Composition for treating pain caused by nerve damage

Abstract

The present invention belongs to the field of pharmaceutical preparations. Specifically, the present invention relates to a composition for treating pain caused by nerve damage. A combination of melogabalin or a pharmaceutically acceptable salt thereof and methylcobalamin in a certain ratio can produce an analgesic enhancement or synergistic effect on neurogenic pain. The preparation of an orally disintegrating tablet containing melogabalin or a pharmaceutically acceptable salt thereof and methylcobalamin can also improve patient medication compliance, improve memory, and alleviate symptoms associated with neurogenic pain, thus having excellent application value.

Description

Technical Field

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

[0002] Physiological pain is an important protective mechanism that serves to warn of danger from potentially harmful stimuli from the external environment. Neuropathic pain is defined as pain triggered or caused by primary damage 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 initial diagnosis, 7.5% of patients already suffer from painful diabetic peripheral neuropathy, and approximately 45-50% will develop this complication 25 years later. Diabetic sensorimotor polyneuropathy (DSPN) is the most common and well-defined neurological manifestation of diabetes, affecting approximately 30% of patients with diabetes. DSPN primarily affects the distal lower extremities, with the sensory system being the first to be affected, particularly in the setting of acute and / or chronic trauma. Skin ulcers and severe tissue destruction in the feet can even lead to sensory loss. Patients also experience varying degrees of acute or chronic pain, such as burning, tearing, stabbing, or electric shock-like sensations, which are particularly exacerbated at night. Another manifestation of DSPN is Charcot's arthropathy, which is accompanied by redness and swelling in both acute and chronic phases. Severe cases can lead to deformity and instability. Importantly, both DSPN and Charcot's arthropathy are associated with an increased mortality rate. While improving and optimizing blood sugar control is traditionally the first step in managing diabetic neuropathic pain, additional pain control medications are often required. Current treatment options include antidepressants such as tricyclics and serotonin-norepinephrine reuptake inhibitors, gamma-aminobutyric acid analogs such as pregabalin, gabapentin, and melogabalin, opioids, and topical therapies. Patent document WO2015165948, "Compositions, methods, and uses for treating diabetic neuropathy," discloses the use of combinations of acamprosate and cinacalcet, cinacalcet and levosimendan, and 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. US11351188 discloses the use of folic acid and two antioxidant components for treating 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). Potential indications include postherpetic neuralgia (PHN), chemotherapy-related neuropathic pain, chronic low back pain, and postoperative neuralgia. On June 28, 2024, melogabalin besylate tablets received approval from the China National Medical Products 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 patients who are "resistant" to analgesics. These patients often require long-term, high-dose treatment, alternating medications, and drug combinations, such as gabapentin and opioids, pregabalin and opioids, gabapentin and nortriptyline, and pregabalin and duloxetine. However, drug combinations fail to provide sustained clinical benefits. For example, the COMBO-DN study found that drug combinations offered no advantage over high-dose single medications (p=0.068), and pain relief remained insufficient for most patients.

[0006] Oral solid preparations are a common form of drug administration. Currently, oral swallowing is considered to be the most patient-compliant way of taking medicine. Its advantages such as safety, stability, convenience, economy, and easy storage and transportation are more friendly to patients with movement disorders and functional diseases. It includes various dosage forms such as tablets and capsules. 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, the physicochemical properties, solubility and other factors of the preparation need to be comprehensively considered and optimized to ensure that the drug can fully exert its therapeutic effect. Therefore, the choice of dosage form should be based on the physicochemical properties of the drug, the needs of clinical treatment, the compliance of clinical medication and the cost of dosage form development.

[0007] Orally disintegrating tablets are a promising option for oral solid dosage forms. Besides the benefits of conventional dosage forms, they also allow patients to absorb the drug from the oral mucosa without the need for water, thereby achieving its intended therapeutic effect. However, combining two or more molecules in an orally disintegrating tablet presents numerous challenges, such as (a) physicochemical compatibility between the different active ingredients and / or between the active ingredients and the excipients used; (b) therapeutic compatibility between the two active ingredients with respect to their pharmacokinetic and / or pharmaceutical properties, so that the combined formulation's positivity allows for safe and effective plasma levels of both drugs; and (c) reducing the incidence of side effects. Achieving adequate content uniformity is a well-known issue, particularly in pharmaceutical formulations containing multiple active ingredients. Because active ingredients are difficult to homogenize, particularly if they have a low dose and high bulk density in the final dosage form, difficulties can arise during capsule filling or tableting, potentially resulting in insufficient content uniformity in the final dosage form. Consequently, adverse effects may occur during treatment. Therefore, the development of orally disintegrating tablets is a challenging undertaking, both promising and challenging in practice. Summary of the Invention

[0008] Developing more effective drugs to relieve or treat neuropathic pain has long been a major goal of the pharmaceutical industry. Through extensive research, the inventors of this case surprisingly discovered that a combination of melogabalin and methylcobalamin in a certain ratio can produce an enhanced analgesic or synergistic effect on neuropathic pain. Furthermore, given the specific molecular structure, pharmacokinetics, and mechanism of action, the background of synergistic effects in combination with other active ingredients for the treatment of neuropathic pain does not allow for inference of a synergistic effect based on the specific combination ratio of the present invention.

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

[0010] In a first aspect, the present invention provides a composition for treating pain caused by nerve damage, comprising melogabalin / mellogabalin besylate and methylcobalamin.

[0011] The inventors of this case surprisingly discovered that the combined use of melogabalin / mellogabalin besylate and methylcobalamin for treating pain caused by nerve damage can be achieved with relatively low drug dosages.

[0012] In one embodiment, the ratio of melegabalin / melegabalin 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 besylate to methylcobalamin (w / w) in the composition is 5 to 30:1, and the ratio of melogabalin / melogabalin besylate 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, the present invention provides use of a composition consisting of melogabalin / mellogabalin besylate and methylcobalamin in the preparation of a medicament for treating pain caused by nerve damage.

[0016] In one embodiment, the ratio of melegabalin / melegabalin 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 melegabalin / melegabalin besylate to methylcobalamin (w / w) in the composition is 5 to 30:1, preferably, the ratio is 10:1.

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

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

[0020] In one embodiment, the ratio of melogabalin / mellogabalin 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 / mellogabalin 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 / mellogabalin 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 will appreciate that, in addition to melogabalin / mellogabalin besylate and methylcobalamin as active ingredients, the medicament of the present invention also contains pharmaceutically acceptable excipients. The excipients are selected from one or more of fillers, disintegrants, lubricants, flavoring agents, essences, fragrances, antioxidants, thickeners, colorants, foaming agents, adhesives, pH regulators, plasticizers, buffers, surfactants, and inclusion agents.

[0024] In a fourth aspect, the present invention provides an orally disintegrating tablet for treating pain caused by nerve damage, comprising 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 melegabalin / melegabalin 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 melegabalin / melegabalin besylate to methylcobalamin (w / w) in the composition is 5 to 30:1, preferably, the ratio is 10:1.

[0027] During the development of orally disintegrating tablets, the inventors discovered that both melogabalin and methylcobalamin, active pharmaceutical ingredients (APIs), are bitter. For orally disintegrating tablets, a good taste is even more important than disintegration speed. Both melogabalin besylate and methylcobalamin APIs have stability issues, particularly sensitivity to ultraviolet radiation. Furthermore, the methylcobalamin raw material is hygroscopic and has poor light and oxygen stability. The melogabalin besylate raw material also has poor compressibility and powder flowability. Therefore, the present invention addresses these issues by adding excipients such as fillers, disintegrants, lubricants, antioxidants, colorants, foaming agents, and flavoring agents to a 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 ferric oxide, ferric oxide, 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:

[0035] 1) Preparation of Melogabalin Besylate Granules: Melogabalin besylate, filler, and foaming agent weighed in appropriate proportions are mixed in a PE bag and sieved. The sieved powder is placed in a fluidized bed granulator and sprayed with a disintegrant binder dissolved in purified water for granulation to obtain Melogabalin Besylate Granules.

[0036] 2) Preparation of Methylcobalamin Granules: Weigh proportional amounts of methylcobalamin and filler, mix in a PE bag, sieve, place the sieved powder in a fluidized bed granulator, spray with a disintegrant binder dissolved in purified water, and granulate to obtain methylcobalamin granules;

[0037] 3) Preparation of compressed tablet granules: Melogabalin besylate granules, methylcobalamin granules, crystalline cellulose, carboxymethyl cellulose, and acesulfame potassium were weighed and mixed according to a proportion, and then magnesium stearate was weighed and mixed according to a proportion to obtain compressed tablet granules;

[0038] 4) Tablet pressing: Use a tablet press to press tablets according to the set tablet mass and pressure;

[0039] 5) Coating: Coating is completed.

[0040] In view of the excellent clinical effects 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.

[0041] In a seventh aspect of the present invention, the present invention has discovered that, in the same subjects receiving the aforementioned combination therapy of melogabalin and methylcobalamin, the present invention has surprisingly positive effects in terms of improving memory and learning, boosting 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 a medicament for improving memory, controlling homocysteine ​​levels, promoting cardiovascular health, enhancing immune system function, and / or ameliorating neurodegenerative diseases.

[0042] Beneficial effects

[0043] (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.

[0044] (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.

[0045] (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 by using melogabalin and methylcobalamin in combination. BRIEF DESCRIPTION OF THE DRAWINGS

[0046] Figure 1 : Dissolution curve of melogabalin besylate in 0.1 mol / L hydrochloric acid solution.

[0047] Figure 2 : Dissolution curve of melogabalin besylate in water.

[0048] Figure 3 : Dissolution curve of melogabalin besylate in acetate solution at pH 4.5.

[0049] Figure 4 : Dissolution curve of melogabalin besylate in pH 6.8 phosphate solution.

[0050] Figure 5 : Dissolution curve of methylcobalamin in 0.1mol / L hydrochloric acid solution.

[0051] Figure 6 : Dissolution curve of methylcobalamin in water.

[0052] Figure 7 : Dissolution curve of methylcobalamin in acetate solution at pH 4.5.

[0053] Figure 8 : Dissolution curve of methylcobalamin in pH 6.8 phosphate solution. DETAILED DESCRIPTION

[0054] In order to make the objectives, technical solutions and advantages of the present invention more clearly understood, the present invention is further described in detail below with reference to the following examples. Unless otherwise specified, the equipment and reagents used in each example and test example can be obtained from commercial sources. Unless otherwise specified, the reagents used in the present invention are all analytical grade reagents. The specific examples described herein are only used to illustrate the present invention and are not intended to limit the present invention.

[0055] (I) Development of orally disintegrating tablets containing melogabalin besylate and methylcobalamin

[0056] 1.1 Filler type and dosage screening

[0057] 1.1.1 Filler Type and Weight Screening for Melogabalin Besylate Granules

[0058] During the study, the flowability, bulk density, mixing uniformity, and compressibility of the 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.

[0059] Table 1 Filler type and dosage screening of melogabalin besylate

[0060] ;

[0061] Preparation method:

[0062] 1. Pretreatment: Pass melogabalin besylate and filler through 80-mesh sieve respectively and set aside; weigh hypromellose and add purified water to dissolve in agitation as a binder;

[0063] 2. Mixing and granulation: Weigh the main drug, mannitol, lactose, microcrystalline cellulose, sorbitol, pregelatinized starch, glycine, and crystalline cellulose in the order prescribed. Place the mixture in a wet granulator at a stirring speed of 300 rpm / min. Take samples after 5, 10, and 15 minutes to check the mixing uniformity. If the mixture is qualified, add the binder and granulate.

[0064] 3. Drying and granulation: Dry the wet granules. When the moisture content of the granules is ≤2.0%, stop drying and granulate them using an 18-mesh sieve.

[0065] 4. Total mixing: Add the prescribed amount (0.5%) of magnesium stearate to the dry granules and mix for 15 minutes.

[0066] 5. Tablet pressing: pressure parameter 10~80KN, hardness control 5~8kg

[0067] Table 2 Screening results of filler types and dosages of melogabalin besylate

[0068] ;

[0069] Judging from the test results, prescription 4 is the best.

[0070] 1.1.2 Screening of filler dosage for methylcobalamin granules

[0071] During the prescription screening process, the flowability, bulk density and uniformity of the primary mixed powder and granules were examined. The compressibility of the granules, the appearance, hardness and friability of the plain tablets were also examined. The test results are shown in Tables 3 and 4.

[0072] Table 3 Screening of filler types and dosages of methylcobalamin

[0073] ;

[0074] Preparation method:

[0075] 1. Pretreatment: Pass methylcobalamin and filler through 80-mesh sieve respectively and set aside; weigh hypromellose, add purified water and stir to dissolve as a binder;

[0076] 2. Mixing and granulation: Weigh the main drug, mannitol, microcrystalline cellulose, pregelatinized starch, and crystalline cellulose according to the prescription, place them in a wet granulator, and stir at 300 rpm / min. Take samples after 5, 10, and 15 minutes to check the mixing uniformity. If the samples meet the requirements, add the binder and granulate.

[0077] 3. Drying and granulation: Dry the wet granules. When the moisture content of the granules is ≤2.0%, stop drying and granulate them using an 18-mesh sieve.

[0078] 4. Total mixing: Add the prescribed amount (0.5%) of magnesium stearate to the dry granules and mix for 15 minutes.

[0079] 5. Tablet pressing: pressure parameter 10~80KN, hardness control 5~8kg

[0080] Table 4 Screening results of filler dosage of methylcobalamin

[0081] ;

[0082] Judging from the test results, prescription 9 is the best.

[0083] 1.2 Adhesive type and dosage screening

[0084] Commonly used binders include hypromellose, low-substituted hydroxypropyl cellulose, sodium carboxymethyl cellulose, povidone K30, carboxymethyl cellulose, and ethyl cellulose. Based on the dosage characteristics of this product, we screened the types and dosages of hypromellose, low-substituted hydroxypropyl cellulose, carboxymethyl cellulose, and povidone K30. We dissolved the various binders in water at the intended dosage to create solutions of a certain concentration. These solutions served as binders for wet granulation, focusing on the drying time, moisture content, compressibility, hardness, friability, and disintegration time of the wet granules produced with the different binders. The test results are shown in Tables 5 and 6.

[0085] Table 5. Adhesive type and dosage screening formula composition (the first column of the formula contains melogabalin besylate as the API, and the second column contains methylcobalamin)

[0086] ;

[0087] Table 6 Results of the adhesive type and dosage screening test

[0088] ;

[0089] The test results show that low-substituted hydroxypropyl cellulose is the best binder of the present invention.

[0090] 1.3 Screening of disintegrant types and dosages

[0091] Based on prescription 13, sodium carboxymethyl starch, cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose and an effervescent disintegrant were selected as disintegrants, 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, with a ratio of 1:1.

[0092] Disintegrants are added during the granulation process, while effervescent disintegrants are added during the final blend. Their 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 selection of disintegrant type and dosage focused on granule moisture, hardness, friability, and disintegration time. The test results are shown in Tables 7 and 8.

[0093] Table 7 Disintegrant type and dosage screening formula composition (the first column of the formula contains melogabalin besylate as the API, and the second column contains methylcobalamin)

[0094] ;

[0095] Table 8 Results of the screening test on adhesive types and dosage

[0096] ;

[0097] According to the test results, the average disintegration time of the plain tablets made with 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 in the later stage of this product, it is necessary to further optimize the dosage and addition method of the disintegrant to obtain more significant disintegration.

[0098] One-half of the prescribed amount of cross-linked polyvinylpolypyrrolidone and effervescent disintegrant (citric acid monohydrate / magnesium aluminum silicate) was added to the primary mixture, and the remaining amount of cross-linked polyvinylpolypyrrolidone and effervescent disintegrant (citric acid monohydrate / magnesium aluminum silicate) was added during the total mixing process. The main purpose was to investigate the disintegration time of the plain tablets after the addition of part of the disintegrant. The test results are shown in Tables 9 and 10.

[0099] Table 9 Disintegrant addition method and formulation composition (API listed first in the formulation is melogabalin besylate, and API listed second is methylcobalamin)

[0100] ;

[0101] Table 10 Results of investigation on disintegrant addition method

[0102] ;

[0103] The test results show that the addition of disintegrant significantly improves the disintegration performance of the plain tablets.

[0104] 1.4 Screening of antioxidants and flavoring agents

[0105] 1.4.1 Screening of antioxidants

[0106] This product is a compound preparation. Melogabalin besylate is oxygen-sensitive, and methylcobalamin is light-sensitive. Therefore, during the preparation process, antioxidants were considered to enhance its stability. Considering the formulation characteristics, sodium metabisulfite, ascorbic acid, cysteine ​​hydrochloride, glutathione, and tocopherol were selected for investigation, with a provisional formulation concentration of 1%. The prepared tablets were exposed to light and high temperature for 10 days. Samples were taken at 0, 5, and 10 days to examine changes in appearance, content, and related substances. The test results are shown in Tables 11, 12, and 13.

[0107] Table 11 Antioxidant type screening (the first API in the prescription is melogabalin besylate, and the second is methylcobalamin)

[0108] ;

[0109] Table 12 Results of the investigation on the factors affecting illumination

[0110] ;

[0111] Table 13 Results of the investigation on the influencing factors at high temperature of 60℃

[0112] ;

[0113] The results showed that tocopherol was the best antioxidant.

[0114] 1.4.2 Investigation of flavoring agents

[0115] During formulation development, sweeteners with a good safety profile should be selected. Common sweeteners include sucrose, sodium saccharin, saccharin, aspartame, sucralose, dipotassium glycyrrhizate, stevioside, and acesulfame potassium. Saccharin sodium and saccharin carry a potential use warning, and sucrose is hygroscopic, potentially leading to tableting irregularities. Therefore, five sweeteners—aspartame, sucralose, dipotassium glycyrrhizate, stevioside, and acesulfame potassium—were ultimately selected for investigation. To ensure uniform distribution of the sweeteners throughout the tablets, solutions were prepared with a binder and added during the granulation process. Each sweetener has a different application range, and preliminary screening was conducted at 1% tablet weight. A taste analyzer was used to assess the suitability of different sweeteners for this product formulation. The formulation composition and test results are shown in Tables 14 and 15.

[0116] Table 14 Composition of sweetener screening formula (API listed first in the formula is melogabalin besylate, and API listed second is methylcobalamin)

[0117] ;

[0118] Table 15 Sample measurement results

[0119] ;

[0120] Note: The standard sample measurement result is the 0-point value. If the measurement result is greater than the 0-point value, the corresponding flavor is present; if the measurement result is less than the 0-point value, the corresponding flavor is absent.

[0121] 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 the addition of acesulfame potassium. Therefore, acesulfame potassium is the best sweetener of the present invention.

[0122] 1.5 Screening of antioxidant dosage

[0123] 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 dose of tocopherol is 85 mg. Combined with the existing research results, the dosage of tocopherol was optimized. Samples prepared with different prescription amounts of tocopherol were investigated respectively. The small 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.

[0124] Table 16 Antioxidant dosage screening formula composition (the first column of the formula contains melogabalin besylate as the API, and the second column contains methylcobalamin)

[0125] ;

[0126] Table 17 Results of light test on influencing factors

[0127] ;

[0128] Table 18 High temperature test results of influencing factors

[0129] ;

[0130] Analysis of Results: The test results showed that when the tocopherol dosage reached 3% or more of the prescribed dosage, the appearance, content, and related substance test results of the pilot sample showed no significant changes after 10 days of observation under high temperature and light conditions, indicating good stability. Based on the test results, the optimal dosage of tocopherol was 3% of the prescribed dosage, or 15.9 mg per tablet.

[0131] 1.6 Film coating weight gain investigation

[0132] 1.6.1 Film coating material selection

[0133] The film coating material must have good film-forming properties 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 small 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.

[0134] Table 19 Coating Weight Gain Investigation (API listed first in the prescription is melogabalin besylate, and API listed second is methylcobalamin)

[0135] ;

[0136] Table 20 Coating weight gain investigation results

[0137] ;

[0138] Analysis of the results showed that controlling the coating weight gain ratio of this product at 3.0% resulted in yellow film-coated tablets with a smooth and neat surface and a faster disintegration rate.

[0139] In summary, the present invention has selected suitable excipients from the group consisting of disintegrants, fillers, binders, diluents, lubricants, glidants, sweeteners and flavorings, which endow the orally disintegrating tablets of the present invention with sufficient uniformity, content uniformity and stability.

[0140] Therefore, the present invention provides a method for preparing an orally disintegrating tablet for treating pain caused by nerve damage, the method comprising:

[0141] 1) Preparation of Melogabalin Besylate Granules: Melogabalin besylate, filler, and foaming agent weighed in appropriate proportions are mixed in a PE bag and sieved. The sieved powder is placed in a fluidized bed granulator and sprayed with a disintegrant binder dissolved in purified water for granulation to obtain Melogabalin Besylate Granules.

[0142] 2) Preparation of Methylcobalamin Granules: Weigh proportional amounts of methylcobalamin and filler, mix in a PE bag, sieve, place the sieved powder in a fluidized bed granulator, spray with a disintegrant binder dissolved in purified water, and granulate to obtain methylcobalamin granules;

[0143] 3) Preparation of compressed tablet granules: Melogabalin besylate granules, methylcobalamin granules, crystalline cellulose, carboxymethyl cellulose, and acesulfame potassium were weighed and mixed according to a proportion, and then magnesium stearate was weighed and mixed according to a proportion to obtain compressed tablet granules;

[0144] 4) Tablet pressing: Use a tablet press to press tablets according to the set tablet mass and pressure;

[0145] 5) Coating: Coating is completed.

[0146] Example 1

[0147] Table 21 Melogabaline Besylate / Methylcobalamin Orally Disintegrating Tablets (5 mg / 0.5 mg / tablet)

[0148] ;

[0149] According to the prescription in Table 21, a method for preparing an orally disintegrating tablet for treating pain caused by nerve damage:

[0150] 1. Prepare the materials: Pass the API (melogabaline besylate, methylcobalamin), mannitol, microcrystalline cellulose, pregelatinized starch, crystalline cellulose, citric acid monohydrate, and magnesium aluminum silicate through an 80-mesh sieve respectively;

[0151] 2. Weighing: Weigh the API and excipients according to the prescribed amount and set aside;

[0152] 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 it, 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;

[0153] 4. Mixing: Place the weighed two active ingredients and the corresponding prescribed 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.

[0154] 5. Granulation: Use the prepared adhesive solution to granulate the two active ingredients respectively. The adhesive addition rate is controlled at 200 ml / min.

[0155] 6 Drying: Spread the wet granules flatly in the corresponding container and dry them at 60℃ until the moisture content of the granules is less than 2.0%.

[0156] 7. Granulate: Pass the dried material through an 18-mesh sieve for granulation;

[0157] 8. Total mixing: Add the prescribed amount of crospovidone, citric acid monohydrate / sodium bicarbonate, magnesium stearate and dry granules into a three-dimensional mixer, cover with the top cover, and mix for 20 minutes;

[0158] 9. Tablet pressing: Adjust the tablet press pressure, hardness 4-7kg, tablet weight range: ±3%;

[0159] 10. Coating: Tablet bed temperature: 50-60°C, core temperature: 30-40°C, spray gun flow rate: 10-20 ml / min. Coating weight gain: 3.0%.

[0160] Example 2

[0161] Table 22 Melogabaline Besylate / Methylcobalamin Orally Disintegrating Tablets (10 mg / 0.75 mg / tablet)

[0162] ;

[0163] The preparation steps are the same as in Example 1, and the amounts of substances used are shown in Table 22.

[0164] Example 3

[0165] Table 23 Melogabaline Besylate / Methylcobalamin Orally Disintegrating Tablets (2.5 mg / 0.5 mg / tablet)

[0166] ;

[0167] The preparation steps are the same as in Example 1, and the amounts of substances used are shown in Table 23.

[0168] Example 4

[0169] Table 24 Melogabaline Besylate / Methylcobalamin Orally Disintegrating Tablets (15 mg / 0.75 mg / tablet)

[0170] ;

[0171] The preparation steps are the same as in Example 1, and the amounts of substances used are shown in Table 24.

[0172] (II) Testing of orally disintegrating tablets for treating pain caused by nerve damage

[0173] Test Example 1: Influencing Factor Test

[0174] The samples of Example 1 were placed under conditions of 5000 lx illumination, 92.5% humidity, and 60°C for 10 days, and the samples were tested for changes in properties, moisture content, disintegration time, content, and related substances. The test results are shown in Table 25, indicating that the orally disintegrating tablets prepared were very stable.

[0175] Table 25: Experimental results of factors affecting Example 1

[0176] ;

[0177] Test Example 2 Dissolution Curve

[0178] 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 tablets prepared by the present invention meets the quality requirements.

[0179] Table 26: Dissolution curve of melogabalin besylate in 0.1 mol / L hydrochloric acid solution

[0180] ;

[0181] Table 27: Dissolution curve of melogabalin besylate in water

[0182] ;

[0183] Table 28: Dissolution curve of melogabalin besylate in pH 4.5 acetate solution

[0184] ;

[0185] Table 29: Dissolution curve of melogabalin besylate in pH 6.8 phosphate solution

[0186] ;

[0187] Table 30 Dissolution curve of methylcobalamin in 0.1 mol / L hydrochloric acid solution

[0188] ;

[0189] Table 31: Dissolution curve of methylcobalamin in water

[0190] ;

[0191] Table 32 Dissolution curve of methylcobalamin in pH 4.5 acetate solution

[0192] ;

[0193] Table 33: Dissolution curve of methylcobalamin in pH 6.8 phosphate solution

[0194] ;

[0195] Test Example 3: Clinical Test Study of the Orally Disintegrating Tablet of the Present Invention

[0196] 1 Materials and Methods

[0197] 1.1 General Data: Eighty patients with diabetic peripheral neuropathy were randomly divided into a study group and a control group, 40 patients in each group. The study group included 23 males and 17 females, aged 58 to 70 years (mean, 64.00 ± 3.12 years), with a disease duration of 1 to 8 years (mean, 4.50 ± 0.45 years). The control group included 24 males and 16 females, aged 60 to 68 years (mean, 64.00 ± 3.02 years), with a disease duration of 2 to 7 years (mean, 4.50 ± 0.50 years). No statistically significant differences in general data were found between the two groups (P > 0.05), indicating comparability. This study was approved by the hospital's Medical Ethics Committee.

[0198] 1.2 Inclusion and Exclusion Criteria: Inclusion criteria: ① All patients had diabetic peripheral neuropathy; ② Complete clinical data; ③ Active participation after the study objectives, content, and methods were clarified. Exclusion criteria: ① A history of drug allergy; ② Presence of neurological disease; ③ Survival of <1 year.

[0199] 1.3 Methods: The control group was given metformin hydrochloride tablets (0.25 g) orally, one tablet three times daily; and melogaba besylate tablets (5 mg) orally, one tablet twice daily, after meals. The study group was given metformin hydrochloride tablets (0.25 g) orally, one tablet three times daily; and Example 1 of the present invention, one tablet twice daily, after meals. Both groups were treated for four consecutive weeks.

[0200] 1.4 Observation indicators: ① Comparison of the treatment efficacy between the two groups: assessment was conducted based on the improvement of clinical symptoms such as numbness, pain, muscle weakness, and burning sensation in the distal limbs; marked efficacy was defined as complete resolution of all the above clinical symptoms after treatment; effective efficacy was defined as relief of all the above symptoms after treatment; ineffective efficacy was defined as patients failing to achieve any of the above indicators; total effective rate = (number of markedly effective cases + number of effective cases) / total number of cases × 100%.

[0201] ② Comparison of pain levels between the two groups before and 4 weeks after treatment: The visual analogue scale (VAS) was used to assess pain, with a total score of 10 points. The score was proportional to the patient's pain sensation.

[0202] ③ Compare the adverse reactions of the two groups: such as nausea, dizziness, weakness, drowsiness, etc.

[0203] 1.5 Statistical methods: SPSS 23.0 statistical software was used for data processing. Quantitative data that met normal distribution were expressed as (xˉ±s) and subjected to t-test. Enumeration data were expressed as number of cases (n) and rate (%) and subjected to χ2 test. P < 0.05 was considered as significant difference.

[0204] The difference was statistically significant.

[0205] 2 Results

[0206] 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.

[0207] Table 34: Therapeutic effectiveness of the orally disintegrating tablet of the present invention

[0208] ;

[0209] 2.2 Comparison of pain conditions between the two groups of patients before and after treatment: Before treatment, the VAS scores of the two groups of patients showed no statistically significant difference (P>0.05); after treatment, the scores of both groups of patients decreased, with the study group having lower scores than the control group, and the difference was statistically significant (P<0.05), see Table 35 below.

[0210] Table 35: Comparison of pain relief effects of orally disintegrating tablets of the present invention

[0211] ;

[0212] *Indicates P < 0.05 compared with the same group before treatment.

[0213] 2.3 Comparison of adverse reactions between the two groups: There was no statistically significant difference in the incidence of adverse reactions between the two groups (P>0.05). Insomnia and memory improved, as shown in Table 36 below.

[0214] Table 36: Comparison of the effects of the orally disintegrating tablets of the present invention on improving insomnia and memory

[0215] ;

[0216] 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 postherpetic neuralgia and postoperative neuropathic pain.

[0217] The above content is a further detailed description of the present invention in conjunction 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, they can make several simple deductions or substitutions without departing from the concept of the present invention, which should be regarded as falling within the scope of protection determined by the claims submitted for the present invention.

Claims

1. An orally disintegrating tablet for treating diabetic peripheral neuropathy, characterized in that: The active pharmaceutical ingredients of the disintegrating tablet are melogabalin benzyl salt and methylcobalamin, and the weight ratio w / w of melogabalin benzyl salt and methylcobalamin is 10:1, or 10:0.75; the disintegrating tablet further contains: a) a filler, wherein the filler consists of D-mannitol, crystalline cellulose, microcrystalline cellulose, and pregelatinized starch; b) a disintegrant consisting of hydroxypropyl cellulose and cross-linked polyvinylpyrrolidone; c) a lubricant consisting of magnesium stearate; d) flavoring agent, consisting of acesulfame potassium; e) an antioxidant consisting of tocopherol; f) a colorant consisting of yellow ferric oxide; g) Foaming agent, consisting of citric acid monohydrate / magnesium aluminum silicate.

2. A method for preparing an orally disintegrating tablet according to claim 1, characterized in that: The method comprises: 1) Preparation of Melogabalin Besylate Granules: Melogabalin besylate, filler, and foaming agent weighed in appropriate proportions are mixed in a PE bag and sieved. The sieved powder is placed in a fluidized bed granulator and sprayed with a disintegrant binder dissolved in purified water for granulation to obtain Melogabalin Besylate Granules. 2) Preparation of Methylcobalamin Granules: Weigh proportional amounts of methylcobalamin and filler, mix in a PE bag, sieve, place the sieved powder in a fluidized bed granulator, spray with a disintegrant binder dissolved in purified water, and granulate to obtain methylcobalamin granules. 3) Preparation of compressed tablet granules: Melogabalin besylate granules, methylcobalamin granules, crystalline cellulose, carboxymethyl cellulose, and acesulfame potassium were weighed and mixed according to a proportion, and then magnesium stearate was weighed and mixed according to a proportion to obtain compressed tablet granules; 4) Tablet pressing: Use a tablet press to press tablets according to the set tablet mass and pressure; 5) Coating: Coating is completed.

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