Melogabalin oral soluble film agent as well as preparation method and application thereof

Abstract

The invention relates to a melogabalin oral soluble film agent as well as a preparation method and application thereof. The melogabalin oral soluble film agent comprises the following components in percentage by mass: 10%-20% of melogabalin, 40%-65% of a film-forming material, 5%-20% of a plasticizer, 4.6%-5% of a buffering agent, 0.5%-8% of an antioxidant, 0.5%-2% of an opacifying agent and 1%-5% of a flavoring agent, wherein the buffer agent is a buffer solution with the pH value of 3-4. The melogabalin oral soluble film agent disclosed by the invention has good stability.

Description

Technical Field

[0001] The present application relates to the field of pharmaceutical preparations, and in particular to a melogabalin orally disintegrating film-forming agent, a preparation method thereof, and an application thereof. Background Art

[0002] Peripheral neuropathic pain (PNP) is a pathological pain condition caused by peripheral nerve damage or dysfunction. Common clinical PNP conditions include diabetic peripheral neuropathy (DPNP), postherpetic neuralgia (PHN), and trigeminal neuralgia (TN). Common pain conditions include spontaneous pain and stimulus-induced pain. Spontaneous pain can manifest as persistent burning pain, intermittent stabbing pain, tearing pain, electric pain, and dysesthesia. Stimulus-induced pain includes hyperalgesia and allodynia. Hyperalgesia refers to pain that is more severe than normal in response to stimuli that would normally cause pain; allodynia refers to pain caused by stimuli that would normally cause pain (such as touch). Many patients suffer from chronic pain symptoms, which can negatively impact both their physical and mental health.

[0003] Melogabalin besylate (active ingredient: melogabalin), developed by the Japanese pharmaceutical company Daiichi Sankyo, is a third-generation calcium channel modulator. It binds to the α2δ subunit of the calcium channel with high affinity, but dissociates slowly from the α2δ-1 subunit (more associated with analgesia) and rapidly from the α2δ-2 subunit (more associated with central nervous system adverse reactions). This provides a better balance between efficacy and safety, and in preclinical studies, it demonstrated stronger and more sustained analgesia. Currently, 2.5mg, 5mg, 10mg, and 15mg tablets, as well as 5mg and 10mg orally disintegrating tablets, have been approved for marketing in Japan. The 2.5mg and 5mg original tablets have been approved for import into China.

[0004] Orodissolving films are a novel oral drug delivery system. They are film-like preparations made by processing a drug substance with a suitable film-forming material (mostly a polymer). In the face of excruciating pain, patients desire rapid onset of pain relief through immediate drug release. Melogabalin besylate formulated into an orodissolving film offers significant clinical advantages. It rapidly disintegrates and releases medication in the mouth, eliminating the need for water for oral administration, making it easier for patients with difficulty swallowing. Furthermore, orodissolving films are compact, lightweight, and portable, overcoming the fragility and resistance of orally disintegrating tablets.

[0005] However, there is currently no technology for preparing melogabalin into an orally disintegrating film, and other traditional orally disintegrating film technologies have the problem of poor stability when applied to melogabalin. Summary of the Invention

[0006] Based on this, the present application provides a melogabalin orally disintegrating film-forming agent with good stability, as well as a preparation method and application thereof.

[0007] In a first aspect of the present application, a melogabalin orally disintegrating film-forming agent is provided, comprising the following components, calculated by mass percentage:

[0008] Melegabalin 10%~20%,

[0009] Film-forming material 40%~65%,

[0010] Plasticizer 5%~20%,

[0011] Buffer 4.6%~5%,

[0012] Antioxidants 0.5%~8%,

[0013] Sunscreen 0.5%~2%, and

[0014] Flavoring agent 1%~5%;

[0015] Wherein, the buffer agent is a buffer solution with a pH value of 3 to 4.

[0016] In some embodiments, the buffer is a citric acid-sodium citrate buffer with a pH value of 3-4.

[0017] In some embodiments, the antioxidant is one or more of α-tocopherol and ascorbyl palmitate.

[0018] In some embodiments, the sunscreen is titanium dioxide.

[0019] In some embodiments, the film-forming material is one or more of polyvinyl alcohol, hydroxypropyl methylcellulose and sodium carboxymethyl cellulose.

[0020] In some embodiments, the melogabalin is melogabalin besylate, and the average particle size D90 is ≤ 10 μm.

[0021] In some embodiments, the plasticizer is one or more of glycerol, polyethylene glycol and propylene glycol.

[0022] In some embodiments, the flavoring agent is one or more of mannitol, stevia, and sucralose.

[0023] In a second aspect of the present application, a method for preparing the orally disintegrating film-forming agent of melogabalin according to the first aspect is provided, comprising the following steps:

[0024] Dispersing the melogabalin, the antioxidant, and the sunscreen in the buffer, adding the flavoring agent and the plasticizer and stirring, and then adding the film-forming material under stirring to prepare a glue solution;

[0025] Degassing the product;

[0026] The deaerated adhesive is formed into a film and dried.

[0027] The third aspect of the present application provides use of the oro-dissolving film-forming agent of melogabalin described in the first aspect in the preparation of a medicament for treating peripheral neuropathic pain.

[0028] The aforementioned melogabalin oro-dissolving film, by combining an antioxidant, a sunscreen, and a buffer solution with a pH of 3-4, can effectively enhance its stability and reduce the generation of oxidative and degradation impurities. Furthermore, the melogabalin oro-dissolving film exhibits excellent flexibility, smoothness, and uniformity, meeting the requirements of an oro-dissolving film. After administration, it rapidly dissolves in the mouth, releasing the drug quickly, thereby rapidly alleviating the patient's pain symptoms. Furthermore, the film is easy to carry, requiring no water for administration, and can be taken anytime, anywhere.

[0029] In addition, during the research process, it was found that by introducing a buffer solution with a pH value of 3 to 4 into the formula, the taste of melogabalin can be effectively improved and the compliance of medication can be increased. DETAILED DESCRIPTION

[0030] The following, in conjunction with specific examples, further details the melogabalin orally disintegrating film-forming agent, its preparation method, and its application. This application can be implemented in many different forms and is not limited to the embodiments described herein. Rather, these embodiments are provided to provide a more thorough and comprehensive understanding of the disclosure herein.

[0031] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art to which this application pertains. The terms used herein in the specification of this application are for the purpose of describing specific embodiments only and are not intended to limit this application.

[0032] As used herein, "one or more" refers to any one, any two, or any two or more of the listed items.

[0033] In this application, terms such as "first aspect," "second aspect," and "third aspect" are used for descriptive purposes only and should not be construed as indicating or implying relative importance or quantity, nor as implicitly indicating the importance or quantity of the technical features indicated. Furthermore, terms such as "first," "second," and "third," etc., are intended only to provide a non-exhaustive enumeration and description and should not constitute a closed-ended limitation on quantity.

[0034] In this application, the technical features described in an open manner include closed technical solutions composed of the listed features, and also include open technical solutions containing the listed features.

[0035] In this application, when referring to numerical ranges, unless otherwise specified, the numerical ranges are considered continuous and include the minimum and maximum values ​​of the range, as well as every value between such minimum and maximum values. Further, when a range refers to an integer, every integer between the minimum and maximum values ​​of the range is included. In addition, when multiple ranges are provided to describe a feature or characteristic, the ranges can be combined. In other words, unless otherwise specified, all ranges disclosed herein should be understood to include any and all subranges subsumed therein.

[0036] Unless otherwise specified, the percentage contents mentioned in this application refer to mass percentage for solid-liquid mixture and solid-solid mixture, and refer to volume percentage for liquid-liquid mixture.

[0037] The percentage concentrations mentioned in this application, unless otherwise specified, refer to the final concentration, which refers to the percentage of the added component in the system after the addition of the component.

[0038] The temperature parameters in this application, unless otherwise specified, allow for both constant temperature treatment and treatment within a certain temperature range. The constant temperature treatment allows for temperature fluctuations within the precision range of instrument control.

[0039] The room temperature in this application generally refers to 4°C to 30°C, preferably 20±5°C.

[0040] Conventional orally disintegrating film technology suffers from poor stability when applied to melogabalin. This may be due to the following structural formula: The amino and carboxyl groups in melogabalin besylate are susceptible to amidation reactions, producing degradation impurities, and are also susceptible to oxidation, producing oxidative impurities. The stability is particularly poor under light and high temperature conditions. Therefore, developing an orally disintegrating film technology for melogabalin and improving its stability are urgent challenges.

[0041]

[0042] Structural formula of melogabalin besylate degradation impurity (Impurity A)

[0043] Some examples of the present application provide a melogabalin orally disintegrating film-forming agent, which comprises the following components in percentage by mass:

[0044] Melegabalin 10%~20%,

[0045] Film-forming material 40%~65%,

[0046] Plasticizer 5%~20%,

[0047] Buffer 4.6%~5%,

[0048] Antioxidants 0.5%~8%,

[0049] Sunscreen 0.5%~2%, and

[0050] Flavoring agent 1%~5%;

[0051] Wherein, the buffer agent is a buffer solution with a pH value of 3 to 4.

[0052] The aforementioned melogabalin orally disintegrating film-dissolving formulation, by combining an antioxidant, a sunscreen, and a buffer solution with a pH of 3-4, can effectively improve the stability of the melogabalin orally disintegrating film-dissolving formulation and reduce the generation of oxidative and degradation impurities. In particular, the use of a buffer solution with a pH of 3-4 can effectively inhibit the amidation reaction of the amino and carboxyl groups in the melogabalin structure, thereby enhancing the stability of the melogabalin orally disintegrating film-dissolving formulation.

[0053] At the same time, the melogabalin oro-dissolving film has good flexibility, smoothness and uniformity, which meets the requirements of oro-dissolving film; it can dissolve quickly in the mouth after taking it, releases the drug quickly, and can quickly relieve the patient's pain symptoms, and is easy to carry, does not require water to take, and can be taken anytime and anywhere.

[0054] In addition, during the research process, it was found that by introducing a buffer solution with a pH value of 3 to 4 into the formula, the taste of melogabalin can be effectively improved and the compliance of medication can be increased.

[0055] Specifically, the pH of the buffer includes, but is not limited to, 3, 3.5, 4, or a range between any two of the foregoing.

[0056] In some examples, the buffer is a citric acid-sodium citrate buffer with a pH of 3-4.

[0057] Without limitation, taking citric acid-sodium citrate buffer as an example, the buffer preparation method (based on a preparation volume of 100 mL) is as follows: citric acid and trisodium citrate are weighed in the amounts shown in Table 1 below, dissolved in water, and the volume is adjusted to 100 mL. Shake well to prepare buffers of varying pH values. The water used to prepare the buffers is removed during the subsequent drying step of the preparation method.

[0058] Table 1

[0059]

[0060] Specifically, the mass percentage of melogabalin includes but is not limited to: 10%, 12%, 15%, 10%, 20% or a range between any two of the foregoing.

[0061] Specifically, the mass percentage of the film-forming material includes, but is not limited to, 40%, 45%, 50%, 55%, 60%, 63.4%, 65% or a range between any two of the foregoing.

[0062] Specifically, the mass percentage of the plasticizer includes, but is not limited to, 5%, 7%, 10%, 15%, 18%, 20%, or a range between any two of the foregoing.

[0063] Specifically, the mass percentage of the buffer includes, but is not limited to, 4.6%, 4.7%, 4.8%, 4.9%, 5%, or a range between any two of the foregoing.

[0064] Specifically, the mass percentage of the antioxidant includes, but is not limited to, 0.5%, 1%, 1.5%, 2%, 3%, 4%, 5%, 6%, 7%, 8% or a range between any two of the foregoing.

[0065] Specifically, the mass percentage of the sunscreen includes but is not limited to: 0.5%, 1%, 1.5%, 2% or a range between any two of the foregoing.

[0066] Specifically, the mass percentage of the flavoring agent includes, but is not limited to, 1%, 1.2%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5% or a range between any two of the foregoing.

[0067] In some examples, the antioxidant is one or more of α-tocopherol and ascorbyl palmitate.

[0068] In some examples, the sunscreen is titanium dioxide.

[0069] It is understandable that the film-forming material is a water-soluble polymer material. In some examples, the film-forming material is one or more of polyvinyl alcohol, hydroxypropyl methylcellulose and sodium carboxymethylcellulose.

[0070] In some examples, the melogabalin is melogabalin besylate. Further, the melogabalin besylate has an average particle size D90 ≤ 10 μm.

[0071] In some examples, the plasticizer is one or more of glycerol, polyethylene glycol (eg, PEG400), and propylene glycol.

[0072] In some examples, the flavoring agent is one or more of mannitol, stevia, and sucralose.

[0073] In some other examples of the present application, a method for preparing the above-mentioned melogabalin orally disintegrating film-forming agent is provided, comprising the following steps:

[0074] Dispersing the melogabalin, the antioxidant, and the sunscreen in the buffer, adding the flavoring agent and the plasticizer and stirring, and then adding the film-forming material under stirring to prepare a glue solution;

[0075] Degassing the said process;

[0076] The deaerated adhesive is formed into a film and dried.

[0077] Without limitation, the degassing method may include vacuum degassing or static degassing.

[0078] Without limitation, the method of forming a film of the deaerated adhesive solution may include applying the deaerated adhesive solution to a polyester tape, drying the film at room temperature, and then peeling the film off the polyester tape.

[0079] In addition, as needed, the step of cutting into required sizes may be included after drying.

[0080] Some other examples of the present application provide the use of the above-mentioned melogabalin orosoluble film-forming agent in the preparation of a drug for treating peripheral neuropathic pain.

[0081] For experimental parameters not specified in the following specific examples, reference is made to the guidance given in this application document, and reference may also be made to experimental manuals in the art or other experimental methods known in the art, or to the experimental conditions recommended by the manufacturer.

[0082] The raw materials and reagents involved in the following specific examples can be obtained from commercial sources or can be prepared by those skilled in the art according to known methods. The raw materials used in the examples and comparative examples, unless otherwise specified, are all APIs with an average particle size D90 < 10 μm.

[0083] Example 1

[0084] This example is an orally disintegrating film-forming tablet of melogabalin besylate with a drug loading of 10%. Prescription quantity: 1000 tablets (specification: 2.5 mg / tablet) or 500 tablets (specification: 5 mg / tablet). The specific formula and preparation method are as follows:

[0085] Melogabalin besylate 4.39g (equivalent to 2.5g of melogabalin, 10%)

[0086] Polyvinyl alcohol 27.83g (63.4%)

[0087] Glycerol 8.78g (20%)

[0088] 100 mL of citric acid-sodium citrate buffer (4.6%) at pH 3.0

[0089] α-Tocopherol 0.22g (0.5%)

[0090] Titanium dioxide 0.22g (0.5%)

[0091] Sucralose 0.44g (1%)

[0092] Weigh the melogabalin besylate raw material, α-tocopherol, and titanium dioxide and disperse them in a citric acid-sodium citrate buffer solution at pH 3.0. Add sucralose and glycerol and stir evenly. Then add polyvinyl alcohol while stirring. Mix evenly. Degas while stirring under vacuum conditions. Use a spatula to evenly apply the glue onto a polyester tape, dry it at room temperature, and cut it according to specifications.

[0093] Example 2

[0094] This example describes an orally disintegrating film-forming tablet of melogabalin besylate with a drug loading of 20%. The dosage is 2000 tablets (2.5 mg / tablet) or 1000 tablets (5 mg / tablet). The specific formulation and preparation method are as follows:

[0095] Melogabalin besylate 8.78g (equivalent to 5.0g of melogabalin, 20%)

[0096] Hydroxypropyl methylcellulose 21.95g (50%)

[0097] Glycerol 8.78g (20%)

[0098] 100 mL of pH 3.5 citric acid-sodium citrate buffer (4.8%)

[0099] α-Tocopherol 0.88g (2%)

[0100] Titanium dioxide 0.88g (2%)

[0101] Stevia 0.53g (1.2%)

[0102] Weigh the melogabalin besylate raw material, α-tocopherol, and titanium dioxide and disperse them in a citric acid-sodium citrate buffer solution at pH 3.5. Add stevia and glycerol and stir evenly. Then add hydropropyl methylcellulose while stirring. Mix evenly. Degas while stirring under vacuum conditions. Spread the glue evenly on a polyester tape with a spatula, dry at room temperature, and cut according to specifications.

[0103] Example 3

[0104] This example describes an orally disintegrating film-forming tablet of melogabalin besylate with a drug loading of 20%. The dosage is 2000 tablets (2.5 mg / tablet) or 1000 tablets (5 mg / tablet). The specific formulation and preparation method are as follows:

[0105] Melogabalin besylate 8.78g (equivalent to 5.0g of melogabalin, 20%)

[0106] Sodium carboxymethyl cellulose 28.54g (65%)

[0107] Macrogol 400 2.20g (5%)

[0108] 100 mL of pH 3.5 citric acid-sodium citrate buffer (4.8%)

[0109] α-Tocopherol 0.88g (2%)

[0110] Titanium dioxide 0.88g (2%)

[0111] Stevia 0.53g (1.2%)

[0112] Weigh the melogabalin besylate raw material, α-tocopherol, and titanium dioxide and disperse them in a citric acid-sodium citrate buffer solution at pH 3.5. Add stevia and polyethylene glycol 400 and stir evenly. Then add sodium carboxymethyl cellulose while stirring. Mix evenly and deaerate under vacuum while stirring. Use a spatula to evenly apply the glue onto a polyester tape, dry it at room temperature, and cut it according to specifications.

[0113] Example 4

[0114] This example describes an orally disintegrating film-forming tablet of melogabalin besylate with a drug loading of 20%. The dosage is 2000 tablets (2.5 mg / tablet) or 1000 tablets (5 mg / tablet). The specific formulation and preparation method are as follows:

[0115] Melogabalin besylate 8.78g (equivalent to 5.0g of melogabalin, 20%)

[0116] Sodium carboxymethyl cellulose 17.56g (40%)

[0117] Propylene glycol 8.78g (20%)

[0118] 100 mL of citric acid-sodium citrate buffer (5.0%) at pH 4.0

[0119] Ascorbyl palmitate 3.51g (8%)

[0120] Titanium dioxide 0.88g (2%)

[0121] Mannitol 2.20g (5%)

[0122] Weigh the melogabalin besylate raw material, ascorbyl palmitate, and titanium dioxide and disperse them in a citric acid-sodium citrate buffer solution at pH 4.0. Add mannitol and propylene glycol and stir evenly. Then add sodium carboxymethyl cellulose while stirring. Mix evenly and deaerate while stirring under vacuum conditions. Use a spatula to evenly apply the glue onto a polyester tape, dry it at room temperature, and cut it according to specifications.

[0123] Comparative Example 1

[0124] This comparative example is an orally disintegrating film preparation of melogabalin besylate, the formulation and preparation method of which are the same as those of Example 1, the main difference being that an equal amount of water is used instead of the pH 3.0 citric acid-sodium citrate buffer solution.

[0125] Comparative Example 2

[0126] This comparative example is an orally disintegrating film-forming agent of melogabalin besylate. The formulation and preparation method are the same as those in Example 1, with the main difference being that a pH 4.5 citric acid-sodium citrate buffer solution is used instead of a pH 3.0 citric acid-sodium citrate buffer solution. The specific formulation is as follows:

[0127] Melogabalin besylate 4.39g (equivalent to 2.5g of melogabalin, 10%)

[0128] Polyvinyl alcohol 27.57g (62.8%)

[0129] Glycerol 8.78g (20%)

[0130] 100 mL of pH 4.5 citric acid-sodium citrate buffer (5.2%)

[0131] α-Tocopherol 0.22g (0.5%)

[0132] Titanium dioxide 0.22g (0.5%)

[0133] Sucralose 0.44g (1%).

[0134] Comparative Example 3

[0135] This comparative example is an orally disintegrating film preparation of melogabalin besylate. The formulation and preparation method are the same as those of Example 1, with the main difference being that the antioxidant α-tocopherol is removed and polyvinyl alcohol is used to make up 100%.

[0136] Comparative Example 4

[0137] This comparative example is an orally disintegrating film preparation of melogabalin besylate. The formulation and preparation method are the same as those of Example 1, with the main difference being that the sunscreen titanium dioxide is removed and polyvinyl alcohol is used to make up 100% of the sunscreen.

[0138] Comparative Example 5

[0139] This comparative example is an orally disintegrating film-forming agent of melogabalin besylate. The formulation and preparation method are the same as those of Example 1, with the main differences being that the mass percentage of the antioxidant α-tocopherol is changed to 10%, the mass percentage of the sunscreen titanium dioxide is changed to 2.5%, and the mass percentage of polyvinyl alcohol is adaptively modified to meet 100%.

[0140] Test Case

[0141] 1. Appearance

[0142] The appearance evaluation basis and corresponding scores are shown in Table 2:

[0143] Table 2

[0144]

[0145] The appearance test results of each example are shown in Table 3 below. The results show that the appearance of the orally disintegrating film preparations of each example meets the quality requirements.

[0146] Table 3

[0147]

[0148] 2. Taste Evaluation

[0149] Five adult males and females were selected as evaluators to orally administer each example. The taste level was evaluated immediately after administration (0 seconds) and 1 minute after the drug was dissolved. The taste evaluation criteria are shown in Table 4.

[0150] Table 4

[0151]

[0152] The taste evaluation results of the embodiments and comparative examples are shown in Table 5 below. The results show that the taste of each embodiment is better than that of the comparative example.

[0153] Table 5

[0154]

[0155] 3. Tensile performance test

[0156] The orally disintegrating films prepared in each example were placed in the upper and lower clamps of a tensile strength tester, with the sample aligned with the center line of the upper and lower clamps, the clamps appropriately tight, and a distance of 60 mm between the two clamps. The tester was operated at a speed of 100 ± 10 mm / min. The tensile strength was measured after the film broke. The tensile strength test results are shown in Table 6. The orally disintegrating films prepared in each example all had a tensile strength greater than 10 N, meeting quality requirements.

[0157] Table 6

[0158]

[0159] 4. Content uniformity determination

[0160] Internal standard solution: Take an appropriate amount of anhydrous caffeine and dilute it with mobile phase to make a solution containing approximately 0.05 mg per 1 mL.

[0161] Test solution: Take one tablet of the oral film-dissolving agent from each example and place it in a 25 mL volumetric flask. Accurately add 5 mL of the internal standard solution (2.5 mg). Alternatively, place it in a 50 mL volumetric flask and accurately add 10 mL of the internal standard solution (5 mg). Add mobile phase and shake to dissolve. Let stand for approximately 20 minutes. Dilute to the mark with mobile phase, shake well, and filter. Repeat the test for 10 tablets.

[0162] Reference solution: Take about 18 mg of melogabalin besylate reference substance, accurately weigh it, place it in a 100 mL volumetric flask, accurately add 20 mL of internal standard solution, dilute to the scale with mobile phase, and shake well.

[0163] Chromatographic conditions: UltraHT Pro C18, 3.0 mm × 50 mm, 2 μm column, 0.01 mol / L diammonium hydrogen phosphate buffer (pH 6.2)-acetonitrile (9:1) as mobile phase for elution, detection wavelength at 210 nm, flow rate adjusted so that the retention time of the main peak of melogabalin was between 5.8 and 6.8 minutes, column temperature at 40°C, and injection volume of 10 μL.

[0164] Accurately measure the test solution and the reference solution, inject them into the liquid chromatograph, and record the chromatogram. Calculate the content of each tablet using the peak area according to the internal standard method. The results are shown in Table 7 below. The content uniformity of each example meets the requirements.

[0165] Table 7

[0166]

[0167] 5. Determination of melting time

[0168] Take the product to be tested and cut it into 6cm pieces 2 Six films of different sizes were sandwiched between two layers of stainless steel mesh with an inner diameter of 2.0 mm. The films were immersed in a 100 mL beaker containing approximately 50 mL of water at 37°C ± 1°C. The height of the stainless steel mesh was adjusted so that the lower surface was at least 10 mm from the bottom of the beaker and the upper surface of the stainless steel mesh was submerged in the water. The beaker was placed in an oscillator at a frequency of 30 vibrations per minute. The time it took for the product to completely dissolve and pass through the mesh was observed and recorded. The results are shown in Table 8 below. The films of each example rapidly dissolved in water and released the drug (≤ 60 s).

[0169] Table 8

[0170]

[0171] 6. Dissolution curve determination

[0172] Dissolution method: paddle method, the dissolution medium is pH 6.8 buffer solution, the medium volume is 900 mL, the rotation speed is 50 rpm, the sampling time points are 5 min, 10 min, 15 min, 30 min, and 45 min, the sampling volume is 10 mL, 5 mL of the initial filtrate is discarded, and the subsequent filtrate is taken.

[0173] Reference Solution: Accurately weigh approximately 39 mg of melogabalin besylate reference substance into a 100 mL volumetric flask. Dissolve with pH 6.8 buffer and quantitatively dilute to the mark. Shake well. Accurately measure 5 mL into a 50 mL volumetric flask. Dissolve with pH 6.8 buffer and quantitatively dilute to the mark. Shake well. Accurately measure 2.5 mL into a 20 mL volumetric flask (2.5 mg), or accurately measure 5 mL into a 20 mL volumetric flask (5 mg), dilute to the mark with pH 6.8 buffer, and shake well.

[0174] Chromatographic conditions: UltraHT Pro C18, 3.0 mm × 50 mm, 2 μm column, 0.01 mol / L diammonium hydrogen phosphate buffer (pH 6.2)-acetonitrile (9:1) as mobile phase for elution, detection wavelength at 210 nm, flow rate adjusted so that the retention time of the main peak of melogabalin was between 5.8 and 6.8 minutes, column temperature at 40°C, injection volume at 50 μL, and sample chamber temperature at 2–8°C.

[0175] The test results are shown in Table 9 below. All examples can be dissolved quickly.

[0176] Table 9

[0177]

[0178] 7. Stability

[0179] Investigation conditions: The examples and comparative examples were exposed to light at 5000±500 Lux for 5 days and 10 days and at a high temperature of 60°C for 10 days and 30 days, and the relevant substances were measured respectively.

[0180] Detection method for related substances: SunShell C18, 2.1 mm × 100 mm, 2.6 μm was used as the chromatographic column, 0.01 mol / L diammonium hydrogen phosphate buffer (pH 6.2) was used as the mobile phase A, methanol-acetonitrile-0.01 mol / L diammonium hydrogen phosphate buffer (pH 6.2) (9:3:4) was used as the mobile phase B, gradient elution was performed according to Table 10 below, the detection wavelength was 215 nm, the flow rate was 0.5 mL per minute, the column temperature was 45°C, and the injection volume was 3 μL.

[0181] Table 10

[0182]

[0183] The samples were placed under a light condition of 5000±500 Lux for 0 days, 5 days, and 10 days. The test results are shown in Table 11:

[0184] Table 11

[0185]

[0186] The test results of the samples after being placed at 60°C for 0 days, 10 days, and 30 days are shown in Table 12:

[0187] Table 12

[0188]

[0189] The results showed that the growth of related substances in each example was significantly slower than that in each comparative example, and the stability of the preparation was significantly improved.

[0190] The technical features of the above-mentioned embodiments can be combined arbitrarily. In order to make the description concise, not all possible combinations of the technical features in the above-mentioned embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0191] The embodiments described above only express several implementation methods of the present application, which are convenient for understanding the technical solutions of the present application in a specific and detailed manner, but they cannot be understood as limiting the scope of protection of the patent application. It should be pointed out that for ordinary technicians in this field, without departing from the concept of the present application, several variations and improvements can be made, which all fall within the scope of protection of the present application. It should be understood that the technical solutions obtained by those skilled in the art through logical analysis, reasoning or limited experiments on the basis of the technical solutions provided in the present application are all within the scope of protection of the claims attached to the present application. Therefore, the scope of protection of the patent application of this application shall be based on the content of the attached claims, and the description can be used to interpret the content of the claims.

Claims

1. A melogabalin orodispersible film-forming agent, characterized in that: In terms of mass percentage, it includes the following components: Melogabalin 10%~20%, Film-forming material 40%~65%, Plasticizer 5%~20%, Buffer 4.6%~5%, Antioxidants 0.5%~8%, Sunscreen 0.5%~2%, and Flavoring agent 1%~5%; Wherein, the buffer is a buffer with a pH value of 3 to 4.

2. The melogabalin orodispersible film-forming agent according to claim 1, characterized in that The buffer is a citric acid-sodium citrate buffer with a pH value of 3-4.

3. The melogabalin orodispersible film-forming agent according to claim 1, characterized in that: The antioxidant is one or more of α-tocopherol and ascorbyl palmitate.

4. The melogabalin orodispersible film-forming agent according to claim 1, characterized in that: The sunscreen is titanium dioxide.

5. The melogabalin orodispersible film-forming agent according to any one of claims 1 to 4, characterized in that: The film-forming material is one or more of polyvinyl alcohol, hydroxypropyl methylcellulose and sodium carboxymethyl cellulose.

6. The melogabalin orodispersible film-forming agent according to any one of claims 1 to 4, characterized in that: The melogabalin is melogabalin besylate, and the average particle size D90 is less than or equal to 10 μm.

7. The melogabalin orodispersible film-forming agent according to any one of claims 1 to 4, characterized in that: The plasticizer is one or more of glycerol, polyethylene glycol and propylene glycol.

8. The melogabalin orodispersible film-forming agent according to any one of claims 1 to 4, characterized in that: The flavoring agent is one or more of mannitol, stevioside and sucralose.

9. The method for preparing the melogabalin orodispersible film-forming agent according to any one of claims 1 to 8, characterized in that: The steps include: Dispersing the melogabalin, the antioxidant, and the sunscreen in the buffer, adding the flavoring agent and the plasticizer and stirring, and then adding the film-forming material under stirring to prepare a glue solution; Degassing the said process; The degassing glue is formed into a film and dried.

10. Use of the melogabalin orodispersible film according to any one of claims 1 to 8 in the preparation of a medicament for treating peripheral neuropathic pain.

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