Agent for suppressing the bitterness of asenapine and method for suppressing the bitterness

Abstract

The purpose of the present invention is to provide a novel agent for suppressing bitterness in asenapine. According to the present invention, there is provided an agent for suppressing bitterness in asenapine, the agent including, as an active ingredient, at least one selected from the group consisting of polyols (other than aromatic polyols), aliphatic hydroxy acids, saccharine, acesulfame potassium, alkyl sulfate, povidone, magnesium stearate, talc, and sodium stearyl fumarate. This agent for suppressing bitterness can be used when administering an asenapine-containing composition, the asenapine-containing composition preferably being a sublingual orally disintegrating tablet, and more preferably being a lyophilized sublingual orally disintegrating tablet.

Description

REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority from prior patent application No. 2019-124969 (filing date: July 4, 2019), the entire disclosure of which is incorporated herein by reference. [Technical field]

[0002] The present invention relates to an agent for suppressing the bitterness of asenapine and a method for suppressing the bitterness of asenapine.The present invention also relates to an oral mucosal absorption-type preparation containing asenapine as an active ingredient and having a suppressed bitterness. [Background technology]

[0003] Asenapine is a drug approved in Japan as a treatment for schizophrenia (product name: Sycrest (trade name) sublingual tablets (asenapine maleate sublingual tablets) 5 mg to 10 mg). Asenapine has a large first-pass effect in liver and gastrointestinal absorption when orally administered, and has a low bioavailability, so it was developed as a fast-disintegrating sublingual tablet that is rapidly absorbed through the oral mucosa (Sycrest Sublingual Tablets Drug Interview Form, April 2018 revised (5th edition)). However, asenapine has a unique bitter taste (Hiroyuki Kamei et al., "Survey on satisfaction with asenapine sublingual tablets, a second-generation antipsychotic, in patients with schizophrenia," Clinical Psychopharmacology, 2018;21:1495-1506), and patients who took the sublingual tablets had to endure the bitter taste. In addition, to avoid reduced drug absorption, patients are required to refrain from eating or drinking for 10 minutes after taking the drug, and it is difficult to alleviate the bitterness by drinking water or eating food (Sycrest Sublingual Tablet Package Insert, Revised March 2018 (3rd Edition)).

[0004] There have been reports of formulations using cyclodextrin to suppress the bitterness of asenapine, but these relate to oral preparations, not limited to oral mucosal absorption preparations, and do not show the effect on absorbability or aftertaste after taking the drug (Patent Document 1). In addition, generally, the bitterness of bitter drugs is suppressed by coating the pharmaceutical preparation to physically block contact between the drug components and the tongue. While this method is effective for oral preparations absorbed in the digestive tract, it has the problem that it cannot be applied to oral mucosal absorption preparations. In addition, although there are known cases in which sweeteners such as sugars have been added to oral preparations (orally disintegrating tablets) of asenapine, it is not intended to suppress the bitterness (Patent Documents 2 and 3). [Prior art documents] [Patent documents]

[0005] [Patent Document 1] Indian Patent Publication IN2240MU2012A [Patent Document 2] International Publication No. 2013 / 041435 [Patent Document 3] International Publication No. 2014 / 127786 Summary of the Invention

[0006] Thus, suppressing the bitterness of asenapine when taken (particularly when taken via the oral mucosa) remains an issue. The present invention has been made in view of this current situation. That is, an object of the present invention is to provide a novel agent for suppressing the bitterness of asenapine and a novel method for suppressing the bitterness. Another object of the present invention is to provide an oral mucosa-absorbable preparation containing asenapine as an active ingredient and having a suppressed bitterness.

[0007] The present inventors have constructed a bitterness evaluation system for asenapine using a taste sensor, and have found that various components including sorbitol have the effect of suppressing the bitterness of asenapine. The present inventors have also found that the bitterness suppression effect is similar when the concentration conditions of asenapine are close to those when actually taken, or when various components are not used simultaneously with asenapine. The present invention is based on these findings.

[0008] According to the present invention, the following inventions are provided. [1] An agent for suppressing the bitterness of asenapine, comprising as an active ingredient 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. [2] The bitterness suppressor according to the above [1], wherein the polyol is an aliphatic polyol having 2 to 3 carbon atoms, a saccharide, a reduced product of a saccharide, or a synthetic polymer having multiple hydroxyl groups. [3] The bitterness suppressor according to the above [2], wherein the aliphatic polyol having 2 to 3 carbon atoms is glycerin or propylene glycol. [4] The bitterness suppressor described in [2] above, wherein the saccharide is a monosaccharide, a disaccharide or a polysaccharide. [5] The bitterness suppressor described in [2] above, wherein the reduced product of the saccharide is a sugar alcohol of a monosaccharide or disaccharide. [6] The bitterness suppressor described in [4] above, wherein the polysaccharide is a dextrin, a starch or a cellulose. [7] The bitterness suppressor according to [1] above, wherein the aliphatic hydroxy acid is citric acid, lactic acid, malic acid or tartaric acid. [8] The bitterness suppressor described in [1] above, wherein the alkyl sulfate is sodium lauryl sulfate or ammonium lauryl sulfate. [9] A bitterness suppressant described in any one of [1] to [8] above, for use before, simultaneously with, or after taking an asenapine-containing composition.

[10] The bitterness suppressant described in [9] above, wherein the asenapine-containing composition is an oral mucosal absorption type preparation.

[11] The bitterness suppressant according to

[10] above, wherein the oral mucosal absorption type preparation is an orally disintegrating tablet, an orally disintegrating film, an oral patch, a sublingual tablet, a buccal tablet, a troche, a jelly or a spray.

[12] A method for suppressing the bitterness of asenapine, characterized by using the active ingredient described in [1] above.

[13] A method for suppressing bitterness described in

[12] above, in which the active ingredient is used before, simultaneously with, or after taking an asenapine-containing composition.

[14] A method for suppressing bitterness described in

[12] above, comprising adding the active ingredient to an asenapine-containing composition.

[15] The method for suppressing bitterness described in

[13] or

[14] above, wherein the asenapine-containing composition is an oral mucosal absorption type preparation.

[16] The method for suppressing bitterness according to the above

[15] , wherein the oral mucosally absorbable preparation is an orally disintegrating tablet, an orally disintegrating film, an oral patch, a sublingual tablet, a buccal tablet, a troche, a jelly, or a spray.

[17] An oral mucosal absorption type preparation containing asenapine as an active ingredient, the oral mucosal absorption type preparation containing one or more ingredients 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, in which the bitterness of asenapine is suppressed.

[18] The oral mucosal absorption formulation according to the above

[17] , wherein the oral mucosal absorption formulation is a sublingual orally disintegrating tablet.

[19] The oral mucosal absorption type formulation according to the above

[18] , wherein the sublingual orally disintegrating tablet is a freeze-dried type.

[0009] According to the present invention, the strong bitter taste of asenapine can be effectively suppressed, and it is expected that the discomfort felt by patients due to the bitter taste will be alleviated even when the drug is taken via the oral mucosa, which will ultimately lead to improved compliance with asenapine administration. [Brief description of the drawings]

[0010] [Figure 1]FIG. 1 shows the measurement procedure of a taste sensor and the sensor output corresponding to the measurement procedure. [Diagram 2] FIG. 2 shows the results of measuring the CPA of asenapine solutions of each concentration using a taste sensor (mean ± SD, n = 3). [Diagram 3] FIG. 3 shows the results of measuring the CPA of lidocaine solutions of various concentrations using a taste sensor (mean ± SD, n = 3). Description of the Invention

[0011] The bitterness suppressing agent of the present invention contains at least one of the components described in [1] above as an active ingredient. In the present invention, the bitterness suppressing active ingredient may be any one of the components described in [1] above, or a combination of some or all of these. In the present invention, the bitterness suppressing active ingredient may be in the form of a pharma- ceutically acceptable salt, and for example, saccharin is used to mean sodium saccharin.

[0012] The "polyol" which is an active ingredient of the bitterness suppressor of the present invention is synonymous with polyhydric alcohol, but aromatic polyols are excluded. In the present invention, the polyol is a compound having a plurality of hydroxyl groups (-OH groups), and may have, for example, 2 to 9 hydroxyl groups (-OH groups). An example of the polyol is an aliphatic polyol having 2 to 3 carbon atoms, and specific examples thereof include glycerin and propylene glycol. Other polyols include saccharides such as monosaccharides, disaccharides, and polysaccharides, and reduced products of saccharides. Examples of the sugars include monosaccharides such as glucose and fructose; disaccharides such as lactose hydrate, trehalose, and sucrose; and polysaccharides such as dextrins, starches (e.g., potato starch), and celluloses (e.g., crystalline cellulose, low-substituted hydroxypropylcellulose (L-HPC), croscarmellose sodium, and carmellose sodium). Examples of the reduced products of the sugars include sugar alcohols (particularly monosaccharide or disaccharide sugar alcohols) such as xylitol, sorbitol, and erythritol.

[0013] Polyols also include synthetic polymers with multiple hydroxyl groups, such as polyethylene glycol (macrogol) and polyvinyl alcohol (PVA).

[0014] The "aliphatic hydroxy acid" which is an active ingredient of the bitterness suppressor of the present invention means an aliphatic carboxylic acid having a hydroxyl group. The number of carbon atoms of the aliphatic hydroxy acid is 2 to 6. Examples of the aliphatic hydroxy acid include citric acid, lactic acid, malic acid, and tartaric acid.

[0015] In addition to the above, other active ingredients of the bitterness suppressant of the present invention include polyethylene glycol (macrogol), acesulfame potassium, alkyl sulfates (e.g., sodium lauryl sulfate, ammonium lauryl sulfate), povidone, magnesium stearate, talc, sodium stearyl fumarate, sodium saccharin, etc.

[0016] The active ingredients of the bitterness suppressant of the present invention are all known as orally ingestible ingredients and can be obtained by known methods such as synthesis, extraction, purification, etc., or commercially available products can be used.

[0017] The form of the bitterness suppressant of the present invention is not particularly limited, and may be in any form such as a solution, suspension, syrup, powder, granules, particles, tablets, candy, gum, etc., depending on the mode of use. The bitterness suppressant of the present invention may be a preparation consisting of only the active ingredient, or a composition containing the active ingredient and other ingredients. The bitterness suppressant of the present invention may be provided in the form of an oral care product such as toothpaste, mouthwash, mouth spray, etc.

[0018] The bitterness suppressant of the present invention is used to suppress the bitterness of asenapine. Asenapine is known as an active ingredient of a drug for treating schizophrenia. In the present invention, "asenapine" means asenapine and its pharma- ceutically acceptable salts, including, but not limited to, the free form, maleate, and pamoate of asenapine.

[0019] In the present invention, "bitterness suppression" means that the bitterness experienced when taking asenapine is reduced. Here, since asenapine acts on the central nervous system, it is ethically difficult to carry out a taste sensory test on humans. For this reason, in the present invention, the effect of bitterness suppression can be evaluated using a taste sensor. For example, when a taste sensor equipped with a lipid membrane electrode is used to evaluate the bitterness suppression, the bitterness suppression effect can be evaluated based on the CPA (Change of membrane Potential caused by Absorption) value calculated from the membrane potential (sensor output) as described in Example 1(1), and the bitterness suppression effect can be evaluated to exist when the rate of change in CPA is minus 10% or more (preferably 20% or more, 30% or more, 40% or more, 50% or more, or 60% or more).

[0020] The bitterness suppressant of the present invention can be used in combination with the asenapine-containing composition when it is taken. For example, the bitterness suppressant of the present invention can be used before, simultaneously with, or after taking the asenapine-containing composition. In particular, when the asenapine-containing composition is for sublingual administration, the bitterness suppressant of the present invention can also be used in contact with the sublingual. The bitterness suppressant of the present invention can also be used by being blended with the asenapine-containing composition. Here, the "asenapine-containing composition" includes a pharmaceutical composition containing asenapine as an active ingredient, and corresponds to an oral mucosal absorption type preparation. For example, pharmaceutical preparations that are retained in the oral cavity for a certain period of time, such as oral disintegrating tablets, oral disintegrating films, oral patches, sublingual tablets, buccal tablets, lozenges, jellies, sprays, etc., can be mentioned.

[0021] When the bitterness suppressant of the present invention is used with asenapine, the ratio of the active ingredient of the bitterness suppressant of the present invention to asenapine (mass ratio, solid content conversion) can be set for each component.

[0022] According to another aspect of the present invention, there is provided a method for suppressing the bitterness of asenapine, which comprises using an active ingredient of the bitterness suppressor of the present invention. The bitterness suppression method of the present invention can be carried out according to the description of the bitterness suppressor of the present invention.

[0023] According to yet another aspect of the present invention, there is provided a pharmaceutical composition containing asenapine as an active ingredient, which contains the active ingredient of the bitterness suppressant of the present invention and in which the bitterness of asenapine is suppressed, and the pharmaceutical composition can be provided as an oral mucosal absorption type preparation. The oral mucosal absorption type preparation of the present invention may be a sublingual orally disintegrating tablet, and the sublingual orally disintegrating tablet can preferably be a freeze-dried sublingual orally disintegrating tablet produced by a freeze-drying method. The pharmaceutical composition and oral mucosal absorption type preparation of the present invention can be produced according to a known production method, except that the active ingredient of the bitterness suppressant of the present invention is mixed with raw materials to produce the pharmaceutical composition.

[0024] According to the present invention, the following is provided:

[0101] 1. An agent for suppressing the bitterness of asenapine, comprising, as an active ingredient, at least one selected from the group consisting of polyols having 2 to 9 hydroxyl groups (excluding aromatic polyols), aliphatic hydroxy acids and saccharin.

[0102] The bitterness suppressor according to the above

[0101] , wherein the polyol is an aliphatic polyol having 2 to 3 carbon atoms, a sugar, or a reduced product of a sugar.

[0103] The bitterness suppressor according to the above-mentioned

[0102] , wherein the aliphatic polyol having 2 to 3 carbon atoms is glycerin and propylene glycol.

[0104] The bitterness suppressor described in the above

[0102] , wherein the sugars are monosaccharides and disaccharides.

[0105] The bitterness suppressor described in the above

[0102] , wherein the reduced product of a sugar is a sugar alcohol of a monosaccharide or disaccharide.

[0106] The bitterness suppressor according to the above

[0101] , wherein the aliphatic hydroxy acid is citric acid.

[0107] A bitterness suppressant described in any of the above

[0101] to

[0106] for use before, simultaneously with, or after taking an asenapine-containing composition.

[0108] A bitterness suppressant described in the above

[0107] , wherein the asenapine-containing composition is an oral mucosal absorption type preparation.

[0109] The bitterness suppressant described in the above-mentioned

[0108] , wherein the oral mucosal absorption type preparation is an orally disintegrating tablet, an orally disintegrating film, an oral patch, a sublingual tablet, a buccal tablet, a troche, a jelly or a spray.

[0110] A method for suppressing the bitterness of asenapine, characterized by using the active ingredient described in the above

[0101] .

[0111] A method for suppressing bitterness as described in the above-mentioned

[0110] , in which the active ingredient is used before, simultaneously with, or after taking an asenapine-containing composition.

[0112] A method for suppressing bitterness described in the above-mentioned

[0110] , which comprises adding the active ingredient to an asenapine-containing composition.

[0113] A method for suppressing bitterness described in

[0111] or

[0112] above, wherein the asenapine-containing composition is an oral mucosal absorption type preparation.

[0114] The method for suppressing bitterness described in the above

[0113] , wherein the oral mucosal absorption type preparation is an orally disintegrating tablet, an orally disintegrating film, an oral patch, a sublingual tablet, a buccal tablet, a troche, a jelly, or a spray.

[0115] An oral mucosal absorption type preparation containing asenapine as an active ingredient, which contains one or more components selected from the group consisting of polyols having 2 to 9 hydroxyl groups, aliphatic hydroxy acids and saccharin, and which has a suppressed bitterness of asenapine.

[0116] The oral mucosal absorption formulation described in the above-mentioned

[0115] , wherein the oral mucosal absorption formulation is a sublingual oral disintegrating tablet.

[0117] The oral mucosal absorption formulation described in the above

[0116] , wherein the sublingual oral disintegrating tablet is a freeze-dried type. EXAMPLES

[0025] The present invention will be described in more detail with reference to the following examples, but the present invention is not limited to these examples.

[0026] Example 1: Evaluation of the bitterness of asenapine using a taste sensor (1) (1) Method A. Sample Asenapine maleate from Meiji Seika Pharma was used. The reference solution required for measurement with the taste sensor was an Intelligent Sensor Technology product, and the water was Japanese Pharmacopoeia purified water (Kyoei Pharmaceutical). The ingredients used to evaluate the bitterness suppression effect of asenapine were glycerin (Japanese Pharmacopoeia "Concentrated Glycerin", Kenei Pharmaceutical), propylene glycol (special grade, Kanto Chemical), macrogol 400 (Japanese Pharmacopoeia, Nikko Pharmaceutical), lactose hydrate (Japanese Pharmacopoeia, DFE Pharma), trehalose (JP, Hayashibara), sucrose (JP "refined white sugar", Itochu Sugar Co., Ltd.), dextrin (JP, Nippon Starch Chemical Co., Ltd.), potato starch (JP, Matsutani Chemical Co., Ltd.), crystalline cellulose (JP, Asahi Kasei Co., Ltd.), low-substituted hydroxypropyl cellulose (JP, Shin-Etsu Chemical Co., Ltd.), croscarmellose sodium (JP, Nichirin Chemical Co., Ltd.), carmellose calcium (JP, Nichirin Chemical Co., Ltd.), glucose (first-class, Kanto Chemical Co., Ltd.), fructose (Ultra, SIGMA), xylitol (JP, Bussan Food Science Co., Ltd.), D-sorbitol (first-class, Fujifilm Wako Pure Chemical Co., Ltd.), erythritol (JP, Mitsubishi Chemical Foods Co., Ltd.), citric acid (JP, Merck Whey), lactic acid (GR, Nacalai Tesque Co., Ltd.), malic acid ( The following acids were used: GR, Nacalai Tesque), tartaric acid (GR, Nacalai Tesque), acetic acid (special grade, Nacalai Tesque), sodium lauryl sulfate (first grade, Wako Pure Chemical Industries), ammonium lauryl sulfate (quasi-drug, Kao Chemical), sodium saccharin (Japan Pharmacopoeia, Yamawa Shoji), acesulfame potassium (Japan Pharmacopoeia, Mitsubishi Corporation Life Sciences), povidone (Japan Pharmacopoeia, BASF), crospovidone (Japan Pharmacopoeia, BASF), copolydone (Japan Pharmacopoeia, BASF), magnesium stearate (Japan Pharmacopoeia, NOF Corp.), calcium stearate (Japan Pharmacopoeia, Taihei Chemical Co.), talc (Japan Pharmacopoeia, Matsumura Sangyo), synthetic aluminum silicate (Japan Pharmacopoeia, Kyowa Chemical Industry Co., Ltd.), sodium stearyl fumarate (Japan Pharmacopoeia, SANAQ), and aspartame (food additive, Ajinomoto Co., Ltd.).

[0027] B. Equipment used A taste recognition device (SA402B, manufactured by Intelligent Sensor Technology) (hereafter referred to as "taste sensor 1") was used as the taste sensor. The measurement procedure of taste sensor 1 is shown in Figure 1. In Figure 1, Vr is the measurement value (sensor output) of a reference solution (10 mM KCl + 0.3 mM tartaric acid solution) equivalent to human saliva, Vs is the measurement value of the sample solution, and Vr' is the value when the sample solution is measured, washed with the reference solution, and then the reference solution is measured again. Vs-Vr represents the taste immediately after putting the sample in the mouth (initial taste), and Vr'-Vr represents the CPA (Change of membrane Potential caused by Absorption) value, which represents the taste that remains in the mouth (aftertaste).

[0028] Taste sensor 1 is composed of an electrode made of a lipid membrane that corresponds to a taste cell, a robot arm that corresponds to a nerve fiber pathway, and a computer for information analysis that corresponds to the human cerebrum. Since the taste of medicines is often evaluated based on CPA, CPA was determined as an index of taste intensity. The type of lipid membrane electrode used was the BT0 electrode, which has a high response to the bitterness of drugs (Uchida, Takahiro, "Evaluation of the Bitterness of Drugs Using a Taste Sensor (Part 1)," Monthly Pharmaceutical Affairs 2003.7;45(8):91-97 and Uchida, Takahiro and Miyanaga, Yoko, "Evaluation of the Bitterness of Drugs Using a Taste Sensor (Part 2)," Monthly Pharmaceutical Affairs 2003.8;45(9):167-174). The concentration of the preparation solution was set based on the solubility of each drug substance and additive.

[0029] (2) Results To evaluate the responsiveness of taste sensor 1 to asenapine, a solution of asenapine at 0 to 1 mg / mL (based on the free form) was measured with the taste sensor. The results are shown in Figure 2. Since the CPA increased with increasing asenapine concentration, it was confirmed that taste sensor 1 responds to the bitterness of asenapine.

[0030] Example 2: Evaluation of asenapine's bitterness suppression by various substances using taste sensor 1 In order to evaluate the bitterness suppression effect of asenapine, various substances, including D-sorbitol, glycerin, propylene glycol, saccharin Na, xylitol, citric acid, fructose, sucrose, glucose, and aspartame, were added to the asenapine solution at various concentrations, and the membrane potential was measured using the taste sensor 1. The asenapine concentration was set to 0.02 mg / mL (CPA = 32.1 mV), which is a good response range for the CPA of the taste sensor 1 at 20 to 50 mV. It was confirmed that the CPA before adding the various substances satisfied the numerical range (recommended value) described in the instruction manual for the taste sensor. In addition, it was determined that there was a bitterness suppression effect when the rate of change in CPA was minus 10% or more. The results are shown in Table 1.

[0031] [Table 1]

[0032] Among the evaluated ingredients, the polyols such as glycerin, propylene glycol, glucose, fructose, lactose hydrate, trehalose, sucrose, dextrin, potato starch, crystalline cellulose, low-substituted hydroxypropylcellulose, croscarmellose sodium, carmellose calcium, macrogol 400, xylitol, D-sorbitol, and erythritol all had a bitterness-suppressing effect. The aliphatic hydroxy acids such as citric acid, lactic acid, malic acid, and tartaric acid had a bitterness-suppressing effect, while acetic acid, an aliphatic carboxylic acid that does not contain a hydroxyl group, had no bitterness-suppressing effect. The alkyl sulfates sodium lauryl sulfate and ammonium lauryl sulfate all had a bitterness-suppressing effect. Other ingredients that had a bitterness-suppressing effect were sodium saccharin, potassium acesulfame, povidone, magnesium stearate, talc, and sodium stearyl fumarate. On the other hand, no bitterness suppression effect was observed in crospovidone and copovidone, which have a structure similar to povidone, calcium stearate, which is a stearate salt like magnesium stearate, or synthetic aluminum silicate, which is a silicate compound like talc. Among the ingredients that were found to have a bitterness suppression effect, the CPA reduction was particularly large when sucrose, sodium lauryl sulfate, ammonium lauryl sulfate, and D-sorbitol were added, and the CPA when added at the concentrations listed in Table 1 was reduced by 94.2%, 92.2%, 79.0%, and 63.1%, respectively, compared to when not added.

[0033] Taste sensor 1 is a device that mimics the mechanism by which humans recognize tastes when taste substances are adsorbed to taste bud cells. The electrode section is made up of multiple artificial lipid membranes made by fixing lipids with polymeric compounds, and the mechanism is that the membrane potential changes when a taste substance is adsorbed to the artificial lipid membrane (Tomoya Nakagawa et al., "Drug development research using taste sensors (2) Masking and formulation development of donepezil hydrochloride OD tablets," PHARM TECH JAPAN 2012.28(3);31-37). In addition, there are three known mechanisms by which the taste sensor 1 detects bitterness masking: (i) bitterness suppressing substances preferentially adsorb to the surface of the artificial lipid membrane, inhibiting the adsorption of the bitter substance to the lipid membrane; (ii) bitterness suppressing substances, such as cyclodextrin, encapsulate the bitter substance, inhibiting its adsorption to the lipid membrane; and (iii) bitterness suppressing substances neutralize the charge of the bitter substance, inhibiting its adsorption to the lipid membrane (Uchida, Takahiro, "Construction of a bitterness evaluation system using a taste sensor and its application to formulation design," Pharmaceutical Science 2008.68(4);220-229).

[0034] Most of the bitterness suppressants of the present invention are classified into the above (i). Since substances with smaller molecular weights generally have a faster rate of adsorption to electrodes, it is believed that substances with smaller molecular weights than asenapine and higher affinity to electrodes are first adsorbed onto the artificial lipid membrane surface. It is also presumed that the presence of hydroxyl groups and sulfonyl groups in the bitterness suppressants of the present invention is related to the affinity to electrodes. As a result, it is believed that adsorption of asenapine to electrodes is hindered, CPA is reduced, and the bitterness suppression effect is exerted.

[0035] In addition, the bitterness suppression effect of asenapine on aspartame, which is known as a sweetener like sucrose, was evaluated using the taste sensor 1. The results are shown in Table 2.

[0036] [Table 2]

[0037] Aspartame did not have a bitterness-suppressing effect even at a concentration (5 mg / mL) where its sweetness was comparable to that of sucrose. This result indicates that not all sweet ingredients have a bitterness-suppressing effect on asenapine, and that the bitterness of asenapine is not simply masked by the sweetness.

[0038] Example 3: Validity of evaluation of bitterness and bitterness suppression effect by taste sensor 1 Since it is ethically difficult to carry out a taste sensory test on humans with asenapine, the bitterness and bitterness suppression effect of asenapine in Example 2 were evaluated using the taste sensor 1. Therefore, in order to confirm the validity of the evaluation, verification was carried out with reference to information on Medcaine (trade name) oral jelly (package insert, created in January 2012 (1st edition)), which contains lidocaine hydrochloride (hereinafter, lidocaine), known as a bitter drug, and is sold as an oral surface anesthetic with suppressed bitterness.

[0039] First, to evaluate the responsiveness of taste sensor 1 to the bitterness of lidocaine, a solution containing 0 to 3 mg / mL lidocaine (FUJIFILM Wako Pure Chemical Industries, Ltd.) was measured with taste sensor 1. The results are shown in Figure 3. As the lidocaine concentration increased, the CPA increased, confirming that taste sensor 1 responded to the bitterness of lidocaine.

[0040] Next, it has been reported that the bitterness of lidocaine is suppressed by citric acid (see JP 2011-074090 A). To verify this, a 1 mg / mL lidocaine solution (CPA = 21.4 mV) in which the CPA of the taste sensor 1 was in the good response range of 20 to 50 mV was added with citric acid (JP, Merck Whey) at concentrations of 2.5 mg / mL and 10 mg / mL, and the sample solution was measured with the taste sensor 1. The results are shown in Table 2. The CPA decreased with increasing concentration of added citric acid, and the CPA when 2.5 mg / mL or 10 mg / mL citric acid was added was reduced by approximately 94% and approximately 88%, respectively, compared to the CPA when no citric acid was added. From these results, it was confirmed that the taste sensor 1 can verify the phenomenon of bitterness suppression by bitterness suppressing substances.

[0041] [Table 3]

[0042] The above verification confirmed the validity of the evaluation of bitterness and bitterness suppression effect by the taste sensor 1.

[0043] Example 4: Verification that bitterness suppressants are specific to bitterness-causing substances In order to verify that the bitterness suppressant found in asenapine is unique to asenapine, saccharin sodium was used as an example, and the bitterness suppression effect of asenapine and lidocaine was evaluated by the taste sensor 1. The results are shown in Table 3. When saccharin was added to asenapine, the change rate became a negative value, and the bitterness suppression effect was observed, whereas when saccharin was added to lidocaine, the change rate became a positive value, and the bitterness was enhanced. From this, it was verified that the bitterness suppressant is not effective against all bitterness-causing substances, but is unique depending on the bitterness-causing substance (drug), and the bitterness suppressant that was found to be effective by the taste sensor 1 was a substance that was particularly effective against asenapine. In addition, just as aspartame was not effective against asenapine, saccharin was not effective against lidocaine, so this result also verified that the bitterness was not suppressed by sweetness.

[0044] [Table 4]

[0045] Example 5: Evaluation of the bitterness of asenapine using a taste sensor (2) In Example 5, a taste sensor different from taste sensor 1 was used to evaluate the bitterness of asenapine under concentration conditions close to those observed when the drug is actually taken.

[0046] (1) Method A. Sample The same sample as described in Example 1(1)A was used.

[0047] B. Equipment used The taste sensor used was the electronic taste system ASTREE (V5, Alpha Moss Japan) (hereafter referred to as "Taste Sensor 2"). Taste Sensor 2 acquires response patterns from seven sensors with partial selectivity for AHS (sourness), CTS (saltiness), NMS (umami), PKS, CPS, ANS, and SCS, and can quantify tastes using a pattern recognition method (principal component analysis) associated with the processing function in the human brain. Taste Sensor 2 is composed of seven sensors, each coated with a different copolymer as a sensitive membrane on the base of a chemical field effect transistor (CHEMFET) that corresponds to the taste sensory organ, a reference electrode, and a computer (corresponding to signal processing in the brain). When a dissolved component comes into contact with the sensitive membrane of Taste Sensor 2, interactions such as ionic bonds, hydrogen bonds, and van der Waals forces are induced, and the change in potential difference between the sensor and the reference electrode (Ag / AgCl) is detected as a signal. The composition of the membrane determines the selectivity of the substance to which it responds, but by combining seven types of sensors that show different broad spectrums, it is possible to respond and distinguish differences in taste with high sensitivity, and many reports have been published on the bitterness of medicines (Yoshida Koichi, "Use of electronic nose and taste systems in drug development," Pharmaceutical Machinery Technology Research Association Journal 2011.20(2);87-91; Takahiro Uchida et al., "Bitterness prediction of H1-antihistamines and prediction of masking effects of artificial sweeteners using an electronic tongue," International Journal of Pharmaceutics.2013.441;121-127; Yoshida Koichi, "Usefulness of electronic taste and nose systems in pediatric drug development," Pharmaceutical Science 2015.75;48-53). Taste Sensor 2 also has a different characteristic from Taste Sensor 1 in that it can measure a wide range of sample concentrations and measurement programs.

[0048] (2) Results Asenapine solutions with concentrations (0 to 3.0 mg / mL (free form basis)) close to those actually taken were measured using the taste sensor 2, and the bitterness response of asenapine was evaluated. The results are shown in Table 5. The first principal component (PC1) value, which had the highest correlation among the sensor values ​​obtained from the principal component analysis using the seven types of sensors as explanatory variables, changed in the positive direction relative to water as the asenapine concentration increased. In addition, the distance of each asenapine solution from water (A0), which was obtained from the comprehensive analysis of the sensor values ​​from PC1 to PC7 (seventh principal component), became farther from water (A0) as the asenapine concentration increased. This was considered to be the result of the taste sensor 2 capturing the state in which the bitterness became stronger with the increase in asenapine concentration. From this result, it was confirmed that the bitterness of asenapine solutions became stronger in a concentration-dependent manner, even in asenapine solutions with concentrations exceeding 1.0 mg / mL, which were difficult to measure with the taste sensor 1, and close to those actually taken.

[0049] [Table 5]

[0050] Example 6: Evaluation of bitterness suppression of asenapine using taste sensor 2 (1) In Example 6, D-sorbitol, one of the active ingredients of a bitterness suppressant whose effectiveness was confirmed by measurements using taste sensor 1, was added to an asenapine solution at various concentrations, and the bitterness suppression effect of asenapine was evaluated using taste sensor 2. The asenapine concentration was set to 1.0 mg / mL, which is close to the concentration when actually taken.

[0051] The results are shown in Table 6. The higher the concentration of D-sorbitol, the smaller the value of PC1 was, and the distance from water (DW) also decreased as the concentration of D-sorbitol increased (the taste became closer to that of water). From these results, the bitterness suppression effect of D-sorbitol confirmed by taste sensor 1 was also confirmed by taste sensor 2, and it was also confirmed that D-sorbitol can suppress the bitterness even in asenapine solution with a concentration close to that when actually taken.

[0052] [Table 6]

[0053] Example 7: Evaluation of bitterness suppression of asenapine using taste sensor 2 (2) The taste sensor 2 has a wide range of adaptability for the program of the measurement sequence, and D-sorbitol, which is a substance that suppresses the bitterness of asenapine, and asenapine liquid can be evaluated consecutively as separate test liquids. Therefore, in Example 7, the sensor response values ​​were compared when the sensor was immersed in water before measuring asenapine liquid and when it was immersed in D-sorbitol before measuring asenapine liquid. The concentration of the asenapine liquid was 1.0 mg / mL, and the concentration of the D-sorbitol liquid, which was used as a separate test liquid, was 1000 mg / mL. The results are shown in Table 7. Compared to the case where the asenapine liquid was measured after being immersed in water, the PC1 value was smaller when the asenapine liquid was measured after being immersed in D-sorbitol liquid, and the distance to water was also closer (the taste is closer to water). From this result, it was considered that the bitterness of asenapine is suppressed even when D-sorbitol is used (for example, gargling) before taking asenapine.

[0054] [Table 7]

Claims

1. A bitterness suppressor for asenapine, comprising one or more active ingredients (excluding cyclodextrin and its derivatives) 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, wherein the polyol is an aliphatic polyol having 2 to 3 carbon atoms, a monosaccharide, a disaccharide, a monosaccharide or disaccharide sugar alcohol, a dextrin, a starch, a cellulose or a polyethylene glycol.

2. 2. The bitterness suppressor according to claim 1, wherein the aliphatic polyol having 2 to 3 carbon atoms is glycerin or propylene glycol.

3. The bitterness suppressor according to claim 1 , wherein the aliphatic hydroxy acid is citric acid, lactic acid, malic acid or tartaric acid.

4. 2. The bitterness suppressor according to claim 1, wherein the alkyl sulfate is sodium lauryl sulfate or ammonium lauryl sulfate.

5. A bitterness suppressant according to any one of claims 1 to 4, for use before, simultaneously with, or after taking an asenapine-containing composition.

6. A bitterness suppressant for use simultaneously with taking an asenapine-containing composition, the bitterness suppressant described in claim 5, wherein the active ingredient is incorporated into the asenapine-containing composition.

7. The bitterness suppressant according to claim 5 or 6, wherein the asenapine-containing composition is an oral mucosal absorption type preparation.

8. The bitterness suppressant according to claim 7, wherein the oral mucosal absorption type preparation is an orally disintegrating tablet, an orally disintegrating film, an oral patch, a sublingual tablet, a buccal tablet, a troche, a jelly or a spray.

9. A method for suppressing the bitterness of asenapine, comprising using the active ingredient described in claim 1, said active ingredient being used separately before taking an asenapine-containing composition.

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