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 is prepared from the following components in dosage: 1 to 2mg of melogabalin besylate, 0.5 to 5mg of a stabilizing agent, 0.05 to 3mg of a bacteriostatic agent, 0.5 to 5mg of a concentrated sweetening agent, 50 to 200mg of a loose sweetening agent, 0.05 to 0.5 mg of a flavoring agent and 0.5 to 5mg of a coloring agent. According to the invention, melogabalin besylate is further prepared into an oral solution dosage form, and a special oral metering small cup is provided, so that a fixed amount of oral liquid can be measured for taking according to symptoms during the taking period of an old patient, thereby solving the problems of forgetting to take a plurality of tablets or confusion of tablets with different sizes and specifications; meanwhile, good medication compliance of a patient with dysphagia is also ensured, and very practical significance is achieved.

Description

Technical Field

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

[0002] Neuropathic pain is one of the most destructive pains and a serious unmet medical need. Neuropathic pain refers to pain caused by damage or lesions in the nervous system, with dull pain, burning and tingling as the main characteristics. Neuropathic pain can be caused by a variety of diseases, including painful neuropathy (diabetes-related or non-diabetes-related), nerve damage (mainly caused by surgery or trauma), herpes zoster, herniated disc, multiple sclerosis, spinal cord injury, head trauma or stroke, tension headache, etc. Tension headache is the most common type of headache with a high prevalence. Patients usually feel dull pain, which may be complicated by insomnia, depression and other intracranial complications, often accompanied by symptoms such as irritability and low mood. The above diseases seriously affect the physical and mental health and quality of life of patients, and they often cannot function normally at work and in life. There are still some unmet needs in the chronic pain market.

[0003] In recent years, although several drugs for the treatment of chronic pain have been approved for marketing, such as Eli Lilly's Emgality (Galcanezumab) and Lundbeck's Vyepti (Eptinezumab), they are mainly antibody drugs for the treatment of migraine. As an oral analgesic approved in this field, melogabalin has unique advantages in terms of both route of administration and indications.

[0004] Melogabalin is an α2δ ligand that specifically binds to the α2δ subunit of voltage-gated calcium channels, reduces the influx of calcium ions at presynaptic terminals, inhibits the release of excitatory neurotransmitters, and thus relieves pain. Existing studies have shown that compared with pregabalin and gabapentin, melogabalin has a higher analgesic effect in relieving DPNP and PHN-related pain, has a wider safety margin, and a relatively low incidence of adverse reactions.

[0005] In January 2019, based on the results of a Phase 3 clinical trial in patients with diabetic peripheral neuropathy (DPNP) and postherpetic neuralgia (PHN), Daiichi Sankyo, a Japanese pharmaceutical company, Melogabaline besylate tablets have been approved in Japan for the treatment of "peripheral neuropathic pain". In addition, the effectiveness of Melogabaline besylate tablets in the treatment of patients with central neuropathic pain has been verified in a phase 3 trial, and its safety has been confirmed. The application to change the indication to "neuropathic pain" was approved in Japan in March 2022.

[0006] The drug is suitable for patients with peripheral neuropathic pain and stroke patients, many of whom are elderly. These patients often have difficulty swallowing and may have difficulties taking traditional tablets (such as film-coated tablets), resulting in poor medication compliance. Orally disintegrating tablets (OD tablets) are a preparation that may help improve compliance. This tablet can be taken without adding water, which is easier to take not only for patients with dysphagia, but also for patients with limited daily activities. Therefore, because orally disintegrating tablets are believed to help improve patients' medication compliance and show stable therapeutic effects, Daiichi Sankyo submitted an application for a new dosage form of orally disintegrating tablets and obtained approval for production and sales in September 2022. The specifications are the same as ordinary tablets: 2.5mg, 5mg, 10mg and 20mg.

[0007] For adults, the initial dose of melogabalin is 5 mg orally twice a day. The dose should be increased or decreased as appropriate within the range of 10 mg to 15 mg each time, based on age and symptoms, and gradually increased by 5 mg at intervals of one week or more, up to a maximum of 15 mg orally twice a day.

[0008] Although orally disintegrating tablets have improved medication compliance for some elderly patients and solved the practical problem of dysphagia, they have posed new challenges to us in the complex and diverse medication environment. For example, since symptoms are difficult to relieve, patients may gradually increase the dosage, and it has become a real challenge for the elderly to take multiple tablets or have multiple specifications available to choose (multiple tablets or large specifications) according to the situation.

[0009] Oral solution preparations are easy to take and have high bioavailability, but the preparation of stable solutions requires appropriate technology and methods. According to patent searches, there are currently no relevant patents for the preparation method of melogabalin oral solution. Summary of the invention

[0010] 1. Technical issues to be solved

[0011] In view of the deficiencies in the prior art, the present invention provides a melogabalin besylate oral solution and a preparation method thereof, which solves the defect that there is no melogabalin oral solution in the prior art.

[0012] (II) Technical solution

[0013] To achieve the above objectives, the present invention is implemented through the following technical scheme: an oral solution of melogabalin besylate, the oral solution formulation comprising the following dosage components: 1-2 mg of melogabalin besylate, 0.5-5 mg of stabilizer, 0.05-3 mg of antibacterial agent, 0.5-5 mg of concentrated sweetener, 50-200 mg of bulk sweetener, 0.05-0.5 mg of flavoring agent, and 0.5-5 mg of colorant.

[0014] Preferably, the concentrated sweetener is one or more combinations of sucrose, fructose, sorbitol, saccharin sodium, sucralose, aspartame, stevia glycosides, and mogrosides, preferably sucralose.

[0015] Preferably, the bulk sweetener is one or more combinations of sorbitol, mannitol, xylitol, sucrose, fructose, and fructose-glucose syrup, preferably sorbitol.

[0016] Preferably, the flavoring agent is one or more combinations of strawberry flavor, orange flavor, apple flavor, mint flavor, lemon flavor, and chocolate flavor, preferably orange flavor.

[0017] Preferably, the stabilizer is one or more combinations of glycerol, sodium alginate, hydroxypropyl methylcellulose, and sodium carboxymethyl cellulose, preferably hydroxypropyl methylcellulose.

[0018] Preferably, the antibacterial agent is one or more combinations of sodium benzoate, methylparaben, sodium methylparaben, propylparaben, potassium sorbate, preferably sodium benzoate.

[0019] Preferably, the colorant is caramel.

[0020] A method for preparing melogabalin besylate oral solution, the preparation method comprising the following steps:

[0021] 1) Add solvent to the liquid preparation tank and heat to 40-60°C;

[0022] 2) premixing the prescribed amount of concentrated sweetener and stabilizer, and after fully mixing, adding the prescribed amount of concentrated sweetener and stabilizer mixture into a liquid preparation tank, stirring until the stabilizer is completely dissolved, to obtain a mixture 1;

[0023] 3) adding the prescribed amount of melogabalin besylate, bulk sweetener, and antibacterial agent to mixture 1, stirring and dissolving, to obtain mixture 2;

[0024] 4) Cooling the mixture 2 to room temperature, adding the prescribed amount of flavoring agent and coloring agent under stirring, stirring to dissolve, and adjusting the pH value to within the range of 3.5-4.5 with a pH adjuster, stirring for 10 minutes, to obtain a mixture 3;

[0025] 5) Add mixture 3 to the full volume and stir for 10 min to obtain mixture 4;

[0026] 6) Fill, cap and package the mixture.

[0027] Preferably, the solvent is water, ethanol or ethanol-water solution.

[0028] Preferably, the pH adjuster is one or more combinations of hydrochloric acid, acetic acid, lactic acid, citric acid, tartaric acid, malic acid, sorbic acid, and succinic acid, preferably citric acid.

[0029] (III) Beneficial effects

[0030] The present invention provides a melogabalin besylate oral solution and a preparation method thereof.

[0031] Beneficial effects:

[0032] The present invention further prepares melogabalin besylate into an oral solution dosage form and is equipped with a special oral metering cup. Elderly patients can take a fixed amount of oral solution according to symptoms during the medication period, which not only solves the problem of forgetting to take multiple tablets or confusing tablets of different sizes, but also ensures good medication compliance of patients with dysphagia, and has very practical significance. DETAILED DESCRIPTION

[0033] The following will be described clearly and completely in conjunction with the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0034] The embodiment of the present invention provides a melogabalin besylate oral solution, and the oral solution formulation includes the following dosage components: melogabalin besylate 1-2 mg, stabilizer 0.5-5 mg, antibacterial agent 0.05-3 mg, strong sweetener 0.5-5 mg, bulk sweetener 50-200 mg, flavoring agent 0.05-0.5 mg, and colorant 0.5-5 mg.

[0035] The concentrated sweetener is one or more combinations of sucrose, fructose, sorbitol, sodium saccharin, sucralose, aspartame, stevia glycosides, and mogrosides, preferably sucralose; the bulk sweetener is one or more combinations of sorbitol, mannitol, xylitol, sucrose, fructose, and fructose-glucose syrup, preferably sorbitol; the flavoring agent is one or more combinations of strawberry flavor, orange flavor, apple flavor, mint flavor, lemon flavor, and chocolate flavor, preferably orange flavor; the stabilizer is one or more combinations of glycerol, sodium alginate, hydroxypropyl methylcellulose, and sodium carboxymethyl cellulose, preferably hydroxypropyl methylcellulose; the antibacterial agent is one or more combinations of sodium benzoate, methylparaben, sodium methylparaben, propylparaben, and potassium sorbate, preferably sodium benzoate; the colorant is caramel.

[0036] A method for preparing melogabalin besylate oral solution, the preparation method comprising the following steps:

[0037] 1) Add a solvent into a liquid preparation tank and heat it to 40-60° C., wherein the solvent is water, ethanol or ethanol-water solution;

[0038] 2) premixing the prescribed amount of concentrated sweetener and stabilizer, and after fully mixing, adding the prescribed amount of concentrated sweetener and stabilizer mixture into a liquid preparation tank, stirring until the stabilizer is completely dissolved, to obtain a mixture 1;

[0039] 3) adding the prescribed amount of melogabalin besylate, bulk sweetener, and antibacterial agent to mixture 1, stirring and dissolving, to obtain mixture 2;

[0040] 4) cooling the mixture 2 to room temperature, adding the prescribed amount of flavoring agent and coloring agent under stirring, stirring to dissolve, and adjusting the pH value to within the range of 3.5-4.5 with a pH adjuster, stirring for 10 minutes, to obtain a mixture 3, wherein the pH adjuster is one or more combinations of hydrochloric acid, acetic acid, lactic acid, citric acid, tartaric acid, malic acid, sorbic acid, and succinic acid, preferably citric acid;

[0041] 5) Add mixture 3 to the full volume and stir for 10 min to obtain mixture 4;

[0042] 6) Fill, cap and package the mixture.

[0043] Embodiment 1:

[0044] The oral solution formulation includes the following dosage components, see Table 1 below;

[0045] Table 1

[0046]

[0047]

[0048] Preparation method:

[0049] 1) Add about 80% purified water into the liquid preparation tank and heat to 40-60°C;

[0050] 2) premixing the prescribed amount of sucralose and hypromellose, and after fully mixing, adding the prescribed amount of the mixture of sucralose and hypromellose into a liquid preparation tank, stirring until the hypromellose is completely dissolved, to obtain a mixture 1;

[0051] 3) adding the prescribed amount of melogabalin besylate, sorbitol and potassium sorbate to mixture 1, stirring and dissolving to obtain mixture 2;

[0052] 4) Cooling the mixture 2 to room temperature, adding the prescribed amount of orange essence and caramel under stirring, stirring to dissolve, and adjusting the pH value to within the range of 3.5-4.5 with citric acid, stirring for 10 minutes, to obtain a mixture 3;

[0053] 5) Add mixture 3 to the full volume and stir for 10 min to obtain mixture 4;

[0054] 6) Fill, cap and package the mixture.

[0055] Embodiment 2:

[0056] The oral solution formulation includes the following dosage components, see Table 2 below;

[0057] Table 2

[0058]

[0059] Preparation method:

[0060] 1) Add about 80% purified water into the liquid preparation tank and heat to 40-60°C;

[0061] 2) premixing the prescribed amount of sucralose and hypromellose, and after fully mixing, adding the prescribed amount of the mixture of sucralose and hypromellose into a liquid preparation tank, stirring until the hypromellose is completely dissolved, to obtain a mixture 1;

[0062] 3) adding the prescribed amount of melogabalin besylate, sorbitol and potassium sorbate to mixture 1, stirring and dissolving to obtain mixture 2;

[0063] 4) Cooling the mixture 2 to room temperature, adding the prescribed amount of orange essence under stirring, stirring to dissolve, and adjusting the pH value to within the range of 3.5-4.5 with citric acid, stirring for 10 minutes, to obtain a mixture 3;

[0064] 5) Add mixture 3 to the full volume and stir for 10 min to obtain mixture 4;

[0065] 6) Fill, cap and package the mixture.

[0066] Embodiment three:

[0067] The oral solution formulation includes the following dosage components, see Table 3 below;

[0068] Table 3

[0069]

[0070] Preparation method:

[0071] 1) Add about 80% purified water into the liquid preparation tank and heat to 40-60°C;

[0072] 2) premixing the prescribed amount of sucralose and hypromellose, and after fully mixing, adding the prescribed amount of the mixture of sucralose and hypromellose into a liquid preparation tank, and stirring until the hypromellose is completely dissolved to obtain a mixture 1;

[0073] 3) adding the prescribed amount of melogabalin besylate, sorbitol and potassium sorbate to mixture 1, stirring and dissolving to obtain mixture 2;

[0074] 4) Cooling the mixture 2 to room temperature, adding the prescribed amount of caramel under stirring, stirring to dissolve, and adjusting the pH value to within the range of 3.5-4.5 with citric acid, stirring for 10 minutes, to obtain a mixture 3;

[0075] 5) Add mixture 3 to the full volume and stir for 10 min to obtain mixture 4;

[0076] 6) Fill, cap and package the mixture.

[0077] In Example 2, no caramel was added. Compared with Example 1, the light test showed that adding caramel was more helpful for the stability of the sample under light conditions; in Example 3, no orange flavor was added. Compared with Example 1, the taste test showed that the sample with orange flavor made the patients more compliant.

[0078] During the preparation process, by adding different amounts of pH adjusters, the changes in appearance, pH value, and related substances of melogabalin besylate oral solution with different pH values ​​at high temperature of 60°C and light exposure of 5000±500l x 10 days were investigated. The results are shown in Table 4;

[0079] Table 4

[0080]

[0081]

[0082] The experimental results are shown in Table 1. The sample with pH value of 3.0 produced brown precipitate during pH adjustment, so it was not sampled for influencing factors. ① Related substances: After being placed at high temperature of 60℃ and light of 5000±500l x for 10 days, the related substances of each sample increased slightly, among which the pH5.0 sample increased most significantly and exceeded the limit. ② Appearance properties: After being placed at high temperature of 60℃ and light of 5000±500l x for 10 days, the color and pH of the pH3.5-pH5.0 samples did not change significantly compared with 0 days. Based on the results of related substances and appearance properties, it is preliminarily shown that the quality of the samples is stable between pH3.5-4.5.

[0083] It should be noted that, in this article, relational terms such as first and second, etc. are only used to distinguish one entity or operation from another entity or operation, and do not necessarily require or imply any such actual relationship or order between these entities or operations. Moreover, the terms "include", "comprise" or any other variants thereof are intended to cover non-exclusive inclusion, so that a process, method, article or device including a series of elements includes not only those elements, but also other elements not explicitly listed, or also includes elements inherent to such process, method, article or device. In the absence of further restrictions, the elements defined by the statement "comprising a reference structure" do not exclude the existence of other identical elements in the process, method, article or device including the elements.

[0084] Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that various changes, modifications, substitutions and variations may be made to the embodiments without departing from the principles and spirit of the present invention, and that the scope of the present invention is defined by the appended claims and their equivalents.

Claims

1. A melogabalin besylate oral solution, characterized in that: The oral solution formulation comprises the following dosage components: 1-2 mg of melogabalin besylate, 0.5-5 mg of a stabilizer, 0.05-3 mg of an antibacterial agent, 0.5-5 mg of a concentrated sweetener, 50-200 mg of a bulk sweetener, 0.05-0.5 mg of a flavoring agent, and 0.5-5 mg of a colorant.

2. The oral solution of melogabalin besylate according to claim 1, characterized in that: The concentrated sweetener is one or more combinations of sucrose, fructose, sorbitol, saccharin sodium, sucralose, aspartame, stevioside, and mogroside, preferably sucralose.

3. The oral solution of melogabalin besylate according to claim 1, characterized in that: The bulk sweetener is one or more combinations of sorbitol, mannitol, xylitol, sucrose, fructose, and fructose-glucose syrup, preferably sorbitol.

4. The oral solution of melogabalin besylate according to claim 1, characterized in that: The flavoring agent is one or more of strawberry flavor, orange flavor, apple flavor, mint flavor, lemon flavor, and chocolate flavor, preferably orange flavor.

5. The oral solution of melogabalin besylate according to claim 1, characterized in that: The stabilizer is one or more combinations of glycerol, sodium alginate, hydroxypropyl methylcellulose, and sodium carboxymethyl cellulose, preferably hydroxypropyl methylcellulose.

6. The oral solution of melogabalin besylate according to claim 1, characterized in that: The antibacterial agent is one or more combinations of sodium benzoate, methylparaben, sodium methylparaben, propylparaben, and potassium sorbate, preferably sodium benzoate.

7. The oral solution of melogabalin besylate according to claim 1, characterized in that: The coloring agent is caramel.

8. A method for preparing a melogabalin besylate oral solution according to any one of claims 1 to 7, characterized in that: The preparation method comprises the following steps: 1) Add solvent to the liquid preparation tank and heat to 40-60°C; 2) premixing the prescribed amount of concentrated sweetener and stabilizer, and after fully mixing, adding the prescribed amount of concentrated sweetener and stabilizer mixture into a liquid preparation tank, stirring until the stabilizer is completely dissolved, to obtain a mixture 1; 3) adding the prescribed amount of melogabalin besylate, bulk sweetener, and antibacterial agent to mixture 1, stirring and dissolving, to obtain mixture 2; 4) Cooling the mixture 2 to room temperature, adding the prescribed amount of flavoring agent and coloring agent under stirring, stirring to dissolve, and adjusting the pH value to within the range of 3.5-4.5 with a pH adjuster, stirring for 10 minutes, to obtain a mixture 3; 5) Add mixture 3 to the full volume and stir for 10 min to obtain mixture 4; 6) Fill, cap and package the mixture.

9. The method for preparing a melogabalin besylate oral solution according to claim 8, characterized in that: The solvent is water, ethanol or ethanol aqueous solution.

10. The method for preparing melogabalin besylate oral solution according to claim 8, characterized in that: The pH adjuster is one or more of hydrochloric acid, acetic acid, lactic acid, citric acid, tartaric acid, malic acid, sorbic acid, and succinic acid, preferably citric acid.

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