Diclofenac ropivacaine composition and preparation method thereof

Abstract

The invention discloses a composition composed of diclofenac and ropivacaine and having amorphous substance characteristics and a preparation method of the composition. The composition has no obvious characteristic XRD (X-Ray Diffraction) peak. The preparation method of the composition comprises a solvent method, a coprecipitation method and a melting method. The diclofenac ropivacaine composition provided by the invention has the advantages of simple preparation process, good long-term storage stability and the like, and has the potential of being developed into a preparation.

Description

Technical Field

[0001] The present invention belongs to the technical field of drug preparation, relates to the preparation of raw materials, and particularly relates to a composition of diclofenac and ropivacaine having amorphous characteristics and a preparation method thereof. Background Art

[0002] The International Association for the Study of Pain defines pain as "an unpleasant sensory and emotional experience associated with, or described in terms of, actual or potential tissue damage." Pain is a global public health problem and remains the most common reason for physician consultations and hospitalizations. It affects all people, regardless of age, sex, economic status, race, or geographic location. Acute pain caused by injury, acute illness, surgery, or arthritis is the most common type of pain and has complex etiologies. The prevalence of postoperative pain ranges from 14% to 70%. Pain caused by musculoskeletal disorders is another common form of acute pain. Inadequate management of acute pain can adversely affect quality of life, physical function, and functional recovery. In addition, inadequate pain management imposes a significant economic burden on healthcare utilization and workforce participation.

[0003] Current pain management options include a variety of options, most of which are based on unimodal analgesic mechanisms. However, acute pain is inherently multidimensional, involving sensory, emotional, cognitive, and behavioral aspects. Therefore, achieving adequate pain control with a single medication may not be beneficial. Furthermore, most analgesics have a ceiling to their efficacy and are associated with serious safety concerns. Multimodal analgesia is defined as the use of two or more analgesics or techniques that target different mechanisms or pathways within the nociceptive system. The combined use of several drugs allows for lower doses of each drug, thereby reducing the side effects of each drug, while maintaining overall efficacy. In theory, this outcome should translate into improved analgesia, enhanced functional recovery, and reduced opioid-related adverse effects.

[0004] Given the clinical significance of these benefits and the current global concern about the opioid epidemic, the American Pain Society, the World Health Organization, and the American College of Rheumatology strongly recommend the combined use of such analgesics. Combining oral opioids (such as codeine or tramadol) with non-opioids (such as acetaminophen) is an excellent option. Furthermore, NSAIDs are more effective than acetaminophen alone or the acetaminophen / codeine combination. Combining NSAIDs with opioids appears to be a more ideal option. Because NSAIDs have opioid-sparing properties, combining these two medications significantly reduces opioid dosage and reduces the incidence of adverse events such as nausea, vomiting, and respiratory depression. Choosing the optimal doses of the appropriate NSAID and opioid is crucial for achieving an effective analgesic combination.

[0005] Diclofenac, chemically known as 2-[(2,6-dichlorophenyl)amino]-phenylacetic acid, has the following chemical structure:

[0006] Diclofenac sodium salt (Diclofenac sodium, C 14 H 10 Cl2NNaO2, CAS: 15307-79-6), potassium salt (Diclofenac potassium, C 14 H 10 Cl2NKO2, CAS: 15307-81-0), diethylamine salt (Diclofenacdiethylamine, C 18 H 22 Cl2N2O2, CAS: 78213-16-8), Diclofenacepolamine, C 20 H 24 Cl2N2O3, CAS: 119623-66-4) has been publicly reported to be in clinical use.

[0007] Diclofenac sodium was synthesized by Alfred Sallmann and Rudolf Pfister and first marketed in 1973 by Ciba-Geigy (now Novartis AG, Basel, Switzerland). Its structure consists of a phenylacetic acid group and a phenyl ring containing two chlorine atoms, which maximizes the distortion of the phenyl ring and provides a good fit in the substrate-binding pocket of the COX enzyme. Although classified as a nonspecific COX inhibitor, diclofenac is actually a specific inhibitor of the COX-2 subtype, effectively inhibiting the synthesis of prostaglandins E2 and thromboxane A2 and exhibiting pronociceptive effects in the peripheral and spinal cord. Compared to other nonsteroidal anti-inflammatory drugs, diclofenac exhibits greater inhibition of platelet aggregation and is a competitive antagonist of the thromboxane-prostaglandin receptor, suggesting potential cardiovascular safety.

[0008] Due to its short biological half-life (approximately 2 hours) and rapid elimination rate (mean elimination half-life 1.2-1.8 hours), diclofenac often requires frequent dosing to maintain therapeutic concentrations, which in turn may increase the risk of adverse events. Given its rapid elimination rate, frequent dosing is expected to impair diclofenac's tolerability. To minimize gastric irritation and make diclofenac dosing regimens safer and more convenient for patients, sustained-release formulations have been introduced. Existing oral diclofenac sodium formulations, including enteric-coated tablets, have established themselves as a primary treatment for rheumatoid arthritis. Intravenous diclofenac formulations have been developed for the treatment of moderate or more severe pain and as an adjunct to more effective medications (such as opioids) for perioperative pain. Topical formulations, such as liquid solutions, gels, or transdermal patches for percutaneous administration, have also been developed for the treatment of certain types of localized pain.

[0009] Injectable diclofenac products have been available in the UK since 1997 and are distributed worldwide. These products typically consist of ampoules containing 75 mg of diclofenac solubilized with propylene glycol and benzyl alcohol, requiring a prolonged infusion time for intravenous administration. An injectable diclofenac product has been developed and approved in the US for use in patients with moderate pain or as part of a multimodal analgesic regimen for perioperative pain management. This diclofenac formulation (Dyloject, Hospira™ Inc., Lake Forest, IL, USA) contains 37.5 mg of diclofenac sodium and includes hydroxypropyl-β-cyclodextrin (HP-β-CD) to enhance solubility (333 mg / mL water), as well as pH modifiers and monothioglycerol. Compared to placebo, HP-β-CD / diclofenac 75 mg rapidly relieved pain in patients undergoing postoperative molar extraction and significantly improved pain intensity and tolerability. These results suggest that intravenous diclofenac sodium is an appropriate option for patients with acute postoperative pain or as part of a multimodal analgesic strategy to achieve perioperative pain control.

[0010] Ropivacaine, chemically known as (S)-(-)-1-propyl-N-(2,6-dimethylphenyl)-2-piperidinecarboxamide, has the following chemical structure:

[0011] Ropivacaine is a free base, and its hydrochloride (Ropivacaine hydrochloride, C 17 H 27 ClN2O, CAS: 98717-15-8) or mesylate (Ropivacaine Mesylate, C 18 H 30 N2O4S, CAS:854056-07-8).

[0012] The analgesic ropivacaine is a new, pure levorotatory, long-acting amide local anesthetic. It inhibits nerve impulse transmission by reducing sodium ion permeability in nerve cell membranes. Compared to bupivacaine, ropivacaine has gained widespread clinical application in recent years due to its lower lipophilicity and stereoselectivity. Its advantages of low cardiotoxicity, prolonged duration of action, and low neurotoxicity make it highly sought after. Clinically, ropivacaine is primarily used for surgical anesthesia, epidural anesthesia, postoperative analgesia, and 72-hour local or regional anesthesia during childbirth.

[0013] Ropivacaine, the pure S(-)-enantiomer of propivacaine, was synthesized in 1957, entered clinical trials in the United States in 1996, and was introduced to China in 1999. Currently, the predominant product on the market is imported ropivacaine hydrochloride injection, produced by Swedish pharmaceutical company AstraZeneca (Wuxi), under the trade name Naropine. This product holds a large share of the domestic market and is relatively expensive.

[0014] Based on the research model of compound analgesics, comparative documents have reported the combined use of ropivacaine and nonsteroidal anti-inflammatory drugs. CN104208698A discloses a compound patch of nonsteroidal anti-inflammatory drugs and ropivacaine, characterized by containing 2 to 6 parts by weight of ropivacaine per 1 part by weight of the nonsteroidal analgesic and anti-inflammatory drug, while also limiting the amount of the drug used in the preparation. Compared to topical patches, the use of subcutaneous injection to prepare a specific long-lasting release formulation has greater advantages and advancements in pain control. There is no literature on the interaction between diclofenac and ropivacaine.

[0015] Therefore, the technical problem solved by the present invention is to discover a diclofenac ropivacaine composition with amorphous characteristics, which has good stability and exhibits good long-term analgesic characteristics when injected subcutaneously. Summary of the Invention

[0016] The first object of the present invention is to provide a diclofenac-ropivacaine composition.

[0017] According to the present invention, the diclofenac and ropivacaine combination has the characteristics of a co-amorphous substance. The co-amorphous substance referred to in the present invention is sometimes also referred to as an amorphous substance. The English name for both is amorphous. In the present invention, it is referred to as "amorphous substance" for short.

[0018] According to the present invention, in the diclofenac and ropivacaine composition, when the molar ratio of diclofenac to ropivacaine is 1:8 to 5:1, a composition with amorphous characteristics can be formed.

[0019] The present invention provides a diclofenac and ropivacaine composition, characterized in that the diclofenac and ropivacaine composition is prepared from diclofenac (or diclofenac sodium, diclofenac potassium, diclofenac diethylamine, diclofenac epolamide) and ropivacaine free base or ropivacaine hydrochloride or ropivacaine methanesulfonate.

[0020] According to the present invention, in one embodiment, the diclofenac and ropivacaine composition has an XRD pattern substantially as shown in Figure 1. More preferably, the diclofenac and ropivacaine composition has an XRD pattern as shown in Figure 1.

[0021] According to the present invention, in one embodiment, the diclofenac and ropivacaine composition has substantially the following Figure 2 More preferably, the diclofenac and ropivacaine composition has the following DSC spectra: Figure 2 The DSC spectrum is shown.

[0022] According to the present invention, the infrared spectrum characteristic absorption peak position (cm -1 ) at 3188~3226, 1655~1686, 1502~1504, 1450~1451, 1373, 1093, 946, 768~769, 745.

[0023] According to the present invention, in a specific embodiment, the infrared spectrum absorption peak (cm -1 ±2cm -1 ) are 3234, 3015, 2958, 2936, 2872, 1686, 1663, 1577, 1559, 1504, 1470, 1451, 1374, 1306, 1286, 1235, 1197, 1045, 941, 768, 745, and 714.

[0024] According to the present invention, in another embodiment, the infrared spectrum absorption peak (cm -1 ±2cm -1 ) are: 3181, 3020, 2954, 2931, 2871, 1685, 1655, 1577, 1560, 1504, 1469, 1452, 1373, 1304, 1285, 1233, 1194, 1043, 945, 769, 745, 715.

[0025] In a preferred embodiment of the present invention, the diclofenac-ropivacaine composition has one or more of the following characteristics: Ⅰ. The X-ray powder diffraction pattern substantially conforms to that of FIG. 1; II. Basically in compliance Figure 2 Differential scanning calorimetry DSC spectrum; III. Basically in compliance Figure 3 Fourier transform infrared FT-IR spectrum.

[0026] Another object of the present invention is to provide a method for preparing the diclofenac and ropivacaine composition.

[0027] The present invention provides a preparation method of a diclofenac-ropivacaine composition, which comprises a solvent method, a coprecipitation method, a melting method and the like.

[0028] The invention provides a solvent method for preparing a diclofenac-ropivacaine composition, comprising the following steps: dissolving diclofenac or a salt thereof and ropivacaine or a salt thereof in a solvent to obtain a clear liquid, and then preparing the composition by adopting an appropriate method.

[0029] According to the present invention, after dissolving diclofenac or its salt and ropivacaine or its salt in a solvent, the method further comprises filtering the obtained solution.

[0030] According to the present invention, the process of dissolving diclofenac or its salt and ropivacaine or its salt in an organic solvent further includes steps such as stirring.

[0031] In the composition preparation method provided by the present invention, the organic solvent is selected from C1-6 alcohols, ketones and sulfones, and the C1-6 alcohols are preferably one or more of methanol, ethanol and tert-butanol; the ketones are selected from one or more of acetone, butanone and methyl isobutyl ketone; and the sulfones are selected from dimethyl sulfoxide.

[0032] The organic solvent provided by the present invention also includes a haloalkane, preferably one of dichloromethane and chloroform.

[0033] In a preferred embodiment of the present invention, the mass ratio of diclofenac or its salt to ropivacaine or its salt is 5:1 to 1:8.

[0034] The present invention provides an operation after diclofenac or its salt and ropivacaine or its salt are dissolved in a solvent, comprising performing reduced pressure evaporation, freeze drying or spray drying on the solution.

[0035] The preparation method of the diclofenac-ropivacaine composition provided by the present invention is characterized in that the solvent is removed under reduced pressure evaporation conditions using a rotary evaporator.

[0036] The reduced pressure evaporation conditions provided by the present invention are: temperature 20-50° C., preferably 25-45° C.; and pressure 10-100 mbar.

[0037] The present invention also provides a method for further drying under reduced pressure to prepare the diclofenac-ropivacaine composition.

[0038] The reduced pressure drying conditions provided by the present invention are a temperature of 20-60° C., a pressure of 10-100 mbar, and a drying time of 24-48 hours.

[0039] The preparation method of the diclofenac-ropivacaine composition provided by the present invention is characterized in that the freeze-drying method comprises the following steps: (1) dissolving diclofenac or its salt and ropivacaine or its salt in an appropriate amount of solvent to obtain a clear and transparent solution; (2) removing the solvent from step (1) by freeze drying under reduced pressure and low temperature conditions using a freeze dryer to obtain a diclofenac ropivacaine composition;

[0040] In step (1), the solvent suitable for lyophilization is tert-butanol or dioxane;

[0041] In step (2), the freeze-drying conditions are 0.1-15 mbar and -40-10° C. for 24-72 hours.

[0042] The present invention also provides a method for preparing a diclofenac-ropivacaine composition using a spray dryer. The spray drying conditions are as follows: the inlet temperature is set at 50-85°C, the vacuum is set at 70-100%, the pump speed is 5%-20%, and the cooling temperature is selected from -25°C to -15°C.

[0043] The present invention also provides a preparation method of the diclofenac-ropivacaine composition by a coprecipitation method.

[0044] The present invention provides a coprecipitation method for preparing a diclofenac-ropivacaine composition, which is characterized by the following steps: (1) Dissolving diclofenac sodium and ropivacaine hydrochloride in deionized water to prepare solutions; (2) mixing the diclofenac sodium solution prepared in step (1) with the ropivacaine hydrochloride solution; (3) Allow to react for 1 to 4 hours until precipitation is complete; (4) Filter the solid and dry it.

[0045] Steps (1) to (4) can be carried out at a temperature between 4°C and 80°C;

[0046] The diclofenac sodium described in step (1) may also be other salt forms, including but not limited to diclofenac potassium, diclofenac diethylamine, and diclofenac epolamide; ropivacaine hydrochloride may also be other salt forms, including but not limited to ropivacaine mesylate;

[0047] The concentrations of diclofenac and ropivacaine described in step (1) are 0.3 to 1 times of their respective saturated solubility at the operating temperature;

[0048] The reaction mode of step (3) is stirring, including magnetic stirring or mechanical stirring, etc., with a stirring speed of 30 to 2000 rpm and a holding time of 1 to 4 hours.

[0049] The drying method of step (4) is natural drying or reduced pressure drying, the drying temperature is 20-60° C., and the drying time is 12-72 hours. In addition, the freeze drying or spray drying mentioned above can also be used.

[0050] The present invention also provides a melting method for preparing a diclofenac-ropivacaine composition, which is characterized in that diclofenac and ropivacaine are mixed uniformly, heated to melt and stirred uniformly, and then quenched to reduce the temperature.

[0051] The invention provides a method for preparing a diclofenac-ropivacaine composition by melting, which is characterized in that the melting temperature is set at 180° C.-200° C.

[0052] The present invention also provides a method for preparing a diclofenac ropivacaine composition by grinding using a ball mill, the steps of which are as follows:

[0053] A diclofenac and ropivacaine composition was prepared using a mechanochemical method with controlled pressure and temperature, using a specific mass ratio of diclofenac and ropivacaine. The ball-to-solid ratio ranged from 1:1 to 10:1, the ball tank speed was set between 10 and 600 rpm, and the grinding time was 0.5 to 12 hours.

[0054] The diclofenac-ropivacaine composition disclosed in the present invention has different powder X-ray diffraction patterns, DSC patterns, and infrared spectra from those of diclofenac and its salts, and ropivacaine and its salts reported in existing literature. Therefore, the solid form is completely different from the form of diclofenac and its salts, and ropivacaine and its salts in the prior art.

[0055] Another object of the present invention is to provide a pharmaceutical composition comprising the diclofenac-ropivacaine composition of the present invention.

[0056] The pharmaceutical composition of the present invention further contains pharmaceutically acceptable excipients.

[0057] According to the present invention, the pharmaceutical composition can be prepared into a specific dosage form and administered via a suitable route, such as parenteral (including subcutaneous, intramuscular, intravenous, or intradermal), rectal, transdermal, nasal, and vaginal routes. Dosage forms suitable for parenteral administration include aqueous or non-aqueous sterile injection solutions, emulsions, or suspensions; dosage forms suitable for rectal administration include suppositories or enemas; dosage forms suitable for transdermal administration include ointments, creams, and patches; dosage forms suitable for nasal administration include aerosols, sprays, and nasal drops; and dosage forms suitable for vaginal administration include suppositories, plugs, gels, pastes, or sprays.

[0058] The pharmaceutical composition can be prepared using methods known in the art. In one embodiment of the present invention, the pharmaceutical composition is a suspension, which is prepared by dispersing the composition in a pharmaceutically acceptable excipient.

[0059] Another object of the present invention is to provide a use of the diclofenac-ropivacaine composition in the preparation of a medicament for treating or alleviating pain in patients with moderate or moderately severe pain.

[0060] The present invention also relates to a method for treating or alleviating pain in a patient suffering from moderate or moderately severe pain.

[0061] According to the present invention, the method comprises administering to a patient in need thereof a therapeutically effective amount of the diclofenac-ropivacaine composition of the present invention, or a pharmaceutical composition containing the diclofenac-ropivacaine composition of the present invention.

[0062] According to the present invention, the moderate or moderately severe pain is inflammatory pain, nociceptive pain, neuropathic pain or mixed pain.

[0063] According to the present invention, the moderate or moderate to severe pain includes but is not limited to: postoperative pain, inflammatory pain, bleeding pain, cancer pain, peripheral neuropathic pain (including but not limited to: back neuralgia, diabetic peripheral neuropathy, postherpetic neuralgia, etc.), central neuropathic pain (including but not limited to: central neuralgia after stroke, spinal cord injury, multiple sclerosis, neurological dysfunction pain, fibromyalgia syndrome, etc.), back pain with nerve damage, migraine, etc.

[0064] The composition of the present invention contains diclofenac and ropivacaine, which have different analgesic mechanisms. Their combined use can relieve moderate or moderately severe pain, especially treating or alleviating mixed pain of nociceptive pain and neuropathic pain. Furthermore, their combined use has a significant synergistic effect, significantly reducing the dosage of each active substance while achieving the same pharmacological effect and minimizing side effects.

[0065] The diclofenac-ropivacaine combination further provides advantages not possessed by the combined use of the two individual drugs, including: (1) Reduce the dose of each active drug to achieve the same efficacy and minimize side effects; (2) Improve the release characteristics compared with the parent drug and achieve sustained release; (3) Compared with the physical mixture of the parent drug, it has a longer-lasting analgesic effect. BRIEF DESCRIPTION OF THE DRAWINGS

[0066] Figure 1a Powder X-ray diffraction patterns of diclofenac and ropivacaine compositions (Examples 1-8);

[0067] Figure 1b Powder X-ray diffraction patterns of diclofenac and ropivacaine combinations (Examples 9-10).

[0068] Figure 2 Differential scanning calorimetry (DSC) spectrum of the combination of diclofenac and ropivacaine.

[0069] Figure 3Infrared spectra of diclofenac, ropivacaine, Example 9, and Example 10.

[0070] Figure 4a XRD pattern of the diclofenac and ropivacaine combination after 12 months at room temperature;

[0071] Figure 4b DSC graph of the diclofenac and ropivacaine composition after storage at room temperature for 12 months.

[0072] Figure 5 In vitro release curve of the combination of diclofenac and ropivacaine.

[0073] Figure 6 Diagram showing the analgesic effect of the combination of diclofenac and ropivacaine in animal experiments. DETAILED DESCRIPTION

[0074] The present invention is further described below with reference to the following examples. It should be noted that the examples are not intended to limit the scope of protection of the present invention, and those skilled in the art will understand that any improvements and variations based on the present invention are within the scope of protection of the present invention.

[0075] The conventional chemical reagents and raw materials used in the following examples are all commercially available.

[0076] In the following examples, the test methods were carried out according to conventional conditions or conditions recommended by the manufacturer.

[0077] The abbreviations used in the present invention are explained as follows: XRD: X-ray powder diffraction analysis DSC: Differential Scanning Calorimetry FT-IR: Fourier Transform Infrared Analysis

[0078] Experiment 1: Preparation and XRD analysis of diclofenac and ropivacaine combination

[0079] Example 1 1.0 g of diclofenac and 1.0 g of ropivacaine were weighed in a mass ratio of 1:1, placed in an eggplant-shaped flask, and an appropriate amount of anhydrous ethanol was added to dissolve the solution to prepare a solution. The solvent was removed by rotary evaporation under reduced pressure (vacuum degree of 100 mbar) in a 45°C water bath. The residue was collected and vacuum dried for 24 hours to obtain a diclofenac-ropivacaine composition.

[0080] Example 2 Weigh 1.0g of diclofenac potassium and dissolve it in 100ml of deionized water. Separately, dissolve 0.5g of ropivacaine mesylate in 100ml of deionized water. Thoroughly mix the two solutions, stir at 100rpm for 4 hours at ~25°C, and filter. Wash the filter cake four times with deionized water and air dry at 60°C for 12 hours to obtain a white solid powder, which is the diclofenac-ropivacaine combination.

[0081] Example 3 Weigh 1.0g of diclofenac epolamide and 3.0g of ropivacaine mesylate raw materials, add an appropriate amount of dichloromethane, and stir to dissolve. Spray dry the solution using a Buchi spray dryer (model B290) equipped with an inert gas recirculator (model B295) to produce a diclofenac-ropivacaine composite powder. Spray conditions were as follows: inlet temperature 50°C, aspirator ratio 100%, pump speed 20%, and cooling temperature -25°C.

[0082] Example 4 2.0 g of diclofenac sodium and 0.4 g of ropivacaine hydrochloride were weighed, an appropriate amount of tert-butyl alcohol was added, and the solution was shaken to dissolve the drugs and prepared. The solution was freeze-dried in a freeze dryer at 0.1 mbar and -20°C for 24 hours, and then returned to room temperature to obtain a diclofenac-ropivacaine composition powder.

[0083] Example 5 Weigh 1.0 g of diclofenac and 2.0 g of ropivacaine, grind them thoroughly, and heat them on a hot plate at 190°C for 1 minute to melt them. Remove the sample and place it on an aluminum plate for quenching to obtain a light yellow block product, which is then ground into powder.

[0084] Example 6 3.0 g of diclofenac diethylamine and 1.0 g of ropivacaine hydrochloride were weighed in a mass ratio of 3:1 and placed in an eggplant-shaped flask. An appropriate amount of acetone was added to dissolve the mixture to prepare a solution. The solvent was removed by rotary evaporation under reduced pressure (vacuum set to 10 mbar) in a 25°C water bath. The residue was collected and dried in vacuum for 24 hours to obtain a diclofenac-ropivacaine composition.

[0085] Example 7 Weigh 1.0g of diclofenac sodium and dissolve it in 100ml of deionized water. Separately, dissolve 6.0g of ropivacaine mesylate in 100ml of deionized water. Mix thoroughly, stir at ~80°C (30 rpm) for 1 hour, and filter. Wash the filter cake four times with deionized water and freeze-dry it in a freeze dryer at 15mbar and -40°C for 72 hours. After returning to room temperature, remove the dried sample to obtain the diclofenac-ropivacaine combination powder.

[0086] Example 8 1.0 g of diclofenac and 8.0 g of ropivacaine raw materials were weighed separately, and an appropriate amount of dimethyl sulfoxide was added to dissolve them to prepare a solution. The solution was dropped into deionized water, stirred continuously, allowed to stand, and filtered. The filter residue was washed 10 times with deionized water. The filter residue was transferred to a dryer box, the temperature was adjusted to 65° C., the vacuum degree was set to 100 mbar, and the vacuum pump was turned on for 12 hours to remove water and dry. To obtain a diclofenac-ropivacaine composition.

[0087] The X-ray powder diffraction patterns of the embodiments of this patent are collected on a MiniFlex X-ray powder diffractometer at a conventional temperature, such as 25°C. The X-ray powder diffraction method parameters are as follows: X-ray reflection parameters: Cu, Kα; wavelength: 1.5406 Å; tube voltage: 45 kV; tube current: 40 mA; step size: 0.01313°; scanning speed: 0.0416 ° / s; scanning range: from 3.0 to 45.0 degrees.

[0088] XRD was used to measure Examples 1-8 and the physical mixture, and the results are shown in FIG1 . The XRD spectrum of the diclofenac-ropivacaine composition has no sharp diffraction peak.

[0089] The contents of diclofenac and ropivacaine in the composition were determined by HPLC, and the molar ratio of diclofenac to ropivacaine was calculated. The results are shown in the following table: Example No. Molar ratio of diclofenac to ropivacaine Example 1 1.07:1 Example 2 1.43:1 Example 3 3.01:8 Example 4 5.04:1 Example 5 1:2.16 Example 6 3.35:1 Example 7 1:6.96 Example 8 1:8.61

[0090] The measurement results showed that the molar ratio of diclofenac to ropivacaine in the composition (Examples 1-8) ranged from 1:8.61 to 5.04:1.

[0091] Experiment 2: Characterization of structural parameters of diclofenac-ropivacaine composition

[0092] Example 9 1.0g of diclofenac and 0.5g of ropivacaine were weighed separately and placed in an eggplant-shaped flask. An appropriate amount of anhydrous ethanol was added to dissolve the mixture to form a solution. The solution was then spray-dried using a Buchi spray dryer to produce a diclofenac-ropivacaine composition powder. The spray conditions were as follows: inlet temperature 85°C, aspirator ratio 70%, pump speed 5%, and cooling temperature -15°C.

[0093] Example 10 Weigh 1.0g of diclofenac sodium and dissolve it in 100ml of deionized water. Separately, dissolve 1.0g of ropivacaine hydrochloride in 100ml of deionized water. Mix thoroughly, stir (2000 rpm) at ~4°C for 1 hour, and filter. Wash the filter cake four times with deionized water and dry it at approximately 20°C under reduced pressure (vacuum set to 10 mbar) for 48 hours to obtain a white solid powder, which is the diclofenac-ropivacaine combination.

[0094] The DSC graphs of the embodiments of this patent were collected on a DSC-500T differential scanning calorimeter. The parameters of the differential scanning calorimetry (DSC) analysis method are: mode: modulation mode; heating rate: 10°C / min.

[0095] The FTIR images of the present invention were collected on a Thermo Nicolet Nexus 470 Fourier transform infrared spectrometer. The parameters of the Fourier transform infrared method are: scanning range: 400-4000 cm -1 , Scan times: 16 times, Background scan: 16 times, Resolution 4 cm -1 .

[0096] The infrared spectrum absorption peak of Example 9 (cm -1 ) is 3226.62, 2957.20, 2165.11, 2114.38, 2050.56, 2012.73, 1971.98, 1686.06, 1663.30, 1577.51, 1559.22, 1503.99, 1451.36, 1373.90, 1304.03, 1233.99, 1195.37, 1150.00, 1093.70, 1044.66, 946.68, 866.79, 768.09, 745.13, and 714.68.

[0097] The infrared spectrum absorption peak of Example 10 (cm -1 ) is: 3188.16, 2955.13, 1686.04, 1655.11, 1577.87, 1560.83, 1503.87, 1451.63, 1373.09, 1304.05, 1234.29, 1194.78, 1150.01, 1094.06, 1044.50, 769.78, 745.51, 715.10.

[0098] The wave number of ropivacaine in the infrared spectrum is 1650.62 cm -1 and diclofenac in the infrared spectrum at 1691.30 cm -1 The peak positions of the carbonyl C=O stretching vibration peaks in the structure are shifted to 1686 cm after forming the composite.-1 (Example 9 and Example 10), 1663.30cm -1 (Example 9) and 1655.11cm -1 (Example 10). In addition, the wave number of the infrared spectrum of ropivacaine raw material is 3168.75 cm -1 The wave number of the infrared spectrum of diclofenac raw material is 3320.48cm -1 The peak positions of the stretching vibration peaks of NH (secondary amide) are shifted to 3226.62 cm after forming the composition. -1 (Example 9) and 3188.16cm -1 (Example 10) This indicates that after the composition is formed, the carbonyl group interacts with the secondary amide, and the secondary amide in the diclofenac and ropivacaine structures acts as a hydrogen bond donor, forming hydrogen bonds with the carbonyl oxygen in the structure.

[0099] Experiment 3: Stability Study of Diclofenac-Ropivacaine Compositions The diclofenac-ropivacaine compositions (Examples 9 and 10) were placed in the dark at room temperature for 12 months, and the crystal forms were detected by XRD. The results were as follows: Figure 5 The XRD pattern characteristics of the diclofenac-ropivacaine composition did not change significantly, indicating that the diclofenac-ropivacaine composition can be stably stored for at least 12 months without any change under long-term storage conditions, and the composition is stable.

[0100] The diclofenac-ropivacaine composition obtained by the present invention is placed at room temperature for 12 months without any crystal transformation, indicating that it has good stability and is suitable for drug production and storage.

[0101] Experiment 4: Determination of in vitro release

[0102] Appropriate amounts of Example 9 and Example 10 were placed in a flow cell, with the release medium being phosphate buffer (pH 7.4), the temperature being 37°C, and the flow rate being 2 ml / min. Appropriate amounts of the filtrate were collected at different times (with fresh release medium added). The concentrations of diclofenac and ropivacaine in the release solution were determined using HPLC, and the release percentages were calculated. A physical mixture of diclofenac sodium and ropivacaine hydrochloride was used as a control, and the flow cell release experiment was also conducted. Results (see Figure 2) Figure 5 As shown in FIG, Examples 9 and 10 exhibit more obvious slow release characteristics, while the physical mixture of diclofenac sodium and ropivacaine hydrochloride is rapidly released in the flow cell, reaching 100%. This result is beyond the expectations of those skilled in the art.

[0103] Experiment 5: Guinea Pig Skin Hill Test

[0104] Fifteen healthy male SPF guinea pigs weighing 250-300 g were selected. Two dermal papules were selected on the back of each guinea pig and injected with equal doses of microparticles ( n = 2), with the sample groups set to Example 9 and Example 10, and the control group to the physical mixture. The size of the pimple was marked. The skin within the pimple area was stimulated six times with a test needle in the order of left, middle, right, upper, middle, and lower, with an interval of 3-5 seconds between each stimulation. A positive response was considered a skin contraction. The number of positive responses at different times after administration was recorded, and the percentage of positive responses to the total number of tests was defined as the percentage of pain inhibition (% inhibition). This percentage was plotted on the y-axis, and the time since administration on the abscissa was plotted as the x-axis.

[0105] See the results Figure 6 All groups took effect within 30 minutes of injection. The local analgesic effect of the physical mixture lasted for 4 to 6 hours. In comparison, the local analgesic effect of Examples 9 and 10 lasted for 12 to 24 hours, significantly extending the analgesic effect and exerting unexpected efficacy.

[0106] The above embodiments are intended only to illustrate the technical concepts and features of the present invention. Their purpose is to enable those skilled in the art to understand the contents of the present invention and implement them accordingly. They are not intended to limit the scope of protection of the present invention. Any equivalent changes or modifications made in accordance with the spirit of the present invention are intended to be included in the scope of protection of the present invention.

Claims

1. An amorphous composition of diclofenac and ropivacaine, characterized in that The molar ratio of diclofenac to ropivacaine in the composition is 5:1 to 1:

8. The powder X-ray diffraction pattern has an XRD pattern as shown in FIG1 , in which no sharp diffraction peaks are present. The differential scanning calorimetry curve of the diclofenac-ropivacaine composition has a DSC pattern as shown in FIG2 .

2. The amorphous composition according to claim 1, wherein The diclofenac and ropivacaine composition is prepared from diclofenac or diclofenac sodium, diclofenac potassium, diclofenac diethylamine, diclofenac epolamide and ropivacaine free base or ropivacaine hydrochloride or ropivacaine methanesulfonate.

3. The amorphous composition according to claim 1, wherein The infrared spectrum characteristic absorption peak position of the amorphous substance (cm -1 )(±2cm -1 ) is characterized by the following peaks: 1655~1686,946.

4. The amorphous composition according to claim 3, wherein The infrared spectrum characteristic absorption peak position of the amorphous substance (cm -1 )(±2cm -1 ) is characterized by the following peaks: 3188~3226, 1655~1686, 1503, 1450, 1373, 1093, 946, 768, 745.

5. In the amorphous composition according to claim 1, the molar ratio of diclofenac to ropivacaine is preferably 1:6 to 3.3:1, more preferably 3:8 to 3.3:1, more preferably 1:2 to 1.4:1, more preferably 1:1 to 1.07:1, and more preferably 1:

1.

6. The method for preparing the diclofenac and ropivacaine amorphous composition according to claim 1, wherein: The composition is prepared by dissolving diclofenac or its salt and ropivacaine or its salt in a solvent to obtain a solution, and then performing one of the following steps: uniform mixing, filtering, evaporating under reduced pressure, spray drying, and freeze drying.

7. The method for preparing the diclofenac and ropivacaine amorphous composition as claimed in claim 6, wherein The mass ratio of diclofenac or diclofenac salt to ropivacaine base or ropivacaine salt is 5:1 to 1:8, preferably 3:1 to 1:6, more preferably 2:1 to 1:3, more preferably a molar ratio of 2:1 to 1:2, and more preferably 1:

1.

8. The preparation method of the diclofenac and ropivacaine composition as claimed in claim 6, wherein The solvent is selected from C1-5 alcohols, ketones, aqueous solutions and sulfones; the C1-6 alcohols are preferably one or more of methanol, ethanol and tert-butanol; the ketones are selected from one or more of acetone, butanone and methyl isobutyl ketone; the aqueous solution is selected from deionized water or buffered salt solution; and the sulfone is selected from dimethyl sulfoxide.

9. The preparation method of the diclofenac and ropivacaine composition as claimed in claim 6, wherein The solution reduced pressure evaporation method comprises the following steps: 1) Using a rotary evaporator, quickly remove the solvent under reduced pressure; 2) further drying under reduced pressure to obtain a diclofenac-ropivacaine composition; The reduced pressure evaporation conditions in step 1) are 20-50°C, preferably 25-45°C, and a pressure of 10-100 mbar; the reduced pressure drying conditions in step 2) are 10-100 mbar, 20-60°C, and drying for 24-48 hours; The present invention also provides a method for removing the solvent in step 1) by using a spray drying method; the spray drying conditions are: an inlet temperature of 50 to 90° C.; an exhaust fan of 70 to 100%, a pump of 5 to 20%, and a cooling temperature of -7 to -20° C.; The freeze drying method uses a freeze dryer to remove the solvent from the clear solution containing diclofenac and ropivacaine by freeze drying under reduced pressure and low temperature conditions to obtain a diclofenac-ropivacaine composition; the freeze drying conditions are 0.1-15 mbar and -40-10°C for 24-72 hours.

10. Use of the diclofenac and ropivacaine amorphous composition and a pharmaceutically acceptable carrier thereof as claimed in claim 1 in the preparation of a medicament for treating or alleviating pain in patients with moderate or moderately severe pain.

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