Melogabalin besylate pharmaceutical composition and preparation method thereof

Abstract

The invention discloses a melogabalin besylate pharmaceutical composition and a preparation method thereof. The invention provides a pharmaceutical composition. The pharmaceutical composition comprises melogabalin besylate, ascorbyl palmitate, a filling agent and a disintegrating agent. According to the pharmaceutical composition provided by the invention, only one antioxidant is added, the antioxidant effect is better than that of a commercial product TARLIGE, the stability of prepared tablets is better, the process production is simple, and the pharmaceutical composition is more suitable for mixing and tabletting the tablets.

Description

Technical Field

[0001] The invention provides a melogabalin besylate pharmaceutical composition and a preparation method thereof. Background Art

[0002] Mirogabalin (also known as Mirogabalin and Minobalin), with a chemical structure as shown in the following formula (I), is chemically named [(1R, 5S, 6S)-6-(aminomethyl)-3-ethylbicyclo[3.2.0]hept-3-en-6-yl]acetic acid monobenzenesulfonate. It is a novel, selective α2δ-1 ligand, and also belongs to the γ-aminobutyric acid analogues (GABA analogues) and the third generation of gabapentinoids. It can act on the α2-δ1 subunit of the voltage-sensitive calcium channel complex (widely present in the nervous system that mediates pain transmission and processing throughout the body), thereby playing a role in treating chronic neuropathic pain.

[0003]

[0004] Gabapentin is a γ-aminobutyric acid (GABA) analog that reduces the release of excitatory neurotransmitters by binding to the α2δ subunit of voltage-gated calcium channels, significantly relieving pain and improving sleep. Pregabalin is a second-generation drug. Unlike gabapentin, it has enhanced affinity for the α2δ subunit and is absorbed linearly (first-order kinetics), reaching maximum blood concentration in 1 hour. Melogabalin, as a third-generation drug, dissociates from the α2δ-1 subunit more slowly than gabapentin and pregabalin, and has a stronger and more lasting analgesic effect.

[0005] From the perspective of the compound structure, the unstable group of melogabalin is the amino group, but the oxidation of the amino group is not a particularly active reaction. Amino drugs generally require the participation of metal ions and free radicals in the catalysis. Oxygen (water or pH) in the air forms free radicals to form nitrogen oxides first, and then further may generate azo substances, resulting in color changes. Therefore, the antioxidant strategy of melogabalin is usually to add antioxidants that can scavenge free radicals or chelate metal ions to the tablets.

[0006] The melogabalin besylate tablets and orodisintegrating tablets developed by Daiichi Sankyo Co., Ltd. of Japan are traded under the name: TARLIGE, including 4 specifications of 2.5mg, 5mg, 10mg, and 15mg, and the indication is: neuropathic pain. The tablets were launched in Japan in January 2019, and the orodisintegrating tablets were launched in Japan in September 2022. Its prescription composition includes tocopherol and citric acid hydrate as antioxidants, and the patent CN 107405322 B authorized by Daiichi Sankyo Co., Ltd. protects a combination of one or two or more antioxidants selected from sodium edetate, citric acid hydrate, butylated hydroxytoluene, propyl gallate, magnesium citrate (anhydrous), soy lecithin, tocopherol, tocopherol acetate, and B-cyclodextrin, among which, for example, tocopherol is an oily antioxidant, which is not convenient for tablet mixing and tableting. Summary of the invention

[0007] The present invention provides a melogabalin besylate pharmaceutical composition and a preparation method thereof in order to overcome the defects of existing melogabalin besylate tablets. The pharmaceutical composition provided by the present invention only adds one antioxidant, has a better antioxidant effect than the commercial product TARLIGE, has better stability of the prepared tablets, and has a simple production process, and is more suitable for tablet mixing and tableting.

[0008] The present invention solves the above technical problems through the following technical solutions.

[0009] The invention provides a pharmaceutical composition comprising melogabalin besylate, ascorbyl palmitate, a filler and a disintegrant.

[0010] In some embodiments of the present invention, the pharmaceutical composition further comprises a glidant and / or a lubricant.

[0011] In some embodiments of the present invention, the filler may be a sugar alcohol, preferably mannitol.

[0012] In some embodiments of the present invention, the disintegrant is selected from one or more of sodium carboxymethyl starch, calcium carboxymethyl cellulose, dry starch, hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, microcrystalline cellulose and sodium lauryl sulfate, preferably sodium carboxymethyl starch.

[0013] In some embodiments of the present invention, the glidant is selected from one or more of colloidal silicon dioxide, light anhydrous silicic acid, crystalline cellulose, synthetic aluminum silicate, titanium oxide, tricalcium phosphate, talc, corn starch and magnesium aluminum metasilicate, preferably colloidal silicon dioxide.

[0014] In some embodiments of the present invention, the lubricant is selected from one or more of cocoa fat, carnauba wax, aluminum hydroxide dry gel, glycerol fatty acid ester, magnesium silicate, light anhydrous silicic acid, crystalline cellulose, hardened oil, synthetic aluminum silicate, white beeswax, magnesium oxide, sodium potassium tartrate, sucrose fatty acid ester, stearic acid, calcium stearate, magnesium stearate, sodium stearyl fumarate, stearyl alcohol and polyethylene glycol 40 stearate, preferably magnesium stearate.

[0015] In some embodiments of the present invention, the mass fraction of ascorbyl palmitate is 0.1%-0.5%, preferably 0.1%, 0.3% or 0.5%.

[0016] The mass fraction described in the present invention is the mass percentage of the mass of each component to the total mass of the pharmaceutical composition.

[0017] In some embodiments of the present invention, the mass fraction of melogabalin besylate is 5%-7%, preferably 4.39%.

[0018] In some embodiments of the present invention, the mass fraction of the filler may be 87.5%-93%, preferably 90.61%, 90.81% or 91.01%.

[0019] In some embodiments of the present invention, the mass fraction of the disintegrant is 1%-5%, preferably 2%.

[0020] In some embodiments of the present invention, the D90 of melogabalin besylate is 50 μm-150 μm, preferably 51 μm-123 μm.

[0021] In some embodiments of the present invention, the D90 of the mannitol is ≤250 μm, such as 100 μm-250 μm.

[0022] In some embodiments of the present invention, the mass fraction of the glidant is 0.2-1.0%, preferably 0.5%.

[0023] In some embodiments of the present invention, the mass fraction of the lubricant is 0.8%-2.5%, preferably 2%.

[0024] In some embodiments of the present invention, the pharmaceutical composition comprises or consists of the following components:

[0025] 5%-7% melogabalin besylate; 0.1%-0.5% ascorbyl palmitate; 87.5%-93% filler; 1%-5% disintegrant; 0.2%-1.0% glidant; 0.8%-2.5% lubricant.

[0026] In some embodiments of the present invention, the pharmaceutical composition comprises or consists of the following components:

[0027] Solution 1:

[0028] 4.39% melogabalin besylate; 0.1% ascorbyl palmitate; 91.01% filler; 2% disintegrant; 0.5% glidant; 2% lubricant;

[0029] Option 2:

[0030] 4.39% melogabalin besylate; 0.3% ascorbyl palmitate; 90.81% filler; 2% disintegrant; 0.5% glidant; 2% lubricant;

[0031] Option 3:

[0032] 4.39% melogabalin besylate; 0.5% ascorbyl palmitate; 90.61% filler; 2% disintegrant; 0.5% glidant; 2% lubricant.

[0033] In some embodiments of the present invention, the pharmaceutical composition comprises or consists of the following components:

[0034] 5%-7% melogabalin besylate; 0.1%-0.5% ascorbyl palmitate; 87.5%-93% mannitol; 1%-5% sodium carboxymethyl starch; 0.2%-1.0% colloidal silicon dioxide; 0.8%-2.5% magnesium stearate.

[0035] In some embodiments of the present invention, the pharmaceutical composition comprises or consists of the following components:

[0036] Solution 1:

[0037] 4.39% melogabalin besylate; 0.1% ascorbyl palmitate; 91.01% mannitol; 2% sodium carboxymethyl starch; 0.5% colloidal silicon dioxide; 2% magnesium stearate;

[0038] Option 2:

[0039] 4.39% melogabalin besylate; 0.3% ascorbyl palmitate; 90.81% mannitol; 2% sodium starch glycolate; 0.5% colloidal silicon dioxide; 2% magnesium stearate;

[0040] Option 3:

[0041] 4.39% melogabalin besylate; 0.5% ascorbyl palmitate; 90.61% mannitol; 2% sodium starch glycolate; 0.5% colloidal silicon dioxide; 2% magnesium stearate.

[0042] In some embodiments of the present invention, the pharmaceutical composition may be a solid preparation, such as a tablet, a capsule, a granule or a powder, preferably a tablet.

[0043] In some embodiments of the present invention, the tablet may be a plain tablet or a coated tablet.

[0044] In some embodiments of the present invention, the pharmaceutical composition further comprises a coating agent (powder).

[0045] In some embodiments of the present invention, the coating agent may be a conventional coating agent for such drugs in the art; the coating agent is selected from one or more of hydroxypropyl methylcellulose, methyl cellulose, ethyl cellulose, methyl cellulose or hydroxypropyl cellulose, polyvinyl alcohol and Opadry (trade name, OPADRY), preferably Opadry.

[0046] In some embodiments of the present invention, in the pharmaceutical composition, relative to the uncoated weight, after coating, the weight gain of the coating agent may be 1%-6%, preferably 4%.

[0047] In some embodiments of the present invention, the pharmaceutical composition consists of the following components:

[0048] Solution 1:

[0049] Tablet core: 4.39% melogabalin besylate; 0.1% ascorbyl palmitate; 91.01% mannitol; 2% sodium carboxymethyl starch; 0.5% colloidal silicon dioxide; 2% magnesium stearate;

[0050] Coating: Compared with the weight of the core tablet, the weight of the coating agent increases by 4%;

[0051] Option 2:

[0052] Tablet core: 4.39% melogabalin besylate; 0.3% ascorbyl palmitate; 90.81% mannitol; 2% sodium carboxymethyl starch; 0.5% colloidal silicon dioxide; 2% magnesium stearate;

[0053] Coating: Compared with the weight of the core tablet, the weight of the coating agent increases by 4%;

[0054] Option 3:

[0055] Tablet core: 4.39% melogabalin besylate; 0.5% ascorbyl palmitate; 90.61% mannitol; 2% sodium carboxymethyl starch; 0.5% colloidal silicon dioxide; 2% magnesium stearate;

[0056] Coating: The weight of the coating agent increased by 4% compared to the weight of the core tablet.

[0057] In some embodiments of the present invention, the content of melogabalin in the unit dosage form of the pharmaceutical composition may be 2 to 10 mg, preferably 2.5 mg or 5 mg (in terms of melogabalin C 12 H 19 NO2). Taking tablets as an example, in the unit dosage form, the content of melogabalin may be 2-10 mg / tablet, such as 2.5 mg / tablet or 5 mg / tablet.

[0058] The present invention also provides a method for preparing the pharmaceutical composition according to any of the above schemes, the preparation method comprising the following steps:

[0059] (1) Mixing: mixing ascorbyl palmitate, filler, disintegrant, glidant and lubricant;

[0060] (2) Tableting;

[0061] (3) Coating: Coating is carried out using a coating pan;

[0062] Preferably, the preparation method comprises the following steps:

[0063] (1) Premixing: Ascorbyl palmitate and a filler are mixed to obtain a mixture I, and then mixed with melogabalin besylate to obtain a mixture II;

[0064] (3) Mixing: Mix the disintegrant, the glidant, the remaining filler and the mixture II to obtain a mixture III, sieve the mixture, transfer the mixture to a universal mixer, and mix to obtain a mixture IV;

[0065] (4) Total mixing: add lubricant and mix;

[0066] (5) Tableting;

[0067] (6) Coating: 1.5 times the amount of coating powder prescribed is mixed with water to obtain a coating solution;

[0068] More preferably, the preparation method comprises the following steps:

[0069] (1) Pretreatment: sieve mannitol, microcrystalline cellulose, ascorbyl palmitate, sodium carboxymethyl starch, colloidal silicon dioxide, and magnesium stearate for later use;

[0070] (2) Premixing: Mix ascorbyl palmitate and 8-12% of the prescription amount of mannitol (preferably 10% of the prescription amount) to obtain mixture I, and then add melogabalin besylate (API) to obtain mixture II;

[0071] (3) Mixing: Mix sodium carboxymethyl starch, colloidal silicon dioxide, and the remaining 88-92% of the prescription amount of mannitol (preferably 90% of the prescription amount) with mixture II to obtain mixture III, sieve the mixture, transfer the mixture to a universal mixer, set the single shaft to 15 rpm, and mix to obtain mixture IV;

[0072] (4) Total mixing: Add magnesium stearate into a universal mixer, set the single shaft to 15 rpm, and mix;

[0073] (5) Tablet compression: 5 mg tablets weighing 200 mg use an 8 mm shallow concave round punch, with a hardness of 120 N to 180 N; 2.5 mg tablets weighing 100 mg use a 6 mm shallow concave round punch, with a hardness of 120 N to 180 N.

[0074] (6) Coating: 1.5 times the prescribed amount of coating powder is mixed with water to prepare a coating solution with a concentration of 10-15% (W / W) (preferably 12% (W / W)). The coating solution is stirred for later use. The plain tablets are placed in a coating pot and preheated to 35-45°C. The inlet air temperature is set to 55-65°C, the tablet bed temperature is controlled to 35-45°C, the pot speed is controlled at 2-10r / min, the spray speed is controlled at 1-5HZ for coating operation, and the weight gain is controlled at 3-5%. After coating, the tablets are dried and the temperature is reduced to room temperature before being discharged.

[0075] In the present invention, D90 refers to the particle size corresponding to when the cumulative particle size distribution number of the component reaches 90%, that is, among all the particles, 90% of the particles have a particle size less than or equal to this value.

[0076] The term "filler", also called "diluent", refers to a class of excipients used in a scientific context to increase the bulk and weight of a pharmaceutical composition product dosage form. Thus, a filler can be, for example: a sugar alcohol (mannitol).

[0077] The term "disintegrant" refers to a class of excipients used in a scientific context to promote the breaking of a pharmaceutical composition product dosage form into smaller fragments in an aqueous environment. Thus, disintegrants can be, for example: sodium carboxymethyl starch, calcium carboxymethyl cellulose, dry starch, hydroxypropyl cellulose, crospovidone, croscarmellose sodium, microcrystalline cellulose and sodium lauryl sulfate.

[0078] The term "lubricant" refers to a class of excipients used in a scientific context to improve the processing of pharmaceutical composition product dosage forms. Thus, lubricants can be, for example, cocoa fat, carnauba wax, aluminum hydroxide xerogel, glycerol fatty acid esters, magnesium silicate, light anhydrous silicic acid, crystalline cellulose, hardened oil, synthetic aluminum silicate, white beeswax, magnesium oxide, sodium potassium tartrate, sucrose fatty acid esters, stearic acid, calcium stearate, magnesium stearate, sodium stearyl fumarate, stearyl alcohol, and polyethylene glycol 40 stearate.

[0079] The term "glidant" refers to a class of excipients that reduce the friction between particles and improve the flowability of powders. Thus, glidants can be, for example: colloidal silicon dioxide, light anhydrous silicic acid, crystalline cellulose, synthetic aluminum silicate, titanium oxide, tricalcium phosphate, talc, corn starch and magnesium aluminum metasilicate.

[0080] The term "coating agent" refers to a class of excipients used in a scientific context to improve the appearance of a pharmaceutical composition product dosage form. Thus, coating agents can be, for example, hypromellose, methylcellulose, ethylcellulose, methylcellulose or hydroxypropylcellulose, polyvinyl alcohol and Opadry (trade name, OPADRY).

[0081] Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

[0082] The reagents and raw materials used in the present invention are commercially available.

[0083] The positive and progressive effects of the present invention are:

[0084] (1) The pharmaceutical composition provided by the present invention, which only contains one antioxidant, has a better antioxidant effect than the commercial product TARLIGE;

[0085] (2) The tablets prepared by the present invention have better stability;

[0086] (3) The production process of the present invention is simple and more suitable for tablet mixing and tableting. DETAILED DESCRIPTION

[0087] The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples. The experimental methods in the following examples without specifying specific conditions are carried out according to conventional methods and conditions, or selected according to the product specifications.

[0088] Unless otherwise specified, the experimental methods used in the following examples are conventional methods.

[0089] Unless otherwise specified, the materials and reagents used in the following examples can be obtained from commercial sources.

[0090] Example 1 Preparation of 5 mg melogabalin besylate tablets

[0091] The components and dosage of 5 mg melogabalin besylate tablets are shown in Table 1:

[0092] Table 1

[0093]

[0094] Preparation method:

[0095] 1) Pretreatment: Pass mannitol, ascorbyl palmitate, sodium carboxymethyl starch, colloidal silicon dioxide and magnesium stearate through a 24-mesh sieve for later use.

[0096] 2) Premixing: Add the prescribed amount of antioxidant ascorbyl palmitate to 8-12% of the prescribed amount of mannitol (preferably 10% of the prescribed amount) and shake it manually to obtain mixture I. Then weigh the prescribed amount of API (melogabalin besylate) and add it to mixture I and mix well to obtain mixture II.

[0097] 3) Mixing: Add the prescribed amount of sodium carboxymethyl starch, colloidal silicon dioxide, and the remaining 88-92% of the prescribed amount of mannitol (preferably 90% of the prescribed amount) to mixture II and mix manually to obtain mixture III. Pass mixture III through a 24-mesh sieve, and finally transfer the materials to a universal mixer, set the single shaft to 15 rpm, and mix for 20 minutes to obtain mixture IV.

[0098] 4) Total mixing: Add the prescribed amount of magnesium stearate into a universal mixer, set the single shaft to 15 rpm, and mix for 5 minutes.

[0099] 5) Tablet compression: 5mg tablets weighing 200mg use 8mm shallow concave round punch, and the hardness is controlled at 120N-180N;

[0100] 6) Coating: Weigh 1.5 times the amount of the prescribed coating powder, mix it with water to prepare a 12% (W / W) concentration of coating solution, stir the coating solution for more than 45 minutes for use, place the plain tablets in the coating pot and preheat to 35-45℃ before coating. During the formal coating, set the inlet temperature to 55-65℃, control the tablet bed temperature to 35-45℃, control the pot speed at 2-10r / min, control the spray speed at 1-5HZ for coating operation, and control the weight gain at 3-5%. After coating, dry for about 20 minutes, wait for the coated tablets to cool down to room temperature, and then take out the tablets.

[0101] Example 2 Preparation of 2.5 mg melogabalin besylate tablets

[0102] The components and dosage of 2.5 mg melogabalin besylate tablets are shown in Table 2:

[0103] Table 2

[0104]

[0105] Preparation method:

[0106] 1) Pretreatment: Pass mannitol, ascorbyl palmitate, sodium carboxymethyl starch, colloidal silicon dioxide and magnesium stearate through a 24-mesh sieve for later use.

[0107] 2) Premixing: Add the prescribed amount of antioxidant ascorbyl palmitate to 8-12% of the prescribed amount of mannitol (preferably 10% of the prescribed amount) and shake it manually to obtain mixture I. Then weigh the prescribed amount of API and add it to mixture I and mix well to obtain mixture II.

[0108] 3) Mixing: Add the prescribed amount of sodium carboxymethyl starch, colloidal silicon dioxide, and the remaining 88-92% of the prescribed amount of mannitol (preferably 90% of the prescribed amount) to mixture II and mix manually to obtain mixture III. Pass mixture III through a 24-mesh sieve, and finally transfer the materials to a universal mixer, set the single shaft to 15 rpm, and mix for 20 minutes to obtain mixture IV.

[0109] 4) Total mixing: Add the prescribed amount of magnesium stearate into a universal mixer, set the single shaft to 15 rpm, and mix for 5 minutes.

[0110] 5) Tablet compression: 2.5mg tablets weighing 100mg use a 6mm shallow concave round die, and the hardness is controlled at 120N-180N;

[0111] 6) Coating: Weigh 1.5 times the amount of the prescribed coating powder, mix it with water to prepare a 12% (W / W) concentration of coating solution, stir the coating solution for more than 45 minutes and set aside, place the plain tablets in the coating pot and preheat to 35-45℃ before coating, set the inlet temperature to 55-65℃ during formal coating, control the tablet bed temperature at 35-45℃, control the pot speed at 2-10r / min, control the spray speed at 1-5HZ for coating operation, and control the weight gain at 3-5%. After coating, dry for about 20 minutes, wait for the coated tablets to cool down to room temperature, and then take out the tablets.

[0112] Example 3 Screening of different antioxidant types and dosages

[0113] Table 3

[0114]

[0115] The preparation method is basically the same as that of Example 1.

[0116] Example 4 Study on the stability of melogabalin besylate tablets

[0117] The A, B, C, D, E, F, G, H and the commercially available reference preparation (specification 10 mg, batch number YCA2070, trade name: TARLIGE) in the prescriptions of Example 1 and Example 3 were placed at 40° C. and 75% relative humidity for 3 months, respectively, at 0 month,

[0118] Relevant substances were detected in October, January and March (analysis method is as follows), and the relative retention time RRT0.38, RRT2.15 and the percentage of total impurities were calculated by area normalization method, as well as the number of impurities with peak area above 0.05% to judge the stability. The results are shown in Table 4.

[0119] Chromatographic conditions for related substances: Pentafluorophenylsilane bonded silica gel was used as filler (Hypersil GOLD TM PFP4.6mm*250mm 5μm), with phosphate buffer (take 5.44g of potassium dihydrogen phosphate, put it in 1000ml water, adjust the pH to 6.0 with 1mol / l sodium hydroxide solution, filter, and ultrasonicate)-acetonitrile = 95:5 as mobile phase A, acetonitrile as mobile phase B, and perform gradient elution according to the table below; the flow rate is 1.0ml / min, the column temperature is 40℃, the detection wavelength is 205nm, and the injection volume is 10μl.

[0120]

[0121] System suitability requirements: In the system suitability solution chromatographic data, the retention time of the melogabalin peak should be about 22 minutes, the separation between the melogabalin peak and the diastereomers should not be less than 1.5, and the separation between the impurities should not be less than 1.2; in the sensitivity solution chromatographic data, the signal-to-noise ratio of the melogabalin peak should not be less than 10.

[0122] The determination method is to accurately measure the test solution, control solution and sensitivity solution, inject them into the liquid chromatograph respectively, and record the chromatographic data.

[0123] Table 4

[0124]

[0125] The stability results of the formulation of Example 1 and the reference preparation and comparative formulations E and F (with tocopherol and citric acid hydrate antioxidants added) show that the formulation with ascorbyl palmitate added (Example 1 placed at 40°C and 75% relative humidity for 3 months had a relative retention time RRT0.38, RRT2.15 and total impurity percentage, as well as the number of impurities with a peak area of ​​more than 0.05% were all smaller than those of the reference preparation formulation with tocopherol and citric acid hydrate antioxidants added, indicating that the antioxidant effect of the formulation with ascorbyl palmitate added is better than that of the commercial product TARLIGE; from the stability results of the formulations B and C, an ideal antioxidant effect can be achieved by adding the antioxidant ascorbyl palmitate in a ratio of 0.1%-0.5%.

[0126] In addition, the compressibility of the pharmaceutical composition of the present invention is improved. The tablet press pressure is continuously increased during the tableting process using the prescription of the present invention. The compressibility is evaluated by testing the tablet hardness. The maximum hardness can be increased to 160N. Prescriptions E and F contain citric acid and tocopherol, and the maximum hardness can only reach 100N. The advantage of a larger hardness increase is the improvement of the subsequent coating batch size during the process production. A larger hardness makes it less likely to break during the coating process.

[0127] Example 5 Condition screening of melogabalin besylate tablets

[0128] (1) Investigation of API particle size

[0129] The API was crushed to obtain API with different particle sizes, which were prepared according to Example 1. The influence of the particle size of the API on the quality of the self-developed product was evaluated by measuring the uniformity of the total mixed powder in the total mixing process (sampling and testing the content at 5 different positions in the total mixing process).

[0130] Table 5. Mixing uniformity results of API with different particle sizes

[0131]

[0132] The results showed that the particle size of the raw material was D90=51μm-123μm, and the mixing uniformity was good. Beyond this range, the mixing uniformity data of D90=212μm and D90=19μm fluctuated greatly, that is, the RSD was large.

[0133] (2) Study on the dosage of disintegrant

[0134] According to Example 1, four disintegration dosage ratios of 1%, 2%, 3% and 5% were selected to design a single factor test, and the effect of the amount of sodium carboxymethyl starch on the product quality was evaluated by the aqueous medium dissolution curve (Table 7), (reference YBA2265 source: Nanjing Baiwei Pharmaceutical Development Co., Ltd.).

[0135] Table 6 Disintegration dosage investigation prescription

[0136]

[0137] Table 7 Dissolution curve of aqueous medium after disintegration dose investigation (n=3)

[0138]

[0139] The results showed that: from the dissolution results, it can be known that when the disintegrant dosage was 1.0%, the dissolution was slower than the reference at 5 minutes, and all the substances were released at 10 minutes. When the disintegrant dosage was 2.0%, the dissolution was more similar to the reference. When the disintegrant dosage was 3.0%, the dissolution was faster than the reference at 5 minutes, and all the substances were released at 10 minutes.

[0140] (3) Investigation of the dosage of colloidal silicon dioxide as a glidant

[0141] According to Example 1, the amount of colloidal silicon dioxide was adjusted to 0.2%, 0.5%, and 1.0%, and a single factor test was designed to evaluate the effect of the amount of flow aid on the product quality by measuring the mixing uniformity (sampling and testing the content at 5 different positions in the total mixing process) and the uniformity of the tableting process.

[0142] Table 8 Colloidal silicon dioxide dosage survey formula

[0143]

[0144] Table 9 Colloidal silicon dioxide dosage to investigate mixing uniformity

[0145]

[0146] Table 10 Colloidal silicon dioxide dosage to investigate the uniformity of tableting process

[0147]

[0148] Note: “Before, during, and after” means that samples were obtained in three time periods, namely before, during, and after tableting; “n=3” means that three parallel tests were performed during this time period.

[0149] The results showed that when the dosage of colloidal silicon dioxide was 0.2%, 0.5% and 1.0% respectively, the mixing uniformity and tableting uniformity of the preparation were both acceptable.

[0150] (4) Investigation of the dosage of lubricant magnesium stearate

[0151] According to Example 1, the dosage of magnesium stearate was adjusted to 1.5%, 2.0%, and 2.5%, and a single factor test was designed to investigate the effect of lubricant dosage on product quality by measuring mixing uniformity, tableting process uniformity, and tableting state results.

[0152] Table 11 Magnesium stearate dosage investigation formula

[0153]

[0154] Table 12 Magnesium stearate dosage to investigate mixing uniformity

[0155]

[0156] Table 13 Magnesium stearate dosage to investigate the uniformity of tableting process

[0157]

[0158] Note: “Before, during, and after” means that samples were obtained in three time periods, namely before, during, and after tableting; “n=3” means that three parallel tests were performed during this time period.

[0159] The results showed that the content uniformity and tableting uniformity of magnesium stearate at 1.5%, 2.0%, and 2.5% were all good.

[0160] (5) Weight gain study of different coatings

[0161] According to Example 1, the coating weight gain was adjusted to 3%, 4%, and 5%, respectively, and the formulation results were evaluated by dissolution curves in aqueous media (Table 15).

[0162] Table 14 Different coating weight gain formulations

[0163]

[0164] Table 15 Dissolution curve results of different coating weight gain formulations

[0165]

[0166] Summary: According to the results of different coating weight gains, when the coating weight gain increases from 3% to 5%, the dissolution result at the 5-minute dissolution point slows down, which may be related to the thickness of the coating film. The dissolution at 15 minutes is greater than 85%, and the coating weight gain of 3% to 5% is appropriate.

Claims

1. A pharmaceutical composition, characterized in that It contains melogabalin besylate, ascorbyl palmitate, a filler, and a disintegrant.

2. The pharmaceutical composition according to claim 1, characterized in that The pharmaceutical composition further comprises a glidant and / or a lubricant.

3. The pharmaceutical composition according to claim 1, characterized in that It meets one or more of the following conditions: (1) The filler is a sugar alcohol, preferably mannitol; (2) The disintegrant is selected from one or more of sodium carboxymethyl starch, calcium carboxymethyl cellulose, dry starch, hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, microcrystalline cellulose and sodium lauryl sulfate, preferably sodium carboxymethyl starch; (3) The mass fraction of ascorbyl palmitate is 0.1%-0.5%, preferably 0.1%, 0.3% or 0.5%; (4) The mass fraction of melogabalin besylate is 5%-7%, preferably 4.39%; (5) The mass fraction of the filler is 87.5%-93%, preferably 90.61%, 90.81% or 91.01%; (6) The mass fraction of the disintegrant is 1%-5%, preferably 2%; (7) The D90 of the melogabalin besylate is 50 μm-150 μm, preferably 51 μm-123 μm.

4. The pharmaceutical composition according to claim 2, characterized in that It meets one or more of the following conditions: (1) The glidant is selected from one or more of colloidal silicon dioxide, light anhydrous silicic acid, crystalline cellulose, synthetic aluminum silicate, titanium oxide, tricalcium phosphate, talc, corn starch and magnesium aluminum metasilicate, preferably colloidal silicon dioxide; (2) The lubricant is selected from one or more of cocoa fat, carnauba wax, aluminum hydroxide xerogel, glycerol fatty acid ester, magnesium silicate, light anhydrous silicic acid, crystalline cellulose, hardened oil, synthetic aluminum silicate, white beeswax, magnesium oxide, sodium potassium tartrate, sucrose fatty acid ester, stearic acid, calcium stearate, magnesium stearate, sodium stearyl fumarate, stearyl alcohol and polyethylene glycol 40 stearate, preferably magnesium stearate; (3) The mass fraction of the glidant is 0.2-1.0%, preferably 0.5%; (4) The mass fraction of the lubricant is 0.8%-2.5%, preferably 2%.

5. The pharmaceutical composition according to any one of claims 1 to 4, characterized in that The pharmaceutical composition comprises or consists of the following components: 5%-7% melogabalin besylate; 0.1%-0.5% ascorbyl palmitate; 87.5%-93% filler; 1%-5% disintegrant; 0.2%-1.0% glidant; 0.8%-2.5% lubricant; Preferably, the pharmaceutical composition comprises or consists of the following components: Solution 1: 4.39% melogabalin besylate; 0.1% ascorbyl palmitate; 91.01% filler; 2% disintegrant; 0.5% glidant; 2% lubricant; Solution 2: 4.39% melogabalin besylate; 0.3% ascorbyl palmitate; 90.81% filler; 2% disintegrant; 0.5% glidant; 2% lubricant; Scheme 3: 4.39% melogabalin besylate; 0.5% ascorbyl palmitate; 90.61% filler; 2% disintegrant; 0.5% glidant; 2% lubricant; More preferably, the pharmaceutical composition comprises or consists of the following components: 5%-7% melogabalin besylate; 0.1%-0.5% ascorbyl palmitate; 87.5%-93% mannitol; 1%-5% sodium carboxymethyl starch; 0.2%-1.0% colloidal silicon dioxide; 0.8%-2.5% magnesium stearate; Optimally, the pharmaceutical composition comprises or consists of the following components: Solution 1: 4.39% melogabalin besylate; 0.1% ascorbyl palmitate; 91.01% mannitol; 2% sodium carboxymethyl starch; 0.5% colloidal silicon dioxide; 2% magnesium stearate; Solution 2: 4.39% melogabalin besylate; 0.3% ascorbyl palmitate; 90.81% mannitol; 2% sodium carboxymethyl starch; 0.5% colloidal silicon dioxide; 2% magnesium stearate; Option 3: 4.39% melogabalin besylate; 0.5% ascorbyl palmitate; 90.61% mannitol; 2% sodium carboxymethyl starch; 0.5% colloidal silicon dioxide; 2% magnesium stearate.

6. The pharmaceutical composition according to claim 4, characterized in that The pharmaceutical composition is a solid preparation, such as a tablet, capsule, granule or powder, preferably a tablet; preferably, the tablet is a plain tablet or a coated tablet.

7. The pharmaceutical composition according to claim 4, characterized in that The pharmaceutical composition further comprises a coating agent; Preferably, the coating agent satisfies the following conditions (1) and / or (2): (1) The coating agent is selected from one or more of hydroxypropyl methylcellulose, methyl cellulose, ethyl cellulose, methyl cellulose or hydroxypropyl cellulose, polyvinyl alcohol and Opadry, preferably Opadry; (2) In the pharmaceutical composition, the weight gain of the coating agent after coating is 1%-6%, preferably 4%, relative to the weight of the uncoated agent.

8. The pharmaceutical composition according to claim 7, characterized in that The pharmaceutical composition consists of the following components: Solution 1: Tablet core: 4.39% melogabalin besylate; 0.1% ascorbyl palmitate; 91.01% mannitol; 2% sodium carboxymethyl starch; 0.5% colloidal silicon dioxide; 2% magnesium stearate; Coating: Compared with the weight of the core tablet, the weight of the coating agent increases by 4%; Option 2: Tablet core: 4.39% melogabalin besylate; 0.3% ascorbyl palmitate; 90.81% mannitol; 2% sodium carboxymethyl starch; 0.5% colloidal silicon dioxide; 2% magnesium stearate; Coating: Compared with the weight of the core tablet, the weight of the coating agent increases by 4%; Option 3: Tablet core: 4.39% melogabalin besylate; 0.5% ascorbyl palmitate; 90.61% mannitol; 2% sodium carboxymethyl starch; 0.5% colloidal silicon dioxide; 2% magnesium stearate; Coating: The weight of the coating agent increased by 4% compared to the weight of the core tablet.

9. The pharmaceutical composition according to claim 4, characterized in that In the unit dosage form of the pharmaceutical composition, the content of melogabalin is 2 to 10 mg, preferably 2.5 mg or 5 mg; taking tablets as an example, in the unit dosage form, the content of melogabalin can be 2 to 10 mg / tablet, for example, 2.5 mg / tablet or 5 mg / tablet.

10. A method for preparing the pharmaceutical composition according to any one of claims 1 to 9, characterized in that: The preparation method comprises the following steps: (1) Mixing: mixing ascorbyl palmitate, filler, disintegrant, glidant and lubricant; (2) Tableting; (3) Coating: Coating is carried out using a coating pan; Preferably, the preparation method comprises the following steps: (1) Premixing: Mix ascorbyl palmitate and 8-12% of the prescribed amount of filler to obtain mixture I, and then mix with melogabalin besylate to obtain mixture II; (3) Mixing: Mix the disintegrant, the glidant, and the remaining 88-92% of the prescribed amount of the filler with the mixture II to obtain a mixture III, sieve the mixture, transfer the mixture to a universal mixer, and mix to obtain a mixture IV; (4) Total mixing: add lubricant and mix; (5) Tableting; (6) Coating: Mix 1.5 times the prescribed amount of coating powder with water to obtain a coating solution.

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