eutectic PEN-DIC and PEN-IND are shown in the table.

[0066] Table 2 Experimental reagents used for equilibrium solubility analysis of eutectics PEN-DIC and PEN-IND

[0067]

[0068] The solubility of the same compound will be different in different solvent systems, solvent temperatures and pressure conditions. Common solubility measurement methods include equilibrium method, dynamic method and thermal analysis method. The equilibrium method, also known as the static method, is to add excess solute to the solvent and stir it continuously for a period of time under constant temperature conditions to ensure that the solid and liquid reach equilibrium.

[0069] Chromatographic conditions: The instrument used for drug concentration determination was Agilent 1260 Infinity II HPLC, and the chromatographic column used for separation was Agilent Poroshell 120 EC-C18 (100mm×4.6mm, 4μm); the mobile phase was acetonitrile: water: acetic acid (35:60:5), and the UV detection wavelength was set to 254nm. The flow rate was 1.0mL / min; the column temperature was 25℃, the injection volume was 20μL, and the isocratic elution time was 9min. The equilibrium solubility test was carried out in pH 1.2, pH 4.5, pH 6.8 and water buffer solutions.

[0070] Drawing of PEN, DIC, and IND standard curves: Accurately weigh 10 mg of PEN into a 10 mL volumetric flask and dilute to 1 mg / mL stock solution with methanol, filter with a 0.45 μm organic filter membrane, and then dilute with methanol to 1, 0.5, 0.25, 0.125, and 0.0625 mg / mL standard solutions, with methanol as the blank control. The injection volume is 20 μL, record the chromatogram, and draw the standard curve.

[0071] Weigh 10 mg of PEN, DIC, IND, PEN-DIC, and PEN-IND into a test tube, and add 2 mL of purified water, pH 1.2 hydrochloric acid buffer, pH 4.5 sodium acetate buffer, and pH 6.8 phosphate buffer, respectively. All test tubes were placed in a constant temperature shaker at 37°C, 100 rpm, and shaken for 24 hours. Pipette 100 μl of the solution in each medium, dilute 5 times with the corresponding buffer, filter through a 0.45 μm organic filter membrane, and perform HPLC analysis. There are 3 parallel samples in each solution sample, and the liquid phase is injected twice to obtain the data.

[0072] The experimental results are shown in Table 3. Although the content of DIC in the eutectic PEN-DIC was below the detection limit at pH 4.5 and pH 1.2, the solubility of DIC in the eutectic PEN-DIC at pH 6.8 was 2.169 mg / mL, which was more than 6 times higher than the solubility of DIC alone at pH 6.8 (0.369 mg / mL); the content of IND in the eutectic PEN-IND was below the detection limit at pH 4.5 and pH 1.2, but the solubility of the eutectic PEN-IND at pH 6.8 was 2.234 mg / mL, which was more than 4 times higher than the solubility of IND alone at pH 6.8 (0.585 mg / mL).

[0073] Table 3 Comparison of equilibrium solubility of PEN, DIC, IND, PEN-DIC, PEN-IND in different media

[0074]

[0075] Note: / indicates below the detection limit

[0076] Example 6: Evaluation of the analgesic effect of eutectic pentoxifylline-diclofenac (PEN-DIC) and pentoxifylline-indomethacin (PEN-IND) in the carrageenan-induced inflammatory pain model

[0077] The experimental animals were female ICR mice (22-30 g), which were housed in an environment with a constant temperature (22±3°C) and a relative humidity of 55±5% and a 12-h light / dark cycle.

[0078] The drugs and reagents used in the carrageenan-induced inflammatory pain experiment are shown in Table 4.

[0079] Table 4 Experimental drugs and reagents used in carrageenan-induced inflammatory pain model

[0080]

[0081] Acute inflammatory pain is one of the most common types of pathological pain in clinical practice. Carrageenan-induced acute inflammatory pain has a high predictive value in the study of analgesics and is often used to evaluate the anti-acute inflammatory pain effects of drugs.

[0082] Table 5 Dosage grouping setting for carrageenan-induced inflammatory pain experiment

[0083]

[0084] ICR mice were randomly divided into negative control group, model group and compound dose groups (see Table 5), with 6 mice in each group. Before injection of carrageenan or saline, the baseline mechanical withdrawal threshold (MWTs, expressed in g) of each mouse was measured. Mechanical allodynia was assessed using a ZH-ZKL mechanical needle analgesia instrument. Mice were acclimated to the environment in an elevated metal grid under a transparent plastic chamber (21×27×15 cm) without restraint. When the mice were adapted for at least 30 minutes, a progressive force was applied to the left hind paw of the mouse, and the analgesia instrument automatically recorded the MWTs of the mouse when the mouse withdrew its hind paw. Each test was repeated three times (inter-trial interval: 30 seconds). Three hours after the injection of 20 μL of 1% carrageenan or saline, the drug or saline was administered orally. MWTs were detected at 0, 30, 60, 90 and 120 minutes after administration.

[0085] The percentage of maximum possible effect (%MPE) was calculated by the following formula: %MPE = (MWT1-MWT2) / (MWT3-MWT2) × 100%, where MWT1 refers to the maximum threshold after drug treatment, MWT2 refers to the threshold after modeling, and MWT3 refers to the threshold of normal mice before modeling. The degree and duration of analgesia were estimated by the area under the curve (AUC). The AUC describing the change of mechanical withdrawal threshold over time was calculated using the approximate trapezoidal rule using GraphPad Prism 9.0 software. The evaluation of drug synergy is usually demonstrated experimentally, and isoradiometric analysis is the gold standard method for evaluating pharmacological interactions between drugs. The core principle of this method is to select an effect level and determine through experiments the dosage of drug A alone, drug B alone, and the combination (a, b) that produces this effect. The line connecting the dosages that produce the same effect is called the isobologram, and the combined drug effect can be represented by a / A+b / B=γ. When γ=1, the interaction between drugs is additive; when γ<1, the interaction between drugs is synergistic; when γ>1, the interaction between drugs is antagonistic.

[0086] The experimental results are as follows Figure 8 As shown in the figure, 3 hours after carrageenan injection, the mechanical threshold of mice was significantly reduced, indicating that the acute inflammatory pain model induced by carrageenan was successfully established. PEN, DIC, IND, low eutectic PEN-DIC and PEN-IND were administered orally in a dose-dependent manner to relieve the acute inflammatory pain induced by carrageenan. The MPE% and 50% maximum effect concentration (ED 50 )

[0087] As shown in Table 6.

[0088] Table 6 Analgesic MPE values ​​and ED of eutectic PEN-DIC and PEN-IND in the acute inflammatory pain model induced by carrageenan 50 value

[0089]

[0090] like Fig. 9 As shown in the results, oral administration of eutectic PEN-DIC and PEN-IND significantly improved the acute inflammatory pain induced by carrageenan, and the analgesic effect was dose-dependent. 50 Actual value ED 50mix =7.594mg / kg, ED 50 Theoretical value ED 50add =92.49mg / kg; ED of eutectic PEN-IND 50 Actual value ED 50mix =6.016mg / kg, ED 50 Theoretical value ED 50add =91.19mg / kg. Fig.10 As shown in Figure 2, isoradiometric analysis shows that the ED of the eutectic PEN-DIC and PEN-IND 50mix Below the predicted additivity line, the interaction index Y(ED 50mix / ED 50add ) were 0.082 and 0.066, respectively, both less than 1, indicating that PEN had synergistic analgesic effects with DIC and IND in the acute inflammatory pain model induced by carrageenan.

[0091] Example 7: Preparation of eutectic compound tablets containing pentoxifylline and nonsteroidal anti-inflammatory drugs Tablet formulation composition

[0092] Table 7 Composition of eutectic compound tablets containing pentoxifylline and nonsteroidal anti-inflammatory drugs

[0093]

[0094]

[0095] The preparation method is as follows: weigh the low eutectic PEN-DIC according to the prescription amount, pass it through a 100-mesh sieve, add starch and dextrin, mix well, and pass it through a 40-60 mesh sieve; then add the above raw materials and auxiliary materials into a blender, dry stir for 8-9 minutes, add ethanol, stir for 5-9 minutes while adding, and make a suitable soft material; granulate with a 18-mesh nylon sieve, ventilate dry at a temperature of 60-70°C, and control the moisture content of the dry granules to 1.5-2.0%; add the prescription amount of magnesium stearate that has passed through a 40-mesh sieve to the dry granules, mix well; granulate and tablet.

[0096] In summary, the present invention provides a eutectic of pentoxifylline and non-steroidal anti-inflammatory drugs, and the eutectic pentoxifylline-diclofenac, pentoxifylline-indomethacin and pentoxifylline-celecoxib are prepared by liquid-assisted grinding or solvent evaporation, and the melting points are 92.9°C ± 5°C, 91.1°C ± 5°C and 88.2°C ± 3°C, respectively, which are lower than the melting point of a single pentoxifylline or non-steroidal anti-inflammatory drug. The solubility of the eutectic pentoxifylline-diclofenac and pentoxifylline-indomethacin is increased by 6 times and 4 times, respectively, compared with the single non-steroidal anti-inflammatory drug. In addition, the eutectic of pentoxifylline and non-steroidal anti-inflammatory drugs has a synergistic analgesic effect, and the analgesic effect is significantly better than that of a single drug. The eutectic of pentoxifylline and non-steroidal anti-inflammatory drugs provided by the present invention has good solubility and analgesic activity, and has a wide range of application prospects.

[0097] The above embodiments only express the implementation methods of the present invention, and the descriptions thereof are relatively specific and detailed, but they cannot be understood as limiting the scope of the invention patent. It should be pointed out that, for ordinary technicians in this field, several variations and improvements can be made without departing from the concept of the present invention, and these all belong to the protection scope of the present invention.

Claims

1. A composition of pentoxifylline and nonsteroidal anti-inflammatory drugs, characterized in that: NSAIDs include diclofenac, indomethacin, celecoxib, acetylsalicylic acid, ibuprofen, and naproxen.

2. A eutectic containing the pentoxifylline and nonsteroidal anti-inflammatory drug composition according to claim 1, characterized in that: The low eutectic is composed of pentoxifylline and diclofenac in a molar ratio of 0.1:0.9 to 0.9:0.1; pentoxifylline and indomethacin in a molar ratio of 0.1:0.9 to 0.9:0.1; and pentoxifylline and celecoxib in a molar ratio of 0.1:0.9 to 0.9:0.

1.

3. The eutectic of the pentoxifylline and nonsteroidal anti-inflammatory drug composition according to claim 2, characterized in that: The melting point of the eutectic formed by pentoxifylline and diclofenac is 92.9°C±5°C; the melting point of the eutectic formed by pentoxifylline and indomethacin is 91.1°C±5°C; the melting point of the eutectic formed by pentoxifylline and celecoxib is 88.2°C±3°C.

4. The composition and eutectic of pentoxifylline and nonsteroidal anti-inflammatory drugs according to claim 2, characterized in that: The molar ratio of pentoxifylline to diclofenac is 0.4:0.6-0.7:0.3; the molar ratio of pentoxifylline to indomethacin is 0.4:0.6-0.8:0.2; and the molar ratio of pentoxifylline to celecoxib is 0.4:0.6-0.7:0.

3.

5. The method for preparing the eutectic of the pentoxifylline and non-steroidal anti-inflammatory drug composition according to claims 2-4, characterized in that: Including grinding method, solvent evaporation method, melt cooling method; The specific steps of the grinding method are as follows: grinding pentoxifylline and non-steroidal anti-inflammatory drugs (in a molar ratio of 0.1:0.9 to 0.9:0.1) with the assistance of a solvent, and finally drying to obtain a low eutectic mixture. The specific steps of the solvent evaporation method are as follows: pentoxifylline and nonsteroidal anti-inflammatory drugs (in a molar ratio of 0.1:0.9 to 0.9:0.1) are stirred and dissolved in a solvent, and then the solvent is removed and dried to obtain the eutectic mixture.

6. The method for preparing the eutectic of the pentoxifylline and nonsteroidal anti-inflammatory drug composition according to claim 5, characterized in that: The solid-liquid ratio of the total drug mass to the solvent in the liquid-assisted grinding method is (1-20) g:1 mL; the solid-liquid ratio of the total drug mass to the solvent in the solvent evaporation method is (10-400) mg:1 mL.

7. The method for preparing the eutectic of the pentoxifylline and nonsteroidal anti-inflammatory drug composition according to claim 5, characterized in that: The solvent is any one or more of benzene, carbon tetrachloride, 1,2-dichloroethane, 1,1-dichloroethylene, 1,1,1-trichloroethane, acetonitrile, aminobenzene, chloroform, cyclohexane, 1,2-dichloroethylene, dichloromethane, 1,2-dimethoxyethane, N,N-dimethylacetamide, dimethylformamide, dioxane, 2-ethoxyethanol, ethylene glycol, formamide, n-hexane, methanol, ethylene glycol methyl ether, methyl butyl ketone, methylcyclohexane, N-methylpyrrolidone, nitromethane, pyridine, sulfolane, 1,2,3,4-tetrahydrotea, toluene, 1,1,2-trichloroethylene, xylene, ethanol, ethyl acetate, cyclopentyl methyl ether, acetone, tetrahydrofuran, heptane, isopropanol, and n-propanol.

8. A pharmaceutical composition, characterized in that The invention comprises the eutectic of pentoxifylline and non-steroidal anti-inflammatory drugs as described in claims 1 to 4 and pharmaceutically acceptable excipients.

9. The pharmaceutical composition according to claim 8, characterized in that: The pharmaceutical composition includes powder, tablet, granule, capsule, pill, film, ointment, suppository or paste.

10. Use of the eutectic of pentoxifylline and a nonsteroidal anti-inflammatory drug according to any one of claims 1 to 4 or the pharmaceutical composition according to any one of claims 8 to 9, characterized in that: The eutectic or pharmaceutical composition is used for preventing, treating or alleviating pain-related symptoms or diseases.

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