Asenapine maleate sublingual tablets

Abstract

To provide asenapine maleate sublingual tablets, in which solubility of asenapine maleate is sufficiently improved.SOLUTION: According to one embodiment of the present invention, an asenapine maleate sublingual tablet comprises asenapine maleate and at least one disintegrant selected from low-substituted hydroxypropylcellulose, crospovidone, and corn starch, or at least one lubricant selected from talc and magnesium stearate.SELECTED DRAWING: None

Description

[Technical field]

[0001] One embodiment of the present invention relates to asenapine maleate sublingual tablets. [Background technology]

[0002] Asenapine maleate is an atypical antipsychotic (second-generation antipsychotic) used as a drug to improve positive symptoms such as hallucinations and delusions in schizophrenia, negative symptoms such as emotional withdrawal and flattening of emotions, anxiety, and depression symptoms by antagonistic action on serotonin receptors and dopamine receptors in the brain. Asenapine maleate has a large first-pass effect in liver and gastrointestinal absorption when orally administered, and has a low bioavailability, it was developed as a sublingual tablet in Japan. Sublingual tablets must be quickly disintegrated in a small amount of saliva under the tongue and the active ingredient must be absorbed through the oral mucosa, so the solubility of asenapine maleate in a small amount of solution must be ensured. The asenapine maleate formulation approved by the Pharmaceutical Affairs Law in Japan is Sycrest sublingual tablets. However, Sycrest sublingual tablets use a freeze-drying method developed by Catalent, and special equipment and machines are required for production (Non-Patent Document 1).

[0003] Prior literature on asenapine maleate has reported the use of one or more selected from the group consisting of polyols (excluding aromatic polyols), aliphatic hydroxy acids, saccharin, acesulfame potassium, alkyl sulfates, povidone, magnesium stearate, talc, and sodium stearyl fumarate as an agent for suppressing the bitterness of asenapine maleate (Patent Document 1). However, in Patent Document 1, no formulation was carried out, and it is unclear whether the solubility of asenapine maleate in a small amount of solution is ensured.

[0004] As a result of the inventor's intensive study, it was suggested that disintegrants and lubricants may inhibit the dissolution of asenapine maleate in a small amount of solution. On the other hand, in order to manufacture a sublingual tablet, a disintegrant for quickly disintegrating the tablet under the tongue and a lubricant for preventing tableting trouble are essential. Therefore, there has been a demand for the development of a sublingual tablet using a disintegrant and a lubricant that do not reduce the solubility of asenapine maleate in a small amount of solution. There has also been a demand for the development of a sublingual tablet that can be easily manufactured using general-purpose equipment and machinery. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] International Publication No. 2021 / 002457 [Non-patent literature]

[0006] [Non-Patent Document 1] Pharmaceutical Interview Form "Sycrest Sublingual Tablets 5mg / 10mg", revised October 2021 (7th edition) Summary of the Invention [Problem to be solved by the invention]

[0007] The present invention aims to solve the above problems, and has as its object to prevent a decrease in the solubility of asenapine maleate in a small amount of solution in an oral tablet containing asenapine maleate. [Means for solving the problem]

[0008] According to one embodiment of the present invention, there is provided an asenapine maleate sublingual tablet comprising asenapine maleate and at least one disintegrant selected from low-substituted hydroxypropyl cellulose, crospovidone, and corn starch, or at least one lubricant selected from talc and magnesium stearate.

[0009] The lubricant may be talc and magnesium stearate, and the weight ratio of asenapine maleate to talc may be 1.00:0.01-0.72. The weight ratio of asenapine maleate to magnesium stearate may be 1.00:0.01-0.14. Preferably, the weight ratio of asenapine maleate to talc may be 1.00:0.35-0.72, and the weight ratio of asenapine maleate to magnesium stearate may be 1.00:0.028-0.057. More preferably, the weight ratio of asenapine maleate to magnesium stearate may be 1.00:0.028-0.036.

[0010] The disintegrant may be corn starch and the lubricants may be talc and magnesium stearate.

[0011] The weight ratio of asenapine maleate:corn starch may be 1.00:0.24-0.49, the weight ratio of asenapine maleate:talc may be 1.00:0.35-0.72, and the weight ratio of asenapine maleate:magnesium stearate may be 1.000:0.036-0.057.

[0012] The at least one disintegrant may be low-substituted hydroxypropyl cellulose, and the weight ratio of asenapine maleate:low-substituted hydroxypropyl cellulose is 1.00:1.20 or greater, and the lubricant may be talc and magnesium stearate, and the weight ratio of asenapine maleate:talc is 1.00:0.35 or greater, and the weight ratio of asenapine maleate:magnesium stearate is 1.000:0.028 or greater.

[0013] More preferably, the at least one disintegrant is low-substituted hydroxypropylcellulose, and the weight ratio of asenapine maleate:low-substituted hydroxypropylcellulose is 1.00:1.20-2.42; the lubricant is talc and magnesium stearate, and the weight ratio of asenapine maleate:talc is 1.00:0.35-0.72; and the weight ratio of asenapine maleate:magnesium stearate is 1.000:0.028-0.057. Effect of the Invention

[0014] According to one embodiment of the present invention, there is provided an asenapine maleate sublingual tablet having substantially improved solubility in small amounts of solution of asenapine maleate. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0015] The asenapine maleate sublingual tablet of the present invention will be described in detail below. However, the asenapine maleate sublingual tablet of the present invention should not be construed as being limited to the description of the following embodiments and examples.

[0016] As a result of the studies by the present inventors, as will be described in the Examples below, depending on the types of disintegrants and lubricants added to asenapine maleate, sufficient solubility of asenapine maleate cannot be obtained. Therefore, it is necessary to study disintegrants and lubricants that can be used in asenapine maleate sublingual tablets.

[0017] As a result of investigations by the present inventors, it has been found that manufacturing concerns such as sticking may occur depending on the blending ratio of the lubricant, and therefore it is necessary to investigate a blending ratio of the lubricant that does not cause manufacturing concerns.

[0018] The asenapine maleate sublingual tablet according to one embodiment of the present invention comprises asenapine maleate and a disintegrant or lubricant. In one embodiment, the disintegrant is at least one selected from low-substituted hydroxypropylcellulose, crospovidone, and corn starch. In one embodiment, the lubricant is at least one selected from talc and magnesium stearate. In the asenapine maleate sublingual tablet according to this embodiment, the solubility of asenapine maleate in a small amount of solution is not decreased or can be maintained by adding at least one disintegrant selected from low-substituted hydroxypropylcellulose, crospovidone, and corn starch, or at least one lubricant selected from talc and magnesium stearate to asenapine maleate.

[0019] Generally, low-substituted hydroxypropylcellulose, crospovidone, corn starch, carmellose, carmellose calcium, croscarmellose sodium, etc. are used as disintegrants. However, depending on the type of disintegrant, whether or not the solubility of asenapine maleate in a small amount of solution can be prevented from decreasing varies greatly. Therefore, it is not easy to select a disintegrant that does not reduce the solubility of asenapine maleate in a small amount of solution. Furthermore, it is very difficult to optimize the disintegrant contained in asenapine maleate sublingual tablets so as not to reduce the solubility of asenapine maleate in a small amount of solution.

[0020] In one embodiment, the disintegrant contained in the asenapine maleate sublingual tablet is low-substituted hydroxypropyl cellulose, and the amount of low-substituted hydroxypropyl cellulose relative to asenapine maleate may be 0.01 to 2.84 times by weight.

[0021] In one embodiment, the disintegrant contained in the asenapine maleate sublingual tablet is crospovidone, and the amount of crospovidone relative to asenapine maleate may be 0.01 to 0.72 times by weight.

[0022] In one embodiment, the disintegrant contained in the asenapine maleate sublingual tablet is corn starch, and the weight of the corn starch may be 0.01 to 4.27 times that of the asenapine maleate.

[0023] Furthermore, as lubricants, talc, magnesium stearate, stearic acid, calcium stearate, sodium stearyl fumarate, etc. are generally used. However, depending on the type of lubricant, whether or not the solubility of asenapine maleate in a small amount of solution can be prevented from decreasing greatly varies. Therefore, it is not easy to select a lubricant that can prevent the solubility of asenapine maleate in a small amount of solution from decreasing. Furthermore, it is very difficult to optimize the lubricant contained in the asenapine maleate sublingual tablet in order to prevent the solubility of asenapine maleate in a small amount of solution from decreasing, and it is even more difficult to optimize the lubricant contained in the asenapine maleate sublingual tablet in combination with the above-mentioned disintegrant. In addition, it is very difficult to optimize the blending ratio of the lubricant that does not cause manufacturing concerns such as sticking.

[0024] In one embodiment, the lubricant contained in the asenapine maleate sublingual tablet is talc, and the weight ratio of talc to asenapine maleate may be 0.01 to 0.72 times, more preferably, the weight ratio of asenapine maleate:talc may be 1.00:0.35 to 0.72.

[0025] In one embodiment, the lubricant contained in the asenapine maleate-containing formulation is magnesium stearate, and the amount of magnesium stearate relative to the amount of asenapine maleate may be 0.01 to 0.14 times by weight, and more preferably 0.01 to 0.057 times by weight.

[0026] Since the amount of saliva produced by a human being per minute is approximately 2 mL, if it is assumed that all of the asenapine maleate administered in one Sycrest sublingual tablet 5 mg (7.03 mg of asenapine maleate) dissolves in saliva, the solubility at that time will be approximately 3.52 mg / mL.

[0027] In the present invention, it is preferable that 70% or more of the asenapine maleate is dissolved in a small amount of solution simulating saliva. When the weight ratio of magnesium stearate to 1 weight of asenapine maleate contained in the asenapine maleate sublingual tablet is 0.028 to 0.057, 70% or more of the asenapine maleate can be dissolved in a small amount of solution simulating saliva, and when the weight ratio of magnesium stearate to asenapine maleate contained in the asenapine maleate sublingual tablet is more than 0.07, it is difficult to dissolve 70% or more of the asenapine maleate in a small amount of solution simulating saliva.

[0028] In one embodiment, the disintegrant contained in the asenapine maleate sublingual tablet may be corn starch, and the lubricant may be talc and magnesium stearate. In one embodiment, the weight ratio of asenapine maleate to corn starch contained in the asenapine maleate sublingual tablet may be 1.00:0.24-0.49. In one embodiment, the weight ratio of asenapine maleate to talc contained in the asenapine maleate sublingual tablet may be 1.00:0.35-0.72. In one embodiment, the weight ratio of asenapine maleate to magnesium stearate contained in the asenapine maleate sublingual tablet may be 1.000:0.036-0.057.

[0029] In one embodiment, the disintegrant contained in the asenapine maleate sublingual tablet may be low-substituted hydroxypropylcellulose, and the lubricant may be talc and magnesium stearate. In one embodiment, the weight ratio of asenapine maleate to low-substituted hydroxypropylcellulose contained in the asenapine maleate sublingual tablet may be 1.00:1.20-2.42. In one embodiment, the weight ratio of asenapine maleate to talc contained in the asenapine maleate sublingual tablet may be 1.00:0.35-0.72. In one embodiment, the weight ratio of asenapine maleate to magnesium stearate contained in the asenapine maleate sublingual tablet may be 1.000:0.028-0.057.

[0030] The asenapine maleate sublingual tablet according to the present invention may further contain one or more pharma- ceutically acceptable additives in addition to the above-mentioned disintegrant or lubricant. Examples of the pharma-ceutically acceptable additives contained in the asenapine maleate sublingual tablet include excipients and binders. One or more of these additives may be selected to constitute the asenapine maleate sublingual tablet.

[0031] The excipient contained in the asenapine maleate sublingual tablet can be selected from known excipients, such as, but not limited to, one or more excipients selected from the group consisting of crystalline cellulose, D-mannitol, lactose hydrate, anhydrous calcium hydrogen phosphate, and calcium hydrogen phosphate hydrate.

[0032] The binder contained in the asenapine maleate sublingual tablet can be selected from known binders, such as, but not limited to, one or more binders selected from the group consisting of hydroxypropyl cellulose, polyvinyl alcohol, povidone, and hypromellose.

[0033] [Manufacturing method of asenapine maleate sublingual tablets] The oral tablet according to the present embodiment can be manufactured according to a manufacturing method known in the pharmaceutical field. For example, after mixing asenapine maleate, mannitol-cornstarch mixture, and crystalline cellulose, the mixture is sieved. The sieved mixture is granulated by a fluidized bed granulation method using a granulation liquid containing hydroxypropyl cellulose and purified water. The granulated product is dried by fluidized bed drying and sized. Microcrystalline cellulose, talc, and magnesium stearate are added to the sized granulated product and mixed using a container blender. The mixed composition is tableted using a rotary tableting machine to obtain the asenapine maleate sublingual tablet according to one embodiment. The obtained plain tablet may also be packaged using a highly moisture-proof vinylidene chloride composite sheet, a desiccant, and an aluminum pillow.

[0034] [Evaluation of solubility] In this specification, the solubility of asenapine maleate in asenapine maleate sublingual tablets is evaluated by dissolving the target composition in 10 mL of dissolution test fluid 2 specified in the Japanese Pharmacopoeia for 10 minutes or more, filtering the obtained solution, and diluting the filtrate 500-fold with dissolution test fluid 2. The diluted filtrate is then diluted 2-fold with a mixture of phosphate buffer (pH 2.7) and acetonitrile in a ratio of 3:2, and the concentration of asenapine maleate in the solution is measured.

[0035] The solubility in a small amount of solution is the solubility when asenapine maleate is dissolved at 7.03 mg or 14.06 mg / 2 mL in dissolution test fluid 2. Since the pH of human saliva is 6.8 and the amount of saliva a person produces per minute is about 2 mL, this was determined using 2 mL of saliva at pH 6.8 per tablet (7.03 mg or 14.06 mg of asenapine maleate) placed sublingually. EXAMPLES

[0036] [Disintegrant study] The disintegrant contained in the asenapine maleate sublingual tablet according to the present invention described above was examined.

[0037] The reference solution was prepared by dissolving 35.15 mg of asenapine maleate alone in 10 mL of dissolution test fluid 2, filtering the resulting solution, and diluting the filtrate 500-fold with dissolution test fluid 2. The diluted filtrate was then diluted 2-fold with a mixture of phosphate buffer (pH 2.7) and acetonitrile in a 3:2 ratio.

[0038] Example 1 As a disintegrant, low-substituted hydroxypropyl cellulose was used. Asenapine maleate was added to the second solution of the dissolution test defined in the 18th revised Japanese Pharmacopoeia to be 35.15 mg / 10 mL and dissolved, and 60.0 mg of low-substituted hydroxypropyl cellulose (L-HPC (registered trademark) NBD-022, Shin-Etsu Chemical Co., Ltd.) was added. Next, the liquid containing the additive was filtered, and the filtrate was diluted 500 times with the second solution of the dissolution test. Furthermore, the diluted filtrate was diluted 2 times with a mixture of phosphate buffer (pH 2.7) and acetonitrile in a ratio of 3:2 to obtain the solution of Example 1.

[0039] The above-mentioned evaluation method was determined using 2 mL of saliva at pH 6.8 per tablet (7.03 mg or 14.06 mg of asenapine maleate) placed sublingually, since the pH of human saliva is pH 6.8 and the amount of saliva produced per minute is approximately 2 mL.

[0040] Example 2 In Example 1, 60.0 mg of low-substituted hydroxypropyl cellulose was used as the disintegrant, whereas in Example 2, 25.0 mg of crospovidone (Kollidon (registered trademark) CL-F, BASF Ltd.) was used as the disintegrant. A solution was obtained in the same manner as in Example 1, except that.

[0041] Example 3 In Example 1, 60.0 mg of low-substituted hydroxypropyl cellulose was used as the disintegrant, whereas in Example 3, 50.0 mg of corn starch (XX16, Nihon Shokuhin Kako Co., Ltd.) was used as the disintegrant. A solution was obtained in the same manner as in Example 1, except that.

[0042] Comparative Example 1 In Example 1, 60.0 mg of low-substituted hydroxypropylcellulose was used as the disintegrant, whereas in Comparative Example 1, 25.0 mg of carmellose (NS300 (registered trademark), Gotoku Pharmaceutical Co., Ltd.) was used as the disintegrant. A solution was obtained in the same manner as in Example 1.

[0043] Comparative Example 2 In Example 1, 60.0 mg of low-substituted hydroxypropylcellulose was used as the disintegrant, whereas in Comparative Example 2, 25.0 mg of carmellose Ca (ECG-505 (registered trademark), Gotoku Pharmaceutical Co., Ltd.) was used as the disintegrant. A solution was obtained in the same manner as in Example 1, except that.

[0044] Comparative Example 3 In Example 1, 60.0 mg of low-substituted hydroxypropyl cellulose was used as the disintegrant, whereas in Comparative Example 3, 25.0 mg of croscarmellose Na (Ac-Di-Sol (registered trademark), FMC Corporation) was used as the disintegrant. A solution was obtained in the same manner as in Example 1, except that.

[0045] The evaluation results of the solubility of asenapine maleate in the above-mentioned disintegrants are shown in Table 1.

[0046] [Table 1]

[0047] The evaluation results of the solubility of asenapine maleate shown in Table 1 reveal that Examples 1 to 3 do not decrease the solubility as compared to the reference solution of asenapine maleate.

[0048] [Lubricant Considerations] The lubricant contained in the asenapine maleate sublingual tablet according to the present invention described above was examined.

[0049] Example 4 Talc was used as a lubricant. Asenapine maleate was dissolved in the second solution of the dissolution test defined in the 18th revised Japanese Pharmacopoeia to a concentration of 35.15 mg / 10 mL, and 25.0 mg of talc (Fuji Talc Kogyo Co., Ltd.) was added. Next, the solution containing the additive was filtered, and the filtrate was diluted 500 times with the second solution of the dissolution test. Furthermore, the diluted filtrate was diluted 2 times with a mixture of phosphate buffer (pH 2.7) and acetonitrile in a ratio of 3:2 to obtain the solution of Example 4.

[0050] Example 5 In Example 4, 25.0 mg of talc (Fuji Talc Industrial Co., Ltd.) was used as the lubricant, whereas in Example 5, 4.5 mg of magnesium stearate (vegetable, NOF Corporation) was used as the lubricant. A solution was obtained in the same manner as in Example 4.

[0051] Comparative Example 4 In Example 4, 25.0 mg of talc (Fuji Talc Industrial Co., Ltd.) was used as the lubricant, whereas in Comparative Example 4, a solution was obtained in the same manner as in Example 4, except that 25.0 mg of stearic acid (vegetable, NOF Corporation) was used as the lubricant.

[0052] Comparative Example 5 In Example 4, 25.0 mg of talc (Fuji Talc Industry Co., Ltd.) was used as the lubricant, while in Comparative Example 5, a solution was obtained in the same manner as in Example 4, except that 20.0 mg of calcium stearate (vegetable, NOF Corporation) was used as the lubricant.

[0053] Comparative Example 6 In Example 4, 25.0 mg of talc (Fuji Talc Industry Co., Ltd.) was used as the lubricant, while in Comparative Example 6, a solution was obtained in the same manner as in Example 4, except that 10.0 mg of sodium stearyl fumarate (PRUV, JRS Pharma) was used as the lubricant.

[0054] The evaluation results of the solubility of asenapine maleate in the above-mentioned lubricants are shown in Table 2.

[0055] [Table 2]

[0056] The evaluation results of the solubility of asenapine maleate shown in Table 2 show that in Examples 4 and 5, 70% or more of asenapine maleate can be dissolved in a small amount of solution, and the solubility of asenapine maleate in a small amount of solution is not reduced.

[0057] [Consideration of the amount of magnesium stearate] In the lubricant contained in the asenapine maleate sublingual tablet according to the present invention described above, the amount of magnesium stearate when talc and magnesium stearate were used in combination was examined.

[0058] [Solubility of asenapine maleate in formulations] Based on the above Examples and Comparative Examples, asenapine maleate sublingual tablets were produced and the solubility of asenapine maleate was investigated.

[0059] Example 6 Asenapine maleate sublingual tablet contains 7.03 mg of asenapine maleate, 17.00 mg of low-substituted hydroxypropylcellulose (NBD-022, Shin-Etsu Chemical Co., Ltd.), and 27.67 mg of crystalline cellulose (PH301, Asahi Kasei Corporation). These were mixed and sieved to give a total content of 7.03 mg of asenapine maleate, 17.00 mg of low-substituted hydroxypropylcellulose (NBD-022, Shin-Etsu Chemical Co., Ltd.), and 27.67 mg of crystalline cellulose (PH301, Asahi Kasei Corporation). The sieved mixture was mixed with purified water to give a total content of 1.80 mg of hydroxypropylcellulose (SSL, Nippon Soda Co., Ltd.) per asenapine maleate sublingual tablet, and granulated by fluidized bed granulation. The granulated product was dried by fluidized bed drying and sized (sieve No. 22). To the granulated product, 40.8 mg of crystalline cellulose (PH-301, Asahi Kasei Corporation), 5.00 mg of talc (Fuji Talc Industrial Co., Ltd.), and 0.20 mg of magnesium stearate (vegetable, NOF Corporation) were added and mixed using a container blender. The mixed composition was compressed using a rotary tablet press to obtain the asenapine maleate sublingual tablet of Example 6. Five tablets obtained were dissolved in 10 mL of the second solution for dissolution test, the obtained solution was filtered, and the filtrate was diluted 500 times with the second solution for dissolution test. Furthermore, the diluted filtrate was diluted 2 times with a mixture of phosphate buffer (pH 2.7) and acetonitrile in a ratio of 3:2 to obtain the solution of Example 6. The concentration of asenapine maleate in the solution of Example 6 was measured.

[0060] Example 7 In Example 6, 40.8 mg of granulated crystalline cellulose and 0.20 mg of magnesium stearate were used, whereas in Example 7, 40.7 mg of granulated crystalline cellulose and 0.30 mg of magnesium stearate were used, so that an asenapine maleate sublingual tablet similar to that of Example 6 was obtained. Furthermore, a solution of Example 7 was obtained similarly to the solution of Example 6. The concentration of asenapine maleate in the solution of Example 7 was measured.

[0061] Example 8 In Example 6, 40.8 mg of granulated crystalline cellulose and 0.20 mg of magnesium stearate were used, whereas in Example 8, 40.6 mg of granulated crystalline cellulose and 0.40 mg of magnesium stearate were used, and other than these, an asenapine maleate sublingual tablet was obtained similar to that of Example 6. Furthermore, a solution of Example 8 was obtained similarly to the solution of Example 6. The concentration of asenapine maleate in the solution of Example 8 was measured.

[0062] Example 9 Except for using 14.06 mg of asenapine maleate, 17.00 mg of low-substituted hydroxypropylcellulose (NBD-022, Shin-Etsu Chemical Co., Ltd.), 20.64 mg of crystalline cellulose, 40.5 mg of granulated crystalline cellulose, and 0.50 mg of magnesium stearate, an asenapine maleate sublingual tablet equivalent to that of Example 6 was obtained. Furthermore, a solution of Example 9 was obtained in the same manner as the solution of Example 6. The concentration of asenapine maleate in the solution of Example 9 was measured.

[0063] Comparative Example 7 In Example 6, 40.8 mg of granulated crystalline cellulose and 0.20 mg of magnesium stearate were used, whereas in Comparative Example 7, 40.5 mg of granulated crystalline cellulose and 0.50 mg of magnesium stearate were used, and other than these, an asenapine maleate sublingual tablet was obtained similar to that of Example 6. Furthermore, a solution of Comparative Example 7 was obtained similarly to the solution of Example 6. The concentration of asenapine maleate in the solution of Comparative Example 7 was measured.

[0064] The solubility evaluation results of asenapine maleate at the above amounts of magnesium stearate are shown in Table 2.

[0065] [Table 3]

[0066] The evaluation results of the solubility of asenapine maleate shown in Table 3 reveal that in Examples 6 to 9, 70% or more of the asenapine maleate was dissolved in a small amount of solution, while the proportion of the asenapine maleate dissolved was less than 70% in Comparative Example 7. It was revealed that the solubility of asenapine maleate was not reduced in a small amount of solution by using, as a lubricant contained in the asenapine maleate sublingual tablets, 0.028 to 0.057 weight percent magnesium stearate in combination with 0.35 to 0.72 weight percent talc per weight of asenapine maleate. In addition, it was found that when asenapine maleate sublingual tablets contain 1.20 to 2.42 weights of low-substituted hydroxypropylcellulose, 0.35 to 0.72 weights of talc, and 0.028 to 0.057 weights of magnesium stearate per weight of asenapine maleate, 70% or more of the asenapine maleate is dissolved and the solubility is not reduced in a small amount of solution.

[0067] Furthermore, it was found that sticking during the manufacturing process of asenapine maleate sublingual tablets can be prevented or suppressed by using 0.028 to 0.057 weight percent magnesium stearate per weight percent asenapine maleate in combination with talc in the lubricant contained in asenapine maleate sublingual tablets. It was also found that sticking and other concerns during the manufacturing process of asenapine maleate sublingual tablets can be eliminated by including 0.35 to 0.72 weight percent talc and 0.028 to 0.057 weight percent magnesium stearate per weight percent asenapine maleate in asenapine maleate sublingual tablets.

[0068] Example 10 Each asenapine maleate sublingual tablet contained 7.03 mg of asenapine maleate, 17.00 mg of mannitol-cornstarch mixture (mixture ratio: D-mannitol 80%, corn starch 20%, PEARLITOL® Flash, Rocket Corporation), and 27.67 mg of microcrystalline cellulose (PH-301, Asahi Kasei Corporation). The mixture was mixed and sieved. The sieved mixture was mixed with purified water to obtain a granulation liquid containing 1.80 mg of hydroxypropylcellulose (SSL, Nippon Soda Co., Ltd.) per asenapine maleate sublingual tablet. The granules were dried by fluidized bed drying and sized (sieve No. 22). To the granulated product, 41.25 mg of crystalline cellulose (PH-301, Asahi Kasei Corporation), 5.00 mg of talc (Fuji Talc Industrial Co., Ltd.), and 0.25 mg of magnesium stearate (vegetable, NOF Corporation) were added and mixed using a container blender. The mixed composition was compressed using a rotary tablet press to obtain the asenapine maleate sublingual tablet of Example 9. Five of the obtained tablets were dissolved in 10 mL of the second solution for dissolution test, the obtained solution was filtered, and the filtrate was diluted 500 times with the second solution for dissolution test. Furthermore, the diluted filtrate was diluted 2 times with a mixture of phosphate buffer (pH 2.7) and acetonitrile in a ratio of 3:2 to obtain the solution of Example 10. The concentration of asenapine maleate in the solution of Example 10 was measured.

[0069] Example 11 In Example 10, 7.03 mg of asenapine maleate, 17.00 mg of mannitol-cornstarch mixture, 27.67 mg of crystalline cellulose, 41.25 mg of granulated crystalline cellulose, and 0.25 mg of magnesium stearate were used, but in Example 10, 14.06 mg of asenapine maleate, 20.64 mg of crystalline cellulose, 41.00 mg of granulated crystalline cellulose, and 0.50 mg of magnesium stearate were used, and other than this, an asenapine maleate sublingual tablet equivalent to that of Example 9 was obtained. Furthermore, a solution of Example 11 was obtained in the same manner as the solution of Example 10. The concentration of asenapine maleate in the solution of Example 11 was measured.

[0070] The evaluation results of the solubility of asenapine maleate in the above-mentioned asenapine maleate sublingual tablets are shown in Table 4.

[0071] [Table 4]

[0072] The evaluation results of the solubility of asenapine maleate shown in Table 4 reveal that 70% or more of the asenapine maleate is dissolved in a small amount of solution in Examples 10 and 11. It was revealed that by containing 0.24 to 0.49 weight of corn starch, 0.35 to 0.72 weight of talc, and 0.036 weight of magnesium stearate per weight of asenapine maleate in the asenapine maleate sublingual tablet, 80% or more of the asenapine maleate is dissolved in a small amount of solution, and the solubility in a small amount of solution is not reduced.

[0073] Furthermore, it was found that the lubricant contained in asenapine maleate sublingual tablets contains 0.35 to 0.72 weights of talc and 0.036 weights of magnesium stearate per weight of asenapine maleate, which eliminates concerns such as sticking during the manufacturing process of asenapine maleate sublingual tablets.

Claims

1. Asenapine maleate, At least one disintegrant selected from low-substituted hydroxypropyl cellulose, crospovidone, and corn starch, or 1. An asenapine maleate sublingual tablet comprising at least one lubricant selected from talc and magnesium stearate.

2. The lubricant is the talc and the magnesium stearate, and the weight ratio of asenapine maleate to talc is 1.00:0.01-0.72, and the weight ratio of asenapine maleate to magnesium stearate is 1.00:0.01-0.

14. The asenapine maleate sublingual tablet according to claim 1.

3. The lubricant is the talc and the magnesium stearate, and the weight ratio of asenapine maleate to talc is 1.00:0.35-0.72, and the weight ratio of asenapine maleate to magnesium stearate is 1.00:0.028-0.

057. The asenapine maleate sublingual tablet according to claim 1.

4. The disintegrant is corn starch, 2. The asenapine maleate sublingual tablet of claim 1, wherein said lubricants are said talc and said magnesium stearate.

5. the weight ratio of the asenapine maleate to the corn starch is 1.00:0.24-0.49; the weight ratio of the asenapine maleate to the talc is 1.00:0.35-0.72; The asenapine maleate sublingual tablet of claim 4, wherein the weight ratio of the asenapine maleate to the magnesium stearate is 1.000:0.028-0.

057.

6. The disintegrant is low-substituted hydroxypropyl cellulose.

2. The asenapine maleate sublingual tablet of claim 1, wherein said lubricants are said talc and said magnesium stearate.

7. The at least one disintegrant is the low-substituted hydroxypropyl cellulose, the weight ratio of the asenapine maleate to the low-substituted hydroxypropyl cellulose is 1.00:1.20-2.42; The lubricant is the talc and the magnesium stearate, the weight ratio of the asenapine maleate to the talc is 1.00:0.35-0.72; The asenapine maleate sublingual tablet of claim 1, wherein the weight ratio of the asenapine maleate to the magnesium stearate is 1.000:0.028-0.057.

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