A tablet of dl-3n-butyphthalide for sublingual administration and a preparation method thereof

Abstract

The application provides a butylphthalide sublingual tablet and a preparation method thereof, wherein the butylphthalide sublingual tablet contains the following components by weight percentage based on 100% of the total weight of the butylphthalide sublingual tablet: 10%-25% of an active substance, 10%-40% of an emulsifier, 10%-75% of an excipient, 0.2%-2% of a binder, 1%-30% of a sweetening agent, and 0.1%-2% of a fragrance agent; and the active substance is butylphthalide or a butylphthalide derivative. The application does not need to add a disintegrating agent, the auxiliary materials used are water-soluble, and the amount is small, so that the preparation can be rapidly disintegrated in the oral cavity without grit feeling, thereby overcoming the slow disintegration in the oral cavity and grit feeling of the oral disintegration tablet prepared by using a direct compression method.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of medicine, in particular, the present application relates to a kind of butylphthalide sublingual tablet and preparation method thereof. BACKGROUND

[0002] Butylphthalide (NBP), chemical name is 3-butyl-1 (3H)-isobenzofuranone, also known as apio aldehyde, trade name is Enbilu, belongs to simple phthalide, is oily liquid, has celery fragrance, is a drug for treating ischemic stroke which is independently researched and developed by China.3-position carbon atom is hand carbon atom, has S-and R-enantiomeric, its structural formula is as follows:

[0003]

[0004] Butylphthalide has improving effect on the damage of central nervous function of acute ischemic stroke patients, and can promote the functional recovery of patients. Animal pharmacodynamic research suggests that butylphthalide can block multiple pathological links of brain damage caused by ischemic stroke, has strong anti-cerebral ischemia effect, significantly reduces the infarction area of local cerebral ischemia of rats, reduces brain edema, improves brain energy metabolism and microcirculation and blood flow of ischemic brain area, inhibits nerve cell apoptosis, and has anti-thrombosis and anti-platelet aggregation effect. Butylphthalide may produce the above pharmacological effects by reducing arachidonic acid content, increasing the level of brain vascular endothelial nitric oxide (NO) and prostaglandin I2 (PGI2), inhibiting glutamic acid release, reducing intracellular calcium concentration, inhibiting oxygen free radicals and improving antioxidant activity.

[0005] The existing oral dosage form of butylphthalide is mainly soft capsule or tablet. But the soft capsule has large shape, and it is difficult for patients to swallow, and the bioavailability is low. In addition, the gelatin in the capsule skin is easy to age during storage, which leads to slow disintegration, so that the product quality is not easy to control during storage, and the in-vivo absorption and drug efficacy are affected. In order to increase the solubility of butylphthalide, a large amount of cyclodextrin or its analogues must be added, which leads to the tablet weight of each tablet reaching 600 mg, increasing the difficulty of patients to take, and affecting the yield of butylphthalide tablets.

[0006] At present, it is urgent to develop a butylphthalide oral preparation which is more beneficial to patients to take and has higher bioavailability. In view of this, the present application is proposed. SUMMARY

[0007] One object of the present application is to provide a butylphthalide sublingual tablet.

[0008] Another object of the present application is to provide a preparation method of the butylphthalide sublingual tablet.

[0009] To achieve the above object, in one aspect, the present application provides a butylphthalide sublingual tablet, which contains the following ingredients in the weight percentage based on 100% of the total weight of the butylphthalide sublingual tablet: active substance 10-25%, emulsifier 10-40%, excipient 10-75%, binder 0.2-2%, sweetener 1-30%, and flavoring agent 0.1-2%; the active substance is butylphthalide or butylphthalide derivative.

[0010] According to some specific embodiments of the present application, the butylphthalide can be artificial synthetic racemic butylphthalide, levorotatory butylphthalide, or apioin or petroselin extracted from celery seeds (the dosage is based on butylphthalide) having the pharmacological activity of butylphthalide.

[0011] According to some specific embodiments of the present application, the butylphthalide derivative is apioin.

[0012] According to some specific embodiments of the present application, the butylphthalide sublingual tablet of the present application does not add disintegrant.

[0013] According to some specific embodiments of the present application, the emulsifier is selected from one or more than two combinations of HS15, vitamin E polyethylene glycol succinate, soybean phospholipid, pluronic F-68, lecithin, dextrin, hydroxypropyl cyclodextrin, and sulfobutyl cyclodextrin.

[0014] According to some specific embodiments of the present application, the excipient is selected from one or more than two combinations of glycine, serine, arginine, mannitol, maltitol, lactitol, erythritol, isomaltitol, dextran, raffinose, maltose, glucose, galactose, trehalose, dextrin, hydroxypropyl cyclodextrin, sodium phosphate, sodium oxide, and aluminum silicate.

[0015] According to some specific embodiments of the present application, the sweetener is selected from one or more than two combinations of aspartame sucralose, sucrose, xylitol, sorbitol, and stevioside.

[0016] According to some specific embodiments of the present application, the binder is selected from one or more than two combinations of xanthan gum, gelatin, pectin, pullulan, alginate, cellulose and its derivatives, hyaluronic acid, modified starch, polyvinyl alcohol, and chitosan.

[0017] According to some specific embodiments of the present application, the flavoring agent is selected from one or more than two combinations of natural or artificial flavoring agents such as mint, sweet orange, pineapple, strawberry, etc.

[0018] According to some specific embodiments of the present application, the butylphthalide sublingual tablet of the present application contains HS 15 5%-15%, Poloxamer 5%-15%, lecithin 5%-15%, mannitol 12%-60%, sucrose 10%-30%, xanthan gum 0.5%-2% and mint flavor 0.2%-2%.

[0019] According to some embodiments of the present application, the present application provides a preparation method of the above-mentioned buccal tablet of dl-3n-butyphthalide, wherein the method comprises: HS 15 5%-15%, Poloxamer 5%-15%, lecithin 5%-15%, mannitol 12%-60%, sucrose 10%-30%, xanthan gum 0.5%-2% and mint flavor 0.2%-2%.

[0020] According to some embodiments of the present application, the Poloxamer is Poloxamer 188 and / or Poloxamer 407.

[0021] According to some embodiments of the present application, the present application provides a preparation method of the above-mentioned buccal tablet of dl-3n-butyphthalide, wherein the method comprises: HS 15 5%-15%, Poloxamer 5%-15%, lecithin 5%-15%, mannitol 12%-60%, sucrose 10%-30%, xanthan gum 0.5%-2% and mint flavor 0.2%-2%.

[0022] According to some embodiments of the present application, the present application provides a preparation method of the above-mentioned buccal tablet of dl-3n-butyphthalide, wherein the method comprises: HS 15 5%-15%, Poloxamer 5%-15%, lecithin 5%-15%, mannitol 20%-45%, sucrose 10%-30%, xanthan gum 0.5%-2% and mint flavor 0.2%-2%.

[0023] According to some embodiments of the present application, the present application provides a preparation method of the above-mentioned buccal tablet of dl-3n-butyphthalide, wherein the method comprises: HS 15 5%-15%, Poloxamer 5%-15%, lecithin 5%-15%, mannitol 20%-42%, sucrose 15%-30%, xanthan gum 0.5%-2% and mint flavor 0.2%-2%.

[0024] In another aspect, the present application provides a preparation method of the above-mentioned buccal tablet of dl-3n-butyphthalide, wherein the method comprises:

[0025] (a) a step of preparing a base solution: adding the active substance, the emulsifying agent, the excipient, the binder, and the sweetening agent and the flavoring agent into purified water to form a uniform mixed solution;

[0026] (b) a step of degassing: degassing the obtained mixed solution;

[0027] (c) a step of injection molding: injecting the degassed mixed solution into a mold;

[0028] (d) pre-freezing step: pre-freezing the mold injected with the mixed solution;

[0029] (e) freeze-drying step: freeze-drying the pre-frozen mold to obtain the butylphthalide sublingual tablet.

[0030] The butylphthalide sublingual tablet manufacturing process adopts the freeze-drying method. After the drug is prepared into a drug solution, it is frozen into a solid at low temperature, and then the water is sublimated and removed from the frozen state under vacuum and low temperature to prepare a freeze-dried tablet. In order to facilitate the freeze-drying of the drug solution during the freeze-drying process, excipients are added to play a supporting skeleton role, and at the same time make the freeze-dried product crystallize uniformly, have a certain solubility and physical strength.

[0031] According to some specific embodiments of the present application, in step (a), the active substance, emulsifier, excipient, binder, and sweetener and flavoring agent are added to purified water, and then stirred at a speed of 10,000 rpm to form a uniform mixed solution.

[0032] According to some specific embodiments of the present application, in step (a), the active substance, emulsifier, excipient, binder, and sweetener and flavoring agent are added to purified water, and then stirred with a dispersion emulsifier to form a uniform mixed solution.

[0033] According to some specific embodiments of the present application, the dispersion emulsifier is a Fluko FM300 type dispersion emulsifier.

[0034] According to some specific embodiments of the present application, the butylphthalide sublingual tablet of the present application contains HS15 5%-15%, poloxamer 5%-15%, and lecithin 5%-15%; step (a) comprises: HS15, poloxamer and lecithin are dissolved in purified water, the active substance is added, and then the excipient, binder, and sweetener and flavoring agent are added and stirred to dissolve.

[0035] According to some specific embodiments of the present application, the pre-freezing process comprises pre-freezing the mold injected with the mixed solution at a pre-freezing temperature for 1-6 h; the pre-freezing temperature is -70°C to -35°C.

[0036] According to some specific embodiments of the present application, the pre-freezing temperature is -40°C to -35°C.

[0037] According to some specific embodiments of the present application, the method comprises a process of cooling the mold before the pre-freezing process: cooling the mold to a pre-freezing intermediate temperature at room temperature, then keeping it at the pre-freezing intermediate temperature for 0.5-1 h, then cooling it to the pre-freezing temperature, and keeping it at the pre-freezing temperature for 1-6 h.

[0038] According to some embodiments of the present application, the pre-freezing intermediate temperature is between 0°C and -10°C.

[0039] According to some embodiments of the present application, the pre-freezing intermediate temperature is -5°C.

[0040] According to some embodiments of the present application, the cooling of the mold to the pre-freezing intermediate temperature at room temperature is performed at a constant rate for 0.5-1 h.

[0041] According to some embodiments of the present application, the cooling to the pre-freezing temperature is performed at a constant rate for 0.5-2 h from the pre-freezing intermediate temperature to the pre-freezing temperature.

[0042] According to some embodiments of the present application, the cooling to the pre-freezing temperature is performed at a constant rate for 1-1.5 h from the pre-freezing intermediate temperature to the pre-freezing temperature.

[0043] According to some embodiments of the present application, the freeze-drying process comprises freezing the pre-frozen mold at a temperature between -40°C and 35°C for 1-20 h.

[0044] According to some embodiments of the present application, the pre-freezing and freeze-drying processes are each independently performed at a pressure between 0.01 mbar and 1 mbar.

[0045] According to some embodiments of the present application, the freeze-drying process comprises warming the pre-frozen mold from the pre-freezing temperature to a sublimation temperature, maintaining the mold at the sublimation temperature for 5-15 h, then warming the mold to a desorption temperature, and maintaining the mold at the desorption temperature for 2-7 h; the sublimation temperature is between -30°C and -20°C, and the desorption temperature is between 25°C and 35°C.

[0046] According to some embodiments of the present application, the maintaining at the sublimation temperature is performed for 8-12 h; preferably, for 10 h.

[0047] According to some embodiments of the present application, the maintaining at the desorption temperature is performed for 5 h.

[0048] According to some embodiments of the present application, the sublimation temperature is between -27°C and -23°C; preferably, -25°C.

[0049] According to some embodiments of the present application, the desorption temperature is between 28°C and 32°C; preferably, 30°C.

[0050] According to some embodiments of the present application, the freeze-drying process comprises warming the pre-frozen mold from the pre-freezing temperature to the sublimation temperature at a constant rate for 1.5-2.5 h.

[0051] According to some specific embodiments of the present application, the freeze-drying process comprises: uniformly increasing the temperature of the pre-frozen mold from the pre-freezing temperature to the sublimation temperature in 2h.

[0052] According to some specific embodiments of the present application, after the freeze-drying process is maintained at the sublimation temperature for 5-15h, the temperature is first uniformly increased to the desorption intermediate temperature in 0.5-1.5h, and then uniformly increased to the desorption dry temperature in 0.5-1.5h; the desorption intermediate temperature is -5℃ to 5℃.

[0053] According to some specific embodiments of the present application, after the freeze-drying process is maintained at the sublimation temperature for 5-15h, the temperature is first uniformly increased to the desorption intermediate temperature in 1h, and then uniformly increased to the desorption dry temperature in 1h.

[0054] According to some specific embodiments of the present application, the desorption intermediate temperature is 0℃.

[0055] It can be understood that the above-mentioned specific embodiments can be combined with each other as long as they are not contradictory.

[0056] In summary, the present application provides a butylphthalide sublingual tablet and a preparation method thereof. The butylphthalide sublingual tablet of the present application has the following advantages:

[0057] (1) The present application does not need to add a disintegrating agent, and the auxiliary materials used are water-soluble and have a small amount, so that the preparation can be rapidly disintegrated in the oral cavity without grittiness, thereby overcoming the slow disintegration and grittiness in the oral cavity of the oral disintegration tablet prepared by the direct tabletting method.

[0058] (2) Compared with the preparation prepared by the disclosed formula, the dosage form of the present application has a large drug loading capacity, good sample stability, and does not need to use water when taken, can be rapidly disintegrated after entering the mouth, is suitable for the medication of patients with difficulty in swallowing such as the elderly and children, is suitable for the medication under the condition of travel without easy access to water, has the advantages of convenient taking, rapid absorption, small first-pass effect, small irritation to the digestive tract mucosa, and the like, and has a wide market application prospect. DETAILED DESCRIPTION

[0059] The implementation process and beneficial effects of the present application are described in detail through specific examples below, which are intended to help the reader better understand the essence and characteristics of the present application, and not as a limitation on the scope of implementation of the present application.

[0060] Example 1

[0061]

[0062] The preparation method comprises the following steps:

[0063] The specific preparation method is as follows: take 80% of the prescription amount of purified water into a beaker, heat to 80°C in a water bath, take the prescription amount of HS15, poloxamer 188, lecithin, into the same beaker, open the stirring to make them all dissolved, add the prescription amount of butylphthalide to it, heat and stir until butylphthalide is completely dissolved, take the prescription amount of xanthan gum, mannitol, sucrose, peppermint essence into the beaker, stir until all are dissolved. Use Fluko FM300 type dispersion emulsifier to form a uniform solution under high speed (10000 rpm) stirring. After vacuum degassing the solution, accurately inject into the mold, freeze-dry according to the freeze-drying curve in Table 1, to obtain the butylphthalide sublingual tablet of the application. The solution is placed without precipitation, the white block has no cracks, the taste is not bitter, there is no odor, no grit feeling, and the disintegration time is within 10s.

[0064] The disintegration method is: add 2 ml of 37°C warm water in a test tube, put the tablet into the oral cavity to disintegrate, and it will completely disintegrate within one minute and pass through a twenty-mesh sieve.

[0065] Table 1

[0066]

[0067]

[0068] Example 2

[0069]

[0070] The preparation method comprises the following steps:

[0071] The specific preparation method is as follows: take 80% of the prescription amount of purified water into a beaker, heat to 80°C in a water bath, take the prescription amount of HS15, poloxamer 188, lecithin, into the same beaker, open the stirring to make them all dissolved, add the prescription amount of butylphthalide to it, heat and stir until butylphthalide is completely dissolved, take the prescription amount of xanthan gum, mannitol, sucrose, peppermint essence into the beaker, stir until all are dissolved. Use Fluko FM300 type dispersion emulsifier to form a uniform solution under high speed (10000 rpm) stirring. After vacuum degassing the solution, accurately inject into the mold, freeze-dry according to the freeze-drying curve in Table 1, to obtain the butylphthalide sublingual tablet of the application. The solution is placed without precipitation, the white block has no cracks, the taste is not bitter, there is no odor, no grit feeling, and the disintegration time is within 10s.

[0072] The disintegration method is: add 2 ml of 37°C warm water in a test tube, put the tablet into the oral cavity to disintegrate, and it will completely disintegrate within one minute and pass through a twenty-mesh sieve.

[0073] Table 2

[0074]

[0075]

[0076] Example 3

[0077]

[0078] The preparation method comprises the following steps:

[0079] The specific preparation method is as follows: 80% of the prescription amount of purified water is measured into a beaker, and heated to 80°C in a water bath; the prescription amount of HS15, poloxamer 188, lecithin, into the same beaker, open the stirring to make it all dissolved, add the prescription amount of butylphthalide to it, heat and stir until butylphthalide is completely dissolved, add the prescription amount of xanthan gum, mannitol, sucrose, peppermint essence into the beaker, stir until all are dissolved. Using Fluko FM300 type dispersion emulsifier, the above solution is formed into a uniform solution under high speed (10000 rpm) stirring. After vacuum degassing the solution, accurately inject into the mold, according to the freeze-drying curve in Table 3, freeze-drying, to obtain the butylphthalide sublingual tablet of the application. The solution is placed without precipitation, the white block has no cracks, the taste is slightly bitter, no odor, no grit feeling, the disintegration time is within 10s.

[0080] The disintegration method is: add 2 milliliters of 37°C warm water in a test tube, put into the mouth and disintegrate the tablet, and it can be completely disintegrated within one minute and pass through a twenty-mesh sieve.

[0081] Table 3

[0082]

[0083]

[0084] Example 4

[0085]

[0086] The preparation method comprises the following steps:

[0087] The specific preparation method is as follows: 80% of the prescription amount of purified water is measured into a beaker, and heated to 80°C in a water bath; the prescription amount of HS15, Poloxamer 188, lecithin, into the same beaker, open the stirring to make it all dissolved, add the prescription amount of butylphthalide to it, heated and stirred until butylphthalide is completely dissolved, take the prescription amount of xanthan gum, mannitol, sucrose, peppermint essence into the beaker, stir until all dissolved. Using Fluko FM300 type dispersion emulsifier, under high speed (10000 rpm) stirring to form a uniform solution. The solution is vacuum degassed, accurately injected into the mold, according to the freeze-drying curve in Table 4, freeze-drying, that is, the butylphthalide sublingual tablet of the application is obtained. The solution is placed without precipitation, the white block has no cracks, the taste is not bitter, no odor, no grit feeling, the disintegration time is within 10s.

[0088] The disintegration method is: add 2 ml of 37℃ warm water in the test tube, put into the mouth to disintegrate the tablet, and completely disintegrate within one minute, and can pass through twenty mesh sieve.

[0089] Table 4

[0090]

[0091]

[0092] Example 5

[0093]

[0094] The preparation method comprises the following steps:

[0095] The specific preparation method is as follows: measure 80% of the prescription amount of purified water into a beaker, heat to 80℃ in water bath, take the prescription amount of HS15, Poloxamer 188, lecithin, into the same beaker, open the stirring to make it all dissolved, add the prescription amount of butylphthalide to it, heated and stirred until butylphthalide is completely dissolved, take the prescription amount of xanthan gum, mannitol, sucrose, peppermint essence into the beaker, stir until all dissolved. Using Fluko FM300 type dispersion emulsifier, under high speed (10000 rpm) stirring to form a uniform solution. The solution is vacuum degassed, accurately injected into the mold, according to the freeze-drying curve in Table 5, freeze-drying, that is, the butylphthalide sublingual tablet of the application is obtained. The solution is placed without precipitation, the white block has no cracks, the taste is not bitter, no odor, no grit feeling, the disintegration time is within 10s.

[0096] The disintegration method is: add 2 ml of 37℃ warm water in the test tube, put into the mouth to disintegrate the tablet, and completely disintegrate within one minute, and can pass through twenty mesh sieve.

[0097] Table 5

[0098]

[0099]

[0100] Example 6

[0101]

[0102] The preparation method comprises the following steps:

[0103] The specific preparation method is as follows: 80% of the prescription amount of purified water is measured into a beaker, and heated to 80°C in a water bath; the prescription amount of HS15, poloxamer 188, lecithin, into the same beaker, open the stirring to make it all dissolved, add the prescription amount of butylphthalide to it, heat and stir until butylphthalide is completely dissolved, weigh the prescription amount of xanthan gum, mannitol, sucrose, peppermint essence into the beaker, stir until all are dissolved. Using Fluko FM300 type dispersion emulsifier, under high speed (10000 rpm) stirring to make the above solution into a uniform solution. After vacuum degassing the solution, accurately inject into the mold, according to the freeze-drying curve in Table 6, freeze-drying, to obtain the butylphthalide sublingual tablet of the application. The solution is placed without precipitation, white block without cracks, no bitter taste, no odor, no grit feeling, disintegration time is within 10s.

[0104] The disintegration method is: add 2ml of 37℃ warm water in a test tube, put into the mouth and disintegrate the tablet, and it can be completely disintegrated within one minute and pass through a twenty mesh sieve.

[0105] Table 6

[0106]

[0107]

[0108] Example 7

[0109]

[0110] The preparation method comprises the following steps:

[0111] The specific preparation method is as follows: 80% of the prescription amount of purified water is measured into a beaker, and heated to 80°C in a water bath; the prescription amount of HS15, Poloxamer 188, lecithin, into the same beaker, open the stirring to make it all dissolved, to which the prescription amount of butylphthalide is added, heated and stirred until butylphthalide is completely dissolved, the prescription amount of xanthan gum, mannitol, sucrose, peppermint flavor is added into the beaker, stirred until all dissolved. Using Fluko FM300 type dispersion emulsifier, under high speed (10000 rpm) stirring to make the above solution into a homogeneous solution. The solution is vacuum degassed, then accurately injected into the mold, according to the freeze-drying curve in Table 7, freeze-drying, the butylphthalide sublingual tablet of the application is obtained. The solution is placed without precipitation, white block has no cracks, no bitter taste, no odor, no grit feeling, the disintegration time is within 10 s.

[0112] The disintegration method is: 2 ml of 37℃ warm water is added into the test tube, the tablet is placed into the oral cavity and disintegrated, and completely disintegrated within one minute and can pass through the twenty mesh sieve.

[0113] Table 7

[0114]

[0115]

[0116] Comparative Example 1

[0117]

[0118] The preparation method comprises the following steps:

[0119] The specific preparation method is as follows: 80% of the prescription amount of purified water is measured into a beaker, heated to 80℃ in a water bath, and the prescription amount of HS15 into the same beaker, open the stirring to make it all dissolved, to which the prescription amount of butylphthalide is added, heated and stirred until butylphthalide is completely dissolved, the prescription amount of mannitol, sucrose, xanthan gum, peppermint flavor is added into the beaker, stirred until all dissolved. Using Fluko FM300 type dispersion emulsifier, under high speed (10000 rpm) stirring to make the above solution into a homogeneous solution. The solution is vacuum degassed, then accurately injected into the mold, according to the freeze-drying curve in Table 8, freeze-drying, the butylphthalide sublingual tablet of the application is obtained. The solution is placed without precipitation, white block has no cracks, no bitter taste, no odor, no grit feeling, the disintegration time is within 13 s.

[0120] The disintegration method is: 2 ml of 37℃ warm water is added into the test tube, the tablet is placed into the oral cavity and disintegrated, and completely disintegrated within one minute and can pass through the twenty mesh sieve.

[0121] Table 8

[0122]

[0123]

[0124] Comparative Example 2

[0125]

[0126] The preparation method comprises the following steps:

[0127] The specific preparation method is as follows: 80% of the prescription amount of purified water is measured into a beaker, heated to 80°C in a water bath, and the prescription amount of vitamin E polyethylene glycol succinate is weighed into the same beaker. Turn on the stirring to dissolve it completely, add the prescription amount of butylphthalide to it, and stir while heating until the butylphthalide is completely dissolved. Weigh the prescription amount of mannitol, sucrose, xanthan gum, and peppermint essence into the beaker, and stir until they are completely dissolved. Use a Fluko FM300 type dispersion emulsifier to form a uniform solution under high-speed (10000 rpm) stirring. After vacuum degassing the solution, accurately inject it into the mold, and freeze-dry according to the freeze-drying curve in Table 9 to obtain the butylphthalide sublingual tablet of the present application. The solution is placed without precipitation, the white block has cracks, the taste is not bitter, there is no odor, no grit feeling, and the disintegration time is within 10s.

[0128] The disintegration method is: add 2 milliliters of 37°C warm water in a test tube, put the tablet into the oral cavity to disintegrate, and wait for one minute to completely disintegrate and pass through a twenty-mesh sieve.

[0129] Table 9

[0130]

[0131]

[0132] Comparative Example 3

[0133]

[0134] The preparation method comprises the following steps:

[0135] The specific preparation method is as follows: 80% of the prescription amount of purified water is measured into a beaker, heated to 80°C in a water bath, and the prescription amount of poloxamer 188 is weighed into the same beaker, and stirred to dissolve completely. The prescription amount of butylphthalide is added, heated and stirred until the butylphthalide is completely dissolved. The prescription amount of mannitol, sucrose, xanthan gum and peppermint flavor is added to the beaker and stirred until completely dissolved. A Fluko FM300 type dispersion emulsifier is used to form a uniform solution under high speed (10000 rpm) stirring. The solution is prone to produce precipitates. After vacuum degassing the solution, accurately inject into the mold, according to the freeze-drying curve in Table 10, freeze-drying, to obtain the butylphthalide sublingual tablet of the application. The solution is prone to produce precipitates, white block-shaped objects without cracks, no bitter taste, no odor, no grit feeling, and the disintegration time is within 15s.

[0136] The disintegration method is: 2ml of 37℃ warm water is added to a test tube, and the tablet is placed in the oral cavity to disintegrate completely within one minute, and can pass through a twenty-mesh sieve.

[0137] Table 10

[0138]

[0139]

[0140] Comparative Example 4

[0141]

[0142] The preparation method comprises the following steps:

[0143] The specific preparation method is as follows: 80% of the prescription amount of purified water is measured into a beaker, heated to 80°C in a water bath, and the prescription amount of poloxamer 188 is weighed into the same beaker, and stirred to dissolve completely. The prescription amount of butylphthalide is added, heated and stirred until the butylphthalide is completely dissolved. The prescription amount of mannitol, sucrose, xanthan gum and peppermint flavor is added to the beaker and stirred until completely dissolved. A Fluko FM300 type dispersion emulsifier is used to form a uniform solution under high speed (10000 rpm) stirring. The solution is prone to produce precipitates. After vacuum degassing the solution, accurately inject into the mold, according to the freeze-drying curve in Table 10, freeze-drying, to obtain the butylphthalide sublingual tablet of the application. The solution is prone to produce precipitates, white block-shaped objects without cracks, no bitter taste, no odor, no grit feeling, and the disintegration time is within 15s.

[0144] The disintegration method is: 2ml of 37℃ warm water is added to a test tube, and the tablet is placed in the oral cavity to disintegrate completely within one minute, and can pass through a twenty-mesh sieve.

[0145] Table 11

[0146]

[0147]

[0148] Comparative Example 5

[0149]

[0150] The preparation method comprises the following steps:

[0151] The specific preparation method is as follows: 80% of the prescription amount of purified water is weighed into a beaker, heated to 80°C in a water bath, and the prescription amount of vitamin E polyethylene glycol succinate is weighed into the same beaker. Turn on the stirring to dissolve it completely, add the prescription amount of butylphthalide to it, and stir while heating until the butylphthalide is completely dissolved. Weigh the prescription amount of xanthan gum, mannitol, sucrose, and peppermint flavor into the beaker, and stir until they are completely dissolved. Use a Fluko FM300 type dispersion emulsifier to form a uniform solution under high-speed (10000 rpm) stirring. After vacuum degassing the solution, accurately inject it into the mold, and freeze-dry according to the freeze-drying curve in Table 12 to obtain the butylphthalide sublingual tablet of the present application. The solution is placed without precipitation, the white block has cracks, the taste is not bitter, there is no odor, no grit feeling, and the disintegration time is within 10s.

[0152] The disintegration method is: add 2ml of 37℃ warm water in a test tube, put the tablet into the oral cavity to disintegrate, and wait for one minute to completely disintegrate and pass through a twenty-mesh sieve.

[0153] Table 12

[0154]

[0155]

[0156] Comparative Example 6

[0157]

[0158] The preparation method comprises the following steps:

[0159] The specific preparation method is as follows: 80% of the prescription amount of purified water is measured into a beaker, heated to 80°C in a water bath, and the prescription amount of lecithin is weighed into the same beaker, and stirred to dissolve completely. The prescription amount of butylphthalide is added, heated and stirred until the butylphthalide is completely dissolved. The prescription amount of xanthan gum, lactose and peppermint flavor are weighed and added to the beaker, and stirred until completely dissolved. A Fluko FM300 type dispersion emulsifier is used to form a uniform solution under high speed (10000 rpm) stirring. The solution is vacuum degassed, and accurately injected into the mold. The freeze-drying curve in Table 13 is used for freeze-drying, and the butylphthalide sublingual tablet of the application is obtained. The solution is placed without precipitation, the white block has cracks, the taste is not bitter, there is no odor, no grit feeling, and the disintegration time is within 12s.

[0160] The disintegration method is: 2ml of 37°C warm water is added to a test tube, and the tablet is placed in the oral cavity and disintegrates completely within one minute, and can pass through a twenty-mesh sieve.

[0161] Table 13

[0162]

[0163]

[0164] As can be seen from the above examples, HS15 5%-15%, poloxamer 188 5%-15%, and lecithin are within the specified dosage range of 5%-15%, at which time the drug solution uniformity and stability are optimal. The use of the emulsifier dosage without the application of the examples does not achieve the effect of the application. The effect is best when HS15 is 8.6%, poloxamer 188 is 11.5%, and lecithin is 14.4%.

[0165] Mannitol 12%-60%, sucrose 10%-30%, xanthan gum 0.5%-2% (this auxiliary material is a binder, which can be replaced by the same auxiliary material), and peppermint flavor 0.2%-2%. The taste is best when the amount of mannitol is 28.7%, sucrose is 17.2%, xanthan gum is 1.1%, and peppermint flavor is 1.1%. Non-essential additives will affect the taste when the dosage is not within the range, but will not affect the effect of the application.

[0166] The effect data of examples 1-9 are summarized as shown in Table 14 below.

[0167] Table 14 Comparison results of examples 1-9

[0168] Item Dissolution rate Taste Appearance (solid) Appearance (liquid) Example 1 10s Good White mass without cracks White liquid without precipitate Example 2 10s Good White mass without cracks White liquid without precipitate Example 3 10s Good White mass without cracks White liquid without precipitate Example 4 10s Good White mass without cracks White liquid without precipitate Example 5 10s Good White mass without cracks White liquid without precipitate Example 6 10s Good White mass without cracks White liquid without precipitate Example 7 10s Good White mass without cracks White liquid without precipitate Comparative Example 1 13s Good White mass with cracks White liquid without precipitate Comparative Example 2 10s Good White mass with cracks White liquid without precipitate Comparative Example 3 15s Good White mass without cracks White liquid with precipitate Comparative Example 4 15s Good White mass without cracks White liquid with precipitate Comparative Example 5 10s Good White mass with cracks White liquid without precipitate Comparative Example 6 12s Good White mass with cracks White liquid without precipitate

[0169] From the above table, it can be seen that the sublingual tablet obtained by the technical scheme of the present application has good appearance, faster disintegration rate, and no precipitate is separated out after dissolution. The product of the comparative example has cracks on the appearance, and precipitate is separated out after dissolution. More importantly, the disintegration time of most of the comparative examples is longer than that of the technical scheme of the present application. Although the disintegration time of the comparative example is only 2-5 seconds longer than that of the present application, it is well known that the sublingual tablet disintegrates in the oral cavity, saliva is rapidly secreted in the oral cavity, further, the person will produce swallowing action. Therefore, if the disintegration time is long, a part of the active substance will enter the gastrointestinal tract with the swallowing action, thereby affecting the bioavailability of mucosal absorption.

[0170] The stability of each embodiment is further investigated, and the results are shown in Table 15.

[0171] Table 15 Stability study data

[0172]

[0173] Chromatographic conditions: the chromatographic column is filled with octadecylsilane bonded silica gel; mobile phase: methanol-water (65:35); flow rate: 1.0 mL / min; column temperature: 35℃; sample size: 20 μl; detection wavelength: 280 nm.

[0174] Preparation of test solution: an appropriate amount of the product (about equivalent to butylphthalide 50 mg) is accurately weighed, dissolved and diluted to the mark in a 100 mL volumetric flask with the mobile phase, and shaken to obtain the test solution.

[0175] Preparation of control solution: 5 mL of the test solution is accurately measured and placed in a 200 mL volumetric flask, diluted to the mark with methanol, and shaken to obtain the control solution.

Claims

1. A lindane sublingual tablet, wherein, which contains the following ingredients in the weight percentage of 10% to 25% of active substance, 0.1% to 2% of sweetening agent, 0.1% to 2% of flavoring agent, 0.1% to 2% of lubricant, 0.1% to 2% of disintegrant, 0.1% to 2% of binder, 0.1% to 2% of diluent, and 0.1% to 2% of antioxidant, based on the total weight of the drug substance, wherein the active substance is benfoitamine or a benfoitamine derivative, the diluent is selected from one or more of glycine, serine, arginine, mannitol, maltitol, lactitol, erythritol, isomaltitol, dextran, raffinose, maltose, glucose, galactose, trehalose, dextrin, hydroxypropyl cyclodextrin, sodium phosphate, sodium oxide, and aluminum silicate, the binder is selected from one or more of xanthan gum, gelatin, pectin, pullulan, alginate, cellulose and its derivatives, hyaluronic acid, modified starch, polyvinyl alcohol, and chitosan, and the benfoitamine derivative is apioin. HS15 5% - 15%, poloxamer 5% - 15%, and lecithin 5% - 15%, excipient 10% ~ 75%, binder 0.2% ~ 2%, sweetening agent 1% ~ 30%, and flavoring agent 0.1% ~ 2%; the active substance is benfoitamine or a benfoitamine derivative; the excipient is selected from one or more of glycine, serine, arginine, mannitol, maltitol, lactitol, erythritol, isomaltitol, dextran, raffinose, maltose, glucose, galactose, trehalose, dextrin, hydroxypropyl cyclodextrin, sodium phosphate, sodium oxide, and aluminum silicate; the binder is selected from one or more of xanthan gum, gelatin, pectin, pullulan, alginate, cellulose and its derivatives, hyaluronic acid, modified starch, polyvinyl alcohol, and chitosan, and the benfoitamine derivative is apioin. The preparation method of the butylphthalide sublingual tablet comprises a freeze-drying method, in which the drug is made into a liquid, frozen into a solid at low temperature, and then the water is sublimated and removed from the frozen state under vacuum and low temperature to form a freeze-dried tablet.

2. The buflomedil sublingual tablet according to claim 1, wherein, The sweetener is selected from one or more than two combinations of aspartame, sucralose, sucrose, xylitol, sorbitol and stevioside.

3. The buflomedil sublingual tablet according to claim 1, wherein, The dl-buprofen sublingual tablet contains HS 15% - 15%, poloxamer 5% - 15%, lecithin 5% - 15%, mannitol 12% - 60%, sucrose 10% - 30%, xanthan gum 0.5% - 2%, and peppermint flavor 0.2% - 2%.

4. The buflomedil sublingual tablet according to claim 1, wherein, The buflomedil sublingual tablet contains the following ingredients by weight percentage: buflomedil 12%-20%, HS15 5%-15%, poloxamer 5%-15%, lecithin 5%-15%, mannitol 20%-45%, sucrose 10%-30%, xanthan gum 0.5%-2%, and peppermint flavor 0.2%-2%.

5. The method for preparing the buflomedil sublingual tablet according to any one of claims 1 to 4, wherein, The method comprises: (a) a step of preparing a base solution: adding active substances, emulsifiers, excipients, binders, and sweeteners and flavoring agents into purified water to form a uniform mixed solution; (b) a step of degassing: degassing the obtained mixed solution; (c) a step of injection molding: injecting the degassed mixed solution into a mold; (d) a step of pre-freezing: pre-freezing the mold injected with the mixed solution; (e) a step of freeze-drying: freeze-drying the pre-frozen mold to obtain the butylphthalide sublingual tablet.

6. The production method according to claim 5, wherein The pre-freezing treatment comprises pre-freezing the mold injected with the mixed solution at -70℃ to -35℃ for 1-6h.

7. The production method according to claim 5 or 6, wherein The freeze-drying treatment comprises freeze-drying the pre-frozen mold at -40℃ to 35℃ for 1-20h.

8. The production method according to claim 7, wherein The freeze-drying treatment comprises freeze-drying the pre-frozen mold at -40℃ to 35℃ under a pressure of 0.01mbar-1mbar for 1-20h.

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