Bitterness inhibitor for pharmacoactive compounds and method for inhibiting bitterness

Abstract

To inhibit the bitterness of a pharmaceutical active compound without requiring a complicated process or a plurality of additives and while reducing the costs.SOLUTION: The present disclosure provides an agent for inhibiting the bitterness of a pharmaceutical active compound containing cyclodextrin and / or a derivative thereof as an active ingredient, the pharmaceutical active compound being 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 a bitter taste inhibitor for a pharmaceutically active compound, a method for inhibiting the bitter taste of a pharmaceutically active compound, and a method for producing a composition containing a bitter taste inhibitor for a pharmaceutically active compound.

Background Art

[0002] Pharmaceutically active compounds are administered via various routes such as oral, nasal, and transdermal routes. Among these, oral administration is an easy, convenient, non-invasive, and well-known drug delivery method as an administration form. However, some pharmaceutically active compounds have extremely unpleasant tastes such as bitterness. Conventional solid forms (such as tablets or capsules) are usually swallowed immediately after ingestion, so it is difficult to feel the bitterness. However, some patients may not be able to tolerate the extremely unpleasant taste caused by bitterness and may not be able to take the medicine. For patients who have difficulty in oral administration with conventional solid forms due to reasons such as low swallowing function (for example, children and elderly patients), liquid forms (for example, solutions, suspensions, syrups, emulsions, or liquids obtained by mixing dry syrup with water, etc.) or dosage forms such as chewable tablets and orally disintegrating tablets are prescribed. However, there is a problem that bitter substances often touch the taste buds and bitterness is easily felt.

[0003] Many medical pharmaceuticals that are frequently used in Japan, for example, those with annual sales in Japan of 5 billion yen or more, contain pharmaceutically active compounds having bitterness as an active ingredient. For example, atomoxetine hydrochloride, a therapeutic agent for attention deficit hyperactivity disorder (ADHD), duloxetine hydrochloride, an antidepressant, donepezil hydrochloride, a therapeutic agent for Alzheimer's disease, aripiprazole, an antipsychotic, and dorzolamide hydrochloride, a therapeutic agent for glaucoma and hypertension, are known to have bitterness. It is important for patients to take the medicine prescribed by a doctor as instructed. However, there may be problems such as patients being unable to tolerate the bitterness of these pharmaceutically active compounds, resulting in a decrease in medication adherence and compliance.

[0004] Therefore, masking the bitterness of pharmacoactive compounds is a crucial challenge. Known masking methods include adding sweeteners (sugar, artificial sweeteners, etc.) or flavorings (fruit, chocolate) to mask the bitterness, or encapsulating the bitterness with coatings or microencapsulation. However, these methods have problems, such as not being able to completely mask the bitterness, or the bitterness being perceived when the compound dissolves in the mouth.

[0005] Patent Document 1 discloses a solid drug formulation comprising a matrix, characterized in that the matrix comprises a pharmaceutically effective amount of atomoxetine or a pharmaceutically acceptable salt thereof and a wax material, and states that the taste of atomoxetine may be masked by a combination of polymer and suspension medium. Patent Document 2 discloses an orally disintegrating tablet comprising a main drug particle containing an unpleasant-tasting drug and having a coating layer covering the drug, and a wicking-type disintegrant and a swelling-type disintegrant, and states that the unpleasant-tasting drug may be donepezil hydrochloride, etc. Patent Document 3 discloses an orally disintegrating 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 primary sweeteners as a taste blocker, and states 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 Publication No. 2013-147470 [Patent Document 3] Special Publication No. 2012-528854 [Overview of the project] [Problems that the invention aims to solve]

[0007] Conventional bitterness suppression technologies required complex processes and multiple additives to reduce the bitterness of pharmacoactive compounds, resulting in high costs. Furthermore, they were unable to adequately mask the bitterness in dosage forms that are easily perceived as bitter, such as chewable tablets, orally disintegrating tablets, or liquid formulations (including dry syrup mixed with water).

[0008] In view of the above situation, the present invention aims to suppress the bitterness of pharmaceutically active compounds without requiring complex processes or multiple additives, while keeping costs down. Furthermore, the present invention aims to provide a pharmaceutically active compound-containing composition that does not taste bitter even when taken in a dosage form that is normally prone to bitterness. [Means for solving the problem]

[0009] The present inventors conducted extensive research to solve the above problems and discovered that the bitterness of pharmacoactive compounds can be reduced by using cyclodextrin as a bitterness inhibitor. This invention is based on this finding. The present invention provides the following: [1] A bitterness inhibitor for a pharmaceutically active compound, comprising cyclodextrin and / or a derivative thereof as an active ingredient, wherein the pharmaceutically active compound is selected from the group consisting of duloxetine hydrochloride, aripiprazole, atomoxetine hydrochloride, donepezil hydrochloride, and dorzolamide hydrochloride. [2] The bitterness inhibitor according to [1], wherein 0.5 moles or more of cyclodextrin and / or its derivatives are used per mole of the above-mentioned pharmaceutically active compound. [3] A bitter taste inhibitor according to [1] or [2], wherein 10 moles or more of cyclodextrin and / or derivatives thereof are used per mole of the above-mentioned pharmaceutically active compound. [4] A bitterness inhibitor according to any one of [1] to [3], wherein the cyclodextrin and / or derivative thereof is β-cyclodextrin.

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

[0011] By using cyclodextrin and / or its derivatives, the bitterness of pharmaceutically active compounds can be reduced. [Modes for carrying out 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, numerical ranges represented by "~" mean a range that includes the numbers written before and after "~" as the lower and upper limits.

[0013] The present invention provides a bitterness inhibitor for a pharmaceutically active compound, comprising cyclodextrin and / or a derivative thereof as an active ingredient, wherein the pharmaceutically active compound is 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) is also known as a cyclic oligosaccharide and is a cyclic α-1,4-glucan. It is produced by an intramolecular transfer reaction when cyclodextrin glucanotransferase acts on α-1,4-glucans such as starch. Its 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" refers collectively to unpleasant sensations, including bitterness and astringency, felt in the oral cavity and pharynx. In this specification, "inhibiting bitterness" means that the bitterness felt when a bitter substance is present in the oral cavity is inhibited, reduced, concealed, or masked, and may also include the inhibition, reduction, concealment, or masking of unpleasant sensations, including astringency, along with bitterness. "Inhibition" means that the "bitterness" felt in the oral cavity when the "bitterness inhibitor" is used is somewhat reduced 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 for the patient. The bitterness inhibitor of the present invention contains cyclodextrin and / or its derivatives as active ingredients and can inhibit the bitterness of pharmaceutically active compounds selected from the group consisting of duloxetine hydrochloride, aripiprazole, atomoxetine hydrochloride, donepezil hydrochloride, and dorzolamide hydrochloride.

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

[0017] Cyclodextrins, viewed three-dimensionally, have a bucket-like or donut-like structure without a bottom. They are characterized by a hydrophilic exterior and a hydrophobic interior. This characteristic allows cyclodextrins to incorporate specific organic molecules (guest molecules) into their cavities, forming an inclusion complex. Generally, inclusion of guest molecules by cyclodextrins can occur when the size of the cyclodextrin cavity matches the size of the guest molecule, or the size of a part of the guest molecule's structure. Furthermore, because the interior of the cyclodextrin cavity is hydrophobic, hydrophobic guest molecules tend to be more easily inclusionated.

[0018] Among cyclodextrins, β-CD is the most commonly used due to its high production volume and low cost. However, β-CD is said to be less suitable for solubilization because of its lower water solubility compared to α-CD and γ-CD. To improve water solubility, derivatives such as hydroxypropylated β-CD and methylated β-CD have been developed. γ-CD has the largest cavity among the three types of CD and therefore has high water solubility. α-CD has a smaller cavity diameter compared to β-CD and γ-CD, so it is thought that it can encapsulate smaller guest molecules compared to β-CD and γ-CD.

[0019] Even if the entire guest molecule is clearly larger than cyclodextrin, the effect of inclusion may sometimes be observed. It is considered that it is sufficient if the guest molecule fits at least partially into the cavity of the host CD. The inclusion ability of CD is affected by the chemical interaction between the host CD and the guest molecule. The interactions between the host CD and the guest molecule include hydrophobic interaction, van der Waals force, ion-ion interaction, dipole interaction, and hydrogen bond, and it is considered that these interactions function cooperatively. Although the present invention is not bound by a specific theory, it is considered that a plurality of CDs and / or their derivatives act on one pharmaceutical active compound molecule, and there are interactions other than inclusion between the CD and / or its derivative and the pharmaceutical active compound molecule.

[0020] The CD and / or its derivative used in the present invention may be in the form of a crystal, an amorphous powder, a syrup, or the like. Further, in addition to the CD and / or its derivative, those containing, for example, maltooligosaccharide, other saccharides, etc., which are by-products in the process of their production and preparation, may be used.

[0021] (Suppression of the bitterness of duloxetine hydrochloride) Duloxetine hydrochloride is a serotonin-norepinephrine reuptake inhibitor whose chemical name is written as (+)-(S)-N-methyl-3-(1-naphthyloxy)-3-(2-thienyl)propylamine monohydrochloride, and is useful for the treatment of depression, depressive state, 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 represented by the following structural formula. [Chemical formula]

[0022] The present invention provides a bitterness inhibitor of duloxetine hydrochloride containing cyclodextrin and / or its derivative as an active ingredient.

[0023] When suppressing the bitterness of duloxetine hydrochloride, the bitterness inhibitor 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 its derivatives per 0.5 moles or more, 1 mole of duloxetine hydrochloride.

[0024] In one embodiment, the bitterness inhibitor of the present invention uses 2 to 50 moles of cyclodextrin and / or its derivatives per mole of duloxetine hydrochloride. This is because using 2 moles or more of cyclodextrin and / or its derivatives per mole of duloxetine hydrochloride suppresses the bitterness of duloxetine hydrochloride to an acceptable level. Furthermore, adding 50 moles or less of cyclodextrin and / or its derivatives per mole of duloxetine hydrochloride keeps costs down, and the mixture of duloxetine hydrochloride and cyclodextrin and / or its derivatives does not take up much space when dried.

[0025] In a preferred embodiment of the present invention, the bitterness inhibitor uses 5 to 40 moles of β-cyclodextrin and / or its derivatives per mole of duloxetine hydrochloride. This is because using 5 moles or more of β-cyclodextrin and / or its derivatives per mole of duloxetine hydrochloride significantly suppresses the bitterness of duloxetine hydrochloride compared to using 5 moles or more of α- or γ-cyclodextrin and / or its derivatives.

[0026] In another preferred embodiment of the present invention, the bitterness inhibitor uses 10 to 40 moles of β-cyclodextrin and / or its derivatives per mole of duloxetine hydrochloride. This is because using 10 moles or more of β-cyclodextrin and / or its derivatives 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 its derivatives. Furthermore, adding 40 moles or less of cyclodextrin and / or its derivatives per mole of duloxetine hydrochloride keeps costs down, and the mixture of duloxetine hydrochloride and cyclodextrin and / or its derivatives does not take up much space when dried.

[0027] The cyclodextrin and / or derivative thereof, which are the active ingredients of the bitterness inhibitor of the present invention, are not limited in type, but β-CD and / or derivative thereof are particularly preferred. This is because β-CD and / or derivative thereof have a high effect in suppressing the bitterness of duloxetine hydrochloride. In one preferred embodiment, the cyclodextrin and / or derivative thereof, which are the active ingredients of the bitterness inhibitor of the present invention, are β-CD and HP-β-CD.

[0028] The duloxetine hydrochloride bitterness inhibitor provided by the present invention can be mixed with duloxetine hydrochloride in a water-containing solvent. This is because the inclusion action of CD or its derivatives occurs in the form of an aqueous solution of CD or its derivatives.

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

[0030] The step of mixing duloxetine hydrochloride and cyclodextrin and / or its derivatives in a solvent can be carried out by dissolving duloxetine hydrochloride and cyclodextrin and / or its derivatives in the solvent. The duloxetine hydrochloride and cyclodextrin and / or its derivatives may be added to the solvent and dissolved either first or simultaneously. Alternatively, the solution can be prepared by adding cyclodextrin (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, it 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 and CD and / or its derivatives can be heated and stirred. When heating and stirring, the solvent can be heated to a temperature of, for example, 60-85°C.

[0031] In the bitterness suppression method 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 its derivatives can be mixed with 1 mole of duloxetine hydrochloride. In one embodiment of the bitterness suppression method of the present invention, the amount of cyclodextrin and / or its derivatives can be 2 to 50 moles per mole of duloxetine hydrochloride. In another embodiment, the amount of cyclodextrin and / or its derivatives can be 10 to 40 moles per mole of duloxetine hydrochloride.

[0032] The cyclodextrin and / or derivatives used in the bitterness suppression method of the present invention are not particularly limited in type, but β-CD and / or derivatives are particularly preferred. This is because β-CD and / or derivatives have a high effect in suppressing the bitterness of duloxetine hydrochloride. The derivative of β-CD is preferably HP-β-CD.

[0033] In the bitterness suppression method of the present invention, in one preferred embodiment, 5 to 50 moles of β-cyclodextrin and / or its derivatives can be used per mole of duloxetine hydrochloride. This is because using 5 moles or more of β-cyclodextrin and / or its derivatives per mole of duloxetine hydrochloride significantly suppresses the bitterness of duloxetine hydrochloride compared to using 5 moles or more of α- or γ-cyclodextrin and / or its derivatives.

[0034] In another preferred embodiment of the bitterness suppression method of the present invention, 10 to 40 moles of β-cyclodextrin and / or its derivatives can be used per mole of duloxetine hydrochloride. This is because using 10 moles or more of β-cyclodextrin and / or its derivatives 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 its derivatives.

[0035] The duloxetine hydrochloride solution, whose bitterness is suppressed according to the present invention, can be powdered by a drying process such as freeze-drying or spray-drying.

[0036] The bitterness suppression method for duloxetine hydrochloride provided by the present invention can be evaluated by a panel sensory evaluation test and / or instrumental measurement (taste recognition device, taste sensor). Regarding bitterness masking, the results of the sensory evaluation and the output of the taste sensor show a high correlation, demonstrating that the 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 pharmaceutical composition containing duloxetine hydrochloride, comprising the step of mixing duloxetine hydrochloride and β-cyclodextrin and / or its derivative in a solvent to obtain a duloxetine hydrochloride-containing solution with reduced bitterness, wherein the amount of β-cyclodextrin and / or its derivative is 0.5 moles or more per mole of duloxetine hydrochloride.

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

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

[0040] The pharmaceutical composition containing duloxetine hydrochloride produced by the manufacturing method of the present invention may contain, in addition to CD, pharmaceutically acceptable additives as needed. Examples of pharmaceutically acceptable additives include, but are not limited to, pH adjusters, stabilizers, excipients, decomposing agents, binders, coating agents, swelling agents, glidants, lubricants, flavoring agents, sweeteners, or solubilizers. More specifically, pharmaceutically acceptable additives include, for example, 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 produced by the manufacturing 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 duloxetine hydrochloride-containing pharmaceutical composition produced by the manufacturing method of the present invention can be used as a therapeutic or preventive agent for subjects suffering from or suspected of suffering from diseases for which duloxetine hydrochloride exerts therapeutic and / or preventive effects. Specifically, it can be used to treat depression / depressive states, pain associated with diabetic neuropathy, pain associated with fibromyalgia, pain associated with chronic lower back pain, and pain associated with osteoarthritis. The target subjects for administration are mammals, including humans.

[0042] In one embodiment, the pharmaceutical composition produced by the manufacturing method of the present invention can be an oral liquid formulation. Although the present invention is not bound by any particular theory, in the manufacturing method of the present invention, it is thought that CD acts on the duloxetine hydrochloride molecule itself to mask the bitterness, and the bitterness is suppressed even in liquid form, so that patients do not perceive bitterness as much as in an oral liquid formulation. Oral liquid formulations are also easy to adjust the dose of. Therefore, according to one embodiment of the present invention, it is possible to provide an oral liquid formulation containing duloxetine hydrochloride that can be administered to patients with impaired swallowing ability and is suitable for careful administration to the elderly because the dose can be easily adjusted. The clinical dose of duloxetine hydrochloride is 20 mg to 60 mg per day in duloxetine equivalent (once daily orally). Since it is easier for elderly patients and patients with dysphagia to take a smaller dose, it is preferable that the concentration of duloxetine hydrochloride in the oral liquid formulation be at least 1.1 mg / mL (1 mg / mL in duloxetine equivalent).

[0043] (Suppression of the bitter taste of aripiprazole) Aripiprazole, whose chemical name is 7-[4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy]-3,4-dihydro-2(1H)-quinolinone, is useful in the treatment of schizophrenia. It is a compound shown by the following structural formula. [ka]

[0044] The present invention provides a bitterness inhibitor for aripiprazole, comprising cyclodextrin and / or its derivatives as an active ingredient.

[0045] When suppressing the bitterness of aripiprazole, the bitterness inhibitor 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 derivatives thereof per mole of aripiprazole.

[0046] In one embodiment, the bitterness inhibitor 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 suppresses the bitterness of aripiprazole to an acceptable level. Furthermore, adding 50 moles or less of cyclodextrin and / or its derivatives per mole of aripiprazole keeps costs down, and the mixture of aripiprazole and cyclodextrin and / or its derivatives does not take up much space when dried.

[0047] In a preferred embodiment of the present invention, the bitterness inhibitor uses 5 to 40 moles of β-cyclodextrin and / or its derivatives per mole of aripiprazole. This is because using 5 moles or more of β-cyclodextrin and / or its derivatives per mole of aripiprazole significantly suppresses the bitterness of aripiprazole compared to using 5 moles or more of α- or γ-cyclodextrin and / or its derivatives.

[0048] In another preferred embodiment, the bitterness inhibitor of the present invention uses 10 to 40 moles of β-cyclodextrin and / or its derivatives per mole of aripiprazole. This is because using 10 moles or more of β-cyclodextrin and / or its derivatives per mole of aripiprazole significantly suppresses the bitterness 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 keeps costs down, and the mixture of aripiprazole and cyclodextrin and / or its derivatives does not take up much space when dried.

[0049] The cyclodextrin and / or derivative thereof, which is the active ingredient of the bitterness inhibitor of the present invention, is not limited to any particular type, but β-CD and / or its derivatives are particularly preferred. This is because β-CD and / or its derivatives have a high effect in suppressing the bitterness of aripiprazole. In one preferred embodiment, the cyclodextrin and / or derivative thereof, which is the active ingredient of the bitterness inhibitor of the present invention, is β-CD.

[0050] The bitterness inhibitor of aripiprazole provided by the present invention can be mixed with aripiprazole in a solvent containing water. This is because the inclusion effect of CD or its derivatives occurs in the aqueous solution state of CD or its derivatives.

[0051] The present invention provides a method for suppressing the bitterness of aripiprazole, comprising the step of mixing aripiprazole with cyclodextrin and / or its derivatives in a solvent, wherein the amount of cyclodextrin and / or its derivatives is 0.2 moles or more per mole of aripiprazole.

[0052] The step of mixing aripiprazole and cyclodextrin and / or its derivatives in a solvent can be carried out by dissolving aripiprazole and cyclodextrin and / or its derivatives in the solvent. The aripiprazole and cyclodextrin and / or its derivatives may be added to the solvent and dissolved either first or simultaneously. Alternatively, the solution can be prepared by adding cyclodextrin in powder or solution form to an aripiprazole solution 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, it 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 cyclodextrin, the solvent containing aripiprazole and cyclodextrin and / or its derivatives can be heated and stirred. When heating and stirring, the solvent can be heated to a temperature of, for example, 60-85°C.

[0053] In the bitterness suppression method 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 its derivatives can be mixed with 1 mole of aripiprazole. In one embodiment of the bitterness suppression method of the present invention, the amount of cyclodextrin and / or its derivatives can be 2 to 50 moles per mole of aripiprazole. In another embodiment, the amount of cyclodextrin and / or its derivatives can be 10 to 40 moles per mole of aripiprazole.

[0054] The cyclodextrin and / or derivatives used in the bitterness suppression method of the present invention are not particularly limited in type, but β-CD and / or derivatives are particularly preferred. This is because β-CD and / or derivatives have a high effect in suppressing the bitterness of aripiprazole.

[0055] In the bitterness suppression method of the present invention, in one preferred embodiment, 2 to 50 moles of β-cyclodextrin and / or its derivatives can be used per mole of aripiprazole. This is because using 2 moles or more of β-cyclodextrin and / or its derivatives per mole of aripiprazole significantly suppresses the bitterness of aripiprazole compared to using 2 moles or more of α- or γ-cyclodextrin and / or its derivatives.

[0056] In another preferred embodiment of the bitterness suppression method of the present invention, 10 to 40 moles of β-cyclodextrin and / or its derivatives can be used per mole of aripiprazole. This is because using 10 moles or more of β-cyclodextrin and / or its derivatives per mole of aripiprazole significantly suppresses the bitterness of aripiprazole compared to using 10 moles or more of α- or γ-cyclodextrin and / or its derivatives.

[0057] The aripiprazole solution, whose bitterness has been suppressed according to the present invention, can be powdered by a drying process such as freeze-drying or spray-drying.

[0058] The bitterness suppression method for aripiprazole provided by the present invention can be evaluated by a panel sensory evaluation test and / or instrumental measurement (taste recognition device, taste sensor). Regarding bitterness masking, the results of the sensory evaluation and the output of the taste sensor show a high correlation, demonstrating 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, comprising the step of mixing aripiprazole with β-cyclodextrin and / or its derivative in a solvent to obtain an aripiprazole-containing solution with reduced bitterness, wherein the amount of β-cyclodextrin and / or its derivative is 0.2 moles or more per mole of aripiprazole.

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

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

[0062] The aripiprazole-containing pharmaceutical composition produced by the manufacturing method of the present invention may contain, in addition to CD, pharmaceutically acceptable additives as needed. Examples of pharmaceutically acceptable additives include, but are not limited to, excipients, decomposing agents, binders, coating agents, swelling agents, glidants, lubricants, flavoring agents, sweeteners, or solubilizers. More specifically, pharmaceutically acceptable additives include, for example, 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 produced by the manufacturing 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 produced by the manufacturing method of the present invention can be used as a therapeutic or prophylactic agent for subjects suffering from or suspected of suffering from a disease for which aripiprazole exerts therapeutic and / or prophylactic effects. Specifically, it can be used for the treatment of schizophrenia. The target subjects for administration are mammals, including humans.

[0064] In one embodiment, the pharmaceutical composition produced by the manufacturing method of the present invention can be an oral liquid formulation. Although the present invention is not bound by any particular theory, in the manufacturing method of the present invention, it is thought that CD acts on the aripiprazole molecule itself to mask the bitterness, and the bitterness is suppressed even in liquid form, so that patients do not perceive bitterness as much as in an oral liquid formulation. Oral liquid formulations are also easy to adjust the dose of. Therefore, according to one embodiment of the present invention, it is possible to provide an aripiprazole-containing oral liquid formulation that can be administered to patients with impaired swallowing ability and is suitable for careful administration to the elderly because the dose can be easily adjusted. The clinical dose of aripiprazole is 6 mg to 24 mg per day (administered orally once or twice a day). Since a smaller dose is easier to take for elderly patients and patients with dysphagia, it is preferable that the aripiprazole concentration in the oral liquid formulation be at least 1.0 mg / mL.

[0065] (Suppression of the bitter taste of atomoxetine hydrochloride) Atomoxetine hydrochloride, whose chemical name is (3R)-N-methyl-3-(2-methylphenoxy)-3-phenylpropane-1-amine monohydrochloride, is useful in the treatment of attention deficit / hyperactivity disorder. It is a compound represented by the following structural formula. [ka]

[0066] The present invention provides a bitterness inhibitor for atomoxetine hydrochloride, comprising cyclodextrin and / or its derivatives as an active ingredient.

[0067] When suppressing the bitterness of atomoxetine hydrochloride, the bitterness inhibitor 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 derivatives thereof per mole of atomoxetine hydrochloride.

[0068] In one embodiment, the bitterness inhibitor of the present invention uses 5 to 50 moles of cyclodextrin and / or its derivatives per mole of atomoxetine hydrochloride. This is because using 5 moles or more of cyclodextrin and / or its derivatives per mole of atomoxetine hydrochloride suppresses the bitterness of atomoxetine hydrochloride to an acceptable level. Furthermore, adding 50 moles or less of cyclodextrin and / or its derivatives per mole of atomoxetine hydrochloride keeps costs down, and the mixture of atomoxetine hydrochloride and cyclodextrin and / or its derivatives does not take up much space when dried.

[0069] In a preferred embodiment of the present invention, the bitterness inhibitor uses 5 to 40 moles of β-cyclodextrin and / or its derivatives per mole of atomoxetine hydrochloride. This is because using 5 moles or more of β-cyclodextrin and / or its derivatives per mole of atomoxetine hydrochloride significantly suppresses the bitterness of atomoxetine hydrochloride compared to using 5 moles or more of α- or γ-cyclodextrin and / or its derivatives.

[0070] In another preferred embodiment of the present invention, the bitterness inhibitor uses 10 to 40 moles of β-cyclodextrin and / or its derivatives per mole of atomoxetine hydrochloride. This is because using 10 moles or more of β-cyclodextrin and / or its derivatives 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 its derivatives. Furthermore, adding 40 moles or less of cyclodextrin and / or its derivatives per mole of atomoxetine hydrochloride keeps costs down, and the mixture of atomoxetine hydrochloride and cyclodextrin and / or its derivatives does not take up much space even when dried.

[0071] The cyclodextrin and / or derivative thereof, which are the active ingredients of the bitterness inhibitor of the present invention, are not limited in type, but β-CD and / or derivative thereof are particularly preferred. This is because β-CD and / or derivative thereof have a high effect in suppressing the bitterness of atomoxetine hydrochloride. In one preferred embodiment, the cyclodextrin and / or derivative thereof, which are the active ingredients of the bitterness inhibitor of the present invention, is β-CD.

[0072] The atomoxetine hydrochloride bitterness inhibitor provided by the present invention can be mixed with atomoxetine hydrochloride in a water-containing solvent. This is because the inclusion action of CD or its derivatives occurs in the form of an aqueous solution of CD or its derivatives.

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

[0074] The step of mixing atomoxetine hydrochloride and cyclodextrin and / or its derivatives in a solvent can be carried out by dissolving atomoxetine hydrochloride and cyclodextrin and / or its derivatives in the solvent. Atomoxetine hydrochloride and cyclodextrin and / or their derivatives may be added to the solvent and dissolved either first or simultaneously. Alternatively, the solution can be prepared by adding CD in powder or solution form to an atomoxetine hydrochloride solution prepared by dissolving atomoxetine 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 atomoxetine hydrochloride, it 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 and CD and / or its derivatives can be heated and stirred. When heating and stirring, the solvent can be heated to a temperature of, for example, 60-85°C.

[0075] In the bitterness suppression method 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 its derivatives can be mixed with 1 mole of atomoxetine hydrochloride. In one embodiment of the bitterness suppression method of the present invention, the amount of cyclodextrin and / or its derivatives can be 5 to 50 moles per mole of atomoxetine hydrochloride. In another embodiment, the amount of cyclodextrin and / or its derivatives can be 10 to 40 moles per mole of atomoxetine hydrochloride.

[0076] The cyclodextrin and / or derivatives used in the bitterness suppression method of the present invention are not particularly limited in type, but β-CD and / or derivatives are particularly preferred. This is because β-CD and / or derivatives have a high effect in suppressing the bitterness of atomoxetine hydrochloride.

[0077] In the bitterness suppression method of the present invention, in one preferred embodiment, 5 to 50 moles of β-cyclodextrin and / or its derivatives can be used per mole of atomoxetine hydrochloride. This is because using 5 moles or more of β-cyclodextrin and / or its derivatives per mole of atomoxetine hydrochloride significantly suppresses the bitterness of atomoxetine hydrochloride compared to using 5 moles or more of α- or γ-cyclodextrin and / or its derivatives.

[0078] In another preferred embodiment of the bitterness suppression method of the present invention, 10 to 40 moles of β-cyclodextrin and / or its derivatives can be used per mole of atomoxetine hydrochloride. This is because using 10 moles or more of β-cyclodextrin and / or its derivatives 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 its derivatives.

[0079] The atomoxetine hydrochloride solution, whose bitterness is suppressed according to the present invention, can be powdered by a drying process such as freeze-drying or spray-drying.

[0080] The bitterness suppression method for atomoxetine hydrochloride provided by the present invention can be evaluated by a panel sensory evaluation test and / or instrumental measurement (taste recognition device, taste sensor). Regarding bitterness masking, the results of the sensory evaluation and the output of the taste sensor show a high correlation, demonstrating that the 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 an atomoxetine hydrochloride-containing pharmaceutical composition, comprising the step of mixing atomoxetine hydrochloride and β-cyclodextrin and / or its derivative in a solvent to obtain an atomoxetine hydrochloride-containing solution with reduced bitterness, wherein the amount of β-cyclodextrin and / or its derivative is 1 mole or more per mole of atomoxetine hydrochloride.

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

[0083] In the method for producing the pharmaceutical composition provided by the present invention, atomoxetine hydrochloride and cyclodextrin and / or derivatives 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 produced by the manufacturing method of the present invention may contain, in addition to CD, pharmaceutically acceptable additives as needed. Examples of pharmaceutically acceptable additives include, but are not limited to, excipients, decomposing agents, binders, coating agents, swelling agents, glidants, lubricants, flavoring agents, sweeteners, or solubilizers. More specifically, pharmaceutically acceptable additives include, for example, 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 produced by the manufacturing 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 manufacturing method of the present invention can be used as a therapeutic or prophylactic agent for subjects suffering from or suspected of suffering from a disease for which atomoxetine hydrochloride exerts therapeutic and / or prophylactic effects. Specifically, it can be used for the treatment of attention deficit / hyperactivity disorder. The target subjects for administration are mammals, including humans.

[0086] In one embodiment, the pharmaceutical composition produced by the manufacturing method of the present invention can be an oral liquid formulation. Although the present invention is not bound by any particular theory, in the manufacturing method of the present invention, it is thought that CD acts on the atomoxetine hydrochloride molecule itself to mask the bitterness, and the bitterness is suppressed even in liquid form, so that patients do not perceive bitterness as much as in an oral liquid formulation. Oral liquid formulations are also easy to adjust the dose of. Therefore, according to one embodiment of the present invention, it is possible to provide an atomoxetine hydrochloride-containing oral liquid formulation that can be administered to patients with impaired swallowing ability and is suitable for careful administration to the elderly because the dose can be easily adjusted. The clinical dose of atomoxetine hydrochloride is 40 mg to 120 mg per day in atomoxetine equivalent (administered orally once or twice a day). Since it is easier for elderly patients and patients with dysphagia to take a smaller dose, it is preferable that the atomoxetine hydrochloride concentration in the oral liquid formulation be at least 4.6 mg / mL (4 mg / mL in atomoxetine equivalent).

[0087] (Suppression of the bitter taste of donepezil hydrochloride) Donepezil hydrochloride, whose chemical name is (2RS)-2-[(1-benzylpiperidine-4-yl)methyl]-5,6-dimethoxy-2,3-dihydro-1H-inden-1-one-hydrochloride, is useful in suppressing the progression of dementia symptoms in Alzheimer's disease and Lewy body dementia. It is a compound shown by the following structural formula. [ka]

[0088] The present invention provides a bitterness inhibitor for donepezil hydrochloride, comprising cyclodextrin and / or its derivatives as an active ingredient.

[0089] When suppressing the bitterness of donepezil hydrochloride, the bitterness inhibitor 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 derivatives thereof per mole of donepezil hydrochloride.

[0090] In one embodiment, the bitterness inhibitor of the present invention uses 1 to 50 moles of cyclodextrin and / or its derivatives per mole of donepezil hydrochloride. This is because using 1 mole or more of cyclodextrin and / or its derivatives per mole of donepezil hydrochloride suppresses the bitterness of donepezil hydrochloride to an acceptable level. Furthermore, adding 50 moles or less of cyclodextrin and / or its derivatives per mole of donepezil hydrochloride keeps costs down, and the mixture of donepezil hydrochloride and cyclodextrin and / or its derivatives does not take up much space when dried.

[0091] In a preferred embodiment of the present invention, the bitterness inhibitor uses 5 to 40 moles of β-cyclodextrin and / or its derivatives per mole of donepezil hydrochloride. This is because using 5 moles or more of β-cyclodextrin and / or its derivatives per mole of donepezil hydrochloride significantly suppresses the bitterness of donepezil hydrochloride compared to using 5 moles or more of α- or γ-cyclodextrin and / or its derivatives.

[0092] In another preferred embodiment of the present invention, the bitterness inhibitor uses 10 to 40 moles of β-cyclodextrin and / or its derivatives per mole of donepezil hydrochloride. This is because using 10 moles or more of β-cyclodextrin and / or its derivatives 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 its derivatives. Furthermore, adding 40 moles or less of cyclodextrin and / or its derivatives per mole of donepezil hydrochloride keeps costs down, and the mixture of donepezil hydrochloride and cyclodextrin and / or its derivatives does not take up much space when dried.

[0093] The cyclodextrin and / or derivative thereof, which are the active ingredients of the bitterness inhibitor of the present invention, are not limited in type, but β-CD and / or derivative thereof are particularly preferred. This is because β-CD and / or derivative thereof have a high effect in suppressing the bitterness of donepezil hydrochloride. In one preferred embodiment, the cyclodextrin and / or derivative thereof, which are the active ingredients of the bitterness inhibitor of the present invention, is β-CD.

[0094] The bitterness inhibitor of donepezil hydrochloride provided by the present invention can be mixed with donepezil hydrochloride in a solvent containing water. This is because the inclusion action of CD or its derivatives occurs in the form of an aqueous solution of CD or its derivatives.

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

[0096] The step of mixing donepezil hydrochloride and cyclodextrin and / or its derivatives in a solvent can be carried out by dissolving donepezil hydrochloride and cyclodextrin and / or its derivatives in the solvent. Donepezil hydrochloride and cyclodextrin and / or its derivatives may be added to the solvent and dissolved either first or simultaneously. Alternatively, the solution can be prepared by adding cyclodextrin in powder or solution form 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, it can be first dissolved in an organic solvent such as polyethylene glycol or glycerin, and then mixed with water. To increase the solubility of cyclodextrin, the solvent to which donepezil hydrochloride and cyclodextrin and / or its derivatives have been added can be heated and stirred. When heating and stirring, the solvent can be heated to a temperature of, for example, 60-85°C.

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

[0098] The cyclodextrin and / or derivatives used in the bitterness suppression method of the present invention are not particularly limited in type, but β-CD and / or derivatives are particularly preferred. This is because β-CD and / or derivatives have a high effect in suppressing the bitterness of donepezil hydrochloride.

[0099] In the bitterness suppression method of the present invention, in one preferred embodiment, 5 to 50 moles of β-cyclodextrin and / or its derivatives can be used per mole of donepezil hydrochloride. This is because using 5 moles or more of β-cyclodextrin and / or its derivatives per mole of donepezil hydrochloride significantly suppresses the bitterness of donepezil hydrochloride compared to using 5 moles or more of α- or γ-cyclodextrin and / or its derivatives.

[0100] In another preferred embodiment of the bitterness suppression method of the present invention, 10 to 40 moles of β-cyclodextrin and / or its derivatives can be used per mole of donepezil hydrochloride. This is because using 10 moles or more of β-cyclodextrin and / or its derivatives 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 its derivatives.

[0101] The donepezil hydrochloride solution, whose bitterness is suppressed according to the present invention, can be powdered by a drying process such as freeze-drying or spray-drying.

[0102] The bitterness suppression method for donepezil hydrochloride provided by the present invention can be evaluated by a panel sensory evaluation test and / or instrumental measurement (taste recognition device, taste sensor). Regarding bitterness masking, the results of the sensory evaluation and the output of the taste sensor show a high correlation, demonstrating 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 donepezil hydrochloride-containing pharmaceutical composition, comprising the step of mixing donepezil hydrochloride and β-cyclodextrin and / or its derivative in a solvent to obtain a donepezil hydrochloride-containing solution with reduced bitterness, wherein the amount of β-cyclodextrin and / or its derivative is 0.1 moles or more per mole of donepezil hydrochloride.

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

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

[0106] The donepezil hydrochloride-containing pharmaceutical composition produced by the manufacturing method of the present invention may contain, in addition to CD, pharmaceutically acceptable additives as needed. Examples of pharmaceutically acceptable additives include, but are not limited to, excipients, decomposing agents, binders, coating agents, swelling agents, glidants, lubricants, flavoring agents, sweeteners, or solubilizers. More specifically, pharmaceutically acceptable additives include, for example, 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 produced by the manufacturing 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 donepezil hydrochloride-containing pharmaceutical composition produced by the manufacturing method of the present invention can be used as a therapeutic or prophylactic agent for subjects suffering from or suspected of suffering from a disease for which donepezil hydrochloride exerts therapeutic and / or prophylactic effects. Specifically, it can be used to suppress the progression of dementia symptoms in Alzheimer's disease and Lewy body dementia. The target subjects for administration are mammals, including humans.

[0108] In one embodiment, the pharmaceutical composition produced by the manufacturing method of the present invention can be an oral liquid formulation. Although the present invention is not bound by any particular theory, in the manufacturing method of the present invention, it is thought that CD acts on the donepezil hydrochloride molecule itself to mask the bitterness, and the bitterness is suppressed even in liquid form, so that patients do not perceive bitterness as much as in an oral liquid formulation. Oral liquid formulations are also easy to adjust the dose of. Therefore, according to one embodiment of the present invention, it is possible to provide an oral liquid formulation containing donepezil hydrochloride that can be administered to patients with impaired swallowing ability and is suitable for careful administration to the elderly because the dose can be easily adjusted. The clinical dose of donepezil hydrochloride is 3 mg to 10 mg of donepezil hydrochloride per day (once daily orally). Since it is easier for elderly patients and patients with dysphagia to take a smaller dose, it is preferable that the concentration of donepezil hydrochloride in the oral liquid formulation be at least 0.15 mg / mL.

[0109] (Suppression of the bitter taste 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 the treatment of glaucoma and ocular hypertension. It is a compound represented by the following structural formula. [ka]

[0110] The present invention provides a bitterness inhibitor for dorzolamide hydrochloride, comprising cyclodextrin and / or its derivatives as an active ingredient.

[0111] When suppressing the bitterness of dorzolamide hydrochloride, the bitterness inhibitor 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 derivatives thereof per mole of dorzolamide hydrochloride.

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

[0113] In a preferred embodiment of the present invention, the bitterness inhibitor uses 5 to 40 moles of γ-cyclodextrin and / or its derivatives per mole of dorzolamide hydrochloride. This is because using 5 moles or more of γ-cyclodextrin and / or its derivatives per mole of dorzolamide hydrochloride significantly suppresses the bitterness of dorzolamide hydrochloride compared to using 5 moles or more of α- or β-cyclodextrin and / or its derivatives.

[0114] In another preferred embodiment, the bitterness inhibitor of the present invention uses 10 to 40 moles of γ-cyclodextrin and / or its derivatives per mole of dorzolamide hydrochloride. This is because using 10 moles or more of γ-cyclodextrin and / or its derivatives 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 derivatives. Furthermore, adding 40 moles or less of cyclodextrin and / or its derivatives per mole of dorzolamide hydrochloride keeps costs down, and the mixture of dorzolamide hydrochloride and cyclodextrin and / or its derivatives does not take up much space even when dried.

[0115] The cyclodextrin and / or derivative thereof, which are the active ingredients of the bitterness inhibitor of the present invention, are not limited in type, but γ-CD and / or derivative thereof are particularly preferred. This is because γ-CD and / or derivative thereof have a high effect in suppressing the bitterness of dorzolamide hydrochloride. In one preferred embodiment, the cyclodextrin and / or derivative thereof, which are the active ingredients of the bitterness inhibitor of the present invention, is γ-CD.

[0116] The bitterness inhibitor of dorzolamide hydrochloride provided by the present invention can be mixed with dorzolamide hydrochloride in a solvent containing water. This is because the inclusion effect of CD or its derivatives occurs in the form of an aqueous solution of CD or its derivatives.

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

[0118] The step of mixing dorzolamide hydrochloride and cyclodextrin and / or its derivatives in a solvent can be carried out by dissolving dorzolamide hydrochloride and cyclodextrin and / or its derivatives in the solvent. Dorzolamide hydrochloride and cyclodextrin and / or its derivatives may be added to the solvent and dissolved either first or simultaneously. Alternatively, the solution can be prepared by adding CD in powder or solution form 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, it 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 to which dorzolamide hydrochloride and CD and / or its derivatives have been added can be heated and stirred. When heating and stirring, the solvent can be heated to a temperature of, for example, 60-85°C.

[0119] In the bitterness suppression method of the present invention, cyclodextrin and / or its derivatives can be mixed with 1 mole of dorzolamide hydrochloride in amounts of 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. In one embodiment of the bitterness suppression method of the present invention, the amount of cyclodextrin and / or its derivatives can be 3 to 50 moles per mole of dorzolamide hydrochloride. In another embodiment, the amount of cyclodextrin and / or its derivatives can be 10 to 40 moles per mole of dorzolamide hydrochloride.

[0120] The cyclodextrin and / or derivatives used in the bitterness suppression method of the present invention are not particularly limited in type, but γ-CD and / or derivatives are particularly preferred. This is because γ-CD and / or derivatives have a high effect in suppressing the bitterness of dorzolamide hydrochloride.

[0121] In the bitterness suppression method of the present invention, in one preferred embodiment, 5 to 50 moles of γ-cyclodextrin and / or its derivatives can be used per mole of dorzolamide hydrochloride. This is because using 5 moles or more of γ-cyclodextrin and / or its derivatives per mole of dorzolamide hydrochloride significantly suppresses the bitterness of dorzolamide hydrochloride compared to using 5 moles or more of α- or β-cyclodextrin and / or its derivatives.

[0122] In another preferred embodiment of the bitterness suppression method of the present invention, 10 to 40 moles of γ-cyclodextrin and / or its derivatives can be used per mole of dorzolamide hydrochloride. This is because using 10 moles or more of γ-cyclodextrin and / or its derivatives 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 derivatives.

[0123] The bitterness suppression method for dorzolamide hydrochloride provided by the present invention can be evaluated by a panel sensory evaluation test and / or instrumental measurement (taste recognition device, taste sensor). Regarding bitterness masking, the results of the sensory evaluation and the output of the taste sensor show a high correlation, demonstrating 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 dorzolamide hydrochloride-containing pharmaceutical composition, comprising the step of mixing dorzolamide hydrochloride and γ-cyclodextrin and / or its derivative in a solvent to obtain a dorzolamide hydrochloride-containing solution with reduced bitterness, wherein the amount of γ-cyclodextrin and / or its derivative is 2 moles or more per 1 mole of dorzolamide hydrochloride.

[0125] The step 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 method for suppressing the bitterness of dorzolamide hydrochloride described above, and the same solvent can be used.

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

[0127] The pharmaceutical composition containing dorzolamide hydrochloride produced by the manufacturing method of the present invention may contain, in addition to CD, pharmaceutically acceptable additives as needed. Examples of pharmaceutically acceptable additives include, but are not limited to, pH adjusters, thickeners, or solubilizers.

[0128] The dorzolamide hydrochloride-containing pharmaceutical composition produced by the manufacturing method of the present invention can be used as a therapeutic or preventive agent for subjects suffering from or suspected of suffering from diseases for which dorzolamide hydrochloride exerts therapeutic and / or preventive effects. Specifically, it can be used for the treatment of glaucoma and ocular hypertension. The target subjects for administration are mammals, including humans.

[0129] In one embodiment, the pharmaceutical composition produced by the manufacturing method of the present invention can be an eye drop. Although the present invention is not bound by any particular theory, in the manufacturing method of the present invention, it is thought that CD acts on the dorzolamide hydrochloride molecule itself to mask the bitterness, thus suppressing the bitterness, and even if the eye drop flows from the nose to the throat, the patient will not perceive much bitterness. The clinical dose of dorzolamide hydrochloride is one drop of a 0.5% dorzolamide solution to be instilled three times a day. The dorzolamide hydrochloride concentration is preferably at least 5.6 mg / mL (5 mg / mL in terms of dorzolamide equivalent). [Examples]

[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 a 10 mM potassium chloride solution to a final concentration of 0.5 mM, and this was prepared as a duloxetine hydrochloride solution. To this solution, α-CD, β-CD, γ-CD, or hydroxypropylated β-CD (HP-β-CD) was added to achieve a final concentration of 0.5 to 10 mM and completely dissolved.

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

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

[0134] [Table 1]

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

[0136] Next, β-CD was dissolved in 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 it was found that this effect increased in a dependent manner with the concentration of addition. These results confirmed that β-CD is effective in suppressing bitterness detected by a taste recognition device in a dose-dependent manner when added in the range of 0.5 to 40 moles per mole of duloxetine hydrochloride.

[0138] [Example 2: Manufacturing example of oral solution containing duloxetine hydrochloride] Manufacturing example: Duloxetine hydrochloride 1.1 mg / mL (equivalent to 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 an aqueous solution of duloxetine hydrochloride. 3. Add the fragrance to the above mixture, and then add purified water to make a total volume of 100 mL. The oral solution produced in this manufacturing example has a suppressed bitterness and a taste that is acceptable for use as a medicine.

[0139] [Example 3: Suppression of the unpleasant bitter taste 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 at final concentrations of 10 mM, 0.5 mM, 30 v / v%, and 0.5–10 mM, respectively.

[0140] The bitterness of aripiprazole was assessed by measuring the CPA (Change of Membrane Potential by Absorption) value (mV) using the taste recognition device "SA402B" (manufactured by Intelligent Sensor Technology Co., Ltd.) and the bitterness sensor AC0. The bitterness-suppressing effect of citric acid (CD) addition to aripiprazole was evaluated based on the CPA value. The CPA value is the average of three measurement data. A higher CPA value indicates stronger bitterness, so a lower CPA value indicates a greater bitterness-suppressing effect from CD addition.

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

[0142] [Table 3]

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

[0144] Next, β-CD was dissolved in aripiprazole solution to a final concentration of 0.1–20 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 it was found that this effect increased in a dependent manner with the concentration of addition. These results confirmed that β-CD is effective in suppressing bitterness detected by taste perception enhancement in a dose-dependent manner when added in the range of 0.2 to 40 moles per mole of aripiprazole.

[0146] [Example 4: Manufacturing example of oral solution] 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 an aqueous solution of aripiprazole. 3. Add the fragrance to the above mixture, and then add purified water to make a total volume of 100 mL. The oral solution produced in this manufacturing example has a suppressed bitterness and a taste that is acceptable for use as a medicine.

[0147] [Example 5: Suppression of the unpleasant bitter taste of atomoxetine hydrochloride] Atomoxetine hydrochloride was dissolved in a 10 mM potassium chloride solution to a final concentration of 0.5 mM, and this was prepared as the atomoxetine hydrochloride solution. To this solution, α-CD, β-CD, γ-CD, or hydroxypropylated β-CD (HP-β-CD) was added to achieve a final concentration of 0.5-5 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 the taste recognition device "SA402B" (manufactured by Intelligent Sensor Technology Co., Ltd.) and the bitterness sensor AC0. The bitterness suppression effect of CD addition to atomoxetine hydrochloride solution was evaluated by the CPA value. The CPA value is the average of three measurement data. A higher CPA value indicates stronger bitterness, so a lower CPA value indicates a greater bitterness suppression effect from CD addition.

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

[0150] [Table 5]

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

[0152] Next, β-CD was dissolved in 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 it was found that this effect increased in a dependent manner with the concentration of addition. These results confirmed that β-CD is effective in suppressing bitterness detected by a taste recognition device in a dose-dependent manner in the range of 1 to 40 moles per mole of atomoxetine hydrochloride.

[0153] [Example 6: Example of manufacturing an oral solution] Manufacturing example: Atomoxetine hydrochloride 4.6 mg / mL (4 mg as atomoxetine) 1. Dissolve 460 mg of atomoxetine hydrochloride in 80 mL of purified water. 2. Dissolve 1.8 g of β-CD in an aqueous solution of atomoxetine hydrochloride. 3. Add the fragrance to the above mixture, and then add purified water to make a total volume of 100 mL. The oral solution produced in this manufacturing example has a suppressed bitterness and a taste that is acceptable for use as a medicine.

[0154] [Example 7: Suppression of the unpleasant bitter taste of donepezil hydrochloride] Donepezil hydrochloride was dissolved in a 10 mM potassium chloride solution to a final concentration of 1 mM, and this was prepared as a donepezil hydrochloride solution. To this solution, α-CD, β-CD, γ-CD, or hydroxypropylated β-CD (HP-β-CD) was added to achieve 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 the taste recognition device "SA402B" (manufactured by Intelligent Sensor Technology Co., Ltd.) and the bitterness sensor AC0. The bitterness suppression effect of CD addition to donepezil hydrochloride solution was evaluated by the CPA value. The CPA value is the average of three measurement data. A higher CPA value indicates stronger bitterness, so a lower CPA value indicates a greater bitterness suppression effect from CD addition.

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

[0157] [Table 7]

[0158] As shown in the table above, a decrease in the CPA value of donepezil hydrochloride solution was observed when α-CD was added at a concentration of 1 mM or higher, when β-CD was added at a concentration of 0.5 mM or higher, when γ-CD was added at a concentration of 1 mM or higher, and when HP-β-CD was added at a concentration of 0.5 mM or higher.

[0159] Next, β-CD was dissolved in 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 it was found that this effect increased in a dependent manner with the concentration of addition. These results confirmed that β-CD is effective in suppressing bitterness detected by a taste recognition device in a dose-dependent manner when added in the range of 0.1 to 20 moles per mole of donepezil hydrochloride.

[0160] [Example 8: Example of manufacturing an oral solution] 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 donepezil hydrochloride aqueous solution. 3. Add the fragrance to the above mixture, and then add purified water to make a total volume of 100 mL. The oral solution produced in this manufacturing example has a suppressed bitterness and a taste that is acceptable for use as a medicine.

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

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

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

[0164] [Table 9]

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

[0166] Next, γ-CD was dissolved in 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 it was found that this effect increased in a dependent manner with the concentration of addition. These results confirmed that γ-CD is effective in suppressing bitterness detected by a taste recognition device in a dose-dependent manner in the range of 2 to 40 moles per mole of dorzolamide hydrochloride.

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

Claims

1. A bitterness inhibitor for a pharmaceutically active compound, comprising a liquid composition or a dried product thereof, containing cyclodextrin as an active ingredient, The aforementioned pharmaceutically active compound is atomoxetine hydrochloride, The cyclodextrin (CD) is selected from the group consisting of α-cyclodextrin (α-CD), β-cyclodextrin (β-CD), γ-cyclodextrin (γ-CD), and hydroxypropylated β-cyclodextrin (HP-β-CD). If the CD is α-CD, γ-CD, or HP-β-CD, In the liquid composition, the concentration of CD is 2.5 mM to 5.0 mM relative to 0.5 mM of the pharmaceutically active compound. In the dry form, the ratio of CD to 10 moles per mole of the pharmaceutically active compound is 5 to 10 moles. If the CD is a β-CD, In the liquid composition, the concentration of CD is 0.5 mM to 20 mM relative to 0.5 mM of the pharmaceutically active compound. In the dried form, the ratio of CD to 1 mole of pharmaceutically active compound is 1 to 40 moles. Bitterness inhibitor.

2. The bitterness inhibitor according to claim 1, wherein the CD is β-CD.

3. A method for suppressing the bitterness of a pharmaceutically active compound in a liquid composition or its dried product obtained by the mixing, comprising the step of mixing a pharmaceutically active compound and cyclodextrin in a solvent, The aforementioned pharmaceutically active compound is atomoxetine hydrochloride, The cyclodextrin (CD) is selected from the group consisting of α-cyclodextrin (α-CD), β-cyclodextrin (β-CD), γ-cyclodextrin (γ-CD), and hydroxypropylated β-cyclodextrin (HP-β-CD). If the CD is α-CD, γ-CD, or HP-β-CD, In the liquid composition, the concentration of CD is 2.5 mM to 5.0 mM relative to 0.5 mM of the pharmaceutically active compound. In the dry form, the ratio of CD to 10 moles per mole of the pharmaceutically active compound is 5 to 10 moles. If the CD is a β-CD, In the liquid composition, the concentration of CD is 0.5 mM to 20 mM relative to 0.5 mM of the pharmaceutically active compound. In the dried form, the ratio of CD to 1 mole of pharmaceutically active compound is 1 to 40 moles. A method for suppressing the bitter taste of pharmacoactive compounds.

4. The bitterness inhibitor according to claim 3, wherein the CD is β-CD.

5. A method for producing a liquid composition containing a pharmaceutically active compound with suppressed bitterness or a dried product thereof, comprising the step of mixing the pharmaceutically active compound with cyclodextrin (CD) in a solvent to obtain a pharmaceutically active compound-containing solution in which bitterness is reduced by the interaction between CD and the pharmaceutically active compound, wherein The aforementioned pharmaceutically active compound is atomoxetine hydrochloride, The aforementioned CD is selected from the group consisting of α-cyclodextrin (α-CD), β-cyclodextrin (β-CD), γ-cyclodextrin (γ-CD), and hydroxypropylated β-cyclodextrin (HP-β-CD). If the CD is α-CD, γ-CD, or HP-β-CD, In the liquid composition, the concentration of CD is 2.5 mM to 5.0 mM relative to 0.5 mM of the pharmaceutically active compound. In the dry form, the ratio of CD to 10 moles per mole of the pharmaceutically active compound is 5 to 10 moles. If the CD is a β-CD, In the liquid composition, the concentration of CD is 0.5 mM to 20 mM relative to 0.5 mM of the pharmaceutically active compound. In the dried form, the ratio of CD to 1 mole of pharmaceutically active compound is 1 to 40 moles. Manufacturing method.

6. The method according to claim 5, further comprising the step of drying the solution containing the pharmaceutically active compound.

7. The manufacturing method according to claim 5, wherein the liquid composition containing the pharmaceutically active compound is an oral liquid formulation.

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