Pharmaceutical composition containing melogabalin besylate and preparation method thereof

Abstract

The invention discloses a pharmaceutical composition containing melogabalin besylate and a preparation method of the pharmaceutical composition. Belongs to the technical field of pharmaceutical preparations. Comprising melogabalin besylate and pharmaceutically acceptable auxiliary materials, the pharmaceutically acceptable auxiliary materials comprise a filler, a disintegrating agent, an adhesive, an antioxidant and a lubricant, the antioxidant comprises vitamin E succinic acid polyethylene glycol ester, and the lubricant comprises vitamin E succinic acid polyethylene glycol ester. The melogabalin besylate as the active ingredient accounts for 2-15% by weight of the pharmaceutical composition, preferably 2-10% by weight of the pharmaceutical composition. According to the pharmaceutical composition, antioxidant particles are prepared by adopting a fluidized bed granulation process, raw material medicines, the antioxidant particles and other auxiliary materials are mixed, tableted and coated, an antioxidant comprises vitamin E succinic acid polyethylene glycol ester and tartaric acid, and the prepared tablet has good stability.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical preparations, and in particular relates to a pharmaceutical composition with Mirogabalin Besilate, a compound capable of inhibiting neuralgia, as an active ingredient, and a preparation method thereof. Background Art

[0002] Neuropathic pain (NP) is pain caused by damage or disease of the human sensory system, which is divided into peripheral neuropathic pain and central neuropathic pain. Peripheral neuropathic pain is more common clinically. The mechanism of neuropathic pain is complex. It is a syndrome caused by many different diseases and damages. There are more than 100 clinical diseases associated with it, which seriously affect the quality of life of patients. At present, the treatment of neuropathic pain still faces challenges, and most patients have refractory pain. In addition, patients often experience serious adverse reactions during treatment.

[0003] Due to the complex mechanism of neuropathic pain, the efficacy of the same drug on different types of neuropathic pain is not the same. The choice of drug should take into account the specific neuropathic pain symptoms and the efficacy / safety ratio of the drug as well as the patient's clinical condition (such as complications, contraindications, and concomitant medication). For example, pregabalin, gabapentin, tricyclic antidepressants, lidocaine, etc. can be used for postherpetic neuralgia; pregabalin, gabapentin, tricyclic antidepressants, norepinephrine reuptake inhibitors (such as duroxetine, venlafaxine) can be used for painful polyneuropathy; pregabalin, gabapentin, tricyclic antidepressants and other drugs can be used for central pain. Among them, pregabalin and gabapentin, as calcium channel regulators, are widely used in neuropathic pain due to their excellent safety and efficacy. Among them, pregabalin is recommended by the treatment guidelines of various countries as a first-line drug for the treatment of various types of neuropathic pain, and it occupies a prominent position in the field of neuropathic pain treatment. The research and development of new calcium channels has always been a hot topic.

[0004] Melogabalin besylate is a novel, highly selective calcium channel inhibitor. It can selectively act on the α2δ subunit of the voltage-gated calcium channel (widely present in the nervous system that mediates pain transmission and processing throughout the body), thereby playing a role in treating chronic neuropathic pain. Compared with pregabalin, melogabalin besylate has a stronger affinity for α2δ-1 and α2δ-2 subunits, a longer dissociation half-life with such subunits, better efficacy, and longer duration of action. Phase III clinical trials also confirmed the safety and effectiveness of melogabalin besylate in the treatment of diabetic peripheral neuropathic pain (DPNP) and post-herpetic neuralgia (PHN) in Asian populations. Japanese pharmaceutical company Daiichi Sankyo announced that the company's melogabalin besylate Tablets (2.5mg, 5mg, 10mg, 15mg specifications) have been approved in Japan for the treatment of peripheral neuropathic pain (PNP). Generally, the initial dose for adult patients is 5mg, taken orally twice a day, and then gradually increased by 5mg at intervals of at least one week to 15mg. Its oral dose has been significantly reduced compared to pregabalin tablets.

[0005] Melegabalin besylate is a small molecule compound, its chemical name is [(1R,5S,6S)-6-(aminomethyl)-3-ethylbicyclo[3.2.0]hept-3-en-6-yl]acetic acid monobenzenesulfonate, molecular formula C 12 H 19 NO 2 ·C 6 H 6 O 3 S, molecular weight 367.46. The structural formula of melogabalin besylate compound is as shown in the formula:

[0006]

[0007] Melogabalin besylate is similar to gabapentin and pregabalin and is a γ-aminobutyric acid (GABA) analog. A notable feature of this type of drug is that it has primary amino and carboxyl groups in its molecular structure. During the synthesis, formulation and storage of the drug, the amino group reacts with its carboxyl functional group to form lactam impurities. At the same time, during the preparation of the preparation, the primary amino group can undergo a Maillard reaction with an excipient with a reducing carbonyl functional group (such as lactose) to produce impurities. In addition, the bicyclic structure in the molecular structure of melogabalin besylate may degrade and open the ring to form impurities. Excessive amounts of this type of impurities produced during the preparation of the drug are very likely to cause toxic side effects.

[0008] In order to ensure the effectiveness and safety of the drug, it is urgently necessary to develop a pharmaceutical composition of melogabalin besylate with strong operability in formulation process, simple preparation process and stability. Summary of the invention

[0009] The present invention provides an oral pharmaceutical composition containing melogabalin besylate, wherein the medicine comprises a stabilizer, thereby ensuring the stability of the pharmaceutical composition during preparation and storage. In addition, the present invention provides a preparation method with simple process steps and capable of ensuring the stability of the pharmaceutical composition during the preparation process.

[0010] The present invention first provides a pharmaceutical composition containing melogabalin besylate, comprising an active ingredient melogabalin besylate and pharmaceutically acceptable excipients, wherein the pharmaceutically acceptable excipients comprise a filler, a disintegrant, a binder, an antioxidant and a lubricant, wherein the antioxidant comprises vitamin E succinate polyethylene glycol ester, and the weight percentage of the active ingredient melogabalin besylate in the pharmaceutical composition is 2-15%, preferably 2-10%.

[0011] In some preferred embodiments of the pharmaceutical composition of the present invention, the antioxidant further comprises one or more of tartaric acid, malic acid, and citric acid.

[0012] In other preferred embodiments of the pharmaceutical composition of the present invention, the antioxidant is a combination of vitamin E succinate polyethylene glycol ester and tartaric acid.

[0013] In some preferred embodiments of the pharmaceutical composition of the present invention, the combination of the antioxidant vitamin E succinate polyethylene glycol ester and tartaric acid accounts for 0.01%-15% of the total weight of the pharmaceutical composition, preferably 2%-11%, and more preferably 2% to 5%.

[0014] In some preferred embodiments of the pharmaceutical composition of the present invention, the antioxidant vitamin E polyethylene glycol succinate accounts for 0.01%-7%, preferably 0.05%-5% of the total weight of the pharmaceutical composition.

[0015] In some preferred embodiments of the pharmaceutical composition of the present invention, the antioxidant tartaric acid accounts for 0.01%-8%, preferably 2%-6% of the total weight of the pharmaceutical composition.

[0016] In some preferred embodiments of the pharmaceutical composition of the present invention, the filler is selected from one or more of sugar alcohols, celluloses, and starches, and the weight percentage of the filler in the pharmaceutical composition is 10-90%, preferably 30-80%.

[0017] The sugar alcohol filler is selected from mannitol, maltitol, erythritol, lactitol, sorbitol or xylitol, preferably spray-dried mannitol.

[0018] The cellulose filler is selected from microcrystalline cellulose, powdered cellulose or silicified microcrystalline cellulose.

[0019] The starch filler is selected from corn starch, potato starch or pregelatinized starch, preferably pregelatinized starch.

[0020] In other preferred embodiments, the filler is mannitol, or a mixture of mannitol and microcrystalline cellulose in a weight ratio of 1:1-8:1, preferably in a weight ratio range of 1:1-3:1.

[0021] In the pharmaceutical composition of the present invention, the disintegrant is selected from one or more of cross-linked sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, and sodium starch glycolate.

[0022] In some preferred embodiments, the disintegrant is croscarmellose sodium.

[0023] In some preferred embodiments, the weight percentage of the disintegrant in the pharmaceutical composition is 1%-15%, preferably 5%-12%.

[0024] In the pharmaceutical composition of the present invention, the lubricant is selected from one or more of magnesium stearate, calcium stearate, zinc stearate, hydrogenated vegetable oil, glyceryl behenate, stearic acid, and sodium stearyl fumarate.

[0025] In some preferred embodiments, the lubricant is selected from magnesium stearate, glyceryl behenate or sodium stearyl fumarate.

[0026] In other preferred embodiments, the weight percentage of the lubricant in the pharmaceutical composition is 0.5-8%, preferably 2-5%.

[0027] In the pharmaceutical composition of the present invention, the binder is selected from one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, methyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose and polyvinyl pyrrolidone.

[0028] In some preferred embodiments, the binder is hypromellose or hydroxypropyl cellulose.

[0029] In other preferred embodiments, the weight percentage of the binder in the pharmaceutical composition is 0-10%, preferably 0.1-5%, more preferably 0.1-3%.

[0030] In some preferred embodiments, the present invention provides a pharmaceutical composition containing melogabalin besylate, comprising the following components in percentage by weight:

[0031]

[0032] In other preferred embodiments, the present invention provides a pharmaceutical composition containing melogabalin besylate, comprising the following components in percentage by weight:

[0033]

[0034] The pharmaceutical composition of the present invention is preferably prepared into a dosage form for oral administration, which can be a tablet, granule or capsule; when the dosage form is a tablet or granule, a coating is applied as needed. The coating is carried out under the condition of adding conventional coating media and film-forming agents familiar to those skilled in the art (generally referred to as coating materials), and these coating materials can be selected from one or more of the following: hydroxypropyl cellulose, hydroxypropyl methylcellulose, ethyl cellulose, polyvinyl pyrrolidone, vinyl pyrrolidone-vinyl acetate copolymer (e.g. VA64, BASF), shellac, copolymers of acrylates and / or methacrylates and trimethylammonium methacrylate, copolymers of dimethylaminomethacrylic acid and neutral methacrylate, polymers of methacrylic acid or methacrylate, ethyl acrylate-methyl methacrylate copolymers, methacrylic acid-methyl acrylate copolymers, propylene glycol, polyethylene glycol, triacetin, triethyl citrate and / or dye additives / pigments such as titanium dioxide, iron oxide, indigo or suitable lakes.

[0035] The present invention also provides a method for preparing any of the above-mentioned pharmaceutical compositions containing melogabalin besylate, comprising the following steps:

[0036] (1) Preparation of antioxidant-containing granules: an antioxidant and a binder are dissolved in water to obtain a binder solution, and the binder solution is then added to a filler or a mixture of a filler and a disintegrant to prepare antioxidant-containing granules.

[0037] (2) Mixing melogabalin besylate, the antioxidant-containing granules obtained in step (1), a filler, a disintegrant, and a lubricant, and directly tableting and coating the mixture, or performing dry granulation, mixing, tableting, and coating the mixture.

[0038] The method for preparing the pharmaceutical composition containing melogabalin besylate of the present invention, in some preferred embodiments, comprises the following steps:

[0039] (1) The filler is mixed uniformly, and the mixing method is selected from mixing with a mixer, a wet granulator or a fluidized bed one-step granulation mixing,

[0040] (2) preparing a binder and / or an antioxidant into a binder solution, and then using a high shear wet granulator or a fluidized bed to uniformly mix the binder solution with the mixture obtained in step (1) to granulate to obtain granules containing an antioxidant,

[0041] (3) uniformly mixing melogabalin besylate with the antioxidant-containing particles obtained in step (2), a filler, a disintegrant, and a lubricant,

[0042] (4) Compressing the mixture obtained in step (3) into tablets.

[0043] In some preferred embodiments, the method further comprises coating the tablets obtained in step (4).

[0044] The pharmaceutical composition of the present invention can be prepared by granulation and tableting techniques commonly used in oral solid preparations, such as wet granulation, fluidized bed granulation, dry granulation, or direct mixing and tableting. In some preferred embodiments, the present invention adopts a preparation process of direct mixing and tableting, which is simple to operate and convenient for industrial production.

[0045] Compared with the prior art, the present invention has the following advantages:

[0046] (1) The pharmaceutical composition containing melogabalin besylate of the present invention has good chemical stability, and the content of related substances in the drug during preparation and storage is low, thereby ensuring the safety and effectiveness of the drug;

[0047] (2) The pharmaceutical composition containing melogabalin besylate of the present invention is an oral solid preparation, which has a simple preparation process, strong operability, good drug stability and low content of related substances. DETAILED DESCRIPTION

[0048] The present invention is further described below by way of examples. It should be understood that the examples of the present invention are provided only for illustrating the present invention, rather than limiting the present invention, and simple improvements to the present invention based on the technical solution of the present invention all fall within the protection scope of the present invention.

[0049] Table 1 Prescriptions for Examples 1 to 5

[0050]

[0051]

[0052] Note: Coating premix is (Gastric soluble).

[0053] Examples 1 to 5 Sample preparation process :

[0054] (1) dissolving vitamin E polysuccinate polyethylene glycol ester, tartaric acid or malic acid or citric acid and hydroxypropyl cellulose in an appropriate amount of purified water to prepare a binder solution containing a stabilizer, and granulating the binder solution and a portion of the filler using a fluidized bed to obtain granules containing an antioxidant;

[0055] (2) mixing melogabalin besylate, mannitol, microcrystalline cellulose, croscarmellose sodium and granules containing an antioxidant uniformly according to weight percentage;

[0056] (3) The material in step (2) is sieved, and the sieve mesh size is 1.143 mm;

[0057] (4) passing sodium stearyl fumarate and magnesium stearate through a 40-mesh sieve respectively, and then mixing them evenly with the mixture obtained in step (3);

[0058] (5) tableting the mixture obtained in step (4), controlling the average weight difference to ±5% and the tablet hardness to 4kg to 14kg;

[0059] (6) Disperse an appropriate amount of coating premix into aqueous solution to prepare a coating solution (mass of coating premix / mass of coating solution)

[0060] =13%);

[0061] (7) coating the tablets prepared in step (4) with the coating solution prepared in step (6);

[0062] (8) Packing the coated tablets obtained in step (7) (aluminum-plastic pillow packaging, with 1 bag of solid pharmaceutical molecular sieve desiccant added inside).

[0063] Table 2 Prescriptions for Examples 6 to 9

[0064]

[0065] Note: Coating premix is (Gastric soluble).

[0066] Examples 6 to 9 Sample Preparation Process :

[0067] (1) dissolving vitamin E polysuccinate polyethylene glycol ester, tartaric acid and hydroxypropyl cellulose in an appropriate amount of purified water to prepare a binder solution containing a stabilizer, and granulating the binder solution and a portion of the filler using a fluidized bed to obtain granules containing an antioxidant;

[0068] (2) mixing melogabalin besylate, mannitol, microcrystalline cellulose, croscarmellose sodium and granules containing an antioxidant uniformly according to weight percentage;

[0069] (3) The material in step (2) is sieved, and the sieve mesh size is 1.143 mm;

[0070] (4) passing sodium stearyl fumarate and magnesium stearate through a 40-mesh sieve respectively, and then mixing them evenly with the mixture obtained in step (3);

[0071] (5) tableting the mixture obtained in step (4), controlling the average weight difference to ±5% and the tablet hardness to 4kg to 14kg;

[0072] (6) Disperse an appropriate amount of coating premix into aqueous solution to prepare a coating solution (mass of coating premix / mass of coating solution)

[0073] =13%);

[0074] (7) coating the tablets prepared in step (4) with the coating solution prepared in step (6);

[0075] (8) Packing the coated tablets obtained in step (7) (aluminum-plastic pillow packaging, with 1 bag of solid pharmaceutical molecular sieve desiccant added inside).

[0076] Test results and comparative analysis

[0077] The prepared melogabalin besylate tablets were subjected to a stability test to examine the effects of placing them at 40°C / 75%RH for one month on related substances. The results are shown in Tables 3 and 4.

[0078] Table 3 Stability test results of melogabalin besylate tablets of Examples 1 to 5

[0079]

[0080] Note: Impurities less than 0.05% in 0 day are not included in the calculation; impurities less than 0.03% in 40℃ / 75%RH-1 month are not included in the calculation.

[0081] The results show that the melogabalin besylate tablets of Example 3 have the best stability when placed under 40°C / 75%RH conditions for 1 month. Compared with the other examples, the growth rate of the impurity EHPO is slower. This impurity is an oxidative degradation impurity of melogabalin besylate. This proves that when only tartaric acid and vitamin E polysuccinate polyethylene glycol ester (Implementation 3) are used in combination, the stability of the melogabalin besylate composition obtained is better than using only one of them or other combinations.

[0082] Table 4 Stability test results of melogabalin besylate tablets of Examples 6 to 9

[0083]

[0084] Note: Impurities less than 0.05% in 0 day are not included in the calculation; impurities less than 0.03% in 40℃ / 75%RH-1 month are not included in the calculation.

[0085] The results show that the melogabalin besylate tablets of Examples 6 to 9 have good stability when placed at 40°C / 75%RH for 1 month, and the growth rate of the impurity EHPO (oxidized impurity) is slow, and the growth of impurities is inhibited, which proves that vitamin E polysuccinate polyethylene glycol ester accounts for 0.05%-5% of the weight of the pharmaceutical composition, and tartaric acid accounts for 2%-8% of the weight of the pharmaceutical composition. The stability of the drugs is good, and the safety of the patients' medication can be guaranteed.

Claims

1. A pharmaceutical composition containing melogabalin besylate, comprising an active ingredient melogabalin besylate and pharmaceutically acceptable excipients, wherein the pharmaceutically acceptable excipients comprise a filler, a disintegrant, a binder, an antioxidant and a lubricant, wherein the antioxidant comprises vitamin E succinate polyethylene glycol ester, and the weight percentage of the active ingredient melogabalin besylate in the pharmaceutical composition is 2-15%, preferably 2-10%.

2. The pharmaceutical composition according to claim 1, wherein the antioxidant further comprises one or more of tartaric acid, malic acid, and citric acid.

3. The pharmaceutical composition according to claim 1, wherein the antioxidant is a combination of vitamin E succinate polyethylene glycol ester and tartaric acid.

4. The pharmaceutical composition according to claim 3, wherein the combination of the antioxidant vitamin E polyethylene glycol succinate and tartaric acid accounts for 0.01%-15%, preferably 2%-11% of the total weight of the pharmaceutical composition.

5. The pharmaceutical composition according to any one of claims 1 to 4, wherein the antioxidant vitamin E polyethylene glycol succinate accounts for 0.01% to 7%, preferably 0.05% to 5% of the total weight of the pharmaceutical composition.

6. The pharmaceutical composition according to any one of claims 2 to 4, wherein the antioxidant tartaric acid accounts for 0.01% to 8%, preferably 2% to 6% of the total weight of the pharmaceutical composition.

7. The pharmaceutical composition according to claim 1, wherein the filler is selected from one or more of sugar alcohols, celluloses, and starches, and the weight percentage of the filler in the pharmaceutical composition is 10-90%, preferably 30-80%. The sugar alcohol filler is selected from mannitol, maltitol, erythritol, lactitol, sorbitol or xylitol, preferably spray-dried mannitol. The cellulose filler is selected from microcrystalline cellulose, powdered cellulose or silicified microcrystalline cellulose, The starch filler is selected from corn starch, potato starch or pregelatinized starch, preferably pregelatinized starch. Preferably, the filler is mannitol, or a mixture of mannitol and microcrystalline cellulose in a weight ratio of 1:1-8:1, preferably in a weight ratio range of 1:1-3:

1.

8. The pharmaceutical composition according to claim 1, wherein the disintegrant is selected from one or more of croscarmellose sodium, low-substituted hydroxypropyl cellulose, and sodium starch glycolate. Preferably, the disintegrant is croscarmellose sodium. The weight percentage of the disintegrant in the pharmaceutical composition is 1%-15%, preferably 5%-12%.

9. The pharmaceutical composition according to claim 1, wherein the lubricant is selected from one or more of magnesium stearate, calcium stearate, zinc stearate, hydrogenated vegetable oil, glyceryl behenate, stearic acid, and sodium stearyl fumarate, Preferably, the lubricant is selected from magnesium stearate, glyceryl behenate or sodium stearyl fumarate, The weight percentage of the lubricant in the pharmaceutical composition is 0.5-8%, preferably 2-5%.

10. The pharmaceutical composition according to claim 1, wherein the binder is selected from one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, methyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose and polyvinyl pyrrolidone, Preferably, the binder is hydroxypropyl methylcellulose or hydroxypropyl cellulose, The weight percentage of the binder in the pharmaceutical composition is 0-10%, preferably 0.1-5%, more preferably 0.1-3%.

11. A pharmaceutical composition containing melogabalin besylate, comprising the following components in percentage by weight: Preferably, the weight percentages of the components are as follows:

12. A method for preparing a pharmaceutical composition containing melogabalin besylate according to any one of claims 1 to 11, comprising the following steps: (1) Preparation of antioxidant-containing granules: an antioxidant and a binder are dissolved in water to obtain a binder solution, and the binder solution is then added to a filler or a mixture of a filler and a disintegrant to prepare antioxidant-containing granules. (2) Mixing melogabalin besylate, the antioxidant-containing granules obtained in step (1), a filler, a disintegrant, and a lubricant, and directly tableting and coating the mixture, or performing dry granulation, mixing, tableting, and coating the mixture.

13. A method for preparing a pharmaceutical composition containing melogabalin besylate according to any one of claims 1 to 11, comprising the following steps: (1) The filler is mixed uniformly, and the mixing method is selected from mixing with a mixer, a wet granulator or a fluidized bed one-step granulation mixing, (2) preparing a binder and / or an antioxidant into a binder solution, and then using a high shear wet granulator or a fluidized bed to uniformly mix the binder solution with the mixture obtained in step (1) to granulate to obtain granules containing an antioxidant, (3) uniformly mixing melogabalin besylate with the antioxidant-containing particles obtained in step (2), a filler, a disintegrant, and a lubricant, (4) compressing the mixture obtained in step (3) into tablets, Preferably, the method further comprises the step of coating the tablets obtained in step (4).

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