Folic acid-containing compositions and uses thereof, orally disintegrating tablets and methods of making

Abstract

The application provides a folic acid-containing composition and application, an orally disintegrating tablet and a preparation method. The folic acid-containing composition comprises folic acid raw materials, escitalopram oxalate and memantine hydrochloride. The weight ratio of the folic acid raw materials, the escitalopram oxalate and the memantine hydrochloride is (0.4-5):(10-20):(5-30). The folic acid raw materials comprise one or more of folic acid and derivatives thereof. The folic acid raw materials, the escitalopram oxalate and the memantine hydrochloride are used in a specific proportion, can be synergistic, can effectively treat post-stroke central neuropathic pain with depression, and can prevent recurrence of stroke, and are beneficial to post-stroke rehabilitation.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of pharmaceutical preparations, in particular to a folate-containing composition and application thereof, an orally disintegrating tablet and a preparation method. BACKGROUND

[0002] In recent years, with the arrival 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 endovascular mechanical thrombectomy are effective recanalization measures recommended by domestic and foreign guidelines, and the key to AIS treatment is to open the occluded blood vessels as soon as possible, but the clinical prognosis of patients is not ideal. In addition to the corresponding sensory and motor dysfunction, 19%-74% of patients will develop neuropathic pain, and the incidence of central neuropathic pain after stroke in the elderly is as high as 25%-50%. Central neuropathic pain after stroke refers to the pain caused by damage to the somatosensory system after stroke, and the clinical features are that pain occurs without pain stimuli, or the degree of pain is not proportional to the received stimuli.

[0003] Post-stroke depression (PSD) is the most common and most serious neuropsychiatric complication after stroke. Post-stroke depression refers to a series of mood disorders that occur after stroke, characterized by low mood and lack of interest, often accompanied by somatic symptoms. Patients with long-term central neuropathic pain after stroke often have anxiety, insomnia, and depression, and the incidence of central neuropathic pain in the general population is as high as 30%-54%. The accumulation of depressive mood increases the patient's pain perception, causing a vicious cycle, which is pain-depression comorbidity, and 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, increased recurrence rate and mortality, etc. In particular, more severe dysfunction, longer hospitalization time, worse rehabilitation outcomes, lower quality of life, and higher mortality occur in the first year after stroke. Therefore, there is an urgent need for drugs that can effectively treat central neuropathic pain and depression after stroke. SUMMARY

[0005] Therefore, the present application provides a folate-containing composition and application thereof, a drug and a preparation method, which can effectively treat central neuropathic pain and depression after stroke, shorten the treatment cycle, and reduce the pain of patients.

[0006] The first aspect of the present application provides a folate-containing composition comprising folate raw materials, escitalopram oxalate and memantine hydrochloride, wherein the weight ratio of the folate raw materials, escitalopram oxalate and memantine hydrochloride is (0.4-5):(10-20):(5-30), and the folate raw materials comprise one or more of folic acid and derivatives thereof.

[0007] In some embodiments, the weight ratio of the folate raw materials, escitalopram oxalate and memantine hydrochloride is (0.4-1.5):(10-15):(10-20).

[0008] In some embodiments, the weight ratio of the folate raw materials, escitalopram oxalate and memantine hydrochloride is (0.4-1.5):(10-20):(10-20).

[0009] In some embodiments, the D90 of the folate raw materials is ≤15 μm; and / or

[0010] The D90 of the memantine hydrochloride is ≤10 μm; and / or

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

[0012] In some embodiments, the folate derivatives comprise one or more of leucovorin, L-methyl folate, pharmaceutically acceptable salts of folic acid, active metabolites of folic acid and active metabolites of pharmaceutically acceptable salts of folic acid.

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

[0014] The third aspect of the present application provides a medicament for treating central neuropathic pain with depression after stroke, the medicament comprising a folate-containing composition, wherein the folate-containing composition comprises, in parts by weight:

[0015] folic acid raw materials 0.4 parts-5 parts, escitalopram oxalate 10 parts-20 parts and memantine hydrochloride 5 parts-30 parts.

[0016] In some embodiments, the folate-containing composition comprises, in parts by weight:

[0017] folic acid raw materials 0.4 parts-1.5 parts, escitalopram oxalate 10 parts-20 parts and memantine hydrochloride 10 parts-20 parts.

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

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

[0020] the D90 of the meloxicam is ≤ 10 μm; and / or

[0021] the D90 of the escitalopram oxalate is ≤ 15 μm;

[0022] (2) the folate derivative comprises one or more of formyltetrahydrofolate, L-methylfolate, a pharmaceutically acceptable salt of folate, an active metabolite of folate, and an active metabolite of a pharmaceutically acceptable salt of folate.

[0023] In some embodiments, the medicine further comprises hypromellose, mannitol, sucrose, alpha-tocopherol, microcrystalline cellulose, citric acid monohydrate, hypromellose and magnesium stearate.

[0024] Optionally, the medicine comprises, in parts by weight: 0.4-5 parts of the folate raw material, 10-20 parts of the escitalopram oxalate, 5-30 parts of the meloxicam, 5-15 parts of the hypromellose, 80-90 parts of the mannitol, 35-45 parts of the sucrose, 0.2-0.5 parts of the alpha-tocopherol, 15-25 parts of the microcrystalline cellulose, 3-8 parts of the citric acid monohydrate, 1-2 parts of the hypromellose and 1-3 parts of the magnesium stearate.

[0025] A fourth aspect of the present application provides a preparation method of a medicine for treating post-stroke central neuropathic pain with depression, comprising the following steps:

[0026] The folate raw material, the escitalopram oxalate, part of the hypromellose, part of the mannitol and the sucrose are mixed, and then wet granulation is performed to prepare folate and escitalopram oxalate granules;

[0027] The alpha-tocopherol is mixed with the microcrystalline cellulose, and then mixed with the meloxicam, the remaining hypromellose, the remaining mannitol and the citric acid monohydrate, and then wet granulation is performed using an aqueous solution containing hypromellose to prepare meloxicam granules;

[0028] The folate and escitalopram oxalate granules, the meloxicam granules and the magnesium stearate are mixed, and then tableting is performed.

[0029] The above-mentioned folate-containing composition can synergistically enhance the effect of treating post-stroke central neuropathic pain with depression by using the folate raw material, the escitalopram oxalate and the meloxicam in a specific ratio, and can prevent recurrence of stroke and is beneficial to post-stroke rehabilitation.

[0030] When preparing the oral disintegrating tablet, mixing eslicarbazepine acetate and folic acid to granulate and granulating meloxicaarbine besylate alone can ensure stable and controllable product quality. The preparation process is simple, the preparation is preferably oral disintegrating tablet, the product has good stability, is convenient to take, has fast effect, and is more suitable for the treatment of patients with central pathologic pain after stroke accompanied by depression. DETAILED DESCRIPTION

[0031] In order to facilitate the understanding of the present application, the present application will be described more fully below with reference to relevant examples. The following describes the preferred embodiments of the present application. However, the present application can be realized 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 disclosure of the present application more thorough and comprehensive.

[0032] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. The terminology used in the description of the application herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the application.

[0033] The selection scope of the terms "and / or", "or / and", "and / or" used herein includes any one of two or more related listed items, and also includes any and all combinations of related listed items, including any 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 / or", it should be understood that in the present application, the technical solution undoubtedly includes the technical solution connected by "logical and", and also undoubtedly includes the technical solution connected by "logical or".

[0034] In the present application, the technical features described in an open manner include both the closed technical solution consisting of the listed features and the open technical solution containing the listed features.

[0035] In the present application, if no special instructions are given, the numerical range is considered to be continuous and includes the minimum value and the maximum value of the range, as well as each value between the minimum value and the maximum value. Further, when the range refers to an integer, each integer between the minimum value and the maximum value of the range is included. In addition, when multiple ranges are provided to describe a feature or a characteristic, the ranges can be combined. In other words, unless otherwise specified, all ranges disclosed herein should be understood to include any and all sub-ranges within the range.

[0036] Only some numerical ranges are specifically disclosed herein. However, any lower limit can be combined with any upper limit to form a range not explicitly recited; and any lower limit can be combined with any other lower limit to form a range not explicitly recited, as can any upper limit with any other upper limit to form a range not explicitly recited. Further, each individual disclosed point or single numerical value can be combined with any other point or single numerical value, either as a lower or upper limit, or with other lower or upper limits, to form a range not explicitly recited.

[0037] The temperature parameters in the present application, if not particularly limited, allow both constant temperature treatment and treatment within a certain temperature range. The constant temperature treatment allows fluctuations within the accuracy of the instrument control. Fluctuations within a range of, for example, ±5°C, ±4°C, ±3°C, ±2°C, ±1°C are allowed.

[0038] In the present application, "suitable", "suitable manner", "any suitable manner" and the like mean that the technical solutions of the present application can be implemented, the technical problems of the present application can be solved, and the intended technical effects of the present application can be achieved.

[0039] In the present application, "further", "still further", "in particular" and the like are used for description purposes, indicating differences in content, but should not be understood as limiting the scope of protection of the present application.

[0040] In the present application, "optionally", "optional" and "optional" mean that it can or can not be present, i.e., it is selected from either of the two parallel schemes "yes" or "no". If there are multiple "optional" in a technical solution, unless otherwise specified, and there is no contradictory or mutual restrictive relationship, each "optional" is independent.

[0041] In the description of the application, "multiple" means at least two, for example, two, three, etc., unless otherwise explicitly specified.

[0042] Unless otherwise specified, all formulations and tests herein occur in an environment of 25°C.

[0043] In the present application, "include", "contain", "comprise", "have", or other variants are intended to cover non-closed inclusion, and there is no distinction between these terms. The term "comprise" means that other steps and ingredients that do not affect the final result can be added. The compositions and methods / processes of the present application comprise, consist of and consist essentially of the essential elements and limitations described herein, and any additional or optional ingredients, components, steps or limitations described herein. There is no distinction between the terms "efficiency", "performance", "effect", "efficacy" herein.

[0044] If there is no special indication, all the embodiments and optional embodiments of the present application can be combined to form new technical solutions. If there is no special indication, all the technical features and optional technical features of the present application can be combined to form new technical solutions.

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

[0046] For post-stroke central neuropathic pain, the current first-line recommendation is two categories of drugs: antiepileptic drugs and antidepressants, the former commonly used carbamazepine, lamotrigine, gabapentin and pregabalin, the latter commonly used tricyclic antidepressants amitriptyline, sertraline, fluoxetine, venlafaxine, duloxetine. Patients with post-stroke depression are often recommended to use antidepressants such as sertraline for treatment.

[0047] Now there are more and more post-stroke central neuropathic pain patients with depression, but at this stage the drug treatment of post-stroke central neuropathic pain with depression can only partially relieve the symptoms, and the sustained effect is uncertain, so it is urgent to provide a drug that can effectively treat post-stroke central neuropathic pain with depression.

[0048] Based on the above problems, the present application uses folic acid raw materials, escitalopram oxalate and meloxicam to cooperate with each other in a specific ratio, and the three of them synergistically to effectively treat post-stroke central neuropathic pain with 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 folic acid raw materials, escitalopram oxalate and meloxicam, and the weight ratio of the folic acid raw materials, escitalopram oxalate and meloxicam is (0.4-5):(10-20):(5-30), and the folic acid raw materials include one or more of folic acid and its derivatives.

[0050] As an example, the weight ratio of the folic acid raw materials, escitalopram oxalate and meloxicam 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) and the like

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

[0052] Meloxicam benzene sulfonic acid is a new chronic pain treatment drug, which binds to voltage-gated calcium channel (VGCC) subunit α2δ (ACNA2D), plays an auxiliary role in the function of potential-dependent calcium channels in the nervous system, and can inhibit calcium current, thereby playing an analgesic role.

[0053] Escitalopram oxalate is a selective serotonin reuptake inhibitor that can selectively inhibit 5-HT transporters, block the reuptake of 5-HT at the presynaptic membrane, prolong and increase the effect of 5-HT, thereby producing an antidepressant effect.

[0054] Understandably, by using folic acid raw materials, escitalopram oxalate and meloxicam benzene sulfonic acid in a specific ratio, a synergistic effect can be achieved, which can effectively treat central neuropathic pain with depression after stroke, prevent recurrence of stroke, and facilitate rehabilitation after stroke.

[0055] As a possible implementation, the weight ratio of folic acid raw materials, escitalopram oxalate and meloxicam benzene sulfonic acid is (0.4-1.5):(10-15):(10-20).

[0056] In some alternative embodiments, the weight ratio of folic acid raw materials, escitalopram oxalate and meloxicam benzene sulfonic acid is (0.4-1.5):(10-20):(10-20).

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

[0058] As a possible implementation, the D90 of meloxicam benzene sulfonic acid is ≤10 μm.

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

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

[0061] In some exemplary embodiments, the folic acid derivative includes one or more of formyltetrahydrofolic acid, L-methyl folic acid, 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 use of the above-mentioned folate-containing composition in the preparation of a medicament for treating post-stroke central neuropathic pain with depression.

[0063] One or more embodiments of the present application also provide an orally disintegrating tablet for treating post-stroke central neuropathic pain with depression, which comprises a folate-containing composition, wherein the folate-containing composition comprises, in parts by weight, 0.4-5 parts of a folate raw material, 10-20 parts of escitalopram oxalate, and 5-30 parts of pregabalin benzenesulfonate.

[0064] By way of non-limiting example, the folate raw material contained in the folate-containing composition can be, but is not limited to, 0.4 parts, 0.6 parts, 0.8 parts, 1 part, 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 a range between any two of the above-mentioned parts by weight, etc.

[0065] By way of non-limiting example, the escitalopram oxalate contained in the folate-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 a range between any two of the above-mentioned parts by weight, etc.

[0066] By way of non-limiting example, the pregabalin benzenesulfonate contained in the folate-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-mentioned parts by weight, etc.

[0067] The orally disintegrating tablet comprises the folate-containing composition, and the folate raw material, escitalopram oxalate, and pregabalin benzenesulfonate are compounded and used in the folate-containing composition, which can have a synergistic effect, effectively treat post-stroke central neuropathic pain with depression, and prevent recurrence of stroke, which is conducive to rehabilitation after stroke. In addition, the orally disintegrating tablet is convenient to take and has a rapid effect, and is more suitable for the treatment of post-stroke central neuropathic pain with depression.

[0068] In some optional embodiments, the folate-containing composition comprises, in parts by weight, 0.4-1.5 parts of a folate raw material, 10-20 parts of escitalopram oxalate, and 10-20 parts of pregabalin benzenesulfonate.

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

[0070] As a possible implementation, the D90 of the meloxicam benzenesulfonate is ≤10 μm.

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

[0072] When the D90 of the folic acid raw material, the D90 of the meloxicam benzenesulfonate, and the D90 of the escitalopram oxalate are within the above ranges respectively, it is beneficial to the uniform mixing of the materials in the process of preparing the orally disintegrating tablets, and the complete dissolution.

[0073] In some implementations, the folic acid derivative includes one or more of formyltetrahydrofolic acid, L-methyl folic acid, 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 includes low-substituted hydroxypropyl cellulose, mannitol, sucrose, α-tocopherol, microcrystalline cellulose, citric acid monohydrate, hypromellose, and magnesium stearate.

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

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

[0077] As non-limiting examples, the weight part of the low-substituted hydroxypropyl cellulose included 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 of the above weight parts, etc.

[0078] As non-limiting examples, the weight part of the mannitol included 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 weight parts, etc.

[0079] By way of non-limiting example, the orodispersible tablet can comprise sucrose in an amount of, but 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 aforementioned parts, by weight.

[0080] By way of non-limiting example, the orodispersible tablet can comprise alpha-tocopherol in an amount of, but not limited to, 0.2 parts, 0.3 parts, 0.4 parts, 0.5 parts, or a range between any two of the aforementioned parts, by weight.

[0081] By way of non-limiting example, the orodispersible tablet can comprise microcrystalline cellulose in an amount of, but 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 of the aforementioned parts, by weight.

[0082] By way of non-limiting example, the orodispersible tablet can comprise citric acid monohydrate in an amount of, but not limited to, 3 parts, 4 parts, 5 parts, 6 parts, 7 parts, 8 parts, or a range between any two of the aforementioned parts, by weight.

[0083] By way of non-limiting example, the orodispersible tablet can comprise hydroxypropyl methylcellulose in an amount of, but 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 aforementioned parts, by weight.

[0084] By way of non-limiting example, the orodispersible tablet can comprise magnesium stearate in an amount of, but not limited to, 1 part, 1.5 parts, 2 parts, 2.5 parts, 3 parts, or a range between any two of the aforementioned parts, by weight.

[0085] In some exemplary embodiments, the orodispersible tablet comprises folic acid 0.8 parts, escitalopram oxalate 15 parts, memantine hydrochloride 15 parts, low-substituted hydroxypropyl cellulose 10 parts, mannitol 85 parts, sucrose 42 parts, alpha-tocopherol 0.3 parts, microcrystalline cellulose 20 parts, citric acid monohydrate 5 parts, hydroxypropyl methylcellulose 1.5 parts, and magnesium stearate 2 parts, by weight.

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

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

[0088] The folic acid and escitalopram oxalate granules, the benzenesulfonic acid mefloquine granules and the magnesium stearate are mixed, and then tableting is performed.

[0089] The folic acid and escitalopram oxalate granules, the benzenesulfonic acid mefloquine granules and the magnesium stearate are mixed, and then tableting is performed.

[0090] The folic acid and escitalopram oxalate granules, the benzenesulfonic acid mefloquine granules and the magnesium stearate are mixed, and then tableting is performed.

[0091] It should be noted that the folic acid and escitalopram oxalate granules, the benzenesulfonic acid mefloquine granules and the magnesium stearate are mixed, and then tableting is performed. This can ensure that the product quality is stable and controllable. The preparation process is simple, the dosage form is optimally selected as an oral disintegrating tablet, the product has good stability, is convenient to take, and has a fast effect, and is more suitable for the treatment of post-stroke central pathological pain with depression.

[0092] In some optional embodiments, the method for preparing the folic acid and escitalopram oxalate granules further comprises: sequentially performing drying and finishing on the wet granules obtained by wet granulation. Optionally, the wet granules are subjected to fluidized bed drying, and the drying temperature is 50-60°C. Optionally, the finishing is performed using a 20-mesh sieve.

[0093] As a non-limiting example, when the folic acid and escitalopram oxalate granules are prepared, the soft material is prepared by adding water, and then granulation is performed using a 20-mesh sieve.

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

[0095] In some exemplary embodiments, the method for preparing the benzenesulfonic acid mefloquine granules further comprises: sequentially performing drying and finishing on the wet granules obtained by wet granulation. Optionally, the wet granules are subjected to fluidized bed drying, and the drying temperature is 50-60°C. Optionally, the finishing is performed using a 20-mesh sieve.

[0096] As a non-limiting example, when the benzenesulfonic acid mefloquine granules are prepared, the soft material is prepared by adding the hydroxypropylmethyl cellulose-containing aqueous solution, and then granulation is performed using a 20-mesh sieve.

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

[0098] The technical solutions of the present invention are described in detail below with reference to specific examples. It should be understood that these examples are intended only to illustrate the present invention and are not intended to limit the scope of the present invention. For experimental methods in the following examples where specific conditions are not specified, reference should be made to the instructions provided in the present invention, or to experimental manuals or conventional conditions in the art, or to conditions recommended by the manufacturer, or to experimental methods known in the art.

[0099] In the following specific examples, 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 testing accuracy or operational accuracy are allowed.

[0100] It should be noted that the raw materials used in the above embodiments and comparative examples can all 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 bregma and 1.5mm to the right of the midline. A microinjector was used to slowly inject 0.2UI·μL of -1 Type IV collagenase (0.2 μL min -1 The injection lasted 10 minutes, with a needle insertion depth of 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 normal saline instead of type IV collagenase.

[0111] The model group and each administration group of rats continue to be given chronic unpredictable mild stress (10 days), mainly including water deprivation, food deprivation for 24 h, behavior restriction for 2 h, night lighting, wet bedding, forced swimming for 5 minutes, cage tilting for 7 h, empty bottle exposure, exposure to foreign objects, and randomly selecting two of the above stimulation methods each day. The normal group of mice is not treated.

[0112] The left foot mechanical withdrawal reflex threshold is detected on the 0th day, the 5th day and the 10th day of model construction, specifically: after ensuring that the experimental environment is quiet and the lighting is appropriate, the rats to be tested are placed on a metal grid with a 3mm*3mm aperture, and each rat is separated by a fixed-size organic glass box. After the rats adapt for 0.5h, the mechanical withdrawal reflex threshold (PWT) is measured. The hind foot of the rat is vertically stimulated with a Von Frey filament of different stimulation intensity for 5s, and the stimulation force is based on the bending of the fiber. If the rat shows a positive response such as lifting or licking the foot, the stimulation intensity value of the fiber that can cause a positive response is recorded, which is the mechanical withdrawal reflex threshold (g). The stimulation intensity starts from 0.4g. When the intensity stimulation cannot cause the rat to lift or lick the foot, the next higher intensity stimulation is given. The interval between each stimulation is 10 minutes, and the measurement is taken three times to obtain the average value. The results of the mechanical withdrawal reflex threshold measurement of the model rats are shown in Table 3.

[0113] Table 3

[0114]

[0115] The forced swimming test is performed on the 0th day, the 5th day and the 10th day of model construction, specifically: the water temperature in the test tank is adjusted before the experiment, and the water temperature should be 23-25℃. The water depth is adjusted according to the animal body weight, so that the animal tail maintains a certain distance from the bottom of the test tank. Each group of rats is pre-swimming one day before the experiment, and then placed in the test tank for forced swimming test 24 hours later. The immobile time, swimming time and climbing time of the rats within 5 minutes are recorded. The results of the forced swimming test of the model rats are shown in Table 4.

[0116] Table 4

[0117]

[0118] The above results show that, compared with the normal group, the mechanical withdrawal reflex threshold of the model group and each administration group is significantly reduced, the immobile time of the forced swimming test is significantly increased, and the swimming time and climbing time are significantly shortened, indicating that the rat model of central neuropathic pain with depression after stroke is successfully prepared.

[0119] (2) Experimental process

[0120] Each administration group of rats was administered with the water solution of corresponding dose of drug by gavage at 1 ml per 100 g of body weight per day, the administration dose was combined with the weight components of Examples 1-5 and Comparative Examples 1-6, and the administration was continuously performed for 8 weeks, and the normal group and the model group were administered with the same volume of normal saline. During the experiment, the animals were not limited in drinking water and feed.

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

[0122] The determination method of mechanical withdrawal reflex threshold and forced swimming test was the same as that in (1) animal model preparation.

[0123] The determination method of thermal stimulation paw withdrawal latency was as follows: the rats were placed in an organic glass box with a 3 mm thick glass plate at the bottom, and adapted to the environment for 15 min. The intensity of the stimulating light source was adjusted to 55℃, the rat hind foot skin was stimulated, and the timer was started at the same time, the time on the stimulator was read when the reaction such as lifting foot, licking foot and escaping occurred, the automatic cut-off time was set to 25 s, and the average value of 3 measurements was taken.

[0124] The determination method of sugar water preference test was as follows: the animals should be single-caged, and the rats were trained to adapt to sugar water 1 day before the test. After the rats were fasted and deprived of water for 23 h, the horizontal bottles containing water and 1% sucrose solution were placed on the rat cage, and the positions of the two bottles were exchanged in the middle, and the amounts of water and sugar water consumed by the rats in 2 h were recorded, and the sugar water consumption rate was calculated. Sugar water consumption rate (%) = sugar water consumption amount / (sugar water consumption amount + water consumption amount) x 100%.

[0125] (3) Experimental results

[0126] The determination results of pain behavior 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 determination results of depression behavior of rats after administration-forced swimming test are shown in Table 6.

[0131] Table 6

[0132]

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

[0134] The determination results of depression behavior of rats after administration-sugar water preference test 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 Table 5-Table 7, it can be seen that the combination of folic acid, escitalopram oxalate and meloxicam benzenesulfonic acid has a significantly better treatment effect on post-stroke central neuropathic pain with depression than single drug or two drugs combination, indicating that the combination of folic acid, escitalopram oxalate and meloxicam benzenesulfonic acid can achieve a synergistic effect.

[0139] II. Preparation of oral disintegration tablets

[0140] 1. Prescription composition and preparation

[0141] The prescription composition of the oral disintegration tablet is shown in Table 8.

[0142] Table 8

[0143]

[0144] The preparation process of the oral disintegration tablet is as follows:

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

[0146] (2) Preparation of folic acid and escitalopram oxalate granules: Mix folic acid, escitalopram oxalate, part of low-substituted hydroxypropyl cellulose, part of mannitol, and sucrose in a wet granulator, add water to make soft material, granulate at 20 mesh, dry in a fluidized bed at 60°C, and size at 20 mesh.

[0147] (3) Preparation of meloxicam benzenesulfonic acid granules: First, mix alpha-tocopherol with microcrystalline cellulose, then add meloxicam benzenesulfonic acid, part of low-substituted hydroxypropyl cellulose, part of mannitol, and citric acid monohydrate to the wet granulator, mix with hydroxypropyl methyl cellulose solution to make soft material, granulate at 20 mesh, dry in a fluidized bed at 60°C, and size at 20 mesh. The preparation method of hydroxypropyl methyl cellulose solution is as follows: Add the prescribed amount of hydroxypropyl methyl cellulose to hot water at 85°C, continuously stir, and fully disperse and hydrate, then cool to room temperature

[0148] (4) Total mixing: Mix the above two kinds of granules and magnesium stearate in a three-dimensional mixer for 5 minutes.

[0149] (5) Tabletting: φ8mm punch tabletting, the theoretical tablet weight is 200mg, and the hardness is 4-7kg.

[0150] 2. Quality evaluation of orally disintegrating tablets

[0151] The orally disintegrating tablets were evaluated in terms of appearance, friability, disintegration time limit and dissolution.

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

[0153] Friability of orally disintegrating tablets: The friability of the orally disintegrating tablets prepared above was checked according to the method for checking tablet friability in the fourth part of the 2020 edition of the Chinese Pharmacopoeia (0923), and the result of the friability showed that the weight loss was 0.54%, and there were no broken, cracked or crushed tablets, which met the requirements of the Pharmacopoeia.

[0154] Disintegration time limit of orally disintegrating tablets: The disintegration of the orally disintegrating tablets prepared above was checked according to the method for checking disintegration time limit in the fourth part of the 2020 edition of the Chinese Pharmacopoeia (0921), and the disintegration time limit test results are shown in Table 9.

[0155] Table 9

[0156]

[0157] The results in Table 9 showed that the disintegration time limit of 6 orally disintegrating tablets was less than 60 seconds, which met the requirements of the Pharmacopoeia.

[0158] Dissolution of orally disintegrating tablets: The dissolution of the orally disintegrating tablets prepared above was detected according to the method for checking dissolution and release in the fourth part of the 2020 edition of the Chinese Pharmacopoeia (0931), the dissolution method was paddle method, the dissolution medium was pH 1.2 hydrochloric acid medium, the medium volume was 500ml, the temperature was 37℃, the rotation speed was 50rpm, the sampling time was 30 minutes, the dissolution was determined, and the dissolution test results are shown in Table 10.

[0159] Table 10

[0160]

[0161] The results in Table 10 showed that the dissolution of 6 orally disintegrating tablets was more than 80%.

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

[0163] The change of related substances of the orally disintegrating tablets prepared in Example 5 was detected under accelerated conditions of 40℃ and 75% RH for 1 month, 2 months, 3 months and 6 months by high performance liquid chromatography.

[0164] The related substance detection method: octadecylsilane bonded silica gel is used as the filler; phosphate buffer solution (potassium dihydrogen phosphate 11.16 g, dipotassium hydrogen phosphate 5.5 g, water 1000 ml, dissolved, and adjusted to pH 5.0 with phosphoric acid) is used as the mobile phase A, and the phosphate buffer solution-methanol (volume ratio of 10:90) is used as the mobile phase B, gradient elution is carried out according to Table 11; the column temperature is 35℃; the flow rate is 0.6 ml / min; the detection wavelength is 254 nm; the sample chamber temperature is 4℃; and the injection volume is 10 μl.

[0165] Table 11

[0166]

[0167] The related substance detection results are shown in Table 12.

[0168] Table 12

[0169]

[0170] It can be seen from the results in Table 12 that the impurities of the composition are within the limit of the single formula preparation pharmacopoeia after 6 months of acceleration, indicating that the composition preparation has good stability.

[0171] The technical features of the above-described embodiments can be combined in any manner. To make the description concise, all possible combinations of the technical features in the above-described embodiments are not described, but as long as the combinations of the technical features do not contradict, they should be considered within the scope of the present disclosure.

[0172] The above-described embodiments only express several embodiments of the present application, and the description is more specific and detailed, but it should not be understood as a limitation on the scope of the patent. It should be pointed out that for ordinary skilled in the art, without departing from the concept of the present application, a number of variations and improvements can be made, which are within the scope of the present application. Therefore, the scope of protection of the present application should be subject to the appended claims.

Claims

1. A folic acid-containing composition for treating central neuropathic pain associated with depression after stroke, characterized in that: The folic acid-containing composition consists of folic acid, escitalopram oxalate and melogabalin besylate, and the weight ratio of the folic acid, escitalopram oxalate and melogabalin besylate is 0.4-5:10-20:5-30.

2. The folic acid-containing composition according to claim 1, wherein The weight ratio of folic acid, escitalopram oxalate and melogabalin besylate is 0.4-1.5:10-20:10-20.

3. The folic acid-containing composition according to claim 1, wherein The D90 of the folic acid is ≤15 μm; and / or Melogabalin besylate has a D90 ≤ 10 μm; and / or The D90 of escitalopram oxalate is ≤15 μm.

4. Use of the folic acid-containing composition according to any one of claims 1 to 3 in the preparation of a medicament for treating central neuropathic pain associated with depression after stroke.

5. An orally disintegrating 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 is composed of the following components in parts by weight: 0.4-5 parts of folic acid, 10-20 parts of escitalopram oxalate and 5-30 parts of melogabalin besylate.

6. The orally disintegrating tablet according to claim 5, wherein The folic acid-containing composition is composed of the following components in parts by weight: 0.4-1.5 parts of folic acid, 10-20 parts of escitalopram oxalate and 10-20 parts of melogabalin besylate.

7. The orally disintegrating tablet according to claim 5, wherein The D90 of the folic acid is ≤15 μm; and / or Melogabalin besylate has a D90 ≤ 10 μm; and / or The D90 of escitalopram oxalate is ≤15 μm.

8. The orally disintegrating tablet according to claim 6, wherein The orally disintegrating tablet further comprises low-substituted hydroxypropyl cellulose, mannitol, sucrose, α-tocopherol, microcrystalline cellulose, citric acid monohydrate, hypromellose and magnesium stearate.

9. The orally disintegrating tablet according to claim 5, wherein In parts by weight, the orally disintegrating tablet comprises: 0.4-5 parts of folic acid, 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 orally disintegrating tablet for treating central neuropathic pain associated with depression after stroke according to any one of claims 8 to 9, characterized in that: The steps include: folic acid, escitalopram oxalate, a portion of low-substituted hydroxypropyl cellulose, a portion of mannitol, and sucrose are mixed, and then wet granulated to prepare folic acid and escitalopram oxalate granules; 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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