Composition for treating pain caused by nerve injury

Abstract

The invention belongs to the field of pharmaceutical preparations, and particularly relates to a composition for treating pain caused by nerve injury. The combination of melogabalin or pharmaceutically acceptable salt thereof and mecobalamin according to a certain proportion can generate analgesic enhancement or synergistic effect on neurogenic injury pain. The prepared orally disintegrating tablet containing melogabalin or pharmaceutically acceptable salt thereof and mecobalamin can also improve the medication compliance of patients, has the effects of improving memory and relieving related symptoms of neurogenic injury pain, and has good popularization and application values.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical preparations, and specifically relates to a composition for treating pain caused by nerve damage. Background Art

[0002] Physiological pain is an important protective mechanism designed to warn of dangers of potentially harmful stimuli from the external environment. Neuropathic pain is defined as pain initiated or caused by a primary injury or dysfunction of the nervous system. Neuropathic pain is often debilitating and leads to loss of work ability and poor quality of life. It also causes economic and social harm. Analgesics currently used to treat neuropathic pain include nonsteroidal anti-inflammatory drugs, antidepressants, opioid analgesics, and anticonvulsants.

[0003] Diabetic neuropathy is one of the most common long-term symptomatic complications in patients with type 1 and type 2 diabetes. At the time of initial diagnosis, 7.5% of patients already suffer from painful diabetic peripheral neuropathy, and approximately 45-50% of patients will develop this complication after 25 years. Diabetic sensorimotor polyneuropathy (DSPN) is the most common and well-defined disease manifestation of diabetic complications in the nervous system, with an incidence of approximately 30% in diabetic patients. DSPN mainly affects the distal parts of the lower limbs, and the patient's sensory system is the first to be affected, especially in the case of acute and / or chronic trauma, skin ulcers and severe tissue destruction in the feet can even lead to loss of sensation. At the same time, patients also have to endure varying degrees of acute or chronic pain such as burning, tearing, pins and needles or electric shocks, which are particularly aggravated at night. Another manifestation of DSPN is Charco's arthropathy with redness and swelling in both acute and chronic stages, which can lead to deformity and instability in standing in severe cases. More importantly, both DSPN and Charcot's osteoarthropathy can increase the mortality rate of patients. Although the first step in the management of diabetic neuropathic pain is traditionally to improve and optimize blood sugar control, additional pain control medications are usually required. Current treatment options include antidepressants such as tricyclic drugs and serotonin-norepinephrine reuptake inhibitors, y-aminobutyric acid analogs such as pregabalin, gabapentin and melogabalin, opioids and topical treatments. Patent document WO2015165948 Compositions, methods and uses for treating diabetic neuropathy discloses the use of acamprosate and cinacalcet, cinacalcet and levosimendan in combination with loxetine or pregabalin for treating diabetic neuropathy. Patent document JP3968347 discloses a preventive / therapeutic agent for diabetic neuropathy, using cytidine 5'-choline diphosphate or a pharmaceutically acceptable salt thereof as an active ingredient for treatment. US11351188 discloses the use of folic acid and two antioxidant components to treat diabetic neuropathy, wherein the first antioxidant component is taurine, β-alanine, citrulline and acetyl-L-carnitine, and the second antioxidant component is methylcobalamin.

[0004] In January 2019, Melogabalin Besylate Tablets were first approved for marketing in Japan for the treatment of peripheral neuropathic pain (PNP), including DPNP and postherpetic neuralgia (PHN). The potential indications of this product are postherpetic neuralgia (PHN), chemotherapy-related neuropathic pain, chronic low back pain and postoperative neuralgia. Since then, the drug has gradually been launched in Asia, including South Korea, Taiwan, China, and Thailand. On June 28, 2024, Melogabalin Besylate Tablets were approved by the China National Drug Administration for the treatment of DPNP in adults, and were officially commercialized on October 18 of the same year.

[0005] At the same time, clinicians often encounter the problem of patients' "resistance" to analgesics. These patients often need long-term high-dose treatment, changing the drugs used and the combination of drugs, such as gabapentin and opioids, pregabalin and opioids, gabapentin and nortriptyline, pregabalin and duloxetine, etc. However, the combination of drugs cannot bring sustained clinical treatment benefits. For example, in the COMBO-DN study, it was found that the combination of drugs was not more advantageous than the use of a single drug in high doses (p=0.068), and for most patients, pain relief was still insufficient.

[0006] Oral solid preparations are a common form of drug administration. At present, oral swallowing is considered to be the most patient-compliant way of taking medicine. Its safety, stability, convenience, economy, and easy storage and transportation are more friendly to patients with movement disorders and functional diseases. It includes tablets, capsules and other dosage forms. However, in the body, oral solid preparations need to go through a series of processes, including disintegration, dissolution, absorption, etc. Differences in preparations may ultimately affect the in vivo process of the drug, thereby leading to changes in bioavailability. In the research and development of oral solid preparations, it is necessary to comprehensively consider and optimize factors such as the physicochemical properties and solubility of the preparation to ensure that the drug can fully exert its therapeutic effect. Therefore, the choice of dosage form should be considered based on the physicochemical properties of the drug, the needs of clinical treatment, the compliance of clinical medication, and the cost of dosage form research and development.

[0007] Orally disintegrating tablets are a good choice for oral solid dosage forms. In addition to the benefits of conventional dosage forms, they can also allow patients to absorb drugs from the oral mucosa without taking water to achieve their desired therapeutic effects. However, there are many challenges in combining two or more molecules in an orally disintegrating tablet, such as (a) physicochemical compatibility between different active ingredients and / or physicochemical compatibility between active ingredients and excipients used; (b) therapeutic compatibility between the two active ingredients with respect to their pharmacokinetics and / or drug properties, so that the posology of the combined formulation allows safe and effective plasma levels of both drugs to be obtained; (c) reducing the incidence of side effects. It is well known that obtaining adequate content uniformity is an important issue, especially in drug formulations containing multiple active ingredients. Since active ingredients are difficult to homogenize, especially if they have a low dose and high bulk density in the final dosage form, difficulties may arise during the process when filling into capsules or tableting, which may result in insufficient content uniformity in the final dosage form. As a result, adverse effects may occur during treatment. Therefore, the development of orally disintegrating tablets is a challenging thing that looks good but is difficult to implement. Summary of the invention

[0008] Developing more effective drugs to relieve or treat neuropathic pain has always been one of the main goals of the pharmaceutical industry. The inventors of this case surprisingly found through long-term research that the combination of melogabalin and methylcobalamin in a certain ratio can produce analgesic enhancement or synergistic effects on neurogenic injury pain. In addition, given the particularity of molecular structure, pharmacokinetics and mechanism of action, the background of synergistic effects in combination with other active ingredients to treat neurogenic injury pain does not allow the inference of the synergistic effects of the specific combination ratio of the present invention.

[0009] In addition, those skilled in the art will appreciate that the use of melogabalin and its pharmaceutically acceptable salt is expected to achieve the same effect. In one example, melogabalin and its pharmaceutically acceptable salt is melogabalin besylate.

[0010] In a first aspect of the present invention, a composition for treating pain caused by nerve damage is provided, wherein the composition comprises melogabalin / melogabalin besylate and methylcobalamin.

[0011] The inventors of the present case surprisingly found that the combined use of melogabalin / melogabalin besylate and methylcobalamin for treating pain caused by nerve damage can use a relatively low amount of drugs.

[0012] In one embodiment, the ratio of melogabalin / melogabalin besylate to methylcobalamin (w / w) in the composition is 2.5-15:0.5-1, more preferably, the ratio is 10:0.75.

[0013] In one embodiment, the ratio of melogabalin / melogabalin benzenesulfonate to methylcobalamin (w / w) in the composition is 5 to 30:1, and the ratio of melogabalin / melogabalin benzenesulfonate to methylcobalamin (w / w) is 6:1, 7:1, 8:1, 9:1, 10:1, 11:1, 12:1, 13:1, 14:1, 15:1, 16:1, 17:1, 18:1, 19:1, 20:1, 21:1, 22:1, 23:1, 24:1, 25:1, 26:1, 27:1, 28:1, 29:1, 30:1. Preferably, the ratio is 10:1.

[0014] In one embodiment, the composition comprises 2.5-15 mg of melogabalin / melogabalin besylate and 0.5-1 mg of methylcobalamin; preferably, the composition contains 5 mg of melogabalin / melogabalin besylate and 0.5 mg of methylcobalamin; more preferably, the composition contains 10 mg of melogabalin / melogabalin besylate and 0.75 mg of methylcobalamin.

[0015] In a second aspect of the present invention, the present invention provides use of a composition consisting of melogabalin / melogabalin besylate and methylcobalamin in the preparation of a medicament for treating pain caused by nerve damage.

[0016] In one embodiment, the ratio of melogabalin / melogabalin besylate to methylcobalamin (w / w) in the composition is 2.5-15:0.5-1, more preferably, the ratio is 10:0.75.

[0017] In one embodiment, the ratio of melogabalin / melogabalin besylate to methylcobalamin (w / w) in the composition is 5 to 30:1, preferably, the ratio is 10:1.

[0018] In a third aspect of the present invention, a drug for treating pain caused by nerve damage is provided, the drug comprising melogabalin / melogabalin besylate, and methylcobalamin.

[0019] In one embodiment, the ratio of melogabalin / melogabalin besylate to methylcobalamin (w / w) in the drug is 2.5-15:0.5-1, and more preferably, the ratio is 10:0.75.

[0020] In one embodiment, the ratio of melogabalin / melogabalin besylate to methylcobalamin (w / w) in the drug is 5 to 30:1, preferably, the ratio is 10:1.

[0021] Those skilled in the art will appreciate that the drug comprising melogabalin / melogabalin besylate and methylcobalamin of the present invention can be prepared into any pharmaceutically feasible dosage form, preferably, the dosage form is an oral preparation.

[0022] In one embodiment, the dosage form of the drug comprising melogabalin / melogabalin besylate and methylcobalamin of the present invention is a tablet, capsule, powder, lozenge or gel. Preferably, the dosage form is an orally disintegrating tablet.

[0023] Those skilled in the art can understand that in addition to melogabalin / melogabalin besylate and methylcobalamin as effective ingredients, the drug of the present invention also contains pharmaceutically acceptable excipients. The excipients are selected from one or more of fillers, disintegrants, lubricants, flavoring agents, flavors, fragrances, antioxidants, thickeners, colorants, foaming agents, adhesives, pH regulators, plasticizers, buffers, surfactants, and inclusion agents.

[0024] In a fourth aspect of the present invention, the present invention provides an orally disintegrating tablet for treating pain caused by nerve damage, wherein the orally disintegrating tablet comprises a composition consisting of melogabalin or a pharmaceutically acceptable salt thereof, and methylcobalamin. Preferably, the pharmaceutically acceptable salt thereof is melogabalin besylate.

[0025] In one embodiment, the ratio of melogabalin / mellogabalin besylate to methylcobalamin (w / w) in the composition is 2.5-15:0.5-1, more preferably, the ratio is 10:0.75.

[0026] In one embodiment, the ratio of melogabalin / mellogabalin besylate to methylcobalamin (w / w) in the composition is 5 to 30:1, preferably, the ratio is 10:1.

[0027] In the process of developing orally disintegrating tablets, the inventors found that both APIs, melogabalin and methylcobalamin, are bitter in nature. For orally disintegrating tablets, good taste is even more important than disintegration speed. Both APIs, melogabalin besylate and methylcobalamin, have stability problems, especially sensitivity to ultraviolet radiation. Furthermore, the methylcobalamin raw material is easy to absorb moisture, has poor light and oxygen stability, and the compressibility and powder flowability of the melogabalin besylate raw material are also poor. Therefore, the present invention solves these problems by adding fillers, disintegrants, lubricants, antioxidants, colorants, foaming agents, and flavoring agents to the composition containing melogabalin besylate and methylcobalamin.

[0028] In one embodiment, the filler is selected from one or more of D-mannitol, crystalline cellulose, microcrystalline cellulose, soluble starch, and pregelatinized starch.

[0029] In one embodiment, the disintegrant is selected from one or more of hydroxypropyl cellulose, crystalline cellulose, sodium starch glycolate, carboxymethyl cellulose, cross-linked polyvinylpyrrolidone, and cross-linked sodium carboxymethyl cellulose.

[0030] In one embodiment, the lubricant is selected from one or more of talc, magnesium stearate, and silicon dioxide.

[0031] In one embodiment, the antioxidant is selected from one or more of ascorbic acid, uric acid, glutathione, melatonin, and tocopherol.

[0032] In one embodiment, the colorant is selected from one or more of edible lake dye, yellow iron trioxide, iron trioxide, titanium oxide, β-carotene, and riboflavin.

[0033] In one embodiment, the foaming agent is selected from one or more of tartaric acid / sodium bicarbonate, citric acid monohydrate / sodium bicarbonate, citric acid monohydrate / magnesium aluminum silicate, and tartaric acid / magnesium aluminum silicate.

[0034] In a fifth aspect of the present invention, the present invention discloses a method for preparing an orally disintegrating tablet for treating pain caused by nerve damage, the method comprising: 1) Preparation of melogabalin besylate granules: melogabalin besylate, filler, and foaming agent weighed in proportion are mixed in a PE bag, sieved, and the sieved powder is placed in a fluidized bed granulator, and a disintegrant binding liquid dissolved in purified water is sprayed, and granulation is performed to obtain melogabalin besylate granules; 2) Preparation of methylcobalamin granules: methylcobalamin and filler weighed in proportion are mixed in a PE bag, sieved, and the sieved powder is placed in a fluidized bed granulator, sprayed with a disintegrant binding liquid dissolved in purified water, and granulated to obtain methylcobalamin granules; 3) Preparation of tableting granules: melogabalin besylate granules, methylcobalamin granules, crystalline cellulose, carboxymethyl cellulose and acesulfame potassium are weighed and mixed according to a proportion, and then magnesium stearate is weighed and mixed according to a proportion to obtain tableting granules; 4) Tablet pressing: Use a tablet press to press tablets according to the set tablet mass and pressure; 5) Coating: coating is done.

[0035] In view of the excellent clinical effect of the present invention, in the sixth aspect of the present invention, the composition of the present invention can also be used to prepare a drug for treating nerve injury pain or other types of pain, including spinal cord injury-related neuropathic pain, diabetic peripheral neuropathy, fibromyalgia, chronic pain, perioperative pain and migraine. In the seventh aspect of the present invention, the present invention has found that in the same subjects receiving the above-mentioned melogabalin combined with methylcobalamin treatment, it has a surprising positive effect in helping memory and learning, enhancing energy, helping to control homocysteine ​​levels, promoting cardiovascular health, enhancing immune system function, and effectively supporting brain and nerve function. Therefore, the composition of the present invention can also be used to prepare drugs for improving memory, controlling homocysteine ​​levels, promoting cardiovascular health, enhancing immune system function and or improving neurodegenerative diseases.

[0036] Beneficial Effects (1) The combination of melogabalin or its pharmaceutically acceptable salt and methylcobalamin found in the present invention has significant synergistic effect in inhibiting pain caused by nerve damage. Both are available raw materials that have been marketed. The combination of the two has good application and promotion value.

[0037] (2) The present invention prepares an orally disintegrating tablet containing melogabalin besylate and methylcobalamin, which has good taste, stability and drug solubility, and improves the compliance of the combined use of melogabalin besylate and methylcobalamin.

[0038] (3) The present invention improves the subject's memory and learning ability, enhances energy, helps control homocysteine ​​levels, promotes cardiovascular health, enhances immune system function, and effectively supports the subject's brain and nerve function through the combined use of melogabalin and methylcobalamin. BRIEF DESCRIPTION OF THE DRAWINGS

[0039] Figure 1 : Dissolution curve of melogabalin besylate in 0.1 mol / L hydrochloric acid solution.

[0040] Figure 2 : Dissolution curve of melogabalin besylate in water.

[0041] Figure 3 : Dissolution curve of melogabalin besylate in pH 4.5 acetate solution.

[0042] Figure 4 : Dissolution curve of melogabalin besylate in pH 6.8 phosphate solution.

[0043] Figure 5 : Dissolution curve of methylcobalamin in 0.1 mol / L hydrochloric acid solution.

[0044] Figure 6 : Dissolution curve of methylcobalamin in water.

[0045] Figure 7 : Dissolution curve of methylcobalamin in pH 4.5 acetate solution.

[0046] Figure 8 : Dissolution curve of methylcobalamin in pH 6.8 phosphate solution. DETAILED DESCRIPTION

[0047] In order to make the purpose, technical scheme and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with the embodiments. The equipment and reagents used in the embodiments and test examples can be obtained from commercial sources unless otherwise specified. Unless otherwise specified, the reagents used in the present invention are all analytical grade reagents. The specific embodiments described herein are only used to explain the present invention and are not intended to limit the present invention.

[0048] (I) Development of orally disintegrating tablets containing melogabalin besylate and methylcobalamin 1.1 Filler type and dosage screening 1.1.1 Filler Type and Weight Screening for Melogabalin Besylate Granules During the study, the flowability, bulk density, mixing uniformity and compressibility of melogabalin besylate mixed powder and granules were investigated. The results of the investigation on filler types and dosages are shown in Tables 1 and 2 below.

[0049] Table 1 Filler type and dosage screening of melogabalin besylate ; Preparation method: 1. Pretreatment: Pass melogabalin besylate and filler through 80-mesh sieve respectively and set aside; weigh hydroxypropyl methylcellulose, add purified water and stir to dissolve as a binder; 2. Mixing and granulation: weigh the main drug, mannitol, lactose, microcrystalline cellulose, sorbitol, pregelatinized starch, glycine, and crystalline cellulose in order according to the prescription, place them in a wet granulator, stir at 300 rpm / min, take samples after 5, 10, and 15 minutes of stirring to test the mixing uniformity, add a binder for granulation after passing the test; 3. Drying and granulation: Dry the wet granules. When the moisture content of the granules is ≤2.0%, the drying is terminated and the granules are sized using an 18-mesh sieve. 4. Total mixing: Add the prescribed amount (0.5%) of magnesium stearate to the dry granules and mix for 15 minutes.

[0050] 5. Tableting: pressure parameter 10~80KN, hardness control 5~8kg Table 2 Results of screening of filler types and dosages of melogabalin besylate ; Judging from the test results, prescription 4 is the best.

[0051] 1.1.2 Screening of filler dosage for methylcobalamin granules During the prescription screening process, the fluidity, bulk density and uniformity of the initial mixed powder and granules were examined, and the compressibility of the granules, the appearance, hardness and friability of the plain tablets were examined. The test results are shown in Tables 3 and 4.

[0052] Table 3 Screening of filler types and dosage of methylcobalamin ; Preparation method: 1. Pretreatment: sieve methylcobalamin and filler through 80 mesh sieve respectively and set aside; weigh hydroxypropyl methylcellulose, add purified water and stir to dissolve as a binder; 2. Mixing and granulation: weigh the main drug, mannitol, microcrystalline cellulose, pregelatinized starch, and crystalline cellulose in order according to the prescription, place them in a wet granulator, stir at 300 rpm / min, take samples after 5, 10, and 15 minutes of stirring to test the mixing uniformity, add a binder for granulation after passing the test; 3. Drying and granulation: Dry the wet granules. When the moisture content of the granules is ≤2.0%, the drying is terminated and the granules are sized using an 18-mesh sieve. 4. Total mixing: Add the prescribed amount (0.5%) of magnesium stearate to the dry granules and mix for 15 minutes.

[0053] 5. Tableting: pressure parameter 10~80KN, hardness control 5~8kg Table 4 Screening results of filler dosage of methylcobalamin ; Judging from the test results, prescription 9 is the best.

[0054] 1.2 Adhesive type and dosage screening Commonly used binders include hydroxypropyl methylcellulose, low-substituted hydroxypropyl cellulose, sodium carboxymethyl cellulose, povidone K30, carboxymethyl cellulose, ethyl cellulose, etc. According to the dosage characteristics of this product, the types and dosages of hydroxypropyl methylcellulose, low-substituted hydroxypropyl cellulose, carboxymethyl cellulose and povidone K30 were selected for screening. Different types of binders were dissolved in water according to the proposed dosage to prepare a solution of a certain concentration, which was used as a binder for wet granulation, focusing on the drying time, moisture, compressibility, hardness, friability and disintegration time of wet granules made of different binders. The test results are shown in Tables 5 and 6.

[0055] Table 5 Adhesive type and dosage screening formula composition (the first column of API in the formula is melogabalin besylate, and the second column is methylcobalamin) ; Table 6 Results of the screening test on adhesive types and dosage ; The test results show that low-substituted hydroxypropyl cellulose is the best binder of the present invention.

[0056] 1.3 Screening of disintegrant types and dosage Based on prescription 13, sodium carboxymethyl starch, cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose and an effervescent disintegrant were selected, wherein the effervescent disintegrant was composed of one of tartaric acid / sodium bicarbonate, citric acid monohydrate / sodium bicarbonate, citric acid monohydrate / magnesium aluminum silicate, and tartaric acid / magnesium aluminum silicate, in a ratio of 1:1, as a disintegrant.

[0057] Disintegrants are added during the granulation process, and effervescent disintegrants are added during the total mixing. The purpose is to work synergistically with the internal disintegrant to accelerate the disintegration of orally disintegrating tablets in the oral cavity and shorten the disintegration time. The type and dosage of disintegrants are mainly examined for granule moisture, hardness, friability and disintegration time. The test results are shown in Tables 7 and 8.

[0058] Table 7 Disintegrant type and dosage screening formulation composition (the first column of API in the formulation is melogabalin besylate, and the second column is methylcobalamin) ; Table 8 Results of the screening test on adhesive types and dosage ; Judging from the test results, the average disintegration time of the plain tablets made from Prescription 16 was less than 60s, indicating that the combination of cross-linked polyvinylpyrrolidone and effervescent disintegrants (citric acid monohydrate / magnesium aluminum silicate) had a certain effect and improved the disintegration performance of the plain tablets. However, the disintegration time of the plain tablets was still relatively long. Considering that a coating process may be introduced into this product in the later stage, it is necessary to further optimize the dosage and addition method of the disintegrant to obtain more significant disintegration.

[0059] 1 / 2 of the prescribed amount of cross-linked polyvinylpyrrolidone and effervescent disintegrant (citric acid monohydrate / magnesium aluminum silicate) was added to the primary mixed material, and the remaining prescribed amount of cross-linked polyvinylpyrrolidone and effervescent disintegrant (citric acid monohydrate / magnesium aluminum silicate) was added during the total mixing process. The disintegration time of the plain tablets after the addition of part of the disintegrant was mainly investigated. The test results are shown in Tables 9 and 10.

[0060] Table 9 Disintegrant addition method prescription composition (the first column of API in the prescription is melogabalin besylate, and the second column is methylcobalamin) ; Table 10 Results of investigation on disintegrant addition method ; The test results show that the disintegration performance of the plain tablets is significantly improved after the disintegrant is added.

[0061] 1.4 Screening of antioxidants and flavor enhancers 1.4.1 Screening of antioxidants This product is a compound preparation. Melogabalin besylate is sensitive to oxygen and methylcobalamin is sensitive to light. Therefore, antioxidants are added during the preparation process to increase the stability of this product. Combined with the dosage form characteristics of this product, sodium pyrosulfite, ascorbic acid, cysteine ​​hydrochloride, glutathione, and tocopherol are selected for investigation, and the provisional prescription amount is 1%. The prepared plain tablets were placed under light and high temperature conditions for 10 days, and samples were taken at 0, 5 and 10 days to detect the changes in the appearance, content and related substances of the plain tablets. The test results are shown in Tables 11, 12 and 13.

[0062] Table 11 Antioxidant type screening (the first column of API in the prescription is melogabalin besylate, and the second column is methylcobalamin) ; Table 12 Results of the investigation on the factors affecting light ; Table 13 Results of the investigation on the influencing factors at high temperature of 60℃ ; The results showed that tocopherol was the best antioxidant.

[0063] 1.4.2 Investigation of flavor correctors Sweeteners with good safety should be selected during the formulation development process. Commonly used sweeteners include sucrose, sodium saccharin, saccharin, aspartame, sucralose, dipotassium glycyrrhizinate, stevioside and acesulfame potassium. Among them, sodium saccharin and saccharin have use warning risks, and sucrose is hygroscopic, which may cause abnormal tableting during tableting. Therefore, five sweeteners, aspartame, sucralose, dipotassium glycyrrhizinate, stevioside and acesulfame potassium, were finally selected for investigation. To ensure that the sweeteners are evenly distributed in the tablets, the above sweeteners are made into solutions together with the adhesive and added during the granulation process. The scope of application of each sweetener is different. During the screening process, a preliminary study was conducted at 1% of the tablet weight, and the applicability of different types of sweeteners in the formulation of this product was judged by a taste analyzer. The formulation composition and test results are shown in Tables 14 and 15.

[0064] Table 14 Composition of the sweetener screening prescription (the first column of API in the prescription is melogabalin besylate, and the second column is methylcobalamin) ; Table 15 Sample measurement results ; Note: The standard sample measurement result is the 0-point value. If the measurement result is greater than the 0-point value, there is a corresponding flavor, and if it is less than the 0-point value, there is no corresponding flavor.

[0065] Analysis of results: Preliminary test results show that when no sweetener is added, the sour taste of the plain tablets is more obvious, which may be related to the citric acid in the prescription. After adding different sweeteners, the sweetness of aspartame, sucralose and stevioside is higher, indicating excessive addition. The tablets of prescription 28 have the lowest sweetness, but the sourness and astringency are significantly increased, which may be related to the potassium contained in the sweetener. The bitterness, astringency and aftertaste of prescription 30 are significantly reduced compared with the standard sample, the sweetness value is moderate, and the richness is significantly improved, indicating that the taste coordination of the tablets is good after adding acesulfame potassium. Therefore, acesulfame potassium is the best sweetener of the present invention.

[0066] 1.5 Screening of dosage of antioxidants Based on the preliminary screening results of antioxidants, the dosage of tocopherol was screened and optimized. According to the FDA "Inactive Ingredients Guide" database, the maximum daily oral dosage of tocopherol is 85 mg. Combined with the existing research results, the dosage of tocopherol was optimized, and samples of tocopherol with different prescription amounts were prepared. The test samples were placed under light (5000lx) and high temperature of 60℃ for 10 days. Samples were taken on 0, 5 and 10 days to detect the changes in the properties, content and related substances of the samples. The test results are shown in Tables 16, 17 and 18.

[0067] Table 16 Antioxidant dosage screening formula composition (the first column of API in the formula is melogabalin besylate, and the second column is methylcobalamin) ; Table 17 Results of light test on influencing factors ; Table 18 High temperature test results of influencing factors ; Result analysis: The test results show that when the dosage of tocopherol reaches 3% or more of the prescription amount, the appearance, content and related substance test results of the small test sample have no obvious change trend under high temperature and light conditions for 10 days, and the stability is good. According to the test results, the dosage of tocopherol is 3% of the prescription amount, that is, 15.9 mg / tablet is the best.

[0068] 1.6 Film coating weight gain study 1.6.1 Film coating material selection The film coating material must have good film-forming and solubility. Ethyl cellulose was selected as the film-forming material, and yellow ferric oxide was used as the colorant and sunscreen. A batch of test samples was prepared, and the plain tablets were coated with different weight gain ratios. The appearance and disintegration time of the coated tablets with different weight gain ratios were examined. The test results are shown in Table 19.

[0069] Table 19 Coating weight gain investigation (the first API in the prescription is melogabalin besylate, and the second API is methylcobalamin) ; Table 20 Coating weight gain investigation results ; Analysis of the results showed that when the coating weight gain ratio of this product was controlled at 3.0%, yellow film-coated tablets with smooth and neat surface were obtained, and the disintegration rate was faster.

[0070] In summary, the present invention has selected suitable excipients from the group including disintegrants, fillers, binders, diluents, lubricants, glidants, sweeteners and flavoring agents, which endows the orally disintegrating tablet of the present invention with sufficient uniformity, content uniformity and stability.

[0071] Therefore, the present invention provides a method for preparing an orally disintegrating tablet for treating pain caused by nerve damage, the method comprising: 1) Preparation of melogabalin besylate granules: melogabalin besylate, filler, and foaming agent weighed in proportion are mixed in a PE bag, sieved, and the sieved powder is placed in a fluidized bed granulator, and a disintegrant binding liquid dissolved in purified water is sprayed, and granulation is performed to obtain melogabalin besylate granules; 2) Preparation of methylcobalamin granules: methylcobalamin and filler weighed in proportion are mixed in a PE bag, sieved, and the sieved powder is placed in a fluidized bed granulator, sprayed with a disintegrant binding liquid dissolved in purified water, and granulated to obtain methylcobalamin granules; 3) Preparation of tableting granules: melogabalin besylate granules, methylcobalamin granules, crystalline cellulose, carboxymethyl cellulose and acesulfame potassium are weighed and mixed according to a proportion, and then magnesium stearate is weighed and mixed according to a proportion to obtain tableting granules; 4) Tablet pressing: Use a tablet press to press tablets according to the set tablet mass and pressure; 5) Coating: coating is done.

[0072] Example 1 Table 21 Melogabaline besylate / methylcobalamin orally disintegrating tablets (5 mg / 0.5 mg / tablet) ; According to the prescription of Table 21, a method for preparing an orally disintegrating tablet for treating pain caused by nerve damage: 1 Preparation: Pass API (melogabalin besylate, methylcobalamin), mannitol, microcrystalline cellulose, pregelatinized starch, crystalline cellulose, citric acid monohydrate, and magnesium aluminum silicate through a 80-mesh sieve respectively; 2 Weighing: Weigh the API and excipients according to the prescription amount and set aside; 3 Preparation of adhesive and coating solution: Take the weighed amount of acesulfame potassium and add it to 1.8 kg of purified water, stir and dissolve, then add L-HPC and continue stirring until it is completely dissolved, set aside; take ethyl cellulose and yellow ferric oxide, add them to 1.59 kg of purified water, stir and dissolve until uniform, set aside; 4 Mixing: Place the weighed two active ingredients and the corresponding prescription amounts of mannitol, microcrystalline cellulose, crystalline cellulose, pregelatinized starch, crospovidone, tocopherol, citric acid monohydrate and sodium bicarbonate in a wet granulator and mix for 15 minutes respectively; 5. Granulation: Use the prepared adhesive solution to granulate the two active ingredients respectively, and the adhesive addition rate is controlled at 200 ml / min; 6 Drying: Spread the wet granules flat in the corresponding container and dry them at 60°C until the moisture content of the granules is less than 2.0%. 7. Granulation: Pass the dried material through an 18-mesh sieve for granulation; 8. Total mixing: Add the prescribed amount of crospovidone, citric acid monohydrate / sodium bicarbonate, magnesium stearate and dry granules into the three-dimensional mixer, cover the top cover, and mix for 20 minutes; 9 Tablet pressing: adjust the tablet press pressure, hardness 4-7kg, tablet weight range: ±3%; 10 Coating: Tablet bed temperature: 50-60°C, tablet core temperature: 30-40°C, spray gun flow rate: 10-20ml / min. Coating weight gain: 3.0%.

[0073] Example 2 Table 22 Melogabaline besylate / methylcobalamin orally disintegrating tablets (10 mg / 0.75 mg / tablet) ; The preparation method steps are the same as in Example 1, and the amounts of substances used are shown in Table 22.

[0074] Example 3 Table 23 Melogabaline besylate / methylcobalamin orally disintegrating tablets (2.5 mg / 0.5 mg / tablet) ; The preparation steps are the same as those in Example 1, and the amounts of substances used are shown in Table 23.

[0075] Example 4 Table 24 Melogabaline besylate / methylcobalamin orally disintegrating tablets (15 mg / 0.75 mg / tablet) ; The preparation method steps are the same as in Example 1, and the amounts of substances used are shown in Table 24.

[0076] 2. Testing of orally disintegrating tablets for the treatment of pain caused by nerve damage Test Example 1 Influencing Factor Test The samples of Example 1 were placed under the conditions of 5000 lx of light, 92.5% of high humidity and 60°C for 10 days to test the properties, moisture, disintegration time, content and changes in related substances of the samples. The test results are shown in Table 25, and the prepared orally disintegrating tablets are very stable.

[0077] Table 25: Experimental results of influencing factors of Example 1 ; Test Example 2 Dissolution Curve The dissolution behavior of the sample of Example 1 in 0.1 mol / L hydrochloric acid solution, water, pH 4.5 acetate solution and pH 6.8 phosphate solution was investigated. The results are shown in Tables 26-33 and Figure 1-8 As shown, the dissolution behavior of the orally disintegrating tablet prepared by the present invention meets the quality requirements.

[0078] Table 26: Dissolution curve of melogabalin besylate in 0.1 mol / L hydrochloric acid solution ; Table 27: Dissolution curve of melogabalin besylate in water ; Table 28: Dissolution curve of melogabalin besylate in pH 4.5 acetate solution ; Table 29: Dissolution curve of melogabalin besylate in pH 6.8 phosphate solution ; Table 30 Dissolution curve of methylcobalamin in 0.1 mol / L hydrochloric acid solution ; Table 31: Dissolution curve of methylcobalamin in water ; Table 32 Dissolution curve of methylcobalamin in pH 4.5 acetate solution ; Table 33: Dissolution curve of methylcobalamin in pH 6.8 phosphate solution ; Test Example 3: Clinical test study of the orally disintegrating tablet of the present invention 1 Materials and methods 1.1 General data: 80 patients with diabetic peripheral neuropathy were selected and divided into a study group and a control group according to the random number table method, with 40 cases in each group. There were 23 males and 17 females in the study group, aged 58-70 years, with an average age of (64.00±3.12) years; the course of disease was 1-8 years, with an average of (4.50±0.45) years. There were 24 males and 16 females in the control group, aged 60-68 years, with an average age of (64.00±3.02) years; the course of disease was 2-7 years, with an average of (4.50±0.50) years. There was no significant difference in the general data of the two groups of patients (P>0.05), and they were comparable. This study has been approved by the Medical Ethics Committee of the hospital.

[0079] 1.2 Inclusion and Exclusion Criteria: Inclusion criteria: ① All patients have diabetic peripheral neuropathy; ② Complete clinical data; ③ Actively participate after clarifying the purpose, content and methods of this study. Exclusion criteria: ① Those with a history of drug allergy; ② Those with neurological diseases; ③ Those with a survival period of <1 year.

[0080] 1.3 Methods: The control group was given metformin hydrochloride tablets (specification 0.25 g), orally, 1 tablet / time, 3 times / day; melogaba besylate tablets (specification: 5 mg) were taken orally, 1 tablet / time, 2 times / day, after meals. The study group was given metformin hydrochloride tablets (specification 0.25 g), orally, 1 tablet / time, 3 times / day; Example 1 of the present invention was taken orally, 1 tablet / time, 2 times / day, after meals. Both groups were treated for 4 consecutive weeks.

[0081] 1.4 Observation indicators: ① Comparison of the treatment effects of the two groups: assessment was carried out based on the improvement of clinical symptoms such as numbness, pain, muscle weakness, and burning sensation in the distal limbs of the patients; marked effect meant that all the above clinical conditions of the patients completely disappeared after treatment; effective meant that the above symptoms of the patients were alleviated after treatment; ineffective meant that the patients did not reach the above indicators; total effective rate = (number of markedly effective cases + number of effective cases) / total number of cases × 100%.

[0082] ② Compare the pain levels of the two groups of patients before treatment and 4 weeks after treatment: The Visual Analogue Scale (VAS) pain assessment scale was used, with a total score of 10 points, and the score was proportional to the patient's pain sensation.

[0083] ③ Compare the adverse reactions of the two groups: such as nausea, dizziness, weakness, drowsiness, etc. 1.5 Statistical methods: SPSS 23.0 statistical software was used for data processing. The measurement data that conformed to the normal distribution were expressed as (xˉ±s) and subjected to t test; the enumeration data were expressed as number of cases (n) and rate (%) and subjected to χ2 test; P < 0.05 was considered as positive. The difference is statistically significant.

[0084] 2 Results 2.1 Comparison of treatment effects between the two groups of patients: The total effective rate of the study group was higher than that of the control group, and the difference was statistically significant (P<0.05), see Table 34 below.

[0085] Table 34: Therapeutic effectiveness of the orally disintegrating tablet of the present invention ; 2.2 Comparison of pain conditions between the two groups of patients before and after treatment: Before treatment, there was no significant difference in VAS scores between the two groups of patients (P>0.05). After treatment, the scores of both groups of patients decreased, with the research group having lower scores than the control group, and the difference was statistically significant (P<0.05), see Table 35 below.

[0086] Table 35: Comparison of pain relief effects of orally disintegrating tablets of the present invention ; *Indicates P<0.05 compared with the same group before treatment.

[0087] 2.3 Comparison of adverse reactions between the two groups of patients after treatment: There was no significant difference in the incidence of adverse reactions between the two groups of patients (P>0.05), and insomnia and memory were improved, see Table 36 below.

[0088] Table 36: Comparison of the effects of the orally disintegrating tablets of the present invention on improving insomnia and memory ; It can thus be seen that the composition according to the present invention has been shown to be surprisingly useful in treating pain caused by diabetic neuropathy, but it is believed that it may also be used to treat pain caused by other types of neuropathy, in particular post-herpetic neuralgia and post-surgical neuropathic pain.

[0089] The above content is a further detailed description of the present invention in combination with specific implementation methods. It cannot be determined that the specific implementation of the present invention is limited to these descriptions. For ordinary technicians in the technical field to which the present invention belongs, several simple deductions or substitutions can be made without departing from the concept of the present invention, which should be regarded as belonging to the scope of protection determined by the claims submitted for the present invention.

Claims

1. A composition for treating pain caused by nerve damage, characterized in that: The composition includes melogabalin / melogabalin besylate, and methylcobalamin.

2. Use of a composition consisting of melogabalin / melogabalin besylate and methylcobalamin in the preparation of a drug for treating pain caused by nerve damage.

3. A drug for treating pain caused by nerve damage, characterized in that: The drugs include melogabalin / melogabalin besylate, and methylcobalamin.

4. The composition according to claim 1, the use according to claim 2 or the medicine according to claim 3, characterized in that: The weight ratio (w / w) of melogabalin / melogabalin besylate and methylcobalamin is 2.5-15:0.5-1, preferably 10:0.

75.

5. The composition according to claim 1, the use according to claim 2 or the medicine according to claim 3, characterized in that: The weight ratio (w / w) of melogabalin / melogabalin besylate to methylcobalamin is 5 to 30:1, preferably 10:

1.

6. The drug according to claim 3, characterized in that The medicine also contains pharmaceutically acceptable excipients.

7. The drug according to claim 3, characterized in that The dosage form of the drug is an oral preparation; preferably, the dosage form is a tablet, capsule, powder, lozenge or gel; more preferably, the dosage form is an orally disintegrating tablet.

8. An orally disintegrating tablet for treating pain caused by nerve damage, characterized in that: The disintegrating tablet comprises melogabalin / melogabalin besylate and methylcobalamin.

9. The orally disintegrating tablet according to claim 8, characterized in that The disintegrating tablet also contains a) filler, selected from one or more of D-mannitol, crystalline cellulose, microcrystalline cellulose, soluble starch, and pregelatinized starch; b) a disintegrant selected from one or more of hydroxypropyl cellulose, crystalline cellulose, sodium carboxymethyl starch, carboxymethyl cellulose, cross-linked polyvinylpyrrolidone, and cross-linked sodium carboxymethyl cellulose; c) a lubricant selected from one or more of talc, magnesium stearate and silicon dioxide; d) flavoring agents, selected from one or more of saccharin sodium, saccharin, aspartame, dipotassium glycyrrhizinate, sucralose, stevia, and acesulfame potassium; e) antioxidants selected from one or more of ascorbic acid, uric acid, glutathione, melatonin and tocopherol; f) a colorant selected from one or more of edible lake dyes, yellow iron trioxide, iron trioxide, titanium oxide, beta-carotene and riboflavin; g) A foaming agent selected from one or more of tartaric acid / sodium bicarbonate, citric acid monohydrate / sodium bicarbonate, citric acid monohydrate / magnesium aluminum silicate, and tartaric acid / magnesium aluminum silicate.

10. A method for preparing an orally disintegrating tablet for treating pain caused by nerve damage, characterized in that: The method comprises: 1) Preparation of melogabalin besylate granules: melogabalin besylate, filler, and foaming agent weighed in proportion are mixed in a PE bag, sieved, and the sieved powder is placed in a fluidized bed granulator, and a disintegrant binding liquid dissolved in purified water is sprayed, and granulation is performed to obtain melogabalin besylate granules; 2) Preparation of methylcobalamin granules: methylcobalamin and filler weighed in proportion are mixed in a PE bag, sieved, and the sieved powder is placed in a fluidized bed granulator, sprayed with a disintegrant binding liquid dissolved in purified water, and granulated to obtain methylcobalamin granules; 3) Preparation of tableting granules: melogabalin besylate granules, methylcobalamin granules, crystalline cellulose, carboxymethyl cellulose and acesulfame potassium are weighed and mixed according to a proportion, and then magnesium stearate is weighed and mixed according to a proportion to obtain tableting granules; 4) Tablet pressing: Use a tablet press to press tablets according to the set tablet mass and pressure; 5) Coating: coating is done.

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