Melogabalin besylate oral solution and preparation method thereof

Abstract

The invention provides a melogabalin besylate oral solution and a preparation method thereof, and relates to the technical field of pharmaceutical preparations. The melogabalin besylate oral solution comprises the following components: melogabalin besylate or pharmaceutically acceptable salt thereof, a solvent, a chelating agent, a preservative, a thickening agent, a sweetening agent and a flavoring agent. The melogabalin besylate oral solution disclosed by the invention is excellent in mouth feel, high in bioavailability, convenient to take and good in stability, and the compliance of a patient is greatly improved.

Description

Technical Field

[0001] The invention relates to the technical field of pharmaceutical preparations, and in particular to a melogabalin besylate oral solution and a preparation method thereof. Background Art

[0002] Neuropathic pain is one of the common symptoms in neurology. It refers to pain felt in the absence of external stimulation. It refers to pain directly caused by damage to the somatic sensory system or disease. It can be caused by trauma and / or disease that causes damage to the peripheral nerves, dorsal roots, spinal cord and certain parts of the central nervous system above it. It can be divided into peripheral neuralgia and central neuralgia.

[0003] The structural formula of melogabalin besylate is as follows:

[0004]

[0005] Milobalin besylate, gabapentin and pregabalin are all calcium channel blockers. Milobalin has a high affinity for both the α2δ-1 (related to analgesia) and α2δ-2 (related to central side effects) subunits of VGCCs, and a longer dissociation half-life for the α2δ-1 subunit. Therefore, it has a long-acting analgesic effect and reduced side effects of γ-aminobutyric acid analogs. Its efficacy and safety are significantly higher than those of pregabalin, providing an alternative treatment option for neuropathic pain.

[0006] Chinese patent CN104334169B discloses a solid composition containing melogabalin besylate, specifically protecting D-mannitol, carboxymethylcellulose calcium, magnesium stearate or sodium stearyl fumarate, and the preparation method is direct tableting. This solid pharmaceutical composition does not contain any sustained-release material and is a common regular-release preparation.

[0007] Chinese patent CN110917164B protects a sustained-release tablet containing milobarlin besylate and its preparation method, specifically protecting a pharmaceutical composition of a skeleton material of high and low viscosity, a diluent mannitol, a binder hydroxypropyl cellulose, and a lubricant magnesium stearate, as well as a preparation process using wet granulation and fluidized bed drying. The composition does not contain a stabilizer in the formulation. The relevant literature of the original research company shows that the main drug of this product is sensitive to moisture and heat. Using this formulation process, the product prepared using this formulation process has problems such as poor stability.

[0008] However, the T max Only 1.00 and 1.50 hours, T 1 / 2It takes only about 3 hours, and it is a drug with a fast onset of action but a short half-life. In order to maintain blood drug concentration, it must be taken multiple times a day to achieve the effect. The oral adult dose is usually an initial dose of 5 mg, twice a day. Then titrate with a dose of 5 mg, with an interval of at least one week, to a dose of 15 mg, twice a day. Depending on age and symptoms, the dose can be increased or decreased within the range of 10 mg to 15 mg twice a day. Therefore, melogabalin besylate tablets have problems with unstable blood drug concentration and poor compliance.

[0009] Based on the disadvantages of existing products, how to improve the dosage form of melogabalin besylate to improve the patient's medication compliance is the research focus in this field. Currently, the only melogabalin besylate available on the market worldwide is tablets, and children are more resistant to the drug. Therefore, a new formulation of melogabalin besylate is urgently needed, which has the advantages of good clinical compliance, good stability and high bioavailability to meet the clinical medication needs of patients. Summary of the invention

[0010] In view of the above problems, the present invention provides a melogabalin besylate oral solution and a preparation method thereof, which has the advantages of good clinical compliance, excellent taste, good stability and high bioavailability.

[0011] To achieve the above purpose, the technical solution adopted by the present invention is as follows:

[0012] In one aspect, the present invention provides a melogabalin besylate oral solution comprising the following components:

[0013] Melogabaline besylate or a pharmaceutically acceptable salt thereof, a solvent, a chelating agent, a preservative, a thickener, a sweetener and a flavoring agent.

[0014] Preferably, the solvent is water.

[0015] Further preferably, the water is selected from at least one of purified water, deionized water and distilled water. More preferably, the water is selected from purified water.

[0016] Preferably, the chelating agent is selected from at least one of citric acid, fumaric acid, L-lactic acid, formic acid, acetic acid, propionic acid, butyric acid, sorbic acid, malic acid, tartaric acid and benzoic acid.

[0017] More preferably, the chelating agent is selected from citric acid.

[0018] Preferably, the preservative is selected from at least one of methyl paraben, propyl paraben, benzyl alcohol, benzoic acid, potassium sorbate, sodium benzoate and ascorbic acid.

[0019] More preferably, the preservative is selected from at least one of methylparaben and propylparaben.

[0020] More preferably, the preservatives are methylparaben and propylparaben.

[0021] Preferably, the thickener is selected from at least one of methyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose, xanthan gum and gelatin.

[0022] More preferably, the thickener is hydroxyethyl cellulose.

[0023] Preferably, the sweetener is at least one selected from sucralose, aspartame, mannitol, sorbitol, xylitol, acesulfame potassium, stevia, glucose, saccharin sodium, fructose, high fructose corn syrup, maltodextrin and sucrose.

[0024] More preferably, the sweetener is selected from sucralose.

[0025] Preferably, the flavoring agent is selected from at least one of raspberry water-soluble flavor, orange flavor and strawberry flavor.

[0026] Preferably, the melogabalin besylate oral solution comprises the following components in parts by mass:

[0027] 5-10 parts of melogabalin besylate or a pharmaceutically acceptable salt thereof, 2-6 parts of a chelating agent, 5-15 parts of a preservative, 2-8 parts of a thickener, 5-15 parts of a sweetener, 1-4 parts of a flavoring agent, and the solvent is diluted to 1 mL.

[0028] Further preferably, the melogabalin besylate oral solution comprises the following components in parts by mass:

[0029] 6-10 parts of melogabalin besylate or a pharmaceutically acceptable salt thereof, 3-5 parts of a chelating agent, 8-13 parts of a preservative, 2-7 parts of a thickener, 8-12 parts of a sweetener, 1-2 parts of a flavoring agent, and the solvent is diluted to 1 mL.

[0030] Preferably, the content of melogabalin besylate in the melogabalin besylate oral solution is 5 mg / mL.

[0031] Preferably, the refractive index of the melogabalin besylate oral solution is 1.1-1.5.

[0032] Further preferably, the refractive index of the melogabalin besylate oral solution is 1.2-1.4.

[0033] Preferably, the viscosity of the melogabalin besylate oral solution is 250-650 mPa·s.

[0034] Further preferably, the viscosity of the melogabalin besylate oral solution is 300-600 mPa·s.

[0035] Preferably, the density of the melogabalin besylate oral solution is 1.0-1.4 g / mL.

[0036] Further preferably, the density of the melogabalin besylate oral solution is 1.1-1.3 g / mL.

[0037] Preferably, the melogabalin besylate is in the free acid form.

[0038] In another aspect, the present invention provides a method for preparing the above-mentioned melogabalin besylate oral solution, comprising the following steps:

[0039] S1: preservative and 50% solvent are mixed at 60-80°C to obtain mixture 1, and the mixture is kept warm;

[0040] S2: Mix the mixture 1 described in S1 with a thickener for 30-50 minutes to obtain a mixture 2;

[0041] S3: cooling to 20-40°C, mixing mixture 2 with melogabalin besylate and a chelating agent to obtain mixture 3;

[0042] S4: Mixture 3 is mixed with the sweetener and flavoring agent at room temperature and filled with water to volume.

[0043] Preferably, the preparation method further comprises step S5: filtering the solution obtained in S4 through an 8-15 μm filter membrane.

[0044] Compared with the prior art, the present invention has the following beneficial effects:

[0045] (1) The melogabalin besylate oral solution of the present invention has excellent taste, high bioavailability, and is easy to take, which greatly improves the patient's compliance.

[0046] (2) The melogabalin besylate oral solution of the present invention has good formulation stability. DETAILED DESCRIPTION

[0047] In order to make the technical means, creative features, purpose and effect of the present invention easy to understand, the present invention is further explained below in conjunction with specific embodiments, but the following embodiments are only preferred embodiments of the present invention, not all. Based on the embodiments in the implementation mode, other embodiments obtained by those skilled in the art without making creative work all belong to the protection scope of the present invention. It is worth noting that the raw materials used in the present invention are all common commercial products, and their sources are not specifically limited. The technology and scientific terms used in the embodiments have the meanings commonly understood by those of ordinary skill in the art to which the present invention belongs.

[0048] Example 1

[0049] A melogabalin besylate oral solution:

[0050] The prescription is shown in Table 1.

[0051] Preparation method:

[0052] 1) Weigh about 50% of the prescribed amount of purified water, heat it to about 65-75° C., add the prescribed amount of methylparaben and propylparaben, and stir to dissolve;

[0053] 2) Add hydroxyethyl cellulose while stirring at 65-75°C and stir for 40 minutes;

[0054] 3) Lower the solution temperature to 20°C-40°C, add the prescribed amount of melogabalin besylate and citric acid, and stir to dissolve;

[0055] 4) adding the prescribed amount of sucralose and raspberry water-soluble flavor at room temperature and mixing evenly, and then adding water to make up to the prescribed amount;

[0056] 5) Finally, filter the obtained solution through a 10 μm PP filter membrane.

[0057] Example 2

[0058] A melogabalin besylate oral solution:

[0059] The prescription is shown in Table 1.

[0060] The preparation method is the same as that in Example 1.

[0061] Example 3

[0062] A melogabalin besylate oral solution:

[0063] The prescription is shown in Table 1.

[0064] The preparation method is the same as that in Example 1.

[0065] Table 1. Prescriptions for Examples 1 to 3

[0066] prescription Example 1 Example 2 Example 3 Name of raw materials Single dose / mg Single dose / mg Single dose / mg Melogabalin Besylate 8.78 8.78 8.78 Citric acid 4 3 5 Methylparaben 11.8 10.8 6.8 Propylparaben 1.2 1.2 1.2 Hydroxyethyl Cellulose 2.5 6.5 4.5 Sucralose 10 8 12 Raspberry water soluble flavor 2 2 2 Purified water Make up to 1 mL Make up to 1 mL Make up to 1 mL total 1mL 1mL 1mL

[0067] Comparative Example 1

[0068] A melogabalin besylate oral solution:

[0069] The prescription is shown in Table 2.

[0070] The preparation method is as follows:

[0071] 1) Weigh about 50% of the prescribed amount of purified water, heat it to about 65-75°C, add the prescribed amount of methylparaben, and stir until it is completely dissolved;

[0072] 2) Add methyl cellulose while stirring at 65-75°C for at least 20 minutes;

[0073] 3) lowering the solution temperature to 20°C-40°C, adding the prescribed amount of melogabalin besylate and tartaric acid, and stirring to dissolve;

[0074] 4) Add the prescribed amount of acesulfame potassium and pomegranate essence at room temperature and mix well, and add water to make up to the prescribed amount;

[0075] 5) Finally, filter the obtained solution through a 10 μm PP filter membrane.

[0076] Comparative Example 2

[0077] A melogabalin besylate oral solution:

[0078] The prescription is shown in Table 2.

[0079] The preparation method is as follows:

[0080] 1) Weigh about 50% of the prescribed amount of purified water, heat it to about 65-75°C, add the prescribed amount of propylparaben, and stir until it is completely dissolved;

[0081] 2) Add methyl cellulose while stirring at 65-75°C for at least 20 minutes;

[0082] 3) lowering the solution temperature to 20°C-40°C, adding the prescribed amount of melogabalin besylate and tartaric acid, and stirring to dissolve;

[0083] 4) Add the prescribed amount of acesulfame potassium and pomegranate essence at room temperature and mix well, and add water to make up to the prescribed amount;

[0084] 5) Finally, filter the obtained solution through a 10 μm PP filter membrane.

[0085] Comparative Example 3

[0086] A melogabalin besylate oral solution:

[0087] The prescription is shown in Table 2.

[0088] The preparation method is as follows:

[0089] 1) Weigh about 50% of the prescribed amount of purified water, heat it to about 65-75°C, add the prescribed amount of methylparaben and propylparaben, and stir until completely dissolved;

[0090] 2) Add methyl cellulose while stirring at 65-75°C for at least 20 minutes;

[0091] 3) lowering the solution temperature to 20°C-40°C, adding the prescribed amount of melogabalin besylate and tartaric acid, and stirring to dissolve;

[0092] 4) Add the prescribed amount of acesulfame potassium and pomegranate essence at room temperature and mix well, and add water to make up to the prescribed amount;

[0093] 5) Finally, filter the obtained solution through a 10 μm PP filter membrane.

[0094] Comparative Example 4

[0095] A melogabalin besylate oral solution:

[0096] The prescription is shown in Table 2.

[0097] The preparation method is as follows:

[0098] 1) Weigh about 50% of the prescribed amount of purified water, heat it to about 65-75°C, add the prescribed amount of sodium benzoate, and stir until it is completely dissolved;

[0099] 2) Add methyl cellulose while stirring at 65-75°C for at least 20 minutes;

[0100] 3) lowering the solution temperature to 20°C-40°C, adding the prescribed amount of melogabalin besylate and tartaric acid, and stirring to dissolve;

[0101] 4) Add the prescribed amount of acesulfame potassium and pomegranate essence at room temperature and mix well, and add water to make up to the prescribed amount;

[0102] 5) Finally, filter the obtained solution through a 10 μm PP filter membrane.

[0103] Comparative Example 5

[0104] A melogabalin besylate oral solution:

[0105] The prescription is shown in Table 2.

[0106] The preparation method is as follows:

[0107] 1) Weigh about 50% of the prescribed amount of purified water, heat it to about 65-75°C, add the prescribed amount of potassium sorbate, and stir until it is completely dissolved;

[0108] 2) Add methyl cellulose while stirring at 65-75°C for at least 20 minutes;

[0109] 3) lowering the solution temperature to 20°C-40°C, adding the prescribed amount of melogabalin besylate and tartaric acid, and stirring to dissolve;

[0110] 4) Add the prescribed amount of acesulfame potassium and pomegranate essence at room temperature and mix well, and add water to make up to the prescribed amount;

[0111] 5) Finally, filter the obtained solution through a 10 μm PP filter membrane.

[0112] Comparative Example 6

[0113] A melogabalin besylate oral solution:

[0114] The prescription is shown in Table 2.

[0115] The preparation method is as follows:

[0116] 1) Weigh about 50% of the prescribed amount of purified water, heat it to about 65-75°C, add the prescribed amount of sodium benzoate and potassium sorbate, and stir until completely dissolved;

[0117] 2) Add methyl cellulose while stirring at 65-75°C for at least 20 minutes;

[0118] 3) lowering the solution temperature to 20°C-40°C, adding the prescribed amount of melogabalin besylate and tartaric acid, and stirring to dissolve;

[0119] 4) Add the prescribed amount of acesulfame potassium and pomegranate essence at room temperature and mix well, and add water to make up to the prescribed amount;

[0120] 5) Finally, filter the obtained solution through a 10 μm PP filter membrane.

[0121] Table 2. Prescriptions for Comparative Examples 1 to 6

[0122]

[0123] Test Example 1. Taste

[0124] Taste evaluation criteria:

[0125] Excellent (10): Good sweetness and excellent acceptance.

[0126] Average (6): Average sweetness, easy to adapt to and accept.

[0127] Poor (2): Too sweet or uncomfortable in the mouth, difficult to accept.

[0128] Very bad (0): The taste is very bad and unacceptable.

[0129] The taste evaluation results of Examples 1 to 3 are shown in Table 3:

[0130] Table 3. Taste evaluation results of Examples 1 to 3

[0131]

[0132] The taste evaluation results of Comparative Examples 1 to 6 are shown in Table 4:

[0133] Table 4. Taste evaluation results of Comparative Examples 1 to 6

[0134] Group Reviewer 1 Reviewer 2 Reviewer 3 Reviewer 4 average Comparative Example 1 2 0 0 0 0.5 Comparative Example 2 0 2 0 0 0.5 Comparative Example 3 2 6 2 0 2.5 Comparative Example 4 2 0 6 2 2.5 Comparative Example 5 2 6 0 2 2.5 Comparative Example 6 2 0 0 0 0.5

[0135] From the comparison of the data in Tables 3-4, it can be seen that, compared with the comparative example, the oral solution of melogabalin besylate prepared in the embodiment of the present invention has a better taste.

[0136] Test Example 2. Stability

[0137] The samples of the oral solution preparations of melogabalin besylate of Examples 1 to 3 and Comparative Examples 1 to 6 were stored at 60° C. for 30 days to observe their stability. The results of the stability study are shown in Tables 5-6:

[0138] Table 5. Stability of Examples 1-3

[0139] Group Stability conditions Characteristics Impurity A% Maximum unknown single impurity % Total impurities% Example 1 60℃, 30 days Light yellow clear viscous liquid 0.02 0.06 0.21 Example 2 60℃, 30 days Light yellow clear viscous liquid 0.05 0.07 0.61 Example 3 60℃, 30 days Light yellow clear viscous liquid 0.08 0.06 0.54

[0140] Table 6. Stability of Comparative Examples 1 to 6

[0141]

[0142] From the stability results, it can be seen that the impurities in the above examples did not show significant growth when placed at 60° C. for 30 days, but Example 1 had the best stability.

[0143] The invention does not require special production conditions, has the characteristics of low production cost, convenient storage and administration, improves the medication compliance of patients, and has broad market prospects.

[0144] Finally, it should be noted that the above content is only used to illustrate the technical solution of the present invention, rather than to limit the scope of protection of the present invention. Simple modifications or equivalent substitutions of the technical solution of the present invention by ordinary technicians in this field do not deviate from the essence and scope of the technical solution of the present invention.

Claims

1. A melogabalin besylate oral solution, characterized in that: Contains the following ingredients: Melogabalin besylate or a pharmaceutically acceptable salt thereof, a solvent, a chelating agent, a preservative, a thickener, a sweetener and a flavoring agent.

2. The oral solution of melogabalin besylate according to claim 1, characterized in that The solvent is water; The chelating agent is selected from at least one of citric acid, fumaric acid, L-lactic acid, formic acid, acetic acid, propionic acid, butyric acid, sorbic acid, malic acid, tartaric acid, and benzoic acid; The preservative is selected from at least one of methyl paraben, propyl paraben, benzyl alcohol, benzoic acid, potassium sorbate, sodium benzoate and ascorbic acid; The preservative is selected from at least one of methyl paraben and propyl paraben; The thickener is selected from at least one of methyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose, xanthan gum and gelatin; The sweetener is selected from at least one of sucralose, aspartame, mannitol, sorbitol, xylitol, acesulfame potassium, stevia, glucose, saccharin sodium, fructose, high fructose corn syrup, maltodextrin and sucrose; The flavor corrector is selected from at least one of raspberry water-soluble flavor, orange flavor and strawberry flavor.

3. The oral solution of melogabalin besylate according to claim 1, characterized in that The melogabalin besylate oral solution comprises the following components in parts by mass: 5-10 parts of melogabalin besylate or a pharmaceutically acceptable salt thereof, 2-6 parts of a chelating agent, 5-15 parts of a preservative, 2-8 parts of a thickener, 5-15 parts of a sweetener, 1-4 parts of a flavoring agent, and the solvent is diluted to 1 mL.

4. The oral solution of melogabalin besylate according to claim 3, characterized in that The melogabalin besylate oral solution comprises the following components in parts by mass: 6-10 parts of melogabalin besylate or a pharmaceutically acceptable salt thereof, 3-5 parts of a chelating agent, 8-13 parts of a preservative, 2-7 parts of a thickener, 8-12 parts of a sweetener, 1-2 parts of a flavoring agent, and the solvent is diluted to 1 mL.

5. The oral solution of melogabalin besylate according to claim 1, characterized in that The content of melogabalin besylate in the melogabalin besylate oral solution is 5 mg / mL.

6. The oral solution of melogabalin besylate according to claim 1, characterized in that The refractive index of the melogabalin besylate oral solution is 1.1-1.

5.

7. The oral solution of melogabalin besylate according to claim 1, characterized in that The viscosity of the melogabalin besylate oral solution is 250-650 mPa·s.

8. The oral solution of melogabalin besylate according to claim 1, characterized in that: The density of the melogabalin besylate oral solution is 1.0-1.4 g / mL.

9. The method for preparing the melogabalin besylate oral solution according to any one of claims 1 to 8, characterized in that: The following steps are involved: S1: preservative and 50% solvent are mixed at 60-80°C to obtain mixture 1, and the mixture is kept warm; S2: Mix the mixture 1 described in S1 with the thickener for 30-50 minutes to obtain a mixture 2; S3: cooling to 20-40°C, mixing mixture 2 with melogabalin besylate and a chelating agent to obtain mixture 3; S4: Mixture 3 is mixed with the sweetener and flavoring agent at room temperature and filled with water to volume.

10. The preparation method according to claim 9, characterized in that: The preparation method further comprises step S5: filtering the solution obtained in S4 through a 8-15 μm filter membrane.

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