Folic acid-containing composition and application thereof, orally disintegrating tablet and preparation method

Abstract

The invention provides a folic acid-containing composition and application thereof, an orally disintegrating tablet and a preparation method, the folic acid-containing composition comprises a folic acid raw material, escitalopram oxalate and melogabalin besylate, and the weight ratio of the folic acid raw material to escitalopram oxalate to melogabalin besylate is (0.4-5): (10-20): (5-30). The folic acid raw materials comprise one or more of folic acid and derivatives thereof. Folic acid raw materials, escitalopram oxalate and melogabalin besylate are used in a matched mode according to a specific proportion, synergistic interaction can be achieved, central nervous pathological pain accompanied by depression after stroke can be effectively treated, meanwhile, relapse of stroke can be prevented, and rehabilitation after stroke is facilitated.

Description

Technical Field

[0001] The present application relates to the technical field of pharmaceutical preparations, and in particular to a folic acid-containing composition and its application, an orally disintegrating tablet and a preparation method. Background Art

[0002] In recent years, with the advent of an aging society, stroke has become the leading cause of death and disability in adults, among which acute ischemic stroke (AIS) is the most common type of stroke. At present, intravenous thrombolysis and intravascular mechanical thrombectomy are effective measures for vascular recanalization recommended by domestic and international guidelines. Opening occluded blood vessels as soon as possible is the key to the treatment of AIS, but the clinical prognosis of patients is not ideal. In addition to the corresponding sensory and motor dysfunction, 19%-74% of patients will experience neuropathic pain, among which the incidence of central neuropathic pain after stroke in the elderly is as high as 25%-50%. Central neuropathic pain after stroke refers to pain caused by damage to the somatic sensory system by cerebral stroke. The clinical characteristics are that pain occurs even without pain stimulation, or the degree of pain is disproportionate to the stimulation received.

[0003] Post-stroke depression (PSD) is the most common and most serious neuropsychiatric complication after stroke. Post-stroke depression refers to a series of affective disorder syndromes that occur after a stroke, characterized by low mood and loss of interest in addition to stroke symptoms, often accompanied by physical symptoms. Patients who suffer from long-term central pain after a stroke are often accompanied by mood changes such as anxiety, insomnia and depression. In the general population, the incidence of depression in patients with central neuropathic pain is as high as 30%-54%. The accumulation of depressive emotions will increase the patient's pain perception, creating a vicious circle. This is the comorbidity of pain and depression, which has a serious impact on the patient's life and rehabilitation.

[0004] Central neuropathic pain and depression after stroke is a chronic process that can lead to a variety of adverse outcomes, including increased disability, recurrence rate, and mortality, especially in the first year after stroke, which can lead to more severe functional impairment, longer hospital stays, worse rehabilitation outcomes, lower quality of life, and higher mortality. Therefore, there is an urgent need for drugs that can effectively treat central neuropathic pain and depression after stroke. Summary of the invention

[0005] Based on this, the present application provides a folic acid composition and its application, medicine and preparation method, so as to effectively treat central neuropathic pain associated with depression after stroke, shorten the treatment cycle and reduce the pain of patients.

[0006] The first aspect of the present application provides a folic acid-containing composition, which includes a folic acid raw material, escitalopram oxalate and melogabalin besylate, wherein the weight ratio of the folic acid raw material, escitalopram oxalate and melogabalin besylate is (0.4-5):(10-20):(5-30), and the folic acid raw material includes one or more of folic acid and its derivatives.

[0007] In some embodiments, the weight ratio of the folic acid raw material, escitalopram oxalate and melogabalin besylate is (0.4-1.5):(10-15):(10-20).

[0008] In some embodiments, the weight ratio of the folic acid raw material, escitalopram oxalate and melogabalin besylate is (0.4-1.5):(10-20):(10-20).

[0009] In some embodiments, the D90 of the folic acid raw material is ≤15 μm; and / or

[0010] Melogabalin besylate D90 ≤ 10 μm; and / or

[0011] The D90 of escitalopram oxalate is ≤15μm.

[0012] In some embodiments, the folic acid derivative includes one or more of folinic acid, L-methylfolate, a pharmaceutically acceptable salt of folic acid, an active metabolite of folic acid, and an active metabolite of a pharmaceutically acceptable salt of folic acid.

[0013] The second aspect of the present application provides a use of the folic acid-containing composition of the first aspect of the present application in the preparation of a medicament for treating central neuropathic pain associated with depression after stroke.

[0014] The third aspect of the present application provides a drug for treating central neuropathic pain associated with depression after stroke, the drug comprising a folic acid composition, wherein the folic acid composition comprises, by weight:

[0015] 0.4-5 parts of folic acid raw materials, 10-20 parts of escitalopram oxalate and 5-30 parts of melogabalin besylate.

[0016] In some embodiments, the folic acid-containing composition comprises, by weight:

[0017] 0.4-1.5 parts of folic acid raw materials, 10-20 parts of escitalopram oxalate and 10-20 parts of melogabalin besylate.

[0018] In some embodiments, the folate-containing composition has at least one of the following characteristics (1)-(2):

[0019] (1) the D90 of the folic acid raw material is ≤15 μm; and / or

[0020] Melogabalin besylate D90 ≤ 10 μm; and / or

[0021] D90 of escitalopram oxalate ≤ 15 μm;

[0022] (2) The folic acid derivatives include one or more of folate, L-methylfolate, pharmaceutically acceptable salts of folic acid, active metabolites of folic acid, and active metabolites of pharmaceutically acceptable salts of folic acid.

[0023] In some embodiments, the drug further comprises low-substituted hydroxypropyl cellulose, mannitol, sucrose, α-tocopherol, microcrystalline cellulose, citric acid monohydrate, hypromellose and magnesium stearate;

[0024] Optionally, the drug includes, by weight: 0.4-5 parts of folic acid raw materials, 10-20 parts of escitalopram oxalate, 5-30 parts of melogabalin besylate, 5-15 parts of low-substituted hydroxypropyl cellulose, 80-90 parts of mannitol, 35-45 parts of sucrose, 0.2-0.5 parts of α-tocopherol, 15-25 parts of microcrystalline cellulose, 3-8 parts of citric acid monohydrate, 1-2 parts of hypromellose and 1-3 parts of magnesium stearate.

[0025] The fourth aspect of the present application provides a method for preparing a drug for treating central neuropathic pain associated with depression after stroke, comprising the following steps:

[0026] The folic acid raw material, escitalopram oxalate, part of low-substituted hydroxypropyl cellulose, part of mannitol and sucrose are mixed, and then wet granulated to prepare folic acid and escitalopram oxalate granules;

[0027] The α-tocopherol is mixed with microcrystalline cellulose, and then mixed with melogabalin besylate, the remaining low-substituted hydroxypropyl cellulose, the remaining mannitol and citric acid monohydrate, and wet granulated with an aqueous solution containing hydroxypropyl methylcellulose to prepare melogabalin besylate granules;

[0028] The folic acid and escitalopram oxalate granules, the melogabalin besylate granules and magnesium stearate are mixed and then tableted.

[0029] The above-mentioned folic acid-containing composition can synergistically enhance the efficacy by combining folic acid raw materials, escitalopram oxalate and melogabalin besylate in a specific ratio, effectively treat central nervous system pathological pain accompanied by depression after stroke, and prevent stroke recurrence, which is beneficial to post-stroke rehabilitation.

[0030] When preparing orodisintegrating tablets, folic acid and escitalopram oxalate are mixed and granulated, and melogabalin besylate is granulated separately, which can ensure that the product quality is stable and controllable. The preparation process is simple, and the preparation is preferably an orodisintegrating tablet. The product has good stability, is easy to take, and has a rapid onset of action, and is more suitable for the treatment of patients with post-stroke central pathological pain and depression. DETAILED DESCRIPTION

[0031] For ease of understanding of the present invention, the application will be described more fully below with reference to relevant embodiments. The following provides preferred embodiments of the application. However, the application can be implemented in many different forms and is not limited to the embodiments described herein. On the contrary, the purpose of providing these embodiments is to make the understanding of the disclosure of the application more thorough and comprehensive.

[0032] 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 belongs. The terms used herein in the specification of this application are only for the purpose of describing specific embodiments and are not intended to limit this application.

[0033] The terms "and / or", "or / and", and "and / or" used herein include any one of two or more related listed items, and also include any and all combinations of the related listed items, wherein the any and all combinations include any combination of two related listed items, any more related listed items, or all related listed items. It should be noted that when at least three items are connected by at least two conjunctions selected from "and / or", "or / and", and "and / or", it should be understood that in the present application, the technical solution undoubtedly includes technical solutions connected by "logical and", and also undoubtedly includes technical solutions connected by "logical or".

[0034] In the present 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 it comes to numerical ranges, unless otherwise specified, the above numerical ranges are deemed to be continuous and include the minimum and maximum values ​​of the range, as well as each value between such minimum and maximum values. Further, when a range refers to an integer, each integer between the minimum and maximum values ​​of the range is included. In addition, when multiple ranges are provided to describe features or characteristics, the ranges can be merged. In other words, unless otherwise specified, all ranges disclosed herein should be understood to include any and all subranges included therein.

[0036] Only some numerical ranges are specifically disclosed herein. However, any lower limit can be combined with any upper limit to form an unspecified range; and any lower limit can be combined with other lower limits to form an unspecified range, and likewise any upper limit can be combined with any other upper limit to form an unspecified range. In addition, each separately disclosed point or single value can itself be combined as a lower limit or upper limit with any other point or single value or with other lower limits or upper limits to form an unspecified range.

[0037] The temperature parameters in this application, unless otherwise specified, allow both constant temperature treatment and treatment within a certain temperature range. The constant temperature treatment allows the temperature to fluctuate within the accuracy range controlled by the instrument. Fluctuations within the range of ±5°C, ±4°C, ±3°C, ±2°C, and ±1°C are allowed.

[0038] Herein, the “suitable” mentioned in “suitable combination”, “suitable method”, “any suitable method”, etc., shall be based on the ability to implement the technical solution of this application, solve the technical problems of this application, and achieve the expected technical effects of this application.

[0039] In the present application, "further", "further", "particularly" and the like are used for descriptive purposes to indicate differences in content, but should not be construed as limiting the scope of protection of the present application.

[0040] In this application, "optionally", "optional", and "optional" mean optional or dispensable, that is, any one of the two parallel schemes of "yes" or "no". If multiple "options" appear in a technical solution, unless otherwise specified and there is no contradiction or mutual restriction, each "optional" is independent.

[0041] In the description of the application, "plurality" means at least two, such as two, three, etc., unless otherwise clearly and specifically defined.

[0042] Unless otherwise specified, all formulations and tests herein took place at 25°C.

[0043] As used herein, "includes," "comprising," "containing," "having," or other variations thereof are intended to encompass non-closed inclusions, and no distinction is made between these terms. The term "comprising" means that other steps and ingredients that do not affect the end result may be added. The compositions and methods / processes of the present invention comprise, consist of, and consist essentially of the essential elements and limitations described herein, as well as any additional or optional ingredients, components, steps, or limitations described herein. As used herein, no distinction is made between the terms "efficacy," "performance," "effect," and "efficacy."

[0044] If there is no special description, all embodiments and optional embodiments of the present application can be combined with each other to form a new technical solution. If there is no special description, all technical features and optional technical features of the present application can be combined with each other to form a new technical solution.

[0045] If there is no special explanation, all the steps of the present application can be performed sequentially or randomly, preferably sequentially.

[0046] For central neuropathic pain after stroke, the current first-line recommendations are two major categories of drugs: antiepileptic drugs and antidepressants. Carbamazepine, lamotrigine, gabapentin and pregabalin are commonly used for the former, while tricyclic antidepressants such as amitriptyline, sertraline, fluoxetine, venlafaxine and duloxetine are commonly used for the latter. Sertraline and other antidepressants are often recommended for patients with stroke depression.

[0047] Nowadays, there are more and more patients suffering from central neuropathic pain and depression after stroke. However, at present, drug treatment for central neuropathic pain and depression after stroke can only partially relieve the symptoms, and the sustained effect is uncertain. There is an urgent need to provide a drug that can effectively treat central neuropathic pain and depression after stroke.

[0048] Based on the above problems, the present application adopts folic acid raw materials, escitalopram oxalate and melogabalin besylate in a specific ratio for use in combination, and the three have synergistic effects to effectively treat post-stroke central nervous system pathological pain accompanied by depression.

[0049] One or more embodiments of the present application provide a folic acid-containing composition, characterized in that the folic acid-containing composition comprises a folic acid raw material, escitalopram oxalate and melogabalin besylate, the weight ratio of the folic acid raw material, escitalopram oxalate and melogabalin besylate is (0.4-5):(10-20):(5-30), and the folic acid raw material comprises one or more of folic acid and its derivatives.

[0050] As an example, the weight ratio of folic acid raw materials, escitalopram oxalate and melogabalin besylate can be, but is not limited to, (0.4-5):(10-20):(5-30), (0.4-4.5):(10-19):(5-29), (0.4-4):(10-18):(6-27), (0.4-3.5):(10-17):(7-26), (0.4-3):(10-16):(8-25), (0.4-2.5):(10-15):(9-24), (0.4-2):(10-13):(10-23) or (0.4-1.5):(10-12):(10-20), etc.

[0051] Folic acid can effectively reduce the concentration of homocysteine ​​in the blood. High homocysteine ​​is an important risk factor for cardiovascular and cerebrovascular diseases, especially stroke. Therefore, folic acid can reduce the recurrence rate of stroke.

[0052] Melegabalin besylate is a new type of chronic pain treatment drug. It binds to the voltage-gated calcium channel (VGCC) subunit α2δ (ACNA2D), plays an auxiliary role in the function of potential-dependent calcium channels in the nervous system, inhibits calcium currents, and thus exerts analgesic effects.

[0053] Escitalopram oxalate is a selective serotonin reuptake inhibitor that selectively inhibits the 5-HT transporter, blocks the reuptake of 5-HT by the presynaptic membrane, prolongs and increases the effect of 5-HT, thereby producing an antidepressant effect.

[0054] Understandably, by using folic acid raw materials, escitalopram oxalate and melogabalin besylate in a specific ratio, a synergistic effect can be achieved to effectively treat post-stroke central nervous system pathological pain associated with depression, while preventing stroke recurrence and facilitating post-stroke rehabilitation.

[0055] As a possible implementation manner, the weight ratio of the folic acid raw material, escitalopram oxalate and melogabalin besylate is (0.4-1.5):(10-15):(10-20).

[0056] In some optional embodiments, the weight ratio of the folic acid raw material, escitalopram oxalate and melogabalin besylate is (0.4-1.5):(10-20):(10-20).

[0057] In some of the embodiments, the D90 of the folate material is ≤15 μm.

[0058] As a possible implementation, D90 of melogabalin besylate is ≤10 μm.

[0059] In some optional embodiments, the D90 of escitalopram oxalate is ≤15 μm.

[0060] When the D90 of the folic acid raw material, the D90 of melogabalin besylate and the D90 of escitalopram oxalate are respectively within the above ranges, it is beneficial to uniform mixing of materials and complete dissolution during the preparation of the orally disintegrating tablets.

[0061] In some exemplary embodiments, the folic acid derivative includes one or more of folinic acid, L-methylfolate, a pharmaceutically acceptable salt of folic acid, an active metabolite of folic acid, and an active metabolite of a pharmaceutically acceptable salt of folic acid.

[0062] One or more embodiments of the present application also provide a use of the above-mentioned folic acid-containing composition in the preparation of a drug for treating central neuropathic pain associated with depression after stroke.

[0063] One or more embodiments of the present application also provide an orodisintegrating tablet for treating central neuropathic pain associated with depression after stroke, the orodisintegrating tablet comprising a folic acid composition, which comprises, by weight, 0.4 to 5 parts of a folic acid raw material, 10 to 20 parts of escitalopram oxalate, and 5 to 30 parts of melogabalin besylate.

[0064] As a non-limiting example, the amount of folic acid raw materials contained in the folic acid-containing composition in parts by weight can be but is not limited to 0.4 parts, 0.6 parts, 0.8 parts, 1 parts, 1.2 parts, 1.4 parts, 1.6 parts, 1.8 parts, 2 parts, 2.2 parts, 2.4 parts, 2.6 parts, 2.8 parts, 3 parts, 3.2 parts, 3.4 parts, 3.6 parts, 3.8 parts, 4 parts or ranges between any two of the above parts by weight, etc.

[0065] As a non-limiting example, in parts by weight, the amount of escitalopram oxalate contained in the folic acid-containing composition can be, but is not limited to, 10 parts, 11 parts, 12 parts, 13 parts, 14 parts, 15 parts, 16 parts, 17 parts, 18 parts, 19 parts, 20 parts, or the like, in the range between any two parts by weight.

[0066] As a non-limiting example, the weight proportion of melogabalin besylate contained in the folic acid-containing composition can be, but is not limited to, 5 parts, 6 parts, 8 parts, 10 parts, 12 parts, 14 parts, 16 parts, 18 parts, 20 parts, 22 parts, 24 parts, 26 parts, 28 parts, 30 parts or a range between any two of the above weight proportions, etc.

[0067] The orodisintegrating tablet comprises a folic acid composition, in which folic acid raw materials, escitalopram oxalate and melogabalin besylate are compounded and used, which can synergistically enhance the effect, effectively treat post-stroke central nervous system pathological pain with depression, and prevent stroke recurrence, which is beneficial to post-stroke rehabilitation. The orodisintegrating tablet is easy to take and has a fast onset of action, and is more suitable for the treatment of patients with post-stroke central nervous system pathological pain with depression.

[0068] In some optional embodiments, the folic acid-containing composition includes, by weight: 0.4-1.5 parts of folic acid raw materials, 10-20 parts of escitalopram oxalate, and 10-20 parts of melogabalin besylate.

[0069] In some of the embodiments, the D90 of the folate material is ≤15 μm.

[0070] As a possible implementation, D90 of melogabalin besylate is ≤10 μm.

[0071] In some optional embodiments, the D90 of escitalopram oxalate is ≤15 μm.

[0072] When the D90 of the folic acid raw material, the D90 of melogabalin besylate and the D90 of escitalopram oxalate are respectively within the above ranges, it is beneficial to uniform mixing of materials and complete dissolution during the preparation of the orally disintegrating tablets.

[0073] In some embodiments, the folic acid derivative includes one or more of folinic acid, L-methylfolate, a pharmaceutically acceptable salt of folic acid, an active metabolite of folic acid, and an active metabolite of a pharmaceutically acceptable salt of folic acid.

[0074] As a possible implementation, the orally disintegrating tablet further comprises low-substituted hydroxypropyl cellulose, mannitol, sucrose, α-tocopherol, microcrystalline cellulose, citric acid monohydrate, hypromellose and magnesium stearate.

[0075] In some optional embodiments, the orally disintegrating tablet includes, by weight: 0.4-5 parts of folic acid raw materials, 10-20 parts of escitalopram oxalate, 5-30 parts of melogabalin besylate, 5-15 parts of low-substituted hydroxypropyl cellulose, 80-90 parts of mannitol, 35-45 parts of sucrose, 0.2-0.5 parts of α-tocopherol, 15-25 parts of microcrystalline cellulose, 3-8 parts of citric acid monohydrate, 1-2 parts of hypromellose and 1-3 parts of magnesium stearate.

[0076] It should be noted that in the orodisintegrating tablets, mannitol and microcrystalline cellulose are fillers, low-substituted hydroxypropyl cellulose is a disintegrant, α-tocopherol is an antioxidant, citric acid monohydrate is a stabilizer, sucrose is a binder and flavoring agent, hypromellose is a binder, and magnesium stearate is a lubricant.

[0077] As a non-limiting example, in parts by weight, the weight proportion of low-substituted hydroxypropyl cellulose contained in the orally disintegrating tablet can be, but is not limited to, 5 parts, 6 parts, 7 parts, 8 parts, 9 parts, 10 parts, 11 parts, 12 parts, 13 parts, 14 parts, 15 parts or a range between any two parts by weight, etc.

[0078] As a non-limiting example, in parts by weight, the weight of mannitol contained in the orally disintegrating tablet can be but is not limited to 80 parts, 81 parts, 82 parts, 83 parts, 84 parts, 85 parts, 86 parts, 87 parts, 88 parts, 89 parts, 90 parts or a range between any two of the above parts by weight, etc.

[0079] As a non-limiting example, in parts by weight, the weight of sucrose contained in the orally disintegrating tablet can be, but is not limited to, 35 parts, 36 parts, 37 parts, 38 parts, 39 parts, 40 parts, 41 parts, 42 parts, 43 parts, 44 parts, 45 parts or a range between any two of the above parts by weight, etc.

[0080] As a non-limiting example, the weight percentage of α-tocopherol contained in the orally disintegrating tablet can be, but is not limited to, 0.2 parts, 0.3 parts, 0.4 parts, 0.5 parts, or a range between any two of the above weight percentages.

[0081] As a non-limiting example, the weight proportion of microcrystalline cellulose contained in the orally disintegrating tablet can be, but is not limited to, 15 parts, 16 parts, 17 parts, 18 parts, 19 parts, 20 parts, 21 parts, 22 parts, 23 parts, 24 parts, 25 parts or a range between any two parts by weight, etc.

[0082] As a non-limiting example, in parts by weight, the weight of citric acid monohydrate contained in the orally disintegrating tablet can be, but is not limited to, 3 parts, 4 parts, 5 parts, 6 parts, 7 parts, 8 parts or a range between any two of the above parts by weight.

[0083] As a non-limiting example, the weight percentage of the hypromellose contained in the orally disintegrating tablet can be, but is not limited to, 1 part, 1.2 parts, 1.4 parts, 1.6 parts, 1.8 parts, 2 parts, or a range between any two of the above weight percentages, etc.

[0084] As a non-limiting example, the weight percentage of magnesium stearate contained in the orally disintegrating tablet can be, but is not limited to, 1 part, 1.5 parts, 2 parts, 2.5 parts, 3 parts, or a range between any two of the above weight percentages.

[0085] In some exemplary embodiments, the orally disintegrating tablet comprises, by weight, 0.8 parts of folic acid raw materials, 15 parts of escitalopram oxalate, 15 parts of melogabalin besylate, 10 parts of low-substituted hydroxypropyl cellulose, 85 parts of mannitol, 42 parts of sucrose, 0.3 parts of α-tocopherol, 20 parts of microcrystalline cellulose, 5 parts of citric acid monohydrate, 1.5 parts of hypromellose and 2 parts of magnesium stearate.

[0086] In some embodiments, the orally disintegrating tablet has a tablet weight of 200 mg and a hardness of 4 kg to 7 kg.

[0087] One or more embodiments of the present application provide a method for preparing an orally disintegrating tablet for treating central neuropathic pain associated with depression after stroke, which can be used to prepare the above-mentioned orally disintegrating tablet for treating central neuropathic pain associated with depression after stroke. The preparation method comprises the following steps:

[0088] The folic acid raw material, escitalopram oxalate, part of low-substituted hydroxypropyl cellulose, part of mannitol and sucrose are mixed, and then wet granulated to prepare folic acid and escitalopram oxalate granules;

[0089] The α-tocopherol is mixed with microcrystalline cellulose, and then mixed with melogabalin besylate, the remaining low-substituted hydroxypropyl cellulose, the remaining mannitol and citric acid monohydrate, and wet granulated with an aqueous solution containing hydroxypropyl methylcellulose to prepare melogabalin besylate granules;

[0090] The folic acid and escitalopram oxalate granules, melogabalin besylate granules and magnesium stearate are mixed and tableted.

[0091] It should be noted that, after preparing folic acid raw materials and escitalopram oxalate into folic acid and escitalopram oxalate granules, preparing melogabalin besylate into melogabalin besylate granules, and then mixing folic acid and escitalopram oxalate granules, melogabalin besylate granules and magnesium stearate for tableting, the product quality can be ensured to be stable and controllable. The preparation process is simple, the dosage form is preferably an orally disintegrating tablet, the product has good stability, is easy to take, and has a rapid onset of action, and is more suitable for the treatment of patients with post-stroke central pathological pain and depression.

[0092] In some optional embodiments, the method for preparing folic acid and escitalopram oxalate granules further comprises: drying and sizing the wet granules obtained by wet granulation in sequence. Optionally, the wet granules are fluidized bed dried at a drying temperature of 50° C. to 60° C. Optionally, a 20-mesh sieve is used for sizing.

[0093] As a non-limiting example, when preparing folic acid and escitalopram oxalate granules, water is added to make a soft material and then the material is sieved through a 20-mesh screen for granulation.

[0094] As a possible implementation, the method for preparing an aqueous solution containing hydroxypropyl methylcellulose includes: adding hydroxypropyl methylcellulose to hot water at 80°C-90°C, stirring continuously, fully dispersing and hydrating, and cooling to room temperature to obtain an aqueous solution containing hydroxypropyl methylcellulose.

[0095] In some exemplary embodiments, the method for preparing melogabalin besylate granules further comprises: sequentially drying and sizing the wet granules obtained by wet granulation. Optionally, the wet granules are fluidized bed dried at a drying temperature of 50° C. to 60° C. Optionally, sizing is performed using a 20-mesh sieve.

[0096] As a non-limiting example, when preparing melogabalin besylate granules, an aqueous solution containing hypromellose is added to make a soft material and then granulated through a 20-mesh sieve.

[0097] In some exemplary embodiments, the punch used for tableting is 8 mm in diameter.

[0098] The technical scheme of the present invention is described in detail below in conjunction with specific embodiments. It should be understood that these embodiments are only used to illustrate the present invention and are not intended to limit the scope of the present invention. The experimental methods for which specific conditions are not specified in the following embodiments are preferably referred to the guidance given in the present invention, and can also be carried out according to the experimental manual or conventional conditions in the art, or according to the conditions recommended by the manufacturer, or with reference to experimental methods known in the art.

[0099] In the following specific embodiments, the measured parameters of raw material components may have slight deviations within the range of weighing accuracy unless otherwise specified. For temperature and time parameters, acceptable deviations caused by instrument test accuracy or operation accuracy are allowed.

[0100] It should be noted that the raw materials used in the above embodiments and comparative examples can be purchased from the market.

[0101] 1. Preparation of the composition

[0102] 1. Prescription composition

[0103] The formulation compositions of Examples 1-5 are shown in Table 1. The formulation compositions of Comparative Examples 1-6 are shown in Table 2.

[0104] Table 1

[0105]

[0106] Table 2

[0107]

[0108] 2. Animal testing

[0109] (1) Animal model preparation

[0110] Healthy male rats aged 7-9 weeks and weighing 290g-310g were selected and randomly divided into 13 groups, 15 in each group, namely normal group, model group and each drug group. The rats in the model group and each drug group were anesthetized with isoflurane, and the right ventral posterolateral nucleus of the thalamus (VPL) was located with a brain stereotaxic instrument at a coordinate of 1.4mm in front of the anterior fontanelle and 1.5mm to the right of the midline. The concentration of 0.2UI·μL was slowly injected with a microinjector -1 Type IV collagenase (0.2 μL min -1 The duration was 10 minutes, the needle depth was 3.6 mm, the needle was stopped for 10 minutes after injection, and suture was performed. The rats in the normal group were injected with an equal volume of saline instead of type IV collagenase.

[0111] The rats in the model group and each drug-treated group were continuously subjected to chronic unpredictable mild stress (10 days), mainly including water and food deprivation for 24 hours, restricted behavior for 2 hours, night lighting, wet bedding, forced swimming for 5 minutes, cage tilting for 7 hours, empty bottle exposure, and foreign body exposure. Two of these stimulation methods were randomly selected every day. The mice in the normal group were not treated.

[0112] The mechanical withdrawal reflex threshold of the left foot was tested on the 0th, 5th and 10th day of model construction. The specific method was as follows: after ensuring that the experimental environment was quiet and the lighting was appropriate, the rats to be tested were placed on a metal grid with a pore size of 3mm×3mm, and each rat was separated by a plexiglass box of a fixed size. After the rats adapted for 0.5h, the mechanical withdrawal reflex threshold (PWT) was measured. Von Frey wires of different stimulation intensities were used to vertically stimulate the soles of the rats' hind limbs for 5s. The stimulation force was based on the bending of the wire. If the rats lifted their feet or licked their feet, it was a positive reaction. The fiber wire stimulation intensity that could cause a positive reaction was recorded, which was the mechanical withdrawal reflex threshold (g). The stimulation intensity started from 0.4g. When the intensity stimulation could not cause lifting or licking of the feet, a higher intensity stimulation was given. The time interval between each stimulation was 10 minutes, and the average value was taken for 3 measurements. The results of the mechanical withdrawal reflex threshold of model rats are shown in Table 3.

[0113] Table 3

[0114]

[0115] Forced swimming experiments were conducted on the 0th, 5th and 10th days of model construction. The specific method was as follows: the water temperature in the test box was adjusted before the experiment. The water temperature should be 23-25°C. The water depth was adjusted according to the weight of the animal so that the tail of the animal was kept at a certain distance from the bottom of the test box. The rats in each group were pre-swimmed one day before the experiment, and the forced swimming experiment was conducted in the test box 24 hours later. The immobility time, swimming time and climbing time of the rats within 5 minutes were recorded. The results of the forced swimming experiment of the model rats are shown in Table 4.

[0116] Table 4

[0117]

[0118] The above results showed that 10 days after modeling, compared with the normal group, the mechanical withdrawal reflex threshold of the model group and each drug-treated group was significantly reduced, the immobility time of the forced swimming test was significantly increased, and the swimming time and climbing time were significantly shortened, indicating that the rat model of central neuropathic pain accompanied by depression after stroke was successfully prepared.

[0119] (2) Experimental process

[0120] Each group of rats was intragastrically administered with an aqueous solution of the corresponding dose of the drug at a volume of 1 ml per 100 g body weight every day. The dosage was based on the weight component combination of Examples 1-5 and Comparative Examples 1-6. The drug was administered for 8 consecutive weeks. The normal group and the model group were administered with an equal volume of physiological saline. During the experiment, the animals were not restricted in drinking water and feeding.

[0121] In the 9th week, the pain and depression behaviors of rats in each group were evaluated. The pain behavior was evaluated by mechanical withdrawal reflex threshold and thermal stimulation withdrawal reflex latency, and the depression behavior was evaluated by forced swimming test and sugar water preference test.

[0122] The determination methods of mechanical withdrawal reflex threshold and forced swimming test are the same as those in (1) Animal model preparation.

[0123] Method for measuring the latency of thermal stimulation paw withdrawal reflex: The rats were placed in a plexiglass box with a 3mm thick glass plate at the bottom and adapted to the environment for 15 minutes. The intensity of the stimulus light source was adjusted to 55℃, and the skin of the middle part of the sole of the rat's hind limb was stimulated. The timing was started at the same time. When the rats showed reactions such as lifting the paw, licking the paw, and escaping, the time on the stimulator was read. The automatic cut-off time was set to 25 seconds, and the average value was taken after three measurements.

[0124] Sugar water preference test method: Animals should be kept in single cages, and rats should be trained to adapt to sugar water 1 day before the test. After the rats were fasted and deprived of water for 23 hours, water and 1% sucrose aqueous solution were placed horizontally on the rat cage, and the positions of the two water bottles were swapped halfway. The amount of water and sugar water consumed by the rats within 2 hours was recorded, and the sugar water consumption rate was calculated. Sugar water consumption rate (%) = sugar water consumption / (sugar water consumption + water consumption) × 100%.

[0125] (3) Experimental results

[0126] The results of pain behavior test of rats after administration are shown in Table 5.

[0127] Table 5

[0128]

[0129] **: p<0.01, *: p<0.05, compared with the model group.

[0130] The results of the forced swimming test on the depressive behavior of rats after drug administration are shown in Table 6.

[0131] Table 6

[0132]

[0133] **: p<0.01, *: p<0.05, compared with the model group.

[0134] The results of the rat depressive behavior-sugar water preference test after drug administration are shown in Table 7.

[0135] Table 7

[0136]

[0137] **: p<0.01, *: p<0.05, compared with the model group.

[0138] From the results of Tables 5 to 7, it can be seen that the combined use of folic acid, escitalopram oxalate and melogabalin besylate has a significantly better therapeutic effect on post-stroke central neuropathic pain associated with depression than the treatment effects of single medication or two-way combination, indicating that the combined use of folic acid, escitalopram oxalate and melogabalin besylate can achieve a synergistic effect.

[0139] 2. Preparation of orally disintegrating tablets

[0140] 1. Prescription composition and preparation

[0141] The formulation composition of the orally disintegrating tablets is shown in Table 8.

[0142] Table 8

[0143]

[0144] The preparation process of orally disintegrating tablets is as follows:

[0145] (1) Crushing and weighing: The particle size D90 of folic acid, the particle size D90 of melogabalin besylate, and the particle size D90 of escitalopram oxalate were adjusted to 9.2 μm, 6.8 μm, and 8.5 μm, and the materials were weighed according to the prescription in Table 8.

[0146] (2) Preparation of folic acid and escitalopram oxalate granules: Folic acid, escitalopram oxalate, part of low-substituted hydroxypropylcellulose, part of mannitol, and sucrose were added to a wet granulator and mixed, water was added to make a soft material, granulated into 20 mesh, dried in a fluidized bed at 60°C, and granulated into 20 mesh;

[0147] (3) Preparation of melogabalin besylate granules: first, α-tocopherol was added to microcrystalline cellulose and mixed evenly, then added to a wet granulator with melogabalin besylate, part of low-substituted hydroxypropyl cellulose, part of mannitol, and citric acid monohydrate, and mixed, and a hydroxypropyl methylcellulose aqueous solution was added to prepare a soft material, granulated with 20 mesh, dried in a fluidized bed at 60°C, and granulated with 20 mesh; wherein, the preparation method of the hydroxypropyl methylcellulose aqueous solution is: add a prescribed amount of hydroxypropyl methylcellulose to hot water at 85°C, stir continuously, fully disperse and hydrate, and cool to room temperature

[0148] (4) Total mixing: Add the above two granules and magnesium stearate into a three-dimensional mixer and mix for 5 minutes;

[0149] (5) Tablet pressing: Tablet pressing with a φ8 mm punch, theoretical tablet weight is 200 mg, and hardness is 4~7 kg.

[0150] 2. Quality evaluation of orally disintegrating tablets

[0151] The orally disintegrating tablets were evaluated for appearance, friability, disintegration time and dissolution.

[0152] Appearance of orally disintegrating tablets: complete and smooth, with uniform color.

[0153] Friability of orally disintegrating tablets: The friability of the orally disintegrating tablets prepared above was checked with reference to the 2020 edition of the Chinese Pharmacopoeia, Part IV, General Chapter 0923, Tablet Friability Test Method. The friability results showed that the weight loss was 0.54%, and there were no broken, cracked or crushed tablets, which was in compliance with the Pharmacopoeia requirements.

[0154] Disintegration time of orally disintegrating tablets: The disintegration of the orally disintegrating tablets prepared above was checked with reference to the disintegration time test method in General Chapter 0921 of Part IV of the 2020 edition of the Chinese Pharmacopoeia. The disintegration time test results are shown in Table 9.

[0155] Table 9

[0156]

[0157] The results in Table 9 show that the disintegration time of the six orally disintegrating tablets is less than 60 seconds, which is in line with the requirements of the pharmacopoeia.

[0158] Dissolution of orally disintegrating tablets: Referring to the dissolution and release determination method 0931 of Part IV of the 2020 edition of the Chinese Pharmacopoeia, the dissolution of the orally disintegrating tablets prepared above was tested. The dissolution method was the paddle method, the dissolution medium was a pH 1.2 hydrochloric acid medium, the medium volume was 500 ml, the temperature was 37°C, the rotation speed was 50 rpm, the sampling time was 30 minutes, and the dissolution results were determined. The dissolution test results are shown in Table 10.

[0159] Table 10

[0160]

[0161] The results in Table 10 show that the dissolution amounts of the six orally disintegrating tablets were all above 80%.

[0162] 3. Determination of related substances in orally disintegrating tablets

[0163] The orally disintegrating tablets prepared in Example 5 were tested by HPLC for changes in related substances when placed under accelerated conditions of 40° C. and 75% RH for 1 month, 2 months, 3 months and 6 months.

[0164] Detection method for related substances: Use octadecylsilane bonded silica gel as filler; use phosphate buffer (weigh 11.16g of potassium dihydrogen phosphate and 5.5g of potassium hydrogen phosphate, add 1000ml of water to dissolve, and adjust the pH value to 5.0 with phosphoric acid) as mobile phase A, and phosphate buffer-methanol (volume ratio of 10:90) as mobile phase B, and perform gradient elution according to Table 11; column temperature is 35℃; flow rate is 0.6ml per minute; detection wavelength is 254nm; sample chamber temperature is 4℃; injection volume is 10µl.

[0165] Table 11

[0166]

[0167] The test results of relevant substances are shown in Table 12.

[0168] Table 12

[0169]

[0170] From the results in Table 12, it can be seen that after 6 months of accelerated storage, all impurities were within the limits of the pharmacopoeia for single-ingredient preparations, indicating that the combination preparation has good stability.

[0171] The technical features of the above-described embodiments may be arbitrarily combined. To make the description concise, not all possible combinations of the technical features in the above-described 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.

[0172] The above-mentioned embodiments only express several implementation methods of the present invention, and the descriptions thereof are relatively specific and detailed, but they cannot be understood as limiting the scope of the invention patent. It should be pointed out that, for ordinary technicians in this field, several variations and improvements can be made without departing from the concept of the present invention, and these all belong to the protection scope of the present invention. Therefore, the protection scope of the patent of the present invention shall be subject to the attached claims.

Claims

1. A folic acid-containing composition, characterized in that: The folic acid-containing composition comprises a folic acid raw material, escitalopram oxalate and melogabalin besylate, wherein the weight ratio of the folic acid raw material, escitalopram oxalate and melogabalin besylate is (0.4-5):(10-20):(5-30), and the folic acid raw material comprises one or more of folic acid and its derivatives.

2. The folic acid-containing composition according to claim 1, characterized in that The weight ratio of the folic acid raw material, escitalopram oxalate and melogabalin besylate is (0.4-1.5):(10-20):(10-20).

3. The folic acid-containing composition according to claim 1, characterized in that The D90 of the folic acid raw material is ≤15 μm; and / or Melogabalin besylate D90 ≤ 10 μm; and / or The D90 of escitalopram oxalate is ≤15μm.

4. The folic acid-containing composition according to any one of claims 1 to 3, characterized in that The folic acid derivatives include one or more of folinic acid, L-methylfolate, pharmaceutically acceptable salts of folic acid, active metabolites of folic acid, and active metabolites of pharmaceutically acceptable salts of folic acid.

5. Use of the folic acid-containing composition according to any one of claims 1 to 4 in the preparation of a medicament for treating central neuropathic pain associated with depression after stroke.

6. An orodisintegrating tablet for treating central neuropathic pain associated with depression after stroke, characterized in that: The orally disintegrating tablet comprises a folic acid-containing composition, which comprises, by weight: 0.4-5 parts of folic acid raw materials, 10-20 parts of escitalopram oxalate and 5-30 parts of melogabalin besylate.

7. The orally disintegrating tablet according to claim 6, wherein In parts by weight, the folic acid-containing composition comprises: 0.4-1.5 parts of folic acid raw materials, 10-20 parts of escitalopram oxalate and 10-20 parts of melogabalin besylate.

8. The orally disintegrating tablet according to claim 6, wherein The folic acid-containing composition has at least one of the following characteristics (1)-(2): (1) the D90 of the folic acid raw material is ≤15 μm; and / or Melogabalin besylate D90 ≤ 10 μm; and / or D90 of escitalopram oxalate ≤ 15 μm; (2) The folic acid derivatives include one or more of folate, L-methylfolate, pharmaceutically acceptable salts of folic acid, active metabolites of folic acid, and active metabolites of pharmaceutically acceptable salts of folic acid.

9. The orally disintegrating tablet according to any one of claims 6 to 8, characterized in that The orally disintegrating tablet further comprises low-substituted hydroxypropyl cellulose, mannitol, sucrose, α-tocopherol, microcrystalline cellulose, citric acid monohydrate, hypromellose and magnesium stearate; Optionally, the orally disintegrating tablet comprises, by weight: 0.4-5 parts of folic acid raw materials, 10-20 parts of escitalopram oxalate, 5-30 parts of melogabalin besylate, 5-15 parts of low-substituted hydroxypropyl cellulose, 80-90 parts of mannitol, 35-45 parts of sucrose, 0.2-0.5 parts of α-tocopherol, 15-25 parts of microcrystalline cellulose, 3-8 parts of citric acid monohydrate, 1-2 parts of hypromellose and 1-3 parts of magnesium stearate.

10. A method for preparing an orodisintegrating tablet for treating central neuropathic pain associated with depression after stroke, characterized in that: The steps include: The folic acid raw material, escitalopram oxalate, part of low-substituted hydroxypropyl cellulose, part of mannitol and sucrose are mixed, and then wet granulated to prepare folic acid and escitalopram oxalate granules; The α-tocopherol is mixed with microcrystalline cellulose, and then mixed with melogabalin besylate, the remaining low-substituted hydroxypropyl cellulose, the remaining mannitol and citric acid monohydrate, and wet granulated with an aqueous solution containing hydroxypropyl methylcellulose to prepare melogabalin besylate granules; The folic acid and escitalopram oxalate granules, the melogabalin besylate granules and magnesium stearate are mixed and then tableted.

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