Bitter taste inhibitor for pharmaceutically active compound and method for inhibiting bitter taste

Abstract

To suppress bitter taste of a pharmaceutically active compound while suppressing cost without requiring a complicated process and a plurality of additives.SOLUTION: The present invention provides a bitterness suppressor for a pharmaceutically active compound, comprising a cyclodextrin and / or a derivative thereof as an active ingredient, wherein the pharmaceutically active compound is any one selected from the group consisting of duloxetine hydrochloride, aripiprazole, atomoxetine hydrochloride, donepezil hydrochloride, and dorzolamide hydrochloride.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to an agent for suppressing the bitterness of a pharmaceutically active compound, a method for suppressing the bitterness of a pharmaceutically active compound, and a method for producing a composition containing the agent for suppressing the bitterness of a pharmaceutically active compound. [Background technology]

[0002] Pharmaceutically active compounds are administered via various routes, including oral, nasal, and transdermal routes. Among these, oral administration is an easy, convenient, non-invasive, and well-known drug delivery method. However, some pharmaceutical active compounds have an extremely unpleasant taste, such as bitterness. Conventional solid forms (e.g., tablets or capsules) are typically swallowed immediately after ingestion, making the bitter taste less noticeable. However, some patients are unable to tolerate the extremely unpleasant bitter taste and are unable to take the medication. For patients (e.g., children and elderly patients) who have difficulty administering conventional solid forms orally due to poor swallowing function or other reasons, liquid forms (e.g., solutions, suspensions, syrups, emulsions, or dry syrups mixed with water) or chewable or orally disintegrating tablets are prescribed. However, these formulations often expose bitter substances to the taste buds, resulting in a high level of bitterness.

[0003] Many prescription drugs commonly used in Japan, with sales of over 5 billion yen in Japan, contain bitter-tasting pharmaceutical active compounds as active ingredients. For example, atomoxetine hydrochloride, a drug used to treat attention-deficit hyperactivity disorder (ADHD), duloxetine hydrochloride, an antidepressant, donepezil hydrochloride, a drug used to treat Alzheimer's disease, aripiprazole, an antipsychotic, and dorzolamide hydrochloride, a drug used to treat glaucoma and ocular hypertension, are known to have a bitter taste. While it is important for patients to take their prescribed medications as directed, patients may be unable to tolerate the bitter taste of these pharmaceutical active compounds, potentially resulting in poor medication adherence and compliance.

[0004] Therefore, masking the bitterness of pharmaceutical active compounds is an important issue. Masking methods include adding sweeteners (sugar, artificial sweeteners, etc.) or flavorings (fruit, chocolate), or confining the bitterness by coating substances or microencapsulation. However, these methods have problems such as not being able to completely mask the bitterness, or the bitterness being felt when the compound dissolves in the mouth.

[0005] Patent Document 1 discloses a solid dosage formulation comprising a matrix, the matrix comprising a pharmaceutically effective amount of atomoxetine or a pharmaceutically acceptable salt thereof and a wax material, and describes that the taste of atomoxetine may be masked by a combination of a polymer and a suspension medium. Patent Document 2 discloses an orally disintegrating tablet comprising active ingredient particles containing an unpleasant-tasting drug and having a coating layer covering the drug, a wicking-type disintegrant, and a swelling-type disintegrant, and describes that the unpleasant-tasting drug may be donepezil hydrochloride, etc. Patent Document 3 discloses an oral fast-dissolving film comprising one or more water-soluble polymers, one or more pharmaceutically active ingredients, a stevioside-based sweetener as an aftertaste improver, and one or more first sweeteners as a taste blocker, and describes that the pharmaceutically active ingredient may be aripiprazole, donepezil, etc. [Prior art documents] [Patent documents]

[0006] [Patent Document 1] Special Publication No. 2007-517050 [Patent Document 2] Japanese Patent Application Laid-Open No. 2013-147470 [Patent Document 3] Special Publication No. 2012-528854 Summary of the Invention [Problem to be solved by the invention]

[0007] Conventional bitterness suppression technologies require complex processes and multiple additives to suppress the bitterness of pharmaceutical active compounds, resulting in high costs. Furthermore, they have not been able to adequately mask the bitterness in dosage forms where bitterness is easily felt, such as chewable tablets, orally disintegrating tablets, or liquid formulations (including liquids made by mixing dry syrup with water).

[0008] In view of the above-mentioned current situation, an object of the present invention is to suppress the bitterness of a pharmaceutically active compound without requiring complicated processes or multiple additives, while keeping costs down. Another object of the present invention is to provide a composition containing a pharmaceutically active compound that is less likely to taste bitter, even when taken in a dosage form that is normally more likely to taste bitter. [Means for solving the problem]

[0009] As a result of extensive research aimed at solving the above problems, the present inventors have found that the bitterness of a pharmaceutically active compound can be reduced by using cyclodextrin as a bitterness suppressor for the compound. The present invention is based on this finding. According to the present invention, the following inventions are provided. [1] A bitterness suppressant for a pharmaceutically active compound, comprising cyclodextrin and / or a derivative thereof as an active ingredient, wherein the pharmaceutically active compound is any one selected from the group consisting of duloxetine hydrochloride, aripiprazole, atomoxetine hydrochloride, donepezil hydrochloride, and dorzolamide hydrochloride. [2] The bitterness suppressant according to [1], wherein 0.5 moles or more of cyclodextrin and / or its derivatives are used per mole of the pharmaceutically active compound. [3] The bitterness suppressant according to [1] or [2], wherein 10 moles or more of cyclodextrin and / or its derivative are used per mole of the pharmaceutically active compound. [4] The bitterness suppressor according to any one of [1] to [3], wherein the cyclodextrin and / or its derivative is β-cyclodextrin.

[0010] [5] A method for suppressing the bitterness of a pharmaceutically active compound, comprising the step of mixing a pharmaceutically active compound with cyclodextrin and / or a derivative thereof in a solvent, wherein the cyclodextrin and / or derivative thereof is 0.5 moles or more per mole of the pharmaceutically active compound, and the pharmaceutically active compound is any one selected from the group consisting of duloxetine hydrochloride, aripiprazole, atomoxetine hydrochloride, donepezil hydrochloride, and dorzolamide hydrochloride. [6] The method for suppressing bitterness according to [5], wherein the cyclodextrin and / or its derivative is β-cyclodextrin. [7] A method for producing a pharmaceutically active compound-containing composition, comprising the step of mixing a pharmaceutically active compound with cyclodextrin and / or a derivative thereof in a solvent to obtain a pharmaceutically active compound-containing solution with reduced bitterness, wherein the cyclodextrin and / or derivative thereof is 0.5 moles or more per mole of the pharmaceutically active compound, and the pharmaceutically active compound is any one selected from the group consisting of duloxetine hydrochloride, aripiprazole, atomoxetine hydrochloride, donepezil hydrochloride, and dorzolamide hydrochloride. [8] The method according to [7], wherein the cyclodextrin and / or its derivative is β-cyclodextrin. [9] The method for producing the composition containing the pharmaceutically active compound according to [7] or [8], wherein the composition is a liquid formulation for oral administration. [Effects of the Invention]

[0011] By using cyclodextrin and / or its derivatives, the bitter taste of pharmaceutically active compounds can be reduced. DETAILED DESCRIPTION OF THE INVENTION

[0012] The following description of the present invention may be based on representative embodiments and specific examples, but the present invention is not limited to such embodiments. In this specification, a numerical range expressed using "to" means a range that includes the numerical values ​​before and after "to" as the lower and upper limits.

[0013] The present invention provides a bitterness suppressant for a pharmaceutically active compound, comprising cyclodextrin and / or a derivative thereof as an active ingredient, wherein the pharmaceutically active compound is any one selected from the group consisting of duloxetine hydrochloride, aripiprazole, atomoxetine hydrochloride, donepezil hydrochloride, and dorzolamide hydrochloride.

[0014] Cyclodextrin (sometimes referred to as "CD" in this specification), also known as cyclic oligosaccharide, is a cyclic α-1,4-glucan that is produced by the intramolecular transfer reaction of α-1,4-glucan such as starch with cyclodextrin glucanotransferase. The degrees of polymerization are mainly 6, 7, and 8, and are called α-CD, β-CD, and γ-CD, respectively.

[0015] In the present invention, "bitterness" collectively refers to unpleasant sensations, including bitterness and astringency, felt in the oral cavity or pharynx. As used herein, "suppressing bitterness" and "bitterness suppression" refer to the suppression, reduction, concealment, or masking of the bitterness felt when a bitter substance is present in the oral cavity, and may include the suppression, reduction, concealment, or masking of unpleasant sensations, including bitterness and astringency, together with the bitterness. "Suppression" refers to a slight reduction in the "bitterness" felt in the oral cavity when the "bitterness suppressant" is used compared to when it is not used, and may include cases where no bitterness is felt at all or where some bitterness is felt but is tolerable to the patient. The bitterness suppressant of the present invention contains cyclodextrin and / or a derivative thereof as an active ingredient and can suppress the bitterness of a pharmaceutically active compound selected from the group consisting of duloxetine hydrochloride, aripiprazole, atomoxetine hydrochloride, donepezil hydrochloride, and dorzolamide hydrochloride.

[0016] The cyclodextrin derivatives of the present invention include those having, as a substituent, a hydroxyalkyl group having 2 to 4 carbon atoms, those having an alkyl group having 1 to 2 carbon atoms, and those having a sugar group consisting of 1 to 2 residues.Specific examples include hydroxypropylated CD, hydroxybutylated CD, methylated CD, and maltosylated CD (branched CD).The cyclodextrin and / or its derivative, which is the active ingredient of the bitterness suppressor of the present invention, can be hydroxypropylated β-CD.This is because hydroxypropylated β-CD has high solubility in water.

[0017] From a three-dimensional perspective, cyclodextrins have a bottomless bucket-like or doughnut-like structure, characterized by the fact that the exterior of the cavity is hydrophilic, while the interior of the cavity is hydrophobic. This characteristic allows CDs to enclose specific organic molecules (guest molecules) in the cavity, forming inclusion complexes. In general, the inclusion of guest molecules by CDs can occur when the size of the cyclodextrin cavity matches the size of the guest molecule or the size of a portion of the guest molecule's structure. Furthermore, because the interior of the CD cavity is hydrophobic, guest molecules tend to be more easily included if they are hydrophobic.

[0018] Among cyclodextrins, β-CD is the most commonly used due to its large production volume and low cost. However, compared to α-CD and γ-CD, β-CD has low water solubility, making it unsuitable for solubilization. To improve its water solubility, derivatives such as hydroxypropylated β-CD and methylated β-CD have been developed. γ-CD has the largest cavity of the three CDs and is highly soluble in water. Because α-CD has a smaller cavity diameter than β-CD and γ-CD, it is thought that smaller guest molecules are included compared to β-CD and γ-CD.

[0019] The inclusion effect may be observed even when the entire guest molecule is significantly larger than cyclodextrin; it is believed that the inclusion effect can be achieved even if the guest molecule only partially fits into the cavity of the host CD. The inclusion ability of CDs is affected by the chemical interactions between the host CD and the guest molecule. Interactions between the host CD and the guest molecule include hydrophobic interactions, van der Waals forces, ion-ion interactions, dipole-dipole interactions, and hydrogen bonds, and these interactions are thought to function cooperatively. While the present invention is not bound by any particular theory, it is believed that multiple CDs and / or their derivatives act on a single pharmaceutically active compound molecule, and that interactions other than inclusion exist between the CDs and / or their derivatives and the pharmaceutically active compound molecule.

[0020] The CD and / or its derivatives used in the present invention may be in the form of a crystalline product, amorphous powder, syrup, etc. In addition to CD and / or its derivatives, products containing by-products from the production or preparation process, such as maltooligosaccharides and other carbohydrates, may also be used.

[0021] (Suppression of the bitterness of duloxetine hydrochloride) Duloxetine hydrochloride, whose chemical name is (+)-(S)-N-methyl-3-(1-naphthyloxy)-3-(2-thienyl)propylamine monohydrochloride, is a serotonin and norepinephrine reuptake inhibitor that is useful for treating depression and depressive states, pain associated with diabetic neuropathy, pain associated with fibromyalgia, pain associated with chronic low back pain, and pain associated with osteoarthritis. It is a compound with the following structural formula: [ka]

[0022] The present invention provides an agent for suppressing the bitterness of duloxetine hydrochloride, which comprises cyclodextrin and / or a derivative thereof as an active ingredient.

[0023] When suppressing the bitterness of duloxetine hydrochloride, the bitterness suppressant of the present invention can use 0.1 moles or more, 0.2 moles or more, 0.5 moles or more, 1 mole or more, 2 moles or more, 3 moles or more, 4 moles or more, 5 moles or more, 10 moles or more, 20 moles or more, 21 moles or more, 22 moles or more, 23 moles or more, 24 moles or more, 25 moles or more, 26 moles or more, 27 moles or more, 28 moles or more, 29 moles or more, 30 moles or more, 40 moles or more, or 50 moles or more of cyclodextrin and / or a derivative thereof per 0.5 moles or more or 1 mole of duloxetine hydrochloride.

[0024] In one embodiment, the bitterness suppressor of the present invention uses 2 to 50 moles of cyclodextrin and / or a derivative thereof per mole of duloxetine hydrochloride. This is because using 2 or more moles of cyclodextrin and / or a derivative thereof per mole of duloxetine hydrochloride reduces the bitterness of duloxetine hydrochloride to an acceptable level. Furthermore, adding 50 or fewer moles of cyclodextrin and / or a derivative thereof per mole of duloxetine hydrochloride reduces costs and does not occupy much space when dried.

[0025] In a preferred embodiment, the bitterness suppressor of the present invention uses 5 to 40 moles of β-cyclodextrin and / or a derivative thereof per mole of duloxetine hydrochloride, because the bitterness of duloxetine hydrochloride is significantly suppressed by using 5 moles or more of β-cyclodextrin and / or a derivative thereof per mole of duloxetine hydrochloride, compared to the case where 5 moles or more of α- or γ-cyclodextrin and / or a derivative thereof is used.

[0026] In another preferred embodiment of the bitterness suppressor of the present invention, 10 to 40 moles of β-cyclodextrin and / or a derivative thereof are used per mole of duloxetine hydrochloride. This is because using 10 moles or more of β-cyclodextrin and / or a derivative thereof per mole of duloxetine hydrochloride significantly suppresses the bitterness of duloxetine hydrochloride compared to using 10 moles or more of α- or γ-cyclodextrin and / or a derivative thereof. Furthermore, adding 40 moles or less of cyclodextrin and / or a derivative thereof per mole of duloxetine hydrochloride reduces costs and does not take up much space when dried.

[0027] The cyclodextrin and / or its derivative, which is the active ingredient of the bitterness suppressor of the present invention, is not limited to any particular type, but β-CD and / or its derivative are particularly preferred because β-CD and / or its derivative are highly effective in suppressing the bitterness of duloxetine hydrochloride. In a preferred embodiment, the cyclodextrin and / or its derivative, which is the active ingredient of the bitterness suppressor of the present invention, is β-CD or HP-β-CD.

[0028] The bitterness suppressant of duloxetine hydrochloride provided by the present invention can be mixed with duloxetine hydrochloride in a solvent containing water, because the inclusion action of CD or its derivative occurs in the state of an aqueous solution of CD or its derivative.

[0029] The present invention provides a method for suppressing the bitterness of duloxetine hydrochloride, which comprises the step of mixing duloxetine hydrochloride with cyclodextrin and / or a derivative thereof in a solvent, wherein the amount of cyclodextrin and / or a derivative thereof is 0.5 moles or more per mole of duloxetine hydrochloride.

[0030] The step of mixing duloxetine hydrochloride with cyclodextrin and / or its derivative in a solvent can be carried out by dissolving duloxetine hydrochloride and cyclodextrin and / or its derivative in the solvent. Either duloxetine hydrochloride or cyclodextrin and / or its derivative may be added to the solvent first, or they may be added simultaneously. Alternatively, the duloxetine hydrochloride solution can be prepared by adding CD in powder or solution form to a duloxetine hydrochloride solution prepared by dissolving duloxetine hydrochloride in a solvent and stirring. The solvent can be selected from sterilized water, purified water, monohydric alcohols such as ethanol, polyhydric alcohols such as glycerol, and mixtures thereof. To increase the solubility of duloxetine hydrochloride, duloxetine hydrochloride can be first dissolved in an organic solvent such as ethanol, polyethylene glycol, or glycerin, and then mixed with water. To increase the solubility of CD, the solvent containing duloxetine hydrochloride, CD, and / or its derivative can be heated and stirred. When heating and stirring, the solvent can be heated to a temperature of 60 to 85°C, for example.

[0031] In the method for suppressing bitterness of the present invention, 0.5 moles or more, 1 mole or more, 2 moles or more, 3 moles or more, 4 moles or more, 5 moles or more, 10 moles or more, 20 moles or more, 21 moles or more, 22 moles or more, 23 moles or more, 24 moles or more, 25 moles or more, 26 moles or more, 27 moles or more, 28 moles or more, 29 moles or more, 30 moles or more, or 40 moles or more of cyclodextrin and / or a derivative thereof can be mixed with 1 mole of duloxetine hydrochloride. In one embodiment, the amount of cyclodextrin and / or a derivative thereof can be 2 to 50 moles per mole of duloxetine hydrochloride. In another embodiment, the amount of cyclodextrin and / or a derivative thereof can be 10 to 40 moles per mole of duloxetine hydrochloride.

[0032] The cyclodextrin and / or its derivatives used in the bitterness suppression method of the present invention are not particularly limited, but β-CD and / or its derivatives are particularly preferred because they are highly effective in suppressing the bitterness of duloxetine hydrochloride. The β-CD derivative is preferably HP-β-CD.

[0033] In a preferred embodiment of the method for suppressing bitterness of the present invention, 5 to 50 moles of β-cyclodextrin and / or a derivative thereof can be used per mole of duloxetine hydrochloride, because the bitterness of duloxetine hydrochloride is significantly suppressed by using 5 moles or more of β-cyclodextrin and / or a derivative thereof per mole of duloxetine hydrochloride, compared to the case where 5 moles or more of α- or γ-cyclodextrin and / or a derivative thereof is used.

[0034] In another preferred embodiment of the method for suppressing bitterness of the present invention, 10 to 40 moles of β-cyclodextrin and / or a derivative thereof can be used per mole of duloxetine hydrochloride, because the bitterness of duloxetine hydrochloride is significantly suppressed by using 10 moles or more of β-cyclodextrin and / or a derivative thereof per mole of duloxetine hydrochloride, compared to the case where 10 moles or more of α- or γ-cyclodextrin and / or a derivative thereof is used.

[0035] The duloxetine hydrochloride solution having reduced bitterness according to the present invention can be powdered through a drying process such as freeze-drying or spray-drying.

[0036] Regarding the method for suppressing the bitterness of duloxetine hydrochloride provided by the present invention, evaluation of bitterness suppression can be carried out by a sensory evaluation test by a panel and / or instrumental measurement (taste recognition device, taste sensor). Regarding bitterness masking, the results of the sensory test are highly correlated with the output of a taste sensor, and it has been shown that a taste sensor can detect bitterness masking (Ono et al. Journal of Pharmaceutical Sciences 100:1935-1943, 2011).

[0037] The present invention provides a method for producing a duloxetine hydrochloride-containing pharmaceutical composition, which comprises the step of mixing duloxetine hydrochloride with β-cyclodextrin and / or a derivative thereof in a solvent to obtain a duloxetine hydrochloride-containing solution with reduced bitterness, wherein the amount of β-cyclodextrin and / or a derivative thereof is 0.5 moles or more per mole of duloxetine hydrochloride.

[0038] The step of mixing duloxetine hydrochloride with β-cyclodextrin and / or a derivative thereof in a solvent to obtain a duloxetine hydrochloride-containing solution with reduced bitterness can be carried out in the same manner as in the above-mentioned method for suppressing the bitterness of duloxetine hydrochloride, and the same solvent can be used.

[0039] In the method for producing a pharmaceutical composition provided by the present invention, duloxetine hydrochloride and cyclodextrin and / or a derivative thereof can be used in the same molar ratio as in the method for suppressing the bitterness of duloxetine hydrochloride described above.

[0040] In addition to CD, the duloxetine hydrochloride-containing pharmaceutical composition prepared by the method of the present invention may contain pharmaceutically acceptable additives as needed. Pharmaceutically acceptable additives include, but are not limited to, pH adjusters, stabilizers, excipients, disintegrants, binders, coating agents, swelling agents, glidants, lubricants, flavorings, sweeteners, or solubilizers. More specifically, pharmaceutically acceptable additives include magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, talc, lactalbumin, gelatin, starch, cellulose and its derivatives, animal and vegetable oils, and polyethylene glycol. The pharmaceutical composition prepared by the method of the present invention may be used in any form, such as granules, powders, coated tablets, microcapsules, syrups, dry syrups, elixirs, suspensions, emulsions, or drops.

[0041] The pharmaceutical composition containing duloxetine hydrochloride produced by the production method of the present invention can be used as a therapeutic or preventive agent for subjects suffering from or suspected of suffering from a disease for which duloxetine hydrochloride has a therapeutic and / or preventive effect. Specifically, it can be used to treat depression / depressive state, pain associated with diabetic neuropathy, pain associated with fibromyalgia, pain associated with chronic lower back pain, and pain associated with osteoarthritis. The subject of administration is mammals, including humans.

[0042] In one embodiment, the pharmaceutical composition produced by the production method of the present invention can be an oral liquid formulation. While the present invention is not bound by any particular theory, it is believed that in the production method of the present invention, CD acts on the duloxetine hydrochloride molecule itself to mask its bitterness. Therefore, the bitterness is suppressed even in liquid form, and patients do not perceive the bitterness of the oral liquid formulation. Oral liquid formulations also facilitate dosage adjustment. Therefore, one embodiment of the present invention provides an oral liquid formulation containing duloxetine hydrochloride that can be administered to patients with impaired swallowing ability and is suitable for careful administration to elderly patients due to its easy dosage adjustment. The clinical dose of duloxetine hydrochloride is 20 mg to 60 mg per day in duloxetine equivalents (oral administration once daily). Because a lower dose is easier for elderly people and patients with swallowing disorders to administer, the concentration of duloxetine hydrochloride in the oral liquid formulation is preferably at least 1.1 mg / mL (1 mg / mL in duloxetine equivalents).

[0043] (Suppressing the bitterness of aripiprazole) Aripiprazole, whose chemical name is 7-[4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy]-3,4-dihydro-2(1H)-quinolinone, is useful for treating schizophrenia. It has the following structural formula: [ka]

[0044] The present invention provides an agent for suppressing the bitterness of aripiprazole, which comprises cyclodextrin and / or a derivative thereof as an active ingredient.

[0045] When suppressing the bitterness of aripiprazole, the bitterness suppressant of the present invention can use 0.2 moles or more, 0.5 moles or more, 1 mole or more, 2 moles or more, 3 moles or more, 4 moles or more, 5 moles or more, 10 moles or more, 20 moles or more, 21 moles or more, 22 moles or more, 23 moles or more, 24 moles or more, 25 moles or more, 26 moles or more, 27 moles or more, 28 moles or more, 29 moles or more, 30 moles or more, 40 moles or more, or 50 moles or more of cyclodextrin and / or a derivative thereof per mole of aripiprazole.

[0046] In one embodiment, the bitterness suppressant of the present invention uses 2 to 50 moles of cyclodextrin and / or its derivatives per mole of aripiprazole. This is because using 2 moles or more of cyclodextrin and / or its derivatives per mole of aripiprazole reduces the bitterness of aripiprazole to an acceptable level. Furthermore, adding 50 moles or less of cyclodextrin and / or its derivatives per mole of aripiprazole reduces costs and does not take up much space when dried.

[0047] In a preferred embodiment, the bitterness suppressor of the present invention uses 5 to 40 moles of β-cyclodextrin and / or a derivative thereof per mole of aripiprazole, because the bitterness of aripiprazole is significantly suppressed by using 5 moles or more of β-cyclodextrin and / or a derivative thereof per mole of aripiprazole compared to the case where 5 moles or more of α- or γ-cyclodextrin and / or a derivative thereof is used.

[0048] In another preferred embodiment, the bitterness suppressor of the present invention uses 10 to 40 moles of β-cyclodextrin and / or its derivatives per mole of aripiprazole. The bitterness of aripiprazole is significantly suppressed by using 10 moles or more of β-cyclodextrin and / or its derivatives per mole of aripiprazole, compared to using 10 moles or more of α- or γ-cyclodextrin and / or its derivatives. Furthermore, adding 40 moles or less of cyclodextrin and / or its derivatives per mole of aripiprazole reduces costs and does not take up much space when dried.

[0049] The cyclodextrin and / or its derivative, which is the active ingredient of the bitterness suppressor of the present invention, is not limited to any particular type, but β-CD and / or its derivative are particularly preferred because β-CD and / or its derivative are highly effective in suppressing the bitterness of aripiprazole. In a preferred embodiment, the cyclodextrin and / or its derivative, which is the active ingredient of the bitterness suppressor of the present invention, is β-CD.

[0050] The agent for suppressing the bitterness of aripiprazole provided by the present invention can be mixed with aripiprazole in a solvent containing water, because the inclusion action of CD or its derivative occurs in the state of an aqueous solution of CD or its derivative.

[0051] The present invention provides a method for reducing the bitterness of aripiprazole, which comprises mixing aripiprazole with cyclodextrin and / or a derivative thereof in a solvent, wherein the amount of cyclodextrin and / or a derivative thereof is 0.2 moles or more per mole of aripiprazole.

[0052] The step of mixing aripiprazole and cyclodextrin and / or its derivative in a solvent can be carried out by dissolving aripiprazole and cyclodextrin and / or its derivative in the solvent. Aripiprazole and cyclodextrin and / or their derivatives can be added to the solvent first, or simultaneously. Alternatively, the aripiprazole solution can be prepared by adding CD in powder or solution form to a solvent containing aripiprazole and stirring. The solvent can be selected from sterilized water, purified water, monohydric alcohols such as ethanol, polyhydric alcohols such as glycerol, and mixtures thereof. To increase the solubility of aripiprazole, aripiprazole can be first dissolved in an organic solvent such as ethanol, polyethylene glycol, or glycerin, and then mixed with water. To increase the solubility of CD, the solvent containing aripiprazole, CD, and / or its derivative can be heated and stirred. When heating and stirring, the solvent can be heated to a temperature of, for example, 60 to 85°C.

[0053] In the method for suppressing bitterness of the present invention, 0.2 moles or more, 0.5 moles or more, 1 mole or more, 2 moles or more, 3 moles or more, 4 moles or more, 5 moles or more, 10 moles or more, 20 moles or more, 21 moles or more, 22 moles or more, 23 moles or more, 24 moles or more, 25 moles or more, 26 moles or more, 27 moles or more, 28 moles or more, 29 moles or more, 30 moles or more, or 40 moles or more of cyclodextrin and / or a derivative thereof can be mixed with 1 mole of aripiprazole. In one embodiment, the amount of cyclodextrin and / or a derivative thereof can be 2 to 50 moles per mole of aripiprazole. In another embodiment, the amount of cyclodextrin and / or a derivative thereof can be 10 to 40 moles per mole of aripiprazole.

[0054] The cyclodextrin and / or its derivatives used in the bitterness suppression method of the present invention are not particularly limited, but β-CD and / or its derivatives are particularly preferred because they are highly effective in suppressing the bitterness of aripiprazole.

[0055] In a preferred embodiment of the method for suppressing bitterness of the present invention, 2 to 50 moles of β-cyclodextrin and / or a derivative thereof can be used per mole of aripiprazole, because the bitterness of aripiprazole is significantly suppressed by using 2 moles or more of β-cyclodextrin and / or a derivative thereof per mole of aripiprazole, compared to the case where 2 moles or more of α- or γ-cyclodextrin and / or a derivative thereof is used.

[0056] In another preferred embodiment of the method for suppressing bitterness of the present invention, 10 to 40 moles of β-cyclodextrin and / or a derivative thereof can be used per mole of aripiprazole, because the bitterness of aripiprazole is significantly suppressed by using 10 moles or more of β-cyclodextrin and / or a derivative thereof per mole of aripiprazole, compared to the case where 10 moles or more of α- or γ-cyclodextrin and / or a derivative thereof is used.

[0057] The aripiprazole solution with reduced bitterness according to the present invention can be powdered through a drying process such as freeze-drying or spray-drying.

[0058] Regarding the method for suppressing the bitterness of aripiprazole provided by the present invention, the evaluation of bitterness suppression can be carried out by a sensory evaluation test by a panel and / or instrumental measurement (taste recognition device, taste sensor). Regarding bitterness masking, the results of the sensory test are highly correlated with the output of the taste sensor, and it has been shown that the taste sensor can detect bitterness masking (Ono et al. Journal of Pharmaceutical Sciences 100:1935-1943, 2011).

[0059] The present invention provides a method for producing an aripiprazole-containing pharmaceutical composition, which comprises the step of mixing aripiprazole with β-cyclodextrin and / or a derivative thereof in a solvent to obtain an aripiprazole-containing solution with reduced bitterness, wherein the amount of β-cyclodextrin and / or a derivative thereof is 0.2 moles or more per mole of aripiprazole.

[0060] The step of mixing aripiprazole with β-cyclodextrin and / or a derivative thereof in a solvent to obtain an aripiprazole-containing solution with reduced bitterness can be carried out in the same manner as in the above-mentioned method for suppressing the bitterness of aripiprazole, and the same solvent can be used.

[0061] In the method for producing a pharmaceutical composition provided by the present invention, aripiprazole and cyclodextrin and / or a derivative thereof can be used in the same molar ratio as in the above-mentioned method for suppressing the bitterness of aripiprazole.

[0062] The aripiprazole-containing pharmaceutical composition prepared by the method of the present invention may contain, in addition to CD, pharmaceutically acceptable additives as needed. Pharmaceutically acceptable additives include, but are not limited to, excipients, disintegrants, binders, coating agents, swelling agents, glidants, lubricants, flavorings, sweeteners, or solubilizers. More specifically, pharmaceutically acceptable additives include magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, talc, lactalbumin, gelatin, starch, cellulose and its derivatives, animal and vegetable oils, and polyethylene glycol. The pharmaceutical composition prepared by the method of the present invention may be used in any form, such as granules, powders, coated tablets, microcapsules, syrups, dry syrups, elixirs, suspensions, emulsions, or drops.

[0063] The aripiprazole-containing pharmaceutical composition prepared by the method of the present invention can be used as a therapeutic or preventive agent for subjects suffering from or suspected of suffering from a disease for which aripiprazole has a therapeutic and / or preventive effect. Specifically, it can be used to treat schizophrenia. The subjects to be administered are mammals, including humans.

[0064] In one embodiment, the pharmaceutical composition produced by the production method of the present invention can be an oral liquid formulation. While the present invention is not bound by any particular theory, it is believed that in the production method of the present invention, CD acts on the aripiprazole molecule itself to mask its bitterness, suppressing the bitterness even in liquid form, and patients are less likely to perceive the bitterness of the oral liquid formulation. Oral liquid formulations also facilitate dosage adjustment. Therefore, one embodiment of the present invention provides an aripiprazole-containing oral liquid formulation that can be administered to patients with impaired swallowing ability and is suitable for careful administration to elderly people because the dosage can be easily adjusted. The clinical dose of aripiprazole is 6 mg to 24 mg per day (administered orally once daily or in divided doses twice daily). Because a lower dose is easier for elderly people and patients with swallowing disorders to administer, the aripiprazole concentration in the oral liquid formulation is preferably at least 1.0 mg / mL.

[0065] (Reducing the bitterness of atomoxetine hydrochloride) Atomoxetine hydrochloride, whose chemical name is (3R)-N-methyl-3-(2-methylphenoxy)-3-phenylpropan-1-amine monohydrochloride, is useful for treating attention-deficit / hyperactivity disorder. It has the following structural formula: [ka]

[0066] The present invention provides an agent for suppressing the bitterness of atomoxetine hydrochloride, which comprises cyclodextrin and / or a derivative thereof as an active ingredient.

[0067] When suppressing the bitterness of atomoxetine hydrochloride, the bitterness suppressant of the present invention can use 1 mole or more, 2 moles or more, 3 moles or more, 4 moles or more, 5 moles or more, 10 moles or more, 20 moles or more, 21 moles or more, 22 moles or more, 23 moles or more, 24 moles or more, 25 moles or more, 26 moles or more, 27 moles or more, 28 moles or more, 29 moles or more, 30 moles or more, 40 moles or more, or 50 moles or more of cyclodextrin and / or a derivative thereof per mole of atomoxetine hydrochloride.

[0068] In one embodiment, the bitterness suppressant of the present invention uses 5 to 50 moles of cyclodextrin and / or a derivative thereof per mole of atomoxetine hydrochloride. This is because using 5 moles or more of cyclodextrin and / or a derivative thereof per mole of atomoxetine hydrochloride reduces the bitterness of atomoxetine hydrochloride to an acceptable level. Furthermore, adding 50 moles or less of cyclodextrin and / or a derivative thereof per mole of atomoxetine hydrochloride reduces costs and does not take up much space when dried as a mixture of atomoxetine hydrochloride and cyclodextrin and / or a derivative thereof.

[0069] In a preferred embodiment, the bitterness suppressor of the present invention uses 5 to 40 moles of β-cyclodextrin and / or a derivative thereof per mole of atomoxetine hydrochloride, because the bitterness of atomoxetine hydrochloride is significantly suppressed by using 5 moles or more of β-cyclodextrin and / or a derivative thereof per mole of atomoxetine hydrochloride, compared to the case where 5 moles or more of α- or γ-cyclodextrin and / or a derivative thereof is used.

[0070] In another preferred embodiment of the bitterness suppressant of the present invention, 10 to 40 moles of β-cyclodextrin and / or a derivative thereof are used per mole of atomoxetine hydrochloride. This is because using 10 moles or more of β-cyclodextrin and / or a derivative thereof per mole of atomoxetine hydrochloride significantly suppresses the bitterness of atomoxetine hydrochloride compared to using 10 moles or more of α- or γ-cyclodextrin and / or a derivative thereof. Furthermore, adding 40 moles or less of cyclodextrin and / or a derivative thereof per mole of atomoxetine hydrochloride reduces costs and does not take up much space when dried.

[0071] The cyclodextrin and / or its derivative, which is the active ingredient of the bitterness suppressor of the present invention, is not limited to any particular type, but β-CD and / or its derivative are particularly preferred because β-CD and / or its derivative are highly effective in suppressing the bitterness of atomoxetine hydrochloride. In a preferred embodiment, the cyclodextrin and / or its derivative, which is the active ingredient of the bitterness suppressor of the present invention, is β-CD.

[0072] The agent for suppressing the bitterness of atomoxetine hydrochloride provided by the present invention can be mixed with atomoxetine hydrochloride in a solvent containing water, because the inclusion action of CD or a derivative thereof occurs in the state of an aqueous solution of CD or a derivative thereof.

[0073] The present invention provides a method for suppressing the bitterness of atomoxetine hydrochloride, which comprises a step of mixing atomoxetine hydrochloride with cyclodextrin and / or a derivative thereof in a solvent, wherein the amount of cyclodextrin and / or a derivative thereof is 1 mole or more per mole of atomoxetine hydrochloride.

[0074] The step of mixing atomoxetine hydrochloride with cyclodextrin and / or its derivative in a solvent can be carried out by dissolving atomoxetine hydrochloride and cyclodextrin and / or its derivative in the solvent. Either atomoxetine hydrochloride or cyclodextrin and / or its derivative may be added to the solvent first, or they may be added simultaneously. Alternatively, the atomoxetine hydrochloride solution can be prepared by adding CD in powder form or as a solution to a solvent containing atomoxetine hydrochloride, followed by stirring. The solvent can be selected from sterilized water, purified water, monohydric alcohols such as ethanol, polyhydric alcohols such as glycerol, and mixtures thereof. To increase the solubility of atomoxetine hydrochloride, atomoxetine hydrochloride can be first dissolved in an organic solvent such as ethanol, polyethylene glycol, or glycerin, and then mixed with water. To increase the solubility of CD, the solvent containing atomoxetine hydrochloride, CD, and / or its derivative can be heated and stirred. When heating and stirring, the solvent can be heated to a temperature of 60 to 85°C, for example.

[0075] In the method for suppressing bitterness of the present invention, 1 mole or more, 2 moles or more, 3 moles or more, 4 moles or more, 5 moles or more, 10 moles or more, 20 moles or more, 21 moles or more, 22 moles or more, 23 moles or more, 24 moles or more, 25 moles or more, 26 moles or more, 27 moles or more, 28 moles or more, 29 moles or more, 30 moles or more, or 40 moles or more of cyclodextrin and / or a derivative thereof can be mixed with 1 mole of atomoxetine hydrochloride. In one embodiment, the amount of cyclodextrin and / or a derivative thereof can be 5 to 50 moles per mole of atomoxetine hydrochloride. In another embodiment, the amount of cyclodextrin and / or a derivative thereof can be 10 to 40 moles per mole of atomoxetine hydrochloride.

[0076] The cyclodextrin and / or its derivatives used in the bitterness suppression method of the present invention are not particularly limited, but β-CD and / or its derivatives are particularly preferred because β-CD and / or its derivatives are highly effective in suppressing the bitterness of atomoxetine hydrochloride.

[0077] In a preferred embodiment of the method for suppressing bitterness of the present invention, 5 to 50 moles of β-cyclodextrin and / or a derivative thereof can be used per mole of atomoxetine hydrochloride, because the bitterness of atomoxetine hydrochloride is significantly suppressed by using 5 moles or more of β-cyclodextrin and / or a derivative thereof per mole of atomoxetine hydrochloride, compared to the case where 5 moles or more of α- or γ-cyclodextrin and / or a derivative thereof is used.

[0078] In another preferred embodiment of the method for suppressing bitterness of the present invention, 10 to 40 moles of β-cyclodextrin and / or a derivative thereof can be used per mole of atomoxetine hydrochloride, because the bitterness of atomoxetine hydrochloride is significantly suppressed by using 10 moles or more of β-cyclodextrin and / or a derivative thereof per mole of atomoxetine hydrochloride, compared to the case where 10 moles or more of α- or γ-cyclodextrin and / or a derivative thereof is used.

[0079] The atomoxetine hydrochloride solution having reduced bitterness according to the present invention can be powdered through a drying process such as freeze-drying or spray-drying.

[0080] Regarding the method for suppressing the bitterness of atomoxetine hydrochloride provided by the present invention, the suppression of bitterness can be evaluated by a sensory evaluation test by a panel and / or instrumental measurement (a taste recognition device, a taste sensor). Regarding bitterness masking, the results of the sensory test are highly correlated with the output of a taste sensor, and it has been shown that a taste sensor can detect bitterness masking (Ono et al. Journal of Pharmaceutical Sciences 100:1935-1943, 2011).

[0081] The present invention provides a method for producing a pharmaceutical composition containing atomoxetine hydrochloride, which comprises the step of mixing atomoxetine hydrochloride with β-cyclodextrin and / or a derivative thereof in a solvent to obtain a solution containing atomoxetine hydrochloride with reduced bitterness, wherein the amount of β-cyclodextrin and / or a derivative thereof is 1 mole or more per mole of atomoxetine hydrochloride.

[0082] The step of mixing atomoxetine hydrochloride with β-cyclodextrin and / or a derivative thereof in a solvent to obtain an atomoxetine hydrochloride-containing solution with reduced bitterness can be carried out in the same manner as in the above-mentioned method for suppressing the bitterness of atomoxetine hydrochloride, and the same solvent can be used.

[0083] In the method for producing a pharmaceutical composition provided by the present invention, atomoxetine hydrochloride and cyclodextrin and / or a derivative thereof can be used in the same molar ratio as in the method for suppressing the bitterness of atomoxetine hydrochloride described above.

[0084] The atomoxetine hydrochloride-containing pharmaceutical composition prepared by the method of the present invention may contain, in addition to CD, pharmaceutically acceptable additives as needed. Pharmaceutically acceptable additives include, but are not limited to, excipients, disintegrants, binders, coating agents, swelling agents, glidants, lubricants, flavorings, sweeteners, or solubilizers. More specifically, pharmaceutically acceptable additives include magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, talc, lactalbumin, gelatin, starch, cellulose and its derivatives, animal and vegetable oils, and polyethylene glycol. The pharmaceutical composition prepared by the method of the present invention may be used in any form, such as granules, powders, coated tablets, microcapsules, syrups, dry syrups, elixirs, suspensions, emulsions, or drops.

[0085] The atomoxetine hydrochloride-containing pharmaceutical composition produced by the production method of the present invention can be used as a therapeutic or preventive agent for subjects suffering from or suspected of suffering from a disease for which atomoxetine hydrochloride has a therapeutic and / or preventive effect. Specifically, it can be used to treat attention-deficit / hyperactivity disorder. The subjects to be administered are mammals, including humans.

[0086] In one embodiment, the pharmaceutical composition produced by the production method of the present invention can be an oral liquid formulation. While the present invention is not bound by any particular theory, it is believed that in the production method of the present invention, CD acts on the atomoxetine hydrochloride molecule itself to mask its bitterness. Therefore, the bitterness is suppressed even in liquid form, and patients do not perceive the bitterness of the oral liquid formulation. Oral liquid formulations also facilitate dose adjustment. Therefore, one embodiment of the present invention provides an atomoxetine hydrochloride-containing oral liquid formulation that can be administered to patients with impaired swallowing ability and is suitable for careful administration to elderly patients due to its easy dose adjustment. The clinical dose of atomoxetine hydrochloride is 40 mg to 120 mg per day in atomoxetine equivalents (oral administration once daily or twice daily in divided doses). Because a lower dose is easier for elderly people and patients with swallowing disorders to administer, the concentration of atomoxetine hydrochloride in the oral liquid formulation is preferably at least 4.6 mg / mL (4 mg / mL in atomoxetine equivalents).

[0087] (Suppression of the bitterness of donepezil hydrochloride) Donepezil hydrochloride, whose chemical name is (2RS)-2-[(1-benzylpiperidin-4-yl)methyl]-5,6-dimethoxy-2,3-dihydro-1H-inden-1-one monohydrochloride, is a compound with the following structural formula that is useful for slowing the progression of dementia symptoms in Alzheimer's disease and dementia with Lewy bodies. [ka]

[0088] The present invention provides an agent for suppressing the bitterness of donepezil hydrochloride, which comprises cyclodextrin and / or a derivative thereof as an active ingredient.

[0089] When suppressing the bitterness of donepezil hydrochloride, the bitterness suppressant of the present invention can use 0.1 moles or more, 0.2 moles or more, 0.5 moles or more, 1 mole or more, 2 moles or more, 3 moles or more, 4 moles or more, 5 moles or more, 10 moles or more, 20 moles or more, 21 moles or more, 22 moles or more, 23 moles or more, 24 moles or more, 25 moles or more, 26 moles or more, 27 moles or more, 28 moles or more, 29 moles or more, 30 moles or more, 40 moles or more, or 50 moles or more of cyclodextrin and / or a derivative thereof per mole of donepezil hydrochloride.

[0090] In one embodiment, the bitterness suppressor of the present invention uses 1 to 50 moles of cyclodextrin and / or a derivative thereof per mole of donepezil hydrochloride. This is because using 1 mole or more of cyclodextrin and / or a derivative thereof per mole of donepezil hydrochloride reduces the bitterness of donepezil hydrochloride to an acceptable level. Furthermore, adding 50 moles or less of cyclodextrin and / or a derivative thereof per mole of donepezil hydrochloride reduces costs and does not take up much space when dried.

[0091] In a preferred embodiment, the bitterness suppressor of the present invention uses 5 to 40 moles of β-cyclodextrin and / or a derivative thereof per mole of donepezil hydrochloride, because the bitterness of donepezil hydrochloride is significantly suppressed by using 5 moles or more of β-cyclodextrin and / or a derivative thereof per mole of donepezil hydrochloride, compared to the case where 5 moles or more of α- or γ-cyclodextrin and / or a derivative thereof is used.

[0092] In another preferred embodiment of the bitterness suppressor of the present invention, 10 to 40 moles of β-cyclodextrin and / or a derivative thereof are used per mole of donepezil hydrochloride. This is because using 10 moles or more of β-cyclodextrin and / or a derivative thereof per mole of donepezil hydrochloride significantly suppresses the bitterness of donepezil hydrochloride compared to using 10 moles or more of α- or γ-cyclodextrin and / or a derivative thereof. Furthermore, adding 40 moles or less of cyclodextrin and / or a derivative thereof per mole of donepezil hydrochloride reduces costs and does not take up much space when dried.

[0093] The cyclodextrin and / or its derivative, which is the active ingredient of the bitterness suppressor of the present invention, is not limited to any particular type, but β-CD and / or its derivative are particularly preferred because β-CD and / or its derivative are highly effective in suppressing the bitterness of donepezil hydrochloride. In a preferred embodiment, the cyclodextrin and / or its derivative, which is the active ingredient of the bitterness suppressor of the present invention, is β-CD.

[0094] The agent for suppressing the bitterness of donepezil hydrochloride provided by the present invention can be mixed with donepezil hydrochloride in a solvent containing water, because the inclusion action of CD or its derivative occurs in the state of an aqueous solution of CD or its derivative.

[0095] The present invention provides a method for suppressing the bitterness of donepezil hydrochloride, which comprises a step of mixing donepezil hydrochloride with cyclodextrin and / or a derivative thereof in a solvent, wherein the amount of cyclodextrin and / or a derivative thereof is 0.1 moles or more per mole of donepezil hydrochloride.

[0096] The step of mixing donepezil hydrochloride with cyclodextrin and / or its derivative in a solvent can be carried out by dissolving donepezil hydrochloride and cyclodextrin and / or its derivative in the solvent. Either donepezil hydrochloride or cyclodextrin and / or its derivative may be added to the solvent first, or they may be added simultaneously. Alternatively, the solution can be prepared by adding CD in powder form or as a solution to a donepezil hydrochloride solution prepared by dissolving donepezil hydrochloride in a solvent and stirring. The solvent can be selected from sterilized water, purified water, monohydric alcohols such as ethanol, polyhydric alcohols such as glycerol, and mixtures thereof. To increase the solubility of donepezil hydrochloride, donepezil hydrochloride can be first dissolved in an organic solvent such as polyethylene glycol or glycerin and then mixed with water. To increase the solubility of CD, the solvent containing donepezil hydrochloride, CD, and / or its derivative can be heated and stirred. When heating and stirring, the solvent can be heated to a temperature of, for example, 60 to 85°C.

[0097] In the method for suppressing bitterness of the present invention, 0.1 moles or more, 0.2 moles or more, 0.5 moles or more, 1 mole or more, 2 moles or more, 3 moles or more, 4 moles or more, 5 moles or more, 10 moles or more, 20 moles or more, 21 moles or more, 22 moles or more, 23 moles or more, 24 moles or more, 25 moles or more, 26 moles or more, 27 moles or more, 28 moles or more, 29 moles or more, 30 moles or more, or 40 moles or more of cyclodextrin and / or a derivative thereof can be mixed with 1 mole of donepezil hydrochloride. In one embodiment, the amount of cyclodextrin and / or a derivative thereof can be 3 to 50 moles per mole of donepezil hydrochloride. In another embodiment, the amount of cyclodextrin and / or a derivative thereof can be 10 to 40 moles per mole of donepezil hydrochloride.

[0098] The cyclodextrin and / or its derivatives used in the bitterness suppression method of the present invention are not particularly limited, but β-CD and / or its derivatives are particularly preferred because β-CD and / or its derivatives are highly effective in suppressing the bitterness of donepezil hydrochloride.

[0099] In a preferred embodiment of the method for suppressing bitterness of the present invention, 5 to 50 moles of β-cyclodextrin and / or a derivative thereof can be used per mole of donepezil hydrochloride, because the bitterness of donepezil hydrochloride is significantly suppressed by using 5 moles or more of β-cyclodextrin and / or a derivative thereof per mole of donepezil hydrochloride, compared to the case where 5 moles or more of α- or γ-cyclodextrin and / or a derivative thereof is used.

[0100] In another preferred embodiment of the method for suppressing bitterness of the present invention, 10 to 40 moles of β-cyclodextrin and / or a derivative thereof can be used per mole of donepezil hydrochloride, because the bitterness of donepezil hydrochloride is significantly suppressed by using 10 moles or more of β-cyclodextrin and / or a derivative thereof per mole of donepezil hydrochloride, compared to the case where 10 moles or more of α- or γ-cyclodextrin and / or a derivative thereof is used.

[0101] The donepezil hydrochloride solution having reduced bitterness according to the present invention can be powdered through a drying process such as freeze-drying or spray-drying.

[0102] Regarding the method for suppressing the bitterness of donepezil hydrochloride provided by the present invention, the evaluation of bitterness suppression can be carried out by a sensory evaluation test by a panel and / or instrumental measurement (taste recognition device, taste sensor). Regarding bitterness masking, the results of the sensory test are highly correlated with the output of the taste sensor, and it has been shown that the taste sensor can detect bitterness masking (Ono et al. Journal of Pharmaceutical Sciences 100:1935-1943, 2011).

[0103] The present invention provides a method for producing a pharmaceutical composition containing donepezil hydrochloride, which comprises the step of mixing donepezil hydrochloride with β-cyclodextrin and / or a derivative thereof in a solvent to obtain a donepezil hydrochloride-containing solution having a reduced bitterness, wherein the amount of β-cyclodextrin and / or a derivative thereof is 0.1 moles or more per mole of donepezil hydrochloride.

[0104] The step of mixing donepezil hydrochloride with β-cyclodextrin and / or a derivative thereof in a solvent to obtain a donepezil hydrochloride-containing solution with reduced bitterness can be carried out in the same manner as in the above-mentioned method for suppressing the bitterness of donepezil hydrochloride, and the same solvent can be used.

[0105] In the method for producing a pharmaceutical composition provided by the present invention, donepezil hydrochloride and cyclodextrin and / or a derivative thereof can be used in the same molar ratio as in the above-mentioned method for suppressing the bitterness of donepezil hydrochloride.

[0106] The donepezil hydrochloride-containing pharmaceutical composition prepared by the method of the present invention may contain, in addition to CD, pharmaceutically acceptable additives as needed. Pharmaceutically acceptable additives include, but are not limited to, excipients, disintegrants, binders, coating agents, swelling agents, glidants, lubricants, flavorings, sweeteners, or solubilizers. More specifically, pharmaceutically acceptable additives include magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, talc, lactalbumin, gelatin, starch, cellulose and its derivatives, animal and vegetable oils, and polyethylene glycol. The pharmaceutical composition prepared by the method of the present invention may be used in any form, such as granules, powders, coated tablets, microcapsules, syrups, dry syrups, elixirs, suspensions, emulsions, or drops.

[0107] The pharmaceutical composition containing donepezil hydrochloride produced by the production method of the present invention can be used as a therapeutic or preventive agent for subjects suffering from or suspected of suffering from a disease for which donepezil hydrochloride has a therapeutic and / or preventive effect. Specifically, it can be used to suppress the progression of dementia symptoms in Alzheimer's disease and dementia with Lewy bodies. The subjects to be administered are mammals, including humans.

[0108] In one embodiment, the pharmaceutical composition produced by the production method of the present invention can be an oral liquid formulation. While the present invention is not bound by any particular theory, it is believed that in the production method of the present invention, CD acts on the donepezil hydrochloride molecule itself to mask its bitterness. Therefore, the bitterness is suppressed even in liquid form, and patients are less likely to perceive the bitterness of the oral liquid formulation. Oral liquid formulations also facilitate dosage adjustment. Therefore, one embodiment of the present invention provides an oral liquid formulation containing donepezil hydrochloride that can be administered to patients with impaired swallowing ability and is suitable for careful administration to elderly patients due to its easy dosage adjustment. The clinical dose of donepezil hydrochloride is 3 mg to 10 mg per day (oral administration once daily). Because a lower dose is easier for elderly people and patients with swallowing disorders to administer, the concentration of donepezil hydrochloride in the oral liquid formulation is preferably at least 0.15 mg / mL.

[0109] (Suppression of the bitterness of dorzolamide hydrochloride) Dorzolamide hydrochloride, whose chemical name is (4S,6S)-4-ethylamino-6-methyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-2-sulfonamide 7,7-dioxide monohydrochloride, is effective in treating glaucoma and ocular hypertension. It is a compound represented by the following structural formula: [ka]

[0110] The present invention provides an agent for suppressing the bitterness of dorzolamide hydrochloride, which comprises cyclodextrin and / or a derivative thereof as an active ingredient.

[0111] When suppressing the bitterness of dorzolamide hydrochloride, the bitterness suppressant of the present invention can use 2 moles or more, 3 moles or more, 4 moles or more, 5 moles or more, 10 moles or more, 20 moles or more, 21 moles or more, 22 moles or more, 23 moles or more, 24 moles or more, 25 moles or more, 26 moles or more, 27 moles or more, 28 moles or more, 29 moles or more, 30 moles or more, 40 moles or more, or 50 moles or more of cyclodextrin and / or its derivative per mole of dorzolamide hydrochloride.

[0112] In one embodiment, the bitterness suppressant of the present invention uses 20 to 50 moles of cyclodextrin and / or its derivative per mole of dorzolamide hydrochloride. This is because using 20 or more moles of cyclodextrin and / or its derivative per mole of dorzolamide hydrochloride reduces the bitterness of dorzolamide hydrochloride to an acceptable level. Furthermore, adding 50 or fewer moles of cyclodextrin and / or its derivative per mole of dorzolamide hydrochloride reduces costs and does not take up much space when dried.

[0113] In a preferred embodiment, the bitterness suppressor of the present invention uses 5 to 40 moles of γ-cyclodextrin and / or its derivatives per mole of dorzolamide hydrochloride, because the bitterness of dorzolamide hydrochloride is significantly suppressed by using 5 moles or more of γ-cyclodextrin and / or its derivatives per mole of dorzolamide hydrochloride compared to the case where 5 moles or more of α- or β-cyclodextrin and / or its derivatives are used.

[0114] In another preferred embodiment of the bitterness suppressor of the present invention, 10 to 40 moles of γ-cyclodextrin and / or its derivative are used per mole of dorzolamide hydrochloride. This is because using 10 moles or more of γ-cyclodextrin and / or its derivative per mole of dorzolamide hydrochloride significantly suppresses the bitterness of dorzolamide hydrochloride compared to using 10 moles or more of α- or β-cyclodextrin and / or its derivative. Furthermore, adding 40 moles or less of cyclodextrin and / or its derivative per mole of dorzolamide hydrochloride reduces costs and does not take up much space when dried.

[0115] The cyclodextrin and / or its derivative, which is the active ingredient of the bitterness suppressor of the present invention, is not limited to any particular type, but γ-CD and / or its derivative are particularly preferred because γ-CD and / or its derivative are highly effective in suppressing the bitterness of dorzolamide hydrochloride. In a preferred embodiment, the cyclodextrin and / or its derivative, which is the active ingredient of the bitterness suppressor of the present invention, is γ-CD.

[0116] The bitterness suppressant of dorzolamide hydrochloride provided by the present invention can be mixed with dorzolamide hydrochloride in a solvent containing water, because the inclusion action of CD or its derivative occurs in the state of an aqueous solution of CD or its derivative.

[0117] The present invention provides a method for suppressing the bitterness of dorzolamide hydrochloride, which includes a step of mixing dorzolamide hydrochloride with cyclodextrin and / or its derivative in a solvent, wherein the cyclodextrin and / or its derivative is at least 2 moles per mole of dorzolamide hydrochloride.

[0118] The step of mixing dorzolamide hydrochloride with cyclodextrin and / or its derivative in a solvent can be carried out by dissolving dorzolamide hydrochloride and cyclodextrin and / or its derivative in the solvent. Either dorzolamide hydrochloride or cyclodextrin and / or its derivative may be added to the solvent first, or they may be added simultaneously. Alternatively, the dorzolamide hydrochloride solution can be prepared by adding CD in powder form or as a solution to a dorzolamide hydrochloride solution prepared by dissolving dorzolamide hydrochloride in a solvent and stirring. The solvent can be selected from sterilized water, purified water, monohydric alcohols such as ethanol, polyhydric alcohols such as glycerol, and mixtures thereof. To increase the solubility of dorzolamide hydrochloride, dorzolamide hydrochloride can be first dissolved in an organic solvent such as polyethylene glycol or glycerin, and then mixed with water. To increase the solubility of CD, the solvent containing dorzolamide hydrochloride, CD, and / or its derivative can be heated and stirred. When heating and stirring, the solvent can be heated to a temperature of 60 to 85°C, for example.

[0119] In the method for suppressing bitterness of the present invention, 2 or more moles, 3 or more moles, 4 or more moles, 5 or more moles, 10 or more moles, 20 or more moles, 21 or more moles, 22 or more moles, 23 or more moles, 24 or more moles, 25 or more moles, 26 or more moles, 27 or more moles, 28 or more moles, 29 or more moles, 30 or more moles, or 40 or more moles of cyclodextrin and / or a derivative thereof can be mixed with 1 mole of dorzolamide hydrochloride. In one embodiment, in the method for suppressing bitterness of the present invention, the amount of cyclodextrin and / or a derivative thereof can be 3 to 50 moles per mole of dorzolamide hydrochloride. In another embodiment, the amount of cyclodextrin and / or a derivative thereof can be 10 to 40 moles per mole of dorzolamide hydrochloride.

[0120] The cyclodextrin and / or its derivatives used in the bitterness suppression method of the present invention are not particularly limited, but γ-CD and / or its derivatives are particularly preferred because they are highly effective in suppressing the bitterness of dorzolamide hydrochloride.

[0121] In a preferred embodiment of the bitterness suppression method of the present invention, 5 to 50 moles of γ-cyclodextrin and / or a derivative thereof can be used per mole of dorzolamide hydrochloride, because the bitterness of dorzolamide hydrochloride is significantly suppressed by using 5 moles or more of γ-cyclodextrin and / or a derivative thereof per mole of dorzolamide hydrochloride, compared to the case where 5 moles or more of α- or β-cyclodextrin and / or a derivative thereof is used.

[0122] In another preferred embodiment of the bitterness suppression method of the present invention, 10 to 40 moles of γ-cyclodextrin and / or a derivative thereof can be used per mole of dorzolamide hydrochloride, because the bitterness of dorzolamide hydrochloride is significantly suppressed by using 10 moles or more of γ-cyclodextrin and / or a derivative thereof per mole of dorzolamide hydrochloride, compared to the case where 10 moles or more of α- or β-cyclodextrin and / or a derivative thereof is used.

[0123] Regarding the method for suppressing the bitterness of dorzolamide hydrochloride provided by the present invention, the evaluation of bitterness suppression can be carried out by a sensory evaluation test by a panel and / or instrumental measurement (taste recognition device, taste sensor). Regarding bitterness masking, the results of the sensory test are highly correlated with the output of the taste sensor, and it has been shown that the taste sensor can detect bitterness masking (Ono et al. Journal of Pharmaceutical Sciences 100:1935-1943, 2011).

[0124] The present invention provides a method for producing a pharmaceutical composition containing dorzolamide hydrochloride, which includes a step of mixing dorzolamide hydrochloride with γ-cyclodextrin and / or a derivative thereof in a solvent to obtain a dorzolamide hydrochloride-containing solution with reduced bitterness, wherein the amount of γ-cyclodextrin and / or a derivative thereof is 2 moles or more per mole of dorzolamide hydrochloride.

[0125] The process of mixing dorzolamide hydrochloride with γ-cyclodextrin and / or its derivatives in a solvent to obtain a dorzolamide hydrochloride-containing solution with reduced bitterness can be carried out in the same manner as the above-mentioned method for suppressing the bitterness of dorzolamide hydrochloride, and the same solvent can be used.

[0126] In the method for producing a pharmaceutical composition provided by the present invention, dorzolamide hydrochloride and cyclodextrin and / or a derivative thereof can be used in the same molar ratio as in the method for suppressing the bitterness of dorzolamide hydrochloride described above.

[0127] The dorzolamide hydrochloride-containing pharmaceutical composition prepared by the method of the present invention may contain, in addition to CD, pharmaceutically acceptable additives, such as, but not limited to, pH adjusters, thickeners, or solubilizers.

[0128] The dorzolamide hydrochloride-containing pharmaceutical composition produced by the production method of the present invention can be used as a therapeutic or preventive agent for subjects suffering from or suspected of suffering from a disease for which dorzolamide hydrochloride has a therapeutic and / or preventive effect. Specifically, it can be used to treat glaucoma and ocular hypertension. The subjects to be administered are mammals, including humans.

[0129] In one embodiment, the pharmaceutical composition produced by the method of the present invention can be an eye drop. While the present invention is not bound by any particular theory, it is believed that in the method of the present invention, CD acts on the dorzolamide hydrochloride molecule itself to mask its bitter taste. This suppresses the bitter taste, making it less likely for patients to perceive the bitterness even when the eye drops flow down the nose and into the throat. The clinical dose of dorzolamide hydrochloride is one drop of a 0.5% dorzolamide solution administered three times daily. The concentration of dorzolamide hydrochloride is preferably at least 5.6 mg / mL (5 mg / mL in dorzolamide equivalent). [Example]

[0130] The present invention will be specifically described based on the following examples, but the present invention is not limited to these examples.

[0131] Example 1: Suppression of the unpleasant bitter taste of duloxetine hydrochloride Duloxetine hydrochloride was dissolved in 10 mM potassium chloride solution to a final concentration of 0.5 mM, and this was used as a duloxetine hydrochloride solution. α-CD, β-CD, γ-CD, or hydroxypropylated β-CD (HP-β-CD) was added to this solution to a final concentration of 0.5 to 10 mM and completely dissolved.

[0132] The bitterness of duloxetine hydrochloride was measured by measuring the CPA (Change of Membrane Potential by Absorption) value (mV) using a taste recognition device "SA402B" (Intelligent Sensor Technology Co., Ltd.) and bitterness sensor AC0. The bitterness-suppressing effect of adding CD to duloxetine hydrochloride was evaluated by the CPA value. The CPA value is the average of three measurements. A higher CPA value indicates a stronger bitterness, so a lower CPA value indicates a stronger bitterness-suppressing effect of adding CD.

[0133] In addition to the CPA values, the table below shows the relative CPA values ​​at each CD concentration, where the CPA value of a solution with a CD concentration of 0 mM is set to 100% and the CPA value of a solution containing only 10 mM potassium chloride is set to 0%.

[0134] [Table 1]

[0135] As shown in the table above, when various CDs were added at 0.5 mM or higher, a decrease in the CPA value of duloxetine hydrochloride solution was observed. The addition of various CDs suppressed bitterness, with the most notable effect being β-CD.

[0136] Next, β-CD was dissolved in the duloxetine hydrochloride solution to a final concentration of 0.25 mM or 20 mM, and the CPA value was measured in the same manner as above, and the relative CPA value was calculated. The results are shown in the table below. [Table 2]

[0137] The CPA value of duloxetine hydrochloride solution was reduced by the addition of β-CD, and the effect increased depending on the concentration of added β-CD. These results confirmed that β-CD was effective in dose-dependently suppressing the bitterness detected by the taste recognition device in the range of 0.5 to 40 moles per mole of duloxetine hydrochloride.

[0138] Example 2: Preparation of oral solution containing duloxetine hydrochloride Manufacturing example: Duloxetine hydrochloride 1.1 mg / mL (1 mg of duloxetine) 1. Dissolve 110 mg of duloxetine hydrochloride in 80 mL of purified water. 2. Dissolve 1.9 g of β-CD in the aqueous solution of duloxetine hydrochloride. 3. Add the flavoring to the above mixture, then add purified water to make 100 mL. The oral solution of this production example has a reduced bitterness and has a taste that is acceptable as a pharmaceutical.

[0139] Example 3: Suppression of the unpleasant bitterness of aripiprazole Potassium chloride, aripiprazole, ethanol, and α-CD, β-CD, γ-CD, or hydroxypropylated β-CD (HP-β-CD) were added to ultrapure water and completely dissolved to final concentrations of 10 mM, 0.5 mM, 30 v / v%, and 0.5 to 10 mM, respectively.

[0140] The bitterness of aripiprazole was measured by measuring the CPA (Change of Membrane Potential by Absorption) value (mV) using a taste recognition device "SA402B" (Intelligent Sensor Technology, Inc.) and a bitterness sensor AC0. The bitterness-suppressing effect of adding CD to aripiprazole was evaluated by the CPA value. The CPA value is the average of three measurements. A higher CPA value indicates a stronger bitterness, so a lower CPA value indicates a stronger bitterness-suppressing effect of adding CD.

[0141] In addition to the CPA values, the table below shows the relative CPA values ​​at each CD concentration, where the CPA value of a solution with a CD concentration of 0 mM is set to 100% and the CPA value of a solution containing only 10 mM potassium chloride is set to 0%.

[0142] [Table 3]

[0143] As shown in the table above, when various CDs were added at 0.5 mM or higher, a decrease in the CPA value of the aripiprazole solution was observed. The addition of various CDs suppressed the bitterness, with the most notable effect being β-CD.

[0144] Next, β-CD was dissolved in the aripiprazole solution to a final concentration of 0.1 to 20 mM, and the CPA value was measured in the same manner as above, and the relative CPA value was calculated. The results are shown in the table below. [Table 4]

[0145] The CPA value of aripiprazole solution was reduced by the addition of β-CD, and the effect increased depending on the concentration of added β-CD. These results confirmed that β-CD was effective in dose-dependently suppressing the bitterness detected by the taste perception test in the range of 0.2 to 40 mol per 1 mol of aripiprazole.

[0146] Example 4: Preparation of oral liquid Manufacturing example: Aripiprazole 1.0 mg / mL 1. Dissolve 100 mg of aripiprazole in 80 mL of purified water. 2. Dissolve 2.5 g of β-CD in the aqueous aripiprazole solution. 3. Add the flavoring to the above mixture, then add purified water to make 100 mL. The oral solution of this production example has a reduced bitterness and has a taste that is acceptable as a pharmaceutical.

[0147] Example 5: Suppression of the unpleasant bitter taste of atomoxetine hydrochloride Atomoxetine hydrochloride was dissolved in 10 mM potassium chloride solution to a final concentration of 0.5 mM, and this was used as the atomoxetine hydrochloride solution. α-CD, β-CD, γ-CD, or hydroxypropylated β-CD (HP-β-CD) was added to the atomoxetine hydrochloride solution to a final concentration of 0.5 to 5 mM, and completely dissolved.

[0148] The bitterness of atomoxetine hydrochloride solution was measured by measuring the CPA (Change of Membrane Potential by Absorption) value (mV) using a taste recognition device "SA402B" (Intelligent Sensor Technology Co., Ltd.) and bitterness sensor AC0. The bitterness-suppressing effect of adding CD to atomoxetine hydrochloride solution was evaluated by the CPA value. The CPA value is the average of three measurements. A higher CPA value indicates a stronger bitterness, so a lower CPA value indicates a stronger bitterness-suppressing effect of adding CD.

[0149] In addition to the CPA values, the table below shows the relative CPA values ​​at each CD concentration, where the CPA value of a solution with a CD concentration of 0 mM is set to 100% and the CPA value of a solution containing only 10 mM potassium chloride is set to 0%.

[0150] [Table 5]

[0151] As shown in the table above, a decrease in the CPA value of atomoxetine hydrochloride solutions was observed when α-CD was added at 2.5 mM or more, β-CD was added at 0.5 mM or more, γ-CD was added at 2.5 mM or more, and HP-β-CD was added at 2.5 mM or more.

[0152] Next, β-CD was dissolved in the atomoxetine hydrochloride solution to a final concentration of 10 mM or 20 mM, and the CPA value was measured in the same manner as above, and the relative CPA value was calculated. The results are shown in the table below. [Table 6] The CPA value of atomoxetine hydrochloride solution was reduced by the addition of β-CD, and the effect increased depending on the concentration of the added β-CD. These results confirmed that β-CD was effective in dose-dependently suppressing the bitterness detected by the taste recognition device in the range of 1 to 40 moles per mole of atomoxetine hydrochloride.

[0153] Example 6: Preparation of oral liquid Manufacturing example: Atomoxetine hydrochloride 4.6 mg / mL (4 mg of atomoxetine) 1. Dissolve 460 mg of atomoxetine hydrochloride in 80 mL of purified water. 2. Dissolve 1.8 g of β-CD in the atomoxetine hydrochloride aqueous solution. 3. Add the flavoring to the above mixture, then add purified water to make 100 mL. The oral solution of this production example has a reduced bitterness and has a taste that is acceptable as a pharmaceutical.

[0154] Example 7: Suppression of the unpleasant bitterness of donepezil hydrochloride Donepezil hydrochloride was dissolved in 10 mM potassium chloride solution to a final concentration of 1 mM, and this was used as the donepezil hydrochloride solution. α-CD, β-CD, γ-CD, or hydroxypropylated β-CD (HP-β-CD) was added to the solution to a final concentration of 0.5 to 10 mM and completely dissolved.

[0155] The bitterness of donepezil hydrochloride solution was measured by measuring the CPA (Change of Membrane Potential by Absorption) value (mV) using a taste recognition device "SA402B" (Intelligent Sensor Technology Co., Ltd.) and bitterness sensor AC0. The bitterness-suppressing effect of adding CD to donepezil hydrochloride solution was evaluated by the CPA value. The CPA value is the average of three measurements. A higher CPA value indicates a stronger bitterness, so a lower CPA value indicates a stronger bitterness-suppressing effect of adding CD.

[0156] In addition to the CPA values, the table below shows the relative CPA values ​​at each CD concentration, where the CPA value of a solution with a CD concentration of 0 mM is set to 100% and the CPA value of a solution containing only 10 mM potassium chloride is set to 0%.

[0157] [Table 7]

[0158] As shown in the table above, the CPA value of donepezil hydrochloride solutions decreased when α-CD was added at 1 mM or more, β-CD was added at 0.5 mM or more, γ-CD was added at 1 mM or more, and HP-β-CD was added at 0.5 mM or more.

[0159] Next, β-CD was dissolved in the donepezil hydrochloride solution to a final concentration of 0.1 mM or 20 mM, and the CPA value was measured in the same manner as above, and the relative CPA value was calculated. The results are shown in the table below. [Table 8] The CPA value of donepezil hydrochloride solution was reduced by the addition of γ-CD, and the effect increased depending on the concentration of added γ-CD. These results confirmed that β-CD was effective in dose-dependently suppressing the bitterness detected by the taste recognition device in the range of 0.1 to 20 moles per mole of donepezil hydrochloride.

[0160] Example 8: Preparation of oral liquid Manufacturing example: Donepezil hydrochloride 0.15 mg / mL 1. Dissolve 15 mg of donepezil hydrochloride in 80 mL of purified water. 2. Dissolve 817.2 mg of β-CD in the aqueous solution of donepezil hydrochloride. 3. Add the flavoring to the above mixture, then add purified water to make 100 mL. The oral solution of this production example has a reduced bitterness and has a taste that is acceptable as a pharmaceutical.

[0161] Example 9: Suppression of the unpleasant bitter taste of dorzolamide hydrochloride Dorzolamide hydrochloride was dissolved in 10 mM potassium chloride solution to a final concentration of 0.5 mM, and this was used as a dorzolamide hydrochloride solution. α-CD, β-CD, γ-CD, or hydroxypropylated β-CD (HP-β-CD) was added to this solution to a final concentration of 0.5 to 5 mM, and completely dissolved.

[0162] The bitterness of dorzolamide hydrochloride was measured by measuring the CPA (Change of Membrane Potential by Absorption) value (mV) using a taste recognition device "SA402B" (Intelligent Sensor Technology Co., Ltd.) and a bitterness sensor AC0. The bitterness-suppressing effect of adding CD to dorzolamide hydrochloride solution was evaluated by the CPA value. The CPA value is the average of three measurements. A higher CPA value indicates a stronger bitterness, so a lower CPA value indicates a stronger bitterness-suppressing effect of adding CD.

[0163] In addition to the CPA values, the table below shows the relative CPA values ​​at each CD concentration, where the CPA value of a solution with a CD concentration of 0 mM is set to 100% and the CPA value of a solution containing only 10 mM potassium chloride is set to 0%.

[0164] [Table 9]

[0165] In the above table, the CPA value of dorzolamide hydrochloride solution decreased when α-CD was added at 10 mM or more, when β-CD was added at 5 mM or more, when γ-CD was added at 2.5 mM or more, and when HP-β-CD was added at 10 mM or more.

[0166] Next, γ-CD was dissolved in the dorzolamide hydrochloride solution to a final concentration of 1 mM or 20 mM, and the CPA value was measured in the same manner as above, and the relative CPA value was calculated. The results are shown in the table below. [Table 10] The CPA value of dorzolamide hydrochloride solution was reduced by the addition of γ-CD, and the effect increased depending on the concentration of added γ-CD. These results confirmed that γ-CD was effective in dose-dependently suppressing the bitterness detected by the taste recognition device in the range of 2 to 40 moles per mole of dorzolamide hydrochloride.

[0167] Example 10: Preparation of eye drops Manufacturing example: Dorzolamide hydrochloride 5.6 mg / mL (5 mg of dorzolamide) 1. Dissolve 560 mg of dorzolamide hydrochloride in 80 mL of purified water. 2. Dissolve 4.0 g of γ-CD in the aqueous solution of dorzolamide hydrochloride. 3. Add purified water to the above mixture to make 100 mL. The eye drops of this production example have a reduced bitterness and have a taste that is acceptable as a pharmaceutical.

Claims

1. A bitterness suppressant for a pharmaceutically active compound, comprising cyclodextrin and / or a derivative thereof as an active ingredient, wherein the pharmaceutically active compound is any one selected from the group consisting of duloxetine hydrochloride, aripiprazole, atomoxetine hydrochloride, donepezil hydrochloride, and dorzolamide hydrochloride.

2. The bitterness suppressant according to claim 1, wherein 0.5 moles or more of cyclodextrin and / or a derivative thereof is used per mole of the pharmaceutically active compound.

3. 3. The bitterness suppressant according to claim 1, wherein 10 moles or more of cyclodextrin and / or its derivative are used per mole of the pharmaceutically active compound.

4. The bitterness suppressor according to any one of claims 1 to 3, wherein the cyclodextrin and / or its derivative is β-cyclodextrin.

5. A method for suppressing the bitterness of a pharmaceutically active compound, comprising the step of mixing a pharmaceutically active compound with cyclodextrin and / or a derivative thereof in a solvent, wherein the cyclodextrin and / or derivative thereof is at least 0.5 moles per mole of the pharmaceutically active compound, and the pharmaceutically active compound is any one selected from the group consisting of duloxetine hydrochloride, aripiprazole, atomoxetine hydrochloride, donepezil hydrochloride, and dorzolamide hydrochloride.

6. 6. The method for suppressing bitterness according to claim 5, wherein the cyclodextrin and / or a derivative thereof is β-cyclodextrin.

7. A method for producing a pharmaceutically active compound-containing composition, comprising the step of mixing a pharmaceutically active compound with cyclodextrin and / or a derivative thereof in a solvent to obtain a pharmaceutically active compound-containing solution having reduced bitterness, wherein the cyclodextrin and / or derivative thereof is used in an amount of 0.5 moles or more per mole of the pharmaceutically active compound, and the pharmaceutically active compound is any one selected from the group consisting of duloxetine hydrochloride, aripiprazole, atomoxetine hydrochloride, donepezil hydrochloride, and dorzolamide hydrochloride.

8. The method according to claim 7, wherein the cyclodextrin and / or its derivative is β-cyclodextrin.

9. The method according to claim 7 or 8, wherein the composition containing a pharmaceutically active compound is a liquid formulation for oral administration.

Images