Tizanidine and meloxicam compound, preparation method therefor, and use thereof

Abstract

The present invention relates to a tizanidine and meloxicam compound. The compound features good stability, remarkable analgesic effect, and better bioavailability in humans. The present invention further relates to a preparation method for and use of the tizanidine and meloxicam compound.

Description

Tizanidine meloxicam complex, and preparation method and use thereof TECHNICAL FIELD

[0001] The present application belongs to the field of pharmaceutical chemistry, and particularly relates to a tizanidine or pharmaceutically acceptable salt thereof and meloxicam complex, and a preparation method and use thereof. BACKGROUND

[0002] Tizanidine is a central skeletal muscle relaxant with imidazoline structure, and is clinically used for treating skeletal muscle tension increase, muscle spasm and muscle rigidity caused by central injury and the like. Tizanidine can relieve spasticity, but does not cause muscle weakness, and the therapeutic dose does not produce psychological dependence, and is a central muscle relaxant with good tolerance and efficacy. At present, hydrochloride of tizanidine is used in clinical treatment. The chemical name of tizanidine is 5-chloro-4-[(2-imidazoline-2-yl)amino]-2,1,3-benzothiadiazole, and the structure is shown as formula I:

[0003] Meloxicam is a high-efficiency non-steroidal anti-inflammatory drug, and has strong anti-inflammatory, analgesic and antipyretic effects. Meloxicam can selectively inhibit the activity of cyclooxygenase-2 (COX-2), thereby blocking the synthesis of prostaglandin, and has stronger inhibitory effect on prostaglandin biosynthesis at the inflammation site than on the prostaglandin biosynthesis of the gastric mucosa or kidney, and is safer than other non-steroidal anti-inflammatory drugs, and is mainly used for relieving pain caused by rheumatoid arthritis, osteoarthritis and ankylosing spondylitis and the like. The chemical name of meloxicam is 2-methyl-4-hydroxy-N-(5-methyl-2-thiazolyl)-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide, and the structure is shown as formula II:

[0004] In some cases, drugs with different mechanisms of action can be combined to achieve the purpose of treatment. Generally, the combination of drugs is achieved by compound preparation, simultaneous administration of multiple drugs and the like.

[0005] Patent document WO 02 / 058620 A2 discloses that tizanidine and meloxicam are combined for use, and compared with single drugs, the combination has a synergistic therapeutic effect in treating pain and pain-related diseases.

[0006] The combined use of tizanidine and meloxicam can significantly reduce the ulcer formation effect induced by meloxicam (ulcer index, pH value and free / total acidity). Tizanidine may exert a gastroprotective effect by stimulating gastric and central α2 adrenaline receptors (Modulation of NSAID-induced antinociceptive and anti-inflammatory effects by α2-adrenoceptor agonists with gastroprotective effects, Life Sciences 70 (2002) 2857–2869).

[0007] Drug co-crystals are also a way to achieve combined drug applications, but the preparation of drug co-crystals is subject to many limitations.

[0008] A pharmaceutical cocrystal is a new solid form of a drug formed by hydrogen bonding or other non-covalent bonds between an active pharmaceutical ingredient (API) and a cocrystal former (CCF). A pharmaceutical cocrystal contains one or more active pharmaceutical ingredients.

[0009] Some successful cocrystal drugs offer advantages in terms of improved solubility, permeability, bioavailability, and stability. However, because these properties are often rare, and many active pharmaceutical ingredients are difficult to form cocrystals, cocrystals are not the preferred choice when studying drug combinations. In contrast, compound preparations and coadministration of multiple drugs are more common. Summary of the Invention

[0010] The inventors of the present invention have unexpectedly discovered through extensive research that the two active pharmaceutical ingredients of tizanidine and meloxicam can form a new substance, a complex, which has obvious advantages over the combined use of tizanidine hydrochloride and meloxicam and the use of meloxicam alone.

[0011] The object of the present invention is to provide a complex comprising tizanidine or a pharmaceutically acceptable salt thereof and meloxicam.

[0012] In the preferred technical solution of the present invention, the pharmaceutically acceptable salt of tizanidine comprises a salt formed by tizanidine and any acid selected from an inorganic acid or an organic acid.

[0013] In a preferred technical solution of the present invention, the inorganic acid is selected from hydrochloric acid, sulfuric acid, nitric acid or hydrobromic acid.

[0014] In the preferred technical solution of the present application, the organic acid is selected from formic acid, acetic acid, citric acid, fumaric acid, maleic acid, succinic acid or methanesulfonic acid.

[0015] In the preferred technical solution of the present application, the pharmaceutically acceptable salt of tizanidine is hydrochloric acid tizanidine.

[0016] In the preferred technical solution of the present application, the molar ratio of tizanidine or its pharmaceutically acceptable salt to meloxicam in the complex is 1:1.

[0017] In the preferred technical solution of the present application, the complex is composed of tizanidine and meloxicam.

[0018] In the preferred technical solution of the present application, the complex has the following structure:

[0019] In the preferred technical solution of the present application, the molar ratio of tizanidine to meloxicam in the complex is 1:1.

[0020] In the preferred technical solution of the present application, the complex is in solid form.

[0021] In the preferred technical solution of the present application, the melting point of the complex is 206-211℃.

[0022] Alternatively, the melting point of the complex is 207-210.5℃.

[0023] Alternatively, the melting point of the complex is 209.5-210.5℃.

[0024] In the preferred technical solution of the present application, the complex has characteristic peaks at the following 2θ angles in the powder X-ray diffraction spectrum: 7.77°, 9.55°, 14.10°, 15.15°, 20.90°, wherein the error range of each characteristic peak 2θ angle is ±0.2°.

[0025] In the preferred technical solution of the present application, the complex has characteristic peaks at the following 2θ angles in the powder X-ray diffraction spectrum: 7.77°, 9.55°, 11.14°, 14.10°, 15.15°, 16.65°, 20.40°, 20.90°, 23.04°, 24.60°, 24.90°, wherein the error range of each characteristic peak 2θ angle is ±0.2°.

[0026] In a preferred technical solution of the present invention, the powder X-ray diffraction pattern of the composite has characteristic peaks at the following 2θ angles: 7.77°, 9.55°, 11.14°, 13.59°, 14.10°, 15.15°, 16.65°, 18.03°, 18.54°, 20.10°, 20.40°, 20.90°, 22.00°, 23.04°, 23.84°, 24.60°, 24.90°, 26.20°, 27.39°, and 29.43°, wherein the error range of the 2θ angle of each characteristic peak is ±0.2°.

[0027] In a preferred technical solution of the present invention, the composite has a powder X-ray diffraction pattern substantially as shown in FIG1 .

[0028] In the preferred technical solution of the present invention, the composite has the following characteristic absorption peaks in the infrared spectrum: 3383.955 cm -1 、3164.282cm -1 、3052.242cm -1 、1655.767cm -1 、1590.711cm -1 、1327.631cm -1 、1165.408cm -1 、765.814cm -1 、571.561cm -1 , the wave number error is ±2cm -1 .

[0029] In the preferred technical solution of the present invention, the composite has the following characteristic absorption peaks in the infrared spectrum: 3383.955 cm -1 、3281.736cm -1 、3164.282cm -1 、3052.242cm -1 、2915.578cm -1 、1655.767cm -1 、1590.711cm -1 、1509.133cm -1 、1390.244cm -1 、1327.631cm -1 、1192.097cm -1 、1165.408cm -1 、1120.096cm -1 、947.173cm -1 、765.814cm -1 、571.561cm-1 Wave number error is ±2 cm -1 .

[0030] In the preferred technical solution of the present application, the complex has an infrared spectrum substantially as shown in Figure 2.

[0031] In the preferred technical solution of the present application, the crystallographic parameters of the complex are: orthorhombic system, space group: Pca21, cell parameters are: α = 90°, β = 90°, γ = 90°, cell volume is

[0032] In the preferred technical solution of the present application, the asymmetric unit diagram of the complex is shown in Figure 4.

[0033] In the preferred technical solution of the present application, the unit cell diagram of the complex is shown in Figure 5.

[0034] Another object of the present application is to provide a preparation method of a complex of tizanidine or a pharmaceutically acceptable salt thereof and meloxicam, the method comprising cooling crystallization or suspension crystallization.

[0035] In one technical solution of the present application, the cooling crystallization comprises the following operation steps: adding tizanidine or a pharmaceutically acceptable salt thereof and meloxicam into an organic solvent, heating under stirring condition to obtain a clear solution, cooling to crystallize, filtering, drying the filter cake, and preparing the complex.

[0036] In the preferred technical solution of the present application, the organic solvent is dimethyl sulfoxide and / or a ketone solvent.

[0037] In the preferred technical solution of the present application, the ketone solvent is acetone and / or 2-butanone, optionally, the ketone solvent is acetone.

[0038] In the preferred technical solution of the present application, the molar ratio of tizanidine or a pharmaceutically acceptable salt thereof to meloxicam is 1:1.

[0039] In the preferred technical solution of the present application, the mass volume ratio of the sum of the mass of tizanidine or a pharmaceutically acceptable salt thereof and meloxicam to the volume of the organic solvent is 1:10-100 g / mL, preferably the mass volume ratio is 1:15-90 g / mL, and further preferably the mass volume ratio is 1:23-83 g / mL.

[0040] In the preferred technical solution of the present application, the heating temperature is 45°C to reflux temperature.

[0041] In the preferred technical solution of the present application, the crystallization temperature is 0°C to room temperature, and preferably 5°C to room temperature.

[0042] In the preferred technical solution of the present application, the crystallization time is 1-24 hours, preferably 2-20 hours, more preferably 3-12 hours, and further preferably 3-5 hours.

[0043] In another technical solution of the present application, the suspension crystallization comprises the following operation steps: adding tizanidine or a pharmaceutically acceptable salt thereof and meloxicam into an organic solvent, reacting at room temperature under stirring, filtering, drying the filter cake, and obtaining the compound.

[0044] In the preferred technical solution of the present application, the organic solvent is dimethyl sulfoxide and / or a ketone solvent.

[0045] In the preferred technical solution of the present application, the ketone solvent is acetone and / or 2-butanone; optionally, the ketone solvent is acetone.

[0046] In the preferred technical solution of the present application, the molar ratio of tizanidine or a pharmaceutically acceptable salt thereof to meloxicam is 1:1.

[0047] In the preferred technical solution of the present application, the mass-volume ratio of the sum of the mass of tizanidine or a pharmaceutically acceptable salt thereof and meloxicam to the volume of the organic solvent is 1:5-50 g / mL, and preferably the mass-volume ratio is 1:10-30 g / mL.

[0048] In the preferred technical solution of the present application, the reaction time is 1-30 hours, and preferably 15-27 hours.

[0049] Another object of the present application is to provide a preparation method of a single crystal of a tizanidine or a pharmaceutically acceptable salt thereof and meloxicam compound, which comprises the following operation steps: adding tizanidine or a pharmaceutically acceptable salt thereof and meloxicam into an organic solvent, heating under stirring to obtain a clear solution, dispensing the solution, standing and cooling to room temperature for crystallization, and taking out the crystals.

[0050] In the preferred technical solution of the present application, the organic solvent is dimethyl sulfoxide and / or a ketone solvent.

[0051] In the preferred technical solution of the present application, the ketone solvent is acetone and / or 2-butanone; optionally, the ketone solvent is acetone.

[0052] In the preferred technical solution of the present application, the molar ratio of tizanidine or a pharmaceutically acceptable salt thereof to meloxicam is 1:1.

[0053] In the preferred technical solution of the present application, the mass-volume ratio of the sum of the tizanidine or its pharmaceutically acceptable salt and meloxicam to the organic solvent is 1:10-100 g / mL, preferably the mass-volume ratio is 1:15-90 g / mL, and further preferably the mass-volume ratio is 1:23-83 g / mL.

[0054] In the preferred technical solution of the present application, the temperature of the heating is 45-65℃, and preferably 50-55℃.

[0055] In the preferred technical solution of the present application, the solution is divided into 6-8 aliquots.

[0056] Another object of the present application is to provide a pharmaceutical composition comprising a complex of tizanidine or its pharmaceutically acceptable salt and meloxicam and a pharmaceutically acceptable excipient.

[0057] In the preferred technical solution of the present application, the pharmaceutically acceptable excipient is one or more selected from the group consisting of a filler, a disintegrant, a glidant, and a lubricant.

[0058] In the preferred technical solution of the present application, the pharmaceutical composition comprises 3-15% of the complex, 60-90% of the filler, 1-15% of the disintegrant, 0.1-5% of the glidant, and 0.1-5% of the lubricant by weight percentage.

[0059] In the preferred technical solution of the present application, the pharmaceutical composition comprises 5-10% of the complex, 80-90% of the filler, 1-5% of the disintegrant, 0.5-2% of the glidant, and 1-3% of the lubricant by weight percentage.

[0060] In the preferred technical solution of the present application, the pharmaceutical composition further comprises a coating material, and the coating material is a gastric-soluble film coating premix.

[0061] In the preferred technical solution of the present application, the filler is selected from the group consisting of any one or a combination of microcrystalline cellulose, anhydrous lactose, mannitol, calcium phosphate, and calcium carbonate.

[0062] In the preferred technical solution of the present application, the disintegrant is selected from the group consisting of any one or a combination of carboxymethyl cellulose, carboxymethyl cellulose calcium, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, cross-linked polyvinyl pyrrolidone, cross-linked sodium carboxymethyl cellulose, and alginic acid.

[0063] In the preferred technical solution of the present application, the glidant is any one or a combination of colloidal silicon dioxide and talc.

[0064] In the preferred technical solution of the present application, the lubricant is selected from any one or a combination of more of stearic acid, magnesium stearate, calcium stearate, glycerol behenate.

[0065] In the preferred technical solution of the present application, the dosage form of the pharmaceutical composition is a tablet, a capsule, a pill, a granule, or a powder.

[0066] Another object of the present application is to provide a use of the tizanidine or a pharmaceutically acceptable salt thereof and the meloxicam complex or the pharmaceutical composition in the preparation of a medicament for treating or relieving pain.

[0067] In another aspect of the present application, a method for treating or relieving pain is provided, which comprises administering to a patient in need thereof an effective amount of the tizanidine or a pharmaceutically acceptable salt thereof and the meloxicam complex or the pharmaceutical composition for treating or relieving the pain.

[0068] In another aspect of the present application, a tizanidine or a pharmaceutically acceptable salt thereof and a meloxicam complex or a pharmaceutical composition are provided for treating or relieving pain.

[0069] In the preferred technical solution of the present application, the pain is selected from traumatic pain, pathological pain, neuropathic pain, or pain caused by a combination of factors.

[0070] In the preferred technical solution of the present application, the traumatic pain refers to a history of mechanical or physical trauma, including acute postoperative pain.

[0071] In the preferred technical solution of the present application, the pathological pain is selected from inflammatory pain, such as periarthritis of shoulder, arthritis, and fibromyalgia.

[0072] In the preferred technical solution of the present application, the arthritis is rheumatoid arthritis, osteoarthritis, or ankylosing spondylitis.

[0073] In the preferred technical solution of the present application, the neuropathic pain is trigeminal neuralgia.

[0074] In the preferred technical solution of the present application, the pain caused by a combination of factors is selected from headache (such as migraine and tension headache), oromaxillofacial pain (such as dental pain), occipital pain (such as cervical myofascial pain), neck and shoulder pain (such as cervical shoulder syndrome), upper limb pain (such as lateral epicondylitis), chest and back pain (such as scapular medial bursitis), and waist and leg pain (such as lumbar muscle strain).

[0075] Compared with the prior art, the present application has the following beneficial technical effects:

[0076] The present application first provides a tizanidine or a pharmaceutically acceptable salt thereof and a meloxicam complex, which has a stable crystal form and does not change in crystal form during long-term storage.

[0077] The complex of tizanidine or a pharmaceutically acceptable salt thereof and meloxicam provided by the present application has excellent chemical stability and is suitable for long-term storage.

[0078] The complex of tizanidine or a pharmaceutically acceptable salt thereof and meloxicam provided by the present application can significantly prolong the analgesic time and has more persistent analgesic effect compared with the combination of tizanidine hydrochloride and meloxicam or the administration of meloxicam alone.

[0079] The complex of tizanidine or a pharmaceutically acceptable salt thereof and meloxicam provided by the present application has a lower incidence of adverse reactions in the digestive tract.

[0080] The complex of tizanidine or a pharmaceutically acceptable salt thereof and meloxicam provided by the present application has more excellent bioavailability in human body.

[0081] The preparation method of the complex of tizanidine or a pharmaceutically acceptable salt thereof and meloxicam provided by the present application has simple preparation process, short reaction time, high yield, good reproducibility and is suitable for industrial production.

[0082] Unless otherwise indicated, the scientific and technical terms used herein have the meanings that would be generally understood by one of ordinary skill in the art. For better understanding of the present application, the definitions and explanations of relevant terms are provided below.

[0083] The term "complex" as used herein refers to a chemical substance that contains covalent bonds within and between the two pharmaceutically active ingredients and non-covalent interactions or non-covalent bonds (such as van der Waals forces, hydrogen bonds, ionic bonds) between the two pharmaceutically active ingredients. These non-covalent bonds allow the ingredients present in the complex to bind to each other, and this binding makes the complex different from the physical mixture of these ingredients.

[0084] The term "room temperature" as used herein refers to a temperature from 10℃ to 35℃, for example 10℃, 15℃, 20℃, 25℃, 30℃ or 35℃.

[0085] The term "reflux temperature" as used herein refers to the temperature at which the solvent or solvent system is refluxed or boiled.

[0086] The term "PXRD" as used herein refers to powder X-ray diffraction. Powder X-ray diffraction technology can be used for analysis of substance state, substance composition, crystal form state, crystal form purity, etc. and is a commonly used means for identifying crystal forms.

[0087] It is understood by one of ordinary skill in the art that the position of the diffraction peaks (2Θ) of a PXRD pattern is primarily dependent on the structure of the crystalline form and is relatively insensitive to experimental details, while the peak height, peak shape, or peak area is dependent on many factors related to sample preparation, orientation of placement, and instrument measurement conditions. Therefore, in some embodiments, the crystalline form of the compound of the present application is characterized by a PXRD pattern having certain 2Θ angles substantially as shown in the PXRD patterns provided in the figures of the present application. Meanwhile, the peak height (absolute and relative), peak shape, peak area, and 2Θ measurement can vary slightly between different instruments and different samples, and therefore the values of the relevant measurements are not to be considered absolute. In the present application, the error range of the 2Θ angles is ±0.2°.

[0088] In the PXRD pattern of a formulation or final product made from the compound of the present application, due to interference factors such as excipients, the characteristic peaks of the compound of the present application in terms of 2Θ angles can be one or several, such as the peak height (absolute and relative), peak shape, peak area, and 2Θ measurement at 7.77°, 11.14°, 14.10°, or 15.15°.

[0089] The term "IR" as used herein refers to infrared spectroscopy.

[0090] The term "SCXRD" as used herein refers to single crystal X-ray diffraction.

[0091] The term "pharmaceutically acceptable excipient" as used herein refers to a substance that is reasonably evaluated in terms of safety in the production of pharmaceutical products and the dispensing of prescriptions, and is included in pharmaceutical preparations in addition to the active ingredient. In addition to excipients, carriers, and / or improving stability, pharmaceutical excipients can also have important functions such as solubilization, cosolubilization, sustained release, and controlled release, and are important ingredients that can affect the quality, safety, and effectiveness of pharmaceutical products. According to their sources, pharmaceutical excipients can be divided into natural products, semi-synthetic products, and synthetic products. According to their functions and uses, pharmaceutical excipients can be divided into carriers, excipients, solvents, propellants, solubilizers, cosolvents, emulsifiers, colorants, binders, disintegrants, fillers, lubricants, humectants, osmotic pressure regulators, stabilizers, flow aids, flavorings, preservatives, suspending agents, coating materials, fragrances, anti-adhesion agents, antioxidants, chelating agents, penetration enhancers, pH regulators, buffers, plasticizers, surfactants, foaming agents, antifoaming agents, thickeners, inclusion agents, humectants, absorbents, diluents, flocculants and deflocculants, filtration aids, release retardants, and the like. The same pharmaceutical excipient can be used in pharmaceutical preparations for different administration routes, and can have different functions and uses. BRIEF DESCRIPTION OF DRAWINGS

[0092] Figure 1 is a powder X-ray diffraction (PXRD) pattern of the tizanidine meloxicam compound prepared in Example 1.

[0093] Figure 2 is an infrared spectrum (IR) of the tizanidine meloxicam complex prepared in Example 1.

[0094] Figure 3 is a powder X-ray diffraction (PXRD) comparison of the tizanidine meloxicam complex prepared in Example 1 with tizanidine and meloxicam.

[0095] Figure 4 is an asymmetric unit diagram of the tizanidine meloxicam complex prepared in Example 4.

[0096] Figure 5 is a unit cell diagram of the tizanidine meloxicam complex prepared in Example 4.

[0097] Figure 6 is a calculated powder X-ray diffraction (PXRD) pattern of the tizanidine meloxicam complex prepared in Example 4.

[0098] Figure 7 is a powder X-ray diffraction (PXRD) comparison of the tizanidine meloxicam complex in the long-term stability experiment in Example 5.

[0099] Figure 8 is a powder X-ray diffraction (PXRD) comparison of the tizanidine meloxicam complex in the accelerated stability experiment in Example 5.

[0100] Figure 9 is a bar graph of the results of the rat peri-orbital mechanical pain threshold in the efficacy study in Example 7. DETAILED DESCRIPTION

[0101] The above description of the present application is further illustrated by the following specific examples, which should not be construed as limiting the subject matter of the present application. Any technical solution realized based on the above description of the present application falls within the scope of the present application.

[0102] Instruments and Test Conditions

[0103] Powder X-ray Diffraction (PXRD)

[0104] Instrument: Powder X-ray diffractometer

[0105] Test Conditions:

[0106] Infrared Spectroscopy (IR)

[0107] Instrument: Infrared spectrometer (Model: Thermo Scientific Nicolet Summit LITE)

[0108] Sample Preparation Method: Potassium bromide tabletting

[0109] Single Crystal X-ray Diffraction (SCXRD)

[0110] Instrument: single crystal X-ray diffractometer.

[0111] Melting point detection

[0112] Instrument: melting point apparatus (model: YRT-3)

[0113] Test method: Take the appropriate amount of the complex, grind into fine powder, dry at 105°C to constant weight, then refer to Chinese Pharmacopoeia 2020 edition general 0612 first method for determination, the heating rate is 3°C per minute. Acceptable error range: ± 1.0°C.

[0114] Example 1 Preparation of tizanidine meloxicam complex

[0115] Weigh 12.70 g of tizanidine and 17.70 g of meloxicam into a reaction bottle, add 2500 mL of acetone, and heat to reflux temperature 57°C under stirring condition to obtain a clear solution. The solution is cooled to room temperature 25°C for 5 hours to crystallize. Filter under reduced pressure, and dry the filter cake at 45°C under reduced pressure for 3 hours to obtain 19.03 g of tizanidine meloxicam complex.

[0116] The melting point of the complex is measured by a melting point apparatus to be 207-210.5°C.

[0117] The powder X-ray diffraction (PXRD) results of the obtained complex are shown in Table 1 and Figure 1, and the infrared spectrum (IR) is shown in Figure 2.

[0118] The powder X-ray diffraction comparison chart of the obtained complex with tizanidine and meloxicam is shown in Figure 3 (from top to bottom: tizanidine, tizanidine meloxicam complex, meloxicam). As can be seen from Figure 3, the powder X-ray diffraction comparison chart of the tizanidine meloxicam complex with tizanidine and meloxicam has obvious differences in the number of diffraction peaks, the position of diffraction peaks, and the intensity of diffraction peaks, etc., indicating that the obtained complex is not a physical mixture of tizanidine and meloxicam. For example, in the powder X-ray diffraction comparison chart, the complex has characteristic peaks different from tizanidine and meloxicam at 7.77°, 9.55°, 14.10°, 15.15°, and 20.90°.

[0119] Table 1

[0120] There can be an error range of ± 0.2° in the position of diffraction peaks (2θ).

[0121] Example 2 Preparation of tizanidine meloxicam complex

[0122] Take 60.03 g of tizanidine and 83.17 g of meloxicam into a reaction bottle, add 1440 mL of acetone, and react at room temperature of 25°C for 22 hours under stirring condition, filter under reduced pressure, dry the filter cake at 45°C under reduced pressure for 3 hours, and obtain 132.67 g of tizanidine-meloxicam complex.

[0123] The melting point of the complex is measured by a melting point apparatus to be 209.5-210.5°C.

[0124] The crystal form of the obtained complex is consistent with that of Example 1.

[0125] Example 3 Preparation of tizanidine-meloxicam complex

[0126] Take 0.7611 g of tizanidine and 1.0578 g of meloxicam into a reaction bottle, add 40 mL of acetone and 2.5 mL of dimethyl sulfoxide, and react at 50°C for 1 hour under stirring condition to obtain a clear solution, cool the solution to 5°C for crystallization for 1 hour, filter under reduced pressure, and dry the filter cake at 50°C under reduced pressure for 8 hours to obtain 1.146 g of tizanidine-meloxicam complex. The crystal form of the obtained complex is consistent with that of Example 1.

[0127] The researchers of the present application have tried various solvent systems to prepare tizanidine-meloxicam complex, but none of them has obtained the target complex (see Comparative Examples 1-4).

[0128] Comparative Example 1

[0129] Take 0.25 g of tizanidine and 0.35 g of meloxicam into a reaction bottle, add 40 mL of methanol, and react at 50°C under stirring condition to obtain a clear solution, cool the solution to 5°C for crystallization for 12 hours, filter under reduced pressure, and dry the filter cake at 50°C under reduced pressure for 10 hours to obtain a solid.

[0130] The obtained solid is a tizanidine-meloxicam-methanol solvate.

[0131] Comparative Example 2

[0132] Take 0.25 g of tizanidine and 0.35 g of meloxicam into a reaction bottle, add 40 mL of acetonitrile, and react at 50°C under stirring condition to obtain a clear solution, cool the solution to 5°C for crystallization for 12 hours, filter under reduced pressure, and dry the filter cake at 50°C under reduced pressure for 10 hours to obtain a solid.

[0133] The obtained solid is a tizanidine-meloxicam-acetonitrile solvate.

[0134] Comparative Example 3

[0135] Take 0.25 g of tizanidine and 0.35 g of meloxicam into a reaction bottle, add 40 mL of N,N-dimethylformamide, and heat to 50°C under stirring to obtain a clear solution. The solution is cooled to 5°C for 12 hours to crystallize. The filter cake is dried at 50°C under reduced pressure for 10 hours to obtain a solid.

[0136] The obtained solid is a tizanidine-meloxicam-N,N-dimethylformamide solvate.

[0137] Comparative Example 4

[0138] Take 0.25 g of tizanidine and 0.35 g of meloxicam into a reaction bottle, add 40 mL of dichloromethane, and heat to 40°C under stirring to obtain a clear solution. The solution is cooled to 5°C for 12 hours to crystallize. The filter cake is dried at 40°C under reduced pressure for 10 hours to obtain a solid.

[0139] The obtained solid is a physical mixture of tizanidine-dichloromethane solvate and meloxicam.

[0140] Example 4 Single crystal preparation of tizanidine-meloxicam complex

[0141] Take 0.2537 g of tizanidine and 0.3526 g of meloxicam into a reaction bottle, add 50 mL of acetone, and heat to 50°C under stirring for 1 hour to obtain a clear solution. The clear hot solution is divided into 10 mL test tubes in 7 equal portions. The test tubes are properly sealed to reduce the solvent evaporation rate. The crystals are obtained by standing at room temperature until the crystals precipitate.

[0142] The single crystal data of the obtained tizanidine-meloxicam complex are shown in Table 2. The schematic diagram of the asymmetric unit is shown in Figure 4, and the schematic diagram of the unit cell is shown in Figure 5. The main crystallographic parameters of the complex are as follows: orthorhombic crystal system, space group: Pca21, cell parameters: α = 90°, β = 90°, γ = 90°, cell volume

[0143] The calculated powder X-ray diffraction (PXRD) pattern of the complex is shown in Figure 6, which is basically consistent with the powder X-ray diffraction pattern of the tizanidine-meloxicam complex in Example 1 (Figure 1).

[0144] Table 2

[0145] Example 5 Stability experiment of tizanidine-meloxicam complex

[0146] 1. Long-term stability experiment

[0147] Experimental operation: the tizanidine meloxicam compound prepared in Example 1 of the present application was placed in the condition of 25±2℃, relative humidity 60±10% for 6 months, and samples were taken in the 1st month, 3rd month and 6th month for powder X-ray diffraction detection, and compared with the crystal form of 0 day.

[0148] Results: the powder X-ray diffraction comparison chart is shown in Figure 7 (from bottom to top, 0 day, 1 month, 3 months, 6 months respectively). As can be seen from Figure 7, the crystal form of the tizanidine meloxicam compound prepared in the present application does not change after 6 months, and the crystal form has good stability.

[0149] 2. Accelerated stability experiment

[0150] Experimental operation: the tizanidine meloxicam compound prepared in Example 1 of the present application was placed in the condition of 40±2℃, relative humidity 75±5% for 6 weeks, and samples were taken in the 1st week, 2nd week, 3rd week, 4th week and 6th week for powder X-ray diffraction detection, and compared with the crystal form of 0 day.

[0151] Results: the powder X-ray diffraction comparison chart is shown in Figure 8 (from bottom to top, 0 day, 1 week, 2 weeks, 3 weeks, 4 weeks, 6 weeks respectively). As can be seen from Figure 8, the crystal form of the tizanidine meloxicam compound prepared in the present application does not change after 6 weeks under the accelerated experimental conditions, and the crystal form has good stability.

[0152] 3. Influence factor experiment

[0153] Experimental operation: the tizanidine meloxicam compound prepared in Example 1 of the present application, the physical mixture of tizanidine and meloxicam, tizanidine hydrochloride and meloxicam were placed in different conditions to investigate their stability. The investigation conditions: high temperature (60℃); light (4500lx±500lx); high humidity (25℃, relative humidity 92.5%).

[0154] The impurity detection was carried out according to the method of <0512 High Performance Liquid Chromatography> in Chinese Pharmacopoeia (2020 edition) Vol. 4 General Rules. The chromatographic conditions were as follows: octadecylsilane bonded silica gel as the filler (Kromasil 100-5-C18, 4.6×250mm, 5μm or a chromatographic column with equivalent performance); 20mmol / L potassium dihydrogen phosphate solution (containing 1% triethylamine, and the pH was adjusted to 7.0 with phosphoric acid) as mobile phase A, and acetonitrile as mobile phase B; gradient elution was carried out; the flow rate was 1mL per minute; the column temperature was 45℃; the detection wavelength was 230nm, 260nm and 350nm; the injection volume was 30μL.

[0155] Gradient elution program:

[0156] The experimental results are shown in Table 3.

[0157] Table 3 influence factor experiment results

[0158] In Table 3, the total amount of impurities refers to the total amount of the content of all impurities in each sample detected under the above chromatographic conditions.

[0159] As shown in Table 3, the total amount of impurities of the tizanidine meloxicam compound is basically unchanged under the conditions of light, high temperature and high humidity, while the number of impurities and the total amount of impurities of the tizanidine meloxicam physical mixture and meloxicam increase to different degrees under the conditions of light and high temperature. Among them, the number of impurities and the total amount of impurities of the tizanidine meloxicam physical mixture increase more obviously, the number of impurities increases by 2 and 6 respectively under the conditions of light and high temperature, and the total amount of impurities increases by 0.018% and 0.076% respectively. The results show that the stability of the tizanidine meloxicam compound prepared by the present application is better than that of meloxicam and also better than that of the physical mixture of meloxicam and tizanidine, and has good stability.

[0160] Example 6 Preparation of tizanidine meloxicam compound tablets

[0161] Table 4 prescription table

[0162] The powder mixing direct compression tablet process is adopted:

[0163] (1) dispersion: disperse the prescription amount of tizanidine meloxicam compound and microcrystalline cellulose, continue to disperse after adding anhydrous lactose, and continue to disperse after adding colloidal silicon dioxide and sodium carboxymethyl starch, to obtain the dispersed material;

[0164] (2) total mixing: add stearic acid to the dispersed material and mix uniformly;

[0165] (3) tabletting and coating: tablet and coat the total mixed material, and the tizanidine meloxicam compound tablets are obtained.

[0166] Example 7 Pharmacodynamic study of tizanidine meloxicam compound on nitroglycerin-induced SD rat migraine model

[0167] Test drugs: tizanidine meloxicam compound (prepared in Example 1), mixed drug of tizanidine hydrochloride and meloxicam, and meloxicam.

[0168] Experimental animals: SPF level SD rats, male, purchased from Chengdu Yakang Biotechnology Co., Ltd. The animal breeding environment is 20℃-26℃, relative humidity 40%-70%, and artificial lighting during the feeding process is 12 hours of day-night rhythm. The rats were adaptively fed for 1 week before the experiment, and free water and food were provided.

[0169] Grouping information: blank control group, model group, low-dose tizanidine and meloxicam compound group, medium-dose tizanidine and meloxicam compound group, high-dose tizanidine and meloxicam compound group, tizanidine hydrochloride and meloxicam mixed drug group, meloxicam group.

[0170] Model establishment: after the animals were adapted for 1 week, the baseline of the mechanical pain threshold of the rats was detected, and the rats were randomly grouped according to the mechanical pain threshold. Except for the blank control group, the remaining groups were subcutaneously injected with nitroglycerin (10 mg / kg; 5 mg / mL of nitroglycerin was diluted to the required concentration with normal saline) every other day (Day 1, Day 3, Day 5, Day 7). About 30 minutes after each modeling, the animals showed phenomena such as red ears, frequent head scratching of the forelimbs, increased climbing cage times, and restlessness, indicating that the model was successfully established.

[0171] Dosing regimen: 1 hour after injection of nitroglycerin on Day 1, the model rats were screened for dosing, with 14 rats in each group (12 rats in the blank control group), and each group was given intragastric administration once a day for 7 consecutive days (immediately after injection of nitroglycerin on Day 3, Day 5, and Day 7). The compound group, the mixed drug group, and the meloxicam group all used corn oil as the solvent. The compound low-, medium-, and high-dose groups were given doses of 0.35 mg / kg, 1.4 mg / kg, and 5.6 mg / kg, respectively. The mixed drug group was given a dose of 1.4 mg / kg (containing 0.587 mg / kg of tizanidine and 0.813 mg / kg of meloxicam). The meloxicam group was given a dose of 0.813 mg / kg. The blank group and the model group were given intragastric administration of the same volume of solvent (corn oil) every day, with a volume of 2.5 mL / kg.

[0172] The dose of tizanidine hydrochloride in the mixed drug group was 0.587 mg / kg, calculated as tizanidine.

[0173] Detection: 1 hour and 6 hours after administration on Day 7 (Day 7), the orbital mechanical pain threshold of the rats was detected.

[0174] Statistical analysis: IBM SPSS Statistics 26.0 software was used for data statistical analysis, all measurement data were expressed as Mean ± SEM, and Graph Pad Prism 8 software was used for plotting.

[0175] Firstly, normality test is performed on the data. If P≤0.05, it is considered that the data does not obey normal distribution; if P>0.05, it is considered that the data obeys normal distribution. For the data obeying normal distribution, Levene's test is used for variance homogeneity test. When the variance is homogeneous (P>0.05), single factor analysis of variance (ANOVA) is used for statistical test. If statistically significant (P≤0.05), LSD test is used for comparison of differences between groups; if statistically insignificant (P>0.05), statistical analysis is ended. When the normality distribution is not met or the variance is not homogeneous (P≤0.05), Kruskal-Wallis H rank sum test (K-W method) is used for statistical analysis. If statistically significant (P≤0.05), Mann-Whitney U test (M-W method) is used for comparison of differences between groups; if statistically insignificant (P>0.05), statistical analysis is ended.

[0176] The experimental results are shown in Table 5 and Figure 9.

[0177] Table 5 Mechanical pain threshold (g) of rats around the orbit Note: Compared with the blank control group: ### P<0.001; compared with the model group: ** P<0.01, *** P<0.001; compared with the compound middle dose group: $ P<0.05, $$ P<0.01.

[0178] As shown in Table 5 and Figure 9, the compound dose groups, the mixed drug group and the meloxicam group all showed analgesic effect, and had significant difference compared with the model group. The analgesic effect of the compound has dose correlation, and the mechanical pain threshold of the high dose group of the compound increased to the level of the blank control group. Six hours after administration on Day 7, the analgesic effect of the tizanidine meloxicam compound dose groups was still equivalent to that after 1 hour of administration, while the therapeutic effect of the mixed drug group and the meloxicam group decreased. At the same dose level, the analgesic effect of the tizanidine meloxicam compound was better than that of the mixed drug group and the meloxicam group after 6 hours of administration, and had significant difference. It is suggested that in the nitroglycerin-induced SD rat migraine model, the tizanidine meloxicam compound has longer analgesic time and more persistent analgesic effect than the combination of tizanidine hydrochloride and meloxicam and the administration of meloxicam alone.

[0179] Example 8 Animal pharmacokinetic test and clinical observation of tizanidine meloxicam compound

[0180] Test drugs: tizanidine meloxicam compound (prepared in Example 1), mixed drug of tizanidine hydrochloride and meloxicam, and meloxicam.

[0181] Experimental animals: 16 male beagles from Suzhou Xishan Zhongke Experimental Animal Co., Ltd. Animal feeding environment: general level animal room, day and night alternating time: 12h / 12h, minimum ventilation frequency: ≥8 times / h, temperature: 16-26℃, relative humidity 40-70%.

[0182] Test design:

[0183] 16 male beagles, weighed 2 days before administration, divided into 4 groups, 4 per group, respectively administered with different drugs (loaded into empty capsules for administration). Fasting: at least 12h before administration, and resume diet 4h after administration; water: freely taken. The administration information is shown in Table 6:

[0184] Table 6 * The dose of tizanidine hydrochloride is calculated based on tizanidine.

[0185] PK sampling time points: 0h before administration, 0.25h, 0.5h, 1h, 2h, 3h, 4h, 6h, 8h, 12h, 24h, 48h after administration. Analysis of biological samples:

[0186] LC-MS / MS method was used to quantitatively detect the concentrations of tizanidine and meloxicam in beagle dog plasma samples.

[0187] Data processing and statistical analysis:

[0188] The original data obtained in the experiment were fitted to obtain the standard curve equation and correlation coefficient by instrument software, and the drug concentrations in the biological samples at each sampling time point and the concentrations of the accompanying quality control samples were calculated. The original concentration data were statistically analyzed, including mean (Mean), standard deviation (SD) and coefficient of variation (CV%); the drug concentration and time data in the samples were calculated for pharmacokinetic parameters by WinNonLin software (version 8.3) according to the non-compartment model method (NCA).

[0189] The results show that there is no statistical difference in the pharmacokinetic parameters of tizanidine and meloxicam in the plasma of beagles between the tizanidine-meloxicam compound group and the mixed drug group or the single administration group at the same dose. By observing and recording the clinical symptoms of beagles during the entire experimental process, it was found that vomiting occurred in the meloxicam group and the mixed drug group during the 48-hour observation period after administration, and the incidence rates of vomiting were 50% (2 cases) and 25% (1 case), respectively, while no vomiting occurred in the low-dose and high-dose tizanidine-meloxicam compound groups during the 48-hour observation period after administration. It is proved that the tizanidine-meloxicam compound of the present application has a lower incidence rate of digestive tract adverse reactions.

[0190] Example 9 Human pharmacokinetic trial of the tizanidine meloxicam combination

[0191] Test samples:

[0192] A, tizanidine meloxicam combination tablets (4.82 mg / 6.68 mg) prepared in Example 6;

[0193] B, Tizanidine hydrochloride 4 mg tablets + Mobicox Meloxicam 7.5 mg tablets;

[0194] C, Tizanidine hydrochloride 4 mg tablets;

[0195] D, Meloxicam 7.5 mg tablets.

[0196] This trial was conducted in 28 healthy adult subjects under fasting conditions, using a single-dose, randomized, open, three-formulation, four-period, four-sequence, four- crossover trial design.

[0197] The washout period between periods was 10 days, subjects fasted for at least 10 hours before dosing, and were prohibited from drinking water (except for 240 ± 2 mL of water during the dosing period) one hour before dosing and one hour after dosing; subjects were prohibited from consuming foods or beverages containing caffeine and / or xanthine (e.g., coffee, tea, and sodas containing caffeine, cola, etc.), cigarettes and tobacco products, and recreational drugs, for 48 hours prior to each period and throughout the trial. Subjects were required to avoid unusual diets (e.g., low- sodium / high-sodium diets, prolonged fasting, single-diet) for at least 21 days prior to enrollment and throughout the trial. Subjects were required to avoid the ingestion of alcohol and its products, grapefruit and its juice, and foods containing poppy components, for at least 72 hours prior to each period and throughout the study.

[0198] Dosing method:

[0199] The subjects remained in a sitting position, the test drug was placed in the subject's mouth, and 240 ± 2 mL of water was consumed to swallow it whole (the subjects were not allowed to chew, crush, or divide the tablets), and the subjects remained in a semi-recumbent position for 4 hours after dosing.

[0200] During each cycle, 3 mL blood samples were collected from subjects before dosing (0.00 h) and at 0.25 h, 0.50 h, 0.75 h, 1.00 h, 1.33 h, 1.67 h, 2.00 h, 2.50 h, 3.00 h, 3.50 h, 4.00 h, 4.50 h, 5.00 h, 5.50 h, 6.00 h, 6.50 h, 7.00 h, 8.00 h, 10.00 h, 12.00 h, 16.00 h, 24.00 h, 36.00 h, 48.00 h, 72.00 h, and 96.00 h after dosing. Relevant pharmacokinetic parameters were calculated.

[0201] C max Peak concentration is the maximum blood drug concentration measured.

[0202] AUC 0-t Calculation is performed using the linear trapezoidal method.

[0203] AUC 0-∞ =AUC 0-t +C t / Kel , t is the sampling time of the last measurable blood drug concentration; C t is the last measurable drug concentration of the sample, K el is the elimination rate constant.

[0204] Test results:

[0205] The test results are shown in Tables 7 to 9. The data in the tables are dose-corrected.

[0206] Table 7 A vs B human pharmacokinetic test results (for tizanidine)

[0207] For tizanidine, the tizanidine-meloxicam complex has a similar C max , while AUC(AUC 0-t , AUC 0-∞ ) is higher (about 8% higher), which means that the tizanidine-meloxicam complex is better absorbed and has higher bioavailability.

[0208] Table 8 A vs B human pharmacokinetic test results (for meloxicam)

[0209] For meloxicam, the tizanidine-meloxicam complex has a higher C max (10.28% higher); with similar AUC (AUC 0-t , AUC 0-∞), meaning that the tizanidine-meloxicam complex has a faster absorption rate and higher bioavailability.

[0210] Table 9 A vs D human pharmacokinetic test results (for meloxicam)

[0211] For meloxicam, the tizanidine-meloxicam complex has a higher C max (12.34% higher); a similar AUC (AUC 0-t , AUC 0-∞ ), meaning that the tizanidine-meloxicam complex has a faster absorption rate and higher bioavailability.

[0212] In summary, the tizanidine-meloxicam complex exhibits a more persistent analgesic effect in the pharmacodynamic study. Although the animal test does not exhibit significant pharmacokinetic differences, the human pharmacokinetic test confirms that, compared to the combination of tizanidine hydrochloride and meloxicam and the administration of meloxicam alone, the tizanidine-meloxicam complex has better bioavailability.

[0213] The above description of the embodiments is only used to help understand the present application and its core idea. It should be noted that, for those skilled in the art, some improvements and modifications can be made to the present application without departing from the principles of the present application, and these improvements and modifications also fall within the protection scope of the claims of the present application.

Claims

1. A composite, characterized in that, The complex comprises tizanidine or a pharmaceutically acceptable salt thereof and meloxicam.

2. The composite of claim 1, wherein, The molar ratio of tizanidine or a pharmaceutically acceptable salt thereof to meloxicam in the complex is 1:1; Optionally, the pharmaceutically acceptable salt of tizanidine comprises a salt of tizanidine and any one acid selected from inorganic acid or organic acid; Optionally, the inorganic acid is selected from hydrochloric acid, sulfuric acid, nitric acid or hydrobromic acid; Optionally, the organic acid is selected from formic acid, acetic acid, citric acid, fumaric acid, maleic acid, succinic acid or methanesulfonic acid. Optionally, the pharmaceutically acceptable salt of tizanidine is tizanidine hydrochloride.

3. The complex according to claim 1 or 2, characterized in that, The complex consists of tizanidine and meloxicam; The complex structure is shown below: Optionally, the complex is in solid form; Optionally, the melting point of the complex is 206-211℃.

4. The composite of claim 3, wherein, The melting point of the complex is 207-210.5℃.

5. The composite of claim 3, wherein, The melting point of the complex is 209.5-210.5℃.

6. The complex according to any one of claims 3-5, characterized in that, The powder X-ray diffraction pattern of the complex has characteristic peaks at the following 2θ angles: 7.77°, 9.55°, 14.10°, 15.15°, 20.90°, wherein the error range of each characteristic peak 2θ angle is ±0.2°; Optionally, the powder X-ray diffraction pattern of the complex has characteristic peaks at the following 2θ angles: 7.77°, 9.55°, 11.14°, 14.10°, 15.15°, 16.65°, 20.40°, 20.90°, 23.04°, 24.60°, 24.90°, wherein the error range of each characteristic peak 2θ angle is ±0.2°; Optionally, the powder X-ray diffraction pattern of the complex has characteristic peaks at the following 2θ angles: 7.77°, 9.55°, 11.14°, 13.59°, 14.10°, 15.15°, 16.65°, 18.03°, 18.54°, 20.10°, 20.40°, 20.90°, 22.00°, 23.04°, 23.84°, 24.60°, 24.90°, 26.20°, 27.39°, 29.43°, wherein the error range of each characteristic peak 2θ angle is ±0.2°; Optionally, the complex has the powder X-ray diffraction pattern shown in Figure 1.

7. The complex according to any one of claims 3-6, characterized in that, The infrared spectrum of the composite has the following characteristic absorption peaks: 3383.955 cm -1 、3164.282cm -1 、3052.242cm -1 、1655.767cm -1 、1590.711cm -1 、1327.631cm -1 、1165.408cm -1 、765.814cm -1 、571.561cm -1 , the wave number error is ±2cm -1 ; Optionally, the complex has the following characteristic absorption peaks in its infrared spectrum: 3383.955 cm -1 , 3281.736 cm -1 , 3164.282 cm -1 , 3052.242 cm -1 , 2915.578 cm -1 , 1655.767 cm -1 , 1590.711 cm -1 , 1509.133 cm -1 , 1390.244 cm -1 , 1327.631 cm -1 , 1192.097 cm -1 , 1165.408 cm -1 , 1120.096 cm -1 , 947.173 cm -1 , 765.814 cm -1 , 571.561 cm -1 , with a wave number error of ± 2 cm -1 ; Optionally, the complex has the infrared spectrum as shown in Figure 2.

8. The complex according to any one of claims 3-7, characterized in that, The crystallographic parameters of the complex are: orthorhombic, space group: Pca21, cell parameters are: α = 90°, β = 90°, γ = 90°, cell volume is 9. A process for the preparation of a complex as claimed in any one of claims 1 to 8, characterised in that, The method comprises cooling crystallization or suspension crystallization; Optionally, the cooling crystallization comprises the following operation steps: tizanidine or a pharmaceutically acceptable salt thereof and meloxicam are added into an organic solvent, heated under stirring to obtain a clear solution, cooled to crystallize, filtered, and the filter cake is dried to obtain the complex; In the cooling crystallization: Preferably, the organic solvent is dimethyl sulfoxide and / or ketone solvent, and further preferably, the ketone solvent is acetone and / or 2-butanone, and optionally, the ketone solvent is acetone. Optionally, the mass volume ratio of the sum of the mass of tiazemine or its pharmaceutically acceptable salt and meloxicam to the volume of organic solvent is 1:10-100 g / mL, preferably the mass volume ratio is 1:15-90 g / mL, further preferably the mass volume ratio is 1:23-83 g / mL; Optionally, the temperature of the heating is 45℃-reflux temperature; Optionally, the temperature of the crystallization is 0℃-room temperature, preferably 5℃-room temperature; Optionally, the time of the crystallization is 1-24 hours, preferably 2-20 hours, more preferably 3-12 hours, further preferably 3-5 hours; Optionally, the suspension crystallization comprises the following operation steps: adding tiazemine or its pharmaceutically acceptable salt and meloxicam into organic solvent, reacting at room temperature under stirring, filtering, drying the filter cake to obtain the complex; In the suspension crystallization, Preferably, the organic solvent is dimethyl sulfoxide and / or ketone solvent, further preferably the ketone solvent is acetone and / or 2-butanone, optionally the ketone solvent is acetone; Optionally, the mass volume ratio of the sum of the mass of tiazemine or its pharmaceutically acceptable salt and meloxicam to the volume of organic solvent is 1:5-50 g / mL, preferably the mass volume ratio is 1:10-30 g / mL; Optionally, the reaction time is 1-30 hours, preferably 15-27 hours.

10. A pharmaceutical composition comprising the complex of any one of claims 1-8 and pharmaceutically acceptable adjuvant.

11. The pharmaceutical composition of claim 10, wherein, The pharmaceutically acceptable adjuvant is one or more selected from the group consisting of filler, disintegrant, glidant and lubricant; Optionally, the pharmaceutical composition comprises 3%-15% of the complex, 60%-90% of the filler, 1%-15% of the disintegrant, 0.1%-5% of the glidant and 0.1%-5% of the lubricant by weight percentage; Optionally, the pharmaceutical composition comprises 5%-10% of the complex, 80%-90% of the filler, 1%-5% of the disintegrant, 0.5%-2% of the glidant and 1%-3% of the lubricant by weight percentage; Optionally, the filler is one or more selected from the group consisting of microcrystalline cellulose, anhydrous lactose, mannitol, calcium phosphate, calcium carbonate; Optionally, the disintegrant is one or more selected from the group consisting of carboxymethyl cellulose, carboxymethyl cellulose calcium, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, alginic acid; Optionally, the glidant is one or a combination of colloidal silicon dioxide and talc; Optionally, the lubricant is one or a combination of stearic acid, magnesium stearate, calcium stearate and glyceryl behenate; Optionally, the pharmaceutical composition further comprises coating material, and the coating material is optionally a gastro-soluble film coating premix; Optionally, the dosage form of the pharmaceutical composition is tablet, capsule, pill, granule or powder.

12. Use of the complex of any one of claims 1-8 or the pharmaceutical composition of claim 10 or 11 in the manufacture of a medicament for the treatment or alleviation of pain; optionally, the pain is traumatic pain, pathological pain, neurogenic pain, or pain caused by a combination of factors; optionally, the pain is postoperative acute pain, inflammatory pain, trigeminal neuralgia, migraine, tension-type headache, orofacial pain, occipital headache, cervical shoulder pain, upper extremity pain, chest back pain, or low back leg pain; optionally, the inflammatory pain is frozen shoulder, arthritis, or fibromyalgia; optionally, the arthritis is rheumatoid arthritis, osteoarthritis, or ankylosing spondylitis.

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