JP2024009146A - Agent and method for inhibiting bitterness of pharmaceutical active compound - Google Patents

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

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 an agent for suppressing the bitterness of a pharmaceutically active compound.

Pharmaceutically active compounds are administered by a variety of routes, including orally, nasally, and transdermally. Among them, oral administration is an easy, convenient, non-invasive and well-known method of drug delivery. However, some pharmaceutically active compounds have extremely unpleasant tastes, such as bitterness. Conventional solid forms (tablets or capsules, etc.) are usually swallowed immediately after administration and are less likely to taste bitter, but some patients may not be able to tolerate the extremely unpleasant taste of bitterness and may not be able to take the medication. Liquid forms (e.g., solutions, suspensions, syrups, emulsions) are recommended for patients who have difficulty administering conventional solid forms orally (e.g., children and elderly patients) due to poor swallowing function. (or liquid mixture of dry syrup mixed with water, etc.), chewable tablets, orally disintegrating tablets, etc. are prescribed, but there is a problem that bitter substances often come into contact with the taste buds, making it easy to perceive bitterness. .

Among the medical drugs that are commonly used in Japan and have sales of over 5 billion yen in Japan, for example, many of them contain bitter-tasting medicinal active compounds as active ingredients. For example, atomoxetine hydrochloride for the treatment of attention-deficit/hyperactivity disorder (ADHD), duloxetine hydrochloride for the antidepressant, donepezil hydrochloride for the treatment of Alzheimer's, aripiprazole for the antipsychotic, and dorzolamide for the treatment of glaucoma and ocular hypertension. Hydrochloride is known to have a bitter taste. Although it is important for patients to take medicines prescribed by their doctors as directed, patients may not be able to tolerate the bitter taste of these pharmaceutically active compounds, leading to problems such as reduced medication adherence and compliance. .

Therefore, masking the bitter taste of pharmaceutically active compounds is an important challenge. Masking techniques are known to mask bitterness by adding sweeteners (sugar, artificial sweeteners, etc.) and flavorings (fruit, chocolate), and to trap bitterness through coating substances and microencapsulation. However, there are problems such as not being able to completely hide the bitter taste, or feeling bitter when dissolved in the mouth.

WO 2005/000001 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, wherein the atomoxetine comprises: It is stated that taste may be masked by a combination of polymer and suspending medium. Patent Document 2 discloses an orally disintegrating tablet comprising main drug particles containing a drug that exhibits an unpleasant taste and having a coating layer covering the drug, a Wicking type disintegrant and a Swelling type disintegrant, It is stated that the drug exhibiting an unpleasant taste may be donepezil hydrochloride or the like. Patent Document 3 includes one or more water-soluble polymers, one or more pharmaceutically active ingredients, a stevioside sweetener as an aftertaste improver, and one or more primary sweeteners as a taste blocker. It discloses a fast-dissolving film for oral use and states that the pharmaceutically active ingredient may be aripiprazole, donepezil, and the like.

Special Publication No. 2007-517050 Japanese Patent Application Publication No. 2013-147470 Special Publication No. 2012-528854

Conventional techniques for suppressing bitterness require complicated processes and multiple additives to suppress the bitterness of pharmaceutically active compounds, resulting in high costs. Furthermore, with dosage forms that tend to be bitter, such as chewable tablets, orally disintegrating tablets, or liquid preparations (including liquids prepared by mixing dry syrup with water), it has not been possible to sufficiently mask the bitterness.

In view of the above-mentioned current situation, it is an object of the present invention to suppress the bitterness of pharmaceutically active compounds without requiring complicated steps or multiple additives, while suppressing costs. Another object of the present invention is to provide a pharmaceutically active compound-containing composition that does not taste bitter even when taken in a dosage form that is normally sensitive to bitterness.

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

[5] A step of mixing a pharmaceutically active compound and a cyclodextrin and/or its derivative in a solvent, the amount of cyclodextrin and/or its derivative being 0.5 mol or more per 1 mol of the pharmaceutically active compound, and the above-mentioned pharmaceutical The method for suppressing the bitter taste of a pharmaceutically active compound, wherein the active compound is any 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 step of mixing a pharmaceutically active compound and a cyclodextrin and/or its derivative in a solvent to obtain a pharmaceutically active compound-containing solution with reduced bitterness, wherein the cyclodextrin and/or its derivative is a pharmaceutically active compound. 0.5 mole or more per mole, and the pharmaceutically active compound is any one selected from the group consisting of duloxetine hydrochloride, aripiprazole, atomoxetine hydrochloride, donepezil hydrochloride, and dorzolamide hydrochloride. Method for producing active compound-containing compositions.
[8] The production method according to [7], wherein the cyclodextrin and/or its derivative is β-cyclodextrin.
[9] The manufacturing method according to [7] or [8], wherein the pharmaceutically active compound-containing composition is a liquid preparation for internal use.

By using cyclodextrin and/or its derivatives, the bitter taste of pharmaceutically active compounds can be reduced.

Although the present invention described below may be described based on typical embodiments and specific examples, the present invention is not limited to such embodiments. In this specification, a numerical range expressed using "~" means a range that includes the numerical values written before and after "~" as lower and upper limits.

The present invention provides a bitter taste suppressor for pharmaceutically active compounds containing cyclodextrin and/or a derivative thereof as an active ingredient, wherein the pharmaceutically active compounds include duloxetine hydrochloride, aripiprazole, atomoxetine hydrochloride, donepezil hydrochloride, and dorzolamide. Provided is a bitter taste suppressor selected from the group consisting of hydrochloride salts.

Cyclodextrin (sometimes referred to as "CD" in this specification), also called cyclic oligosaccharide, is a cyclic α-1,4-glucan, and cyclodextrin glucanotransferase is used to transfer α- It is produced by acting on 1,4-glucan through its intramolecular transfer reaction. Their degree of polymerization is mainly 6, 7, and 8, and they are called α-CD, β-CD, and γ-CD, respectively.

In the present invention, "bitter taste" is a general term for an unpleasant unpleasant sensation, including bitterness and astringency, felt in the oral cavity and pharynx. As used herein, "suppressing bitterness" and "suppressing bitterness" refer to the suppression, reduction, concealment, or masking of the bitterness felt when bitter substances are present in the oral cavity, and include unpleasant tastes including bitterness and astringency. This may include suppressing, reducing, concealing, or masking the discomfort. "Suppression" refers to the fact that the "bitter taste" felt in the oral cavity is somewhat reduced when a "bitter taste suppressant" is used, compared to when it is not used. This may include cases where it is acceptable to the patient. The bitter taste suppressant of the present invention contains cyclodextrin and/or a derivative thereof as an active ingredient, and contains a pharmaceutically active compound selected from the group consisting of duloxetine hydrochloride, aripiprazole, atomoxetine hydrochloride, donepezil hydrochloride, and dorzolamide hydrochloride. Bitterness can be suppressed.

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

When viewed three-dimensionally, cyclodextrin has a so-called bottomless bucket-like or donut-shaped structure, and has the characteristic that the outside of the cavity is hydrophilic, while the inside of the cavity is hydrophobic. Due to this feature, the CD exhibits a phenomenon (inclusion) in which a specific organic molecule (guest molecule) is wrapped and incorporated into the cavity, and an inclusion complex is formed. In general, inclusion of a guest molecule by a CD can occur when the size of the cyclodextrin cavity and the size of the guest molecule or the size of a part of the structure of the guest molecule match. Furthermore, since the inside of the CD cavity is hydrophobic, when the guest molecule is hydrophobic, it tends to be included relatively easily.

Among cyclodextrins, β-CD is the most commonly used because it is produced in large quantities and is inexpensive. However, β-CD has a lower water solubility than α-CD and γ-CD, so it is said to be disadvantageous for solubilization. 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 has high water solubility. Since α-CD has a smaller inner cavity diameter than β-CD and γ-CD, it is thought that the size of the guest molecules to be included is also smaller compared to β-CD and γ-CD. ing.

The effect of inclusion may be observed even when the entire guest molecule is clearly larger than the cyclodextrin, and it is considered that the guest molecule only needs to fit, even partially, into the cavity of the host CD. The inclusion ability of CDs is influenced by the chemical interaction between host CDs and guest molecules. The interactions between host CDs and guest molecules include hydrophobic effects, van der Waals forces, ion-ion interactions, dipole interactions, and hydrogen bonds, and these interactions are thought to function cooperatively. It will be done. Although the present invention is not bound by any particular theory, it is believed that a plurality of CDs and/or derivatives thereof act on one pharmaceutically active compound molecule, and that CDs and/or derivatives thereof and pharmaceuticals It is believed that interactions other than inclusion exist between active compound molecules.

The CD and/or its derivatives used in the present invention may be in the form of crystals, amorphous powders, syrup, or the like. Furthermore, in addition to CD and/or its derivatives, those containing, for example, malto-oligosaccharides and other carbohydrates, which are included as by-products in the process of producing or preparing CDs, may be used.

(Suppression of bitterness of duloxetine hydrochloride)
Duloxetine hydrochloride is a serotonin noradrenaline reuptake agent whose chemical name is (+)-(S)-N-methyl-3-(1-naphthyloxy)-3-(2-thienyl)propylamine monohydrochloride. It is an inhibitor and is useful in the treatment of depression/depression, pain associated with diabetic neuropathy, pain associated with fibromyalgia, pain associated with chronic low back pain, and pain associated with osteoarthritis. This is a compound represented by the following structural formula.

The present invention provides a bitter taste suppressant for duloxetine hydrochloride, which contains cyclodextrin and/or a derivative thereof as an active ingredient.

When suppressing the bitter taste of duloxetine hydrochloride, the bitter taste suppressor of the present invention can be used in amounts of 0.1 mol or more, 0.2 mol or more, or 0.5 mol for 0.5 mol or more and 1 mol of duloxetine hydrochloride. 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 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 can be used.

In one embodiment of the bitter taste suppressor of the present invention, 2 to 50 moles of cyclodextrin and/or its derivatives are used per mole of duloxetine hydrochloride. This is because the bitterness of duloxetine hydrochloride is suppressed to an acceptable level by using 2 moles or more of cyclodextrin and/or its derivatives with respect to 1 mole of duloxetine hydrochloride. In addition, if 50 moles or less of cyclodextrin and/or its derivatives are added to 1 mole of duloxetine hydrochloride, the cost can be reduced, and the mixture of duloxetine hydrochloride and cyclodextrin and/or its derivatives can be used as a dry product. This is because it is not too bulky.

In a preferred embodiment of the bitter taste suppressor of the present invention, 5 to 40 moles of β-cyclodextrin and/or its derivatives are used per mole of duloxetine hydrochloride. By using 5 moles or more of β-cyclodextrin and/or its derivatives for 1 mole of duloxetine hydrochloride, compared with using 5 moles or more of α- or γ-cyclodextrin and/or its derivatives. This is because the bitter taste of duloxetine hydrochloride is significantly suppressed.

In another preferred embodiment of the bitter taste suppressor of the present invention, 10 to 40 moles of β-cyclodextrin and/or its derivatives are used per mole of duloxetine hydrochloride. By using 10 moles or more of β-cyclodextrin and/or its derivatives for 1 mole of duloxetine hydrochloride, compared with using 10 moles or more of α- or γ-cyclodextrin and/or its derivatives. This is because the bitter taste of duloxetine hydrochloride is significantly suppressed. In addition, if 40 moles or less of cyclodextrin and/or its derivatives are added to 1 mole of duloxetine hydrochloride, the cost can be reduced, and the mixture of duloxetine hydrochloride and cyclodextrin and/or its derivatives can be added in a dry form. This is because it is not bulky.

The type of cyclodextrin and/or its derivatives that are the active ingredients of the bitter taste suppressor of the present invention is not limited, but β-CD and/or its derivatives are particularly preferred. This is because β-CD and/or its derivatives are highly effective in suppressing the bitter taste of duloxetine hydrochloride. In one preferred embodiment, the cyclodextrin and/or its derivatives which are the active ingredients of the bitter taste suppressor of the present invention are β-CD and HP-β-CD.

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

According to the present invention, the method includes a step of mixing duloxetine hydrochloride and cyclodextrin and/or a derivative thereof in a solvent, and the amount of cyclodextrin and/or its derivative is 0.5 mol or more per 1 mol of duloxetine hydrochloride. A method for suppressing the bitter taste of duloxetine hydrochloride is provided.

The step of mixing duloxetine hydrochloride and cyclodextrin and/or its derivative in a solvent can be carried out by dissolving duloxetine hydrochloride and cyclodextrin and/or its derivative in a solvent, and duloxetine hydrochloride and cyclodextrin and/or its derivatives may be added to the solvent first and dissolved therein, or may be added and dissolved at the same time. Alternatively, it can also be prepared by adding CD as a powder or solution to a duloxetine hydrochloride solution in which duloxetine hydrochloride is dissolved in a solvent, and stirring the mixture. The solvent can be selected from sterile or 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, glycerin, and then mixed with water. In order to increase the solubility of CD, the solvent to which duloxetine hydrochloride and CD and/or its derivatives are added can be heated and stirred. When heating and stirring, the solvent can be heated, for example, to a temperature of 60 to 85°C.

In the bitterness suppression method of the present invention, 0.5 mol or more, 1 mol or more, 2 mol or more, 3 mol or more, 4 mol or more, 5 mol or more, 10 mol or more, 20 mol or more per 1 mol of duloxetine hydrochloride. 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 derivatives thereof can be mixed. In the method for suppressing bitterness of the present invention, in one embodiment, the amount of cyclodextrin and/or its derivative can be 2 to 50 mol per 1 mol of duloxetine hydrochloride. In another embodiment, the amount of cyclodextrin and/or its derivative may be 10 to 40 moles per mole of duloxetine hydrochloride.

The type of cyclodextrin and/or its derivatives used in the bitter taste suppression method of the present invention is not particularly limited, but β-CD and/or its derivatives are particularly preferred. This is because β-CD and/or its derivatives are highly effective in suppressing the bitter taste of duloxetine hydrochloride. Preferably, the derivative of β-CD is HP-β-CD.

In the method for suppressing bitterness of the present invention, in a preferred embodiment, 5 to 50 mol of β-cyclodextrin and/or its derivative can be used per 1 mol of duloxetine hydrochloride. By using 5 moles or more of β-cyclodextrin and/or its derivatives for 1 mole of duloxetine hydrochloride, compared with using 5 moles or more of α- or γ-cyclodextrin and/or its derivatives. This is because the bitter taste of duloxetine hydrochloride is significantly suppressed.

In another preferred embodiment of the method for suppressing bitterness of the present invention, 10 to 40 moles of β-cyclodextrin and/or its derivatives can be used per mole of duloxetine hydrochloride. By using 10 moles or more of β-cyclodextrin and/or its derivatives for 1 mole of duloxetine hydrochloride, compared with using 10 moles or more of α- or γ-cyclodextrin and/or its derivatives. This is because the bitter taste of duloxetine hydrochloride is significantly suppressed.

The duloxetine hydrochloride solution with suppressed bitterness according to the present invention can be powdered through a drying process such as freeze drying or spray drying.

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

According to the present invention, the method includes a 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; A method for producing a duloxetine hydrochloride-containing pharmaceutical composition is provided, in which the amount of the derivative is 0.5 mol or more per 1 mol of duloxetine hydrochloride.

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 is a method similar to the method for suppressing the bitterness of duloxetine hydrochloride described above. and similar solvents can be used.

In the method for producing a pharmaceutical composition provided by the present invention, duloxetine hydrochloride and cyclodextrin and/or its derivatives can be used in the same molar ratio as in the method for suppressing the bitter taste of duloxetine hydrochloride described above.

The duloxetine hydrochloride-containing pharmaceutical composition produced by the production method of the present invention can contain a pharmaceutically acceptable additive in addition to CD, if necessary. Pharmaceutically acceptable additives include pH regulators, stabilizers, excipients, decomposers, binders, coatings, swelling agents, glidants, lubricants, flavorings, sweeteners or additives. Examples include, but are not limited to, solubilizing agents. More specifically, pharmaceutically acceptable excipients such as magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, talc, lactalbumin, gelatin, starch, cellulose and its derivatives, animal and vegetable oils, and It is polyethylene glycol. The pharmaceutical composition produced by the production method of the present invention may be used in any form such as granules, powder, coated tablets, microcapsules, syrups, dry syrups, elixirs, suspensions, emulsions, or drops.

The duloxetine hydrochloride-containing pharmaceutical composition produced by the production method of the present invention is a therapeutic or prophylactic agent for subjects suffering from or suspected of suffering from diseases for which duloxetine hydrochloride has therapeutic and/or preventive effects. It can be used as an agent. Specifically, it can be used to treat depression/depressed state, pain associated with diabetic neuropathy, pain associated with fibromyalgia, pain associated with chronic low back pain, and pain associated with osteoarthritis. The subject of administration is mammals including humans.

In one embodiment, the pharmaceutical composition produced by the production method of the present invention can be a liquid preparation for internal use. Although the present invention is not bound by any particular theory, in the production method of the present invention, it is thought that CD acts on the molecules of duloxetine hydrochloride itself and masks the bitter taste, and even in liquid form, the bitter taste is suppressed and the internal Even when taken as a liquid preparation, patients are less likely to perceive bitterness. Liquid preparations for internal use also allow easy dosage adjustment. Therefore, according to one embodiment of the present invention, a drug containing duloxetine hydrochloride, which can be administered even to patients with reduced swallowing ability and is suitable for careful administration to the elderly because the dose can be easily adjusted, is provided. Liquid formulations for internal use can be provided. The clinical dose of duloxetine hydrochloride is 20 mg to 60 mg per day (once daily oral administration) in terms of duloxetine. Since smaller doses are easier for elderly people and patients with swallowing disorders, the concentration of duloxetine hydrochloride in oral liquid preparations should be at least 1.1 mg/mL (duloxetine equivalent: 1 mg/mL). It is preferable to do so.

(Suppression of bitterness of aripiprazole)
Aripiprazole, whose chemical name is 7-[4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy]-3,4-dihydro-2(1H)-quinolinone, is used to treat schizophrenia. Useful. This is a compound represented by the following structural formula.

The present invention provides a bitter taste suppressant for aripiprazole, which contains cyclodextrin and/or a derivative thereof as an active ingredient.

When suppressing the bitterness of aripiprazole, the bitterness suppressor of the present invention can be used in amounts of 0.2 mol or more, 0.5 mol or more, 1 mol or more, 2 mol or more, 3 mol or more, 4 mol or more per 1 mol of aripiprazole. 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 can be used.

In one embodiment of the bitter taste suppressor of the present invention, 2 to 50 moles of cyclodextrin and/or its derivatives are used per mole of aripiprazole. This is because by using 2 moles or more of cyclodextrin and/or its derivatives for 1 mole of aripiprazole, the bitterness of aripiprazole can be suppressed to an acceptable level. In addition, if 50 moles or less of cyclodextrin and/or its derivatives are added to 1 mole of aripiprazole, the cost can be reduced, and even if the mixture of aripiprazole and cyclodextrin and/or its derivatives is dried, it is not bulky. This is because there is no

In a preferred embodiment of the bitter taste suppressor of the present invention, 5 to 40 moles of β-cyclodextrin and/or its derivatives are used per mole of aripiprazole. By using 5 moles or more of β-cyclodextrin and/or its derivatives for 1 mole of aripiprazole, compared to using 5 moles or more of α- or γ-cyclodextrin and/or its derivatives. This is because the bitter taste of aripiprazole is significantly suppressed.

In another preferred embodiment of the bitter taste suppressor of the present invention, 10 to 40 moles of β-cyclodextrin and/or its derivatives are used per mole of aripiprazole. By using 10 moles or more of β-cyclodextrin and/or its derivatives for 1 mole of aripiprazole, compared to using 10 moles or more of α- or γ-cyclodextrin and/or its derivatives. This is because the bitter taste of aripiprazole is significantly suppressed. In addition, if 40 moles or less of cyclodextrin and/or its derivatives are added to 1 mole of aripiprazole, the cost can be reduced, and even if the mixture of aripiprazole and cyclodextrin and/or its derivatives is dried, it is not bulky. It's for a reason.

The type of cyclodextrin and/or its derivatives that are the active ingredients of the bitter taste suppressor of the present invention is not limited, but β-CD and/or its derivatives are particularly preferred. This is because β-CD and/or its derivatives are highly effective in suppressing the bitter taste of aripiprazole. In one preferred embodiment, the cyclodextrin and/or its derivative which is the active ingredient of the bitter taste suppressor of the present invention is β-CD.

The bitterness suppressant 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 derivative occurs in the state of an aqueous solution of CD or its derivative.

According to the present invention, the bitter taste of aripiprazole is suppressed by mixing aripiprazole and cyclodextrin and/or its derivative in a solvent, and the cyclodextrin and/or its derivative is 0.2 mol or more per 1 mol of aripiprazole. A method is provided.

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 a solvent. The derivatives may be added to the solvent first and dissolved therein, or may be added and dissolved at the same time. Alternatively, it can also be prepared by adding CD as a powder or solution to an aripiprazole solution in which aripiprazole is dissolved in a solvent and stirring. The solvent can be selected from sterile or 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, glycerin, and then mixed with water. In order to increase the solubility of CD, the solvent to which aripiprazole and CD and/or its derivatives are added can be heated and stirred. When heating and stirring, the solvent can be heated, for example, to a temperature of 60 to 85°C.

In the bitterness suppression method of the present invention, 0.2 mol or more, 0.5 mol or more, 1 mol or more, 2 mol or more, 3 mol or more, 4 mol or more, 5 mol or more, 10 mol or more per 1 mol of aripiprazole. 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 cyclodextrins and/or derivatives thereof can be mixed. In the method for suppressing bitterness of the present invention, in one embodiment, the amount of cyclodextrin and/or its derivative can be 2 to 50 mol per 1 mol of aripiprazole. In another embodiment, the amount of cyclodextrin and/or its derivative may be 10 to 40 moles per mole of aripiprazole.

The type of cyclodextrin and/or its derivatives used in the bitter taste suppression method of the present invention is not particularly limited, but β-CD and/or its derivatives are particularly preferred. This is because β-CD and/or its derivatives are highly effective in suppressing the bitter taste of aripiprazole.

In the method for suppressing bitterness of the present invention, in a preferred embodiment, 2 to 50 moles of β-cyclodextrin and/or its derivative can be used per mole of aripiprazole. By using 2 moles or more of β-cyclodextrin and/or its derivatives for 1 mole of aripiprazole, compared to using 2 moles or more of α- or γ-cyclodextrin and/or its derivatives. This is because the bitter taste of aripiprazole is significantly suppressed.

In another preferred embodiment of the method for suppressing bitterness of the present invention, 10 to 40 moles of β-cyclodextrin and/or its derivatives can be used per mole of aripiprazole. By using 10 moles or more of β-cyclodextrin and/or its derivatives for 1 mole of aripiprazole, compared to using 10 moles or more of α- or γ-cyclodextrin and/or its derivatives. This is because the bitter taste of aripiprazole is significantly suppressed.

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.

Regarding the method for suppressing bitterness of aripiprazole provided by the present invention, evaluation of bitterness suppression can be performed by a sensory evaluation test by a panelist and/or instrumental measurement (taste recognition device, taste sensor). Regarding bitterness masking, the results of sensory tests and taste sensor output are highly correlated, indicating that taste sensors can detect bitterness masking (Ono et al. Journal of Pharmaceutical Sciences 100:1935-1943, 2011).

According to the present invention, aripiprazole and β-cyclodextrin and/or its derivatives are mixed in a solvent to obtain an aripiprazole-containing solution with reduced bitterness, wherein β-cyclodextrin and/or its derivative is aripiprazole 1. Provided is a method for producing a pharmaceutical composition containing aripiprazole in which the amount is 0.2 mole to mole or more.

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

In the method for producing a pharmaceutical composition provided by the present invention, aripiprazole and cyclodextrin and/or its derivatives can be used in the same molar ratio as in the method for suppressing the bitter taste of aripiprazole described above.

The aripiprazole-containing pharmaceutical composition produced by the production method of the present invention can contain pharmaceutically acceptable additives in addition to CD, if necessary. Pharmaceutically acceptable additives may include excipients, disintegrating agents, binders, coating agents, swelling agents, glidants, lubricants, flavoring agents, sweeteners or solubilizing agents. , but not limited to. More specifically, pharmaceutically acceptable excipients such as magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, talc, lactalbumin, gelatin, starch, cellulose and its derivatives, animal and vegetable oils, and It is polyethylene glycol. The pharmaceutical composition produced by the production method of the present invention may be used in any form such as granules, powder, coated tablets, microcapsules, syrups, dry syrups, elixirs, suspensions, emulsions, or drops.

The aripiprazole-containing pharmaceutical composition produced by the production method of the present invention can be used as a therapeutic or prophylactic agent for subjects suffering from or suspected of suffering from diseases for which aripiprazole has therapeutic and/or preventive effects. Can be done. Specifically, it can be used to treat schizophrenia. The subject of administration is mammals including humans.

In one embodiment, the pharmaceutical composition produced by the production method of the present invention can be a liquid preparation for internal use. Although the present invention is not bound by any particular theory, in the production method of the present invention, it is thought that CD acts on the molecule itself of aripiprazole and masks the bitter taste, and even in liquid form, the bitter taste is suppressed, and the liquid for internal use is Even as a preparation, patients are less likely to perceive bitterness. Liquid preparations for internal use also allow easy dosage adjustment. Therefore, according to one embodiment of the present invention, an oral drug containing aripiprazole can be administered even to patients with reduced swallowing ability, and the dose can be easily adjusted, making it suitable for careful administration to elderly people. Liquid formulations can be provided. The clinical dose of aripiprazole is 6 mg to 24 mg per day (orally administered once or twice a day. Lower doses are easier for elderly people and patients with swallowing disorders to administer). The concentration of aripiprazole in the liquid preparation for internal use is preferably at least 1.0 mg/mL.

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

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

When suppressing the bitterness of atomoxetine hydrochloride, the bitterness suppressor of the present invention can be used in amounts of 1 mol or more, 2 mol or more, 3 mol or more, 4 mol or more, 5 mol or more, 10 mol or more per 1 mol of atomoxetine hydrochloride. 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 can be used.

In one embodiment of the bitter taste suppressant of the present invention, 5 to 50 moles of cyclodextrin and/or its derivatives are used per mole of atomoxetine hydrochloride. This is because the bitterness of atomoxetine hydrochloride can be suppressed to an acceptable level by using 5 moles or more of cyclodextrin and/or its derivatives for 1 mole of atomoxetine hydrochloride. In addition, if 50 moles or less of cyclodextrin and/or its derivatives are added to 1 mole of atomoxetine hydrochloride, the cost can be reduced, and the mixture of atomoxetine hydrochloride and cyclodextrin and/or its derivatives can be added in a dry form. This is because it is not too bulky.

In a preferred embodiment of the bitter taste suppressor of the present invention, 5 to 40 moles of β-cyclodextrin and/or its derivatives are used per mole of atomoxetine hydrochloride. By using 5 moles or more of β-cyclodextrin and/or its derivatives per 1 mole of atomoxetine hydrochloride, compared with using 5 moles or more of α- or γ-cyclodextrin and/or its derivatives. This is because the bitter taste of atomoxetine hydrochloride is significantly suppressed.

In another preferred embodiment of the bitter taste suppressor of the present invention, 10 to 40 moles of β-cyclodextrin and/or its derivatives are used per 1 mole of atomoxetine hydrochloride. By using 10 moles or more of β-cyclodextrin and/or its derivatives for 1 mole of atomoxetine hydrochloride, compared with using 10 moles or more of α- or γ-cyclodextrin and/or its derivatives. This is because the bitter taste of atomoxetine hydrochloride is significantly suppressed. In addition, if 40 moles or less of cyclodextrin and/or its derivatives are added to 1 mole of atomoxetine hydrochloride, the cost can be reduced, and the mixture of atomoxetine hydrochloride and cyclodextrin and/or its derivatives can be added in a dry form. This is because it is not bulky.

The type of cyclodextrin and/or its derivatives which are the active ingredients of the bitter taste suppressor of the present invention is not limited, but β-CD and/or its derivatives are particularly preferred. This is because β-CD and/or its derivatives are highly effective in suppressing the bitter taste of atomoxetine hydrochloride. In one preferred embodiment, the cyclodextrin and/or its derivative, which is the active ingredient of the bitter taste suppressor of the present invention, is β-CD.

The bitterness suppressant of atomoxetine hydrochloride provided by the present invention can be mixed with atomoxetine hydrochloride in a solvent containing water. This is because the inclusion effect of CD or its derivative occurs in the state of an aqueous solution of CD or its derivative.

According to the present invention, the method includes a step of mixing atomoxetine hydrochloride and cyclodextrin and/or a derivative thereof in a solvent, wherein the amount of cyclodextrin and/or its derivative is 1 mole or more per 1 mole of atomoxetine hydrochloride. A method for suppressing the bitterness of salt is provided.

The step of mixing atomoxetine hydrochloride and cyclodextrin and/or its derivative in a solvent can be carried out by dissolving atomoxetine hydrochloride and cyclodextrin and/or its derivative in a solvent, and atomoxetine hydrochloride and cyclodextrin and/or its derivatives may be added to the solvent first and dissolved therein, or may be added and dissolved at the same time. Alternatively, it can also be prepared by adding CD as a powder or solution to an atomoxetine hydrochloride solution in which atomoxetine hydrochloride is dissolved in a solvent, and stirring the mixture. The solvent can be selected from sterile or 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, glycerin, and then mixed with water. In order to increase the solubility of CD, the solvent to which atomoxetine hydrochloride and CD and/or its derivatives are added can be heated and stirred. When heating and stirring, the solvent can be heated, for example, to a temperature of 60 to 85°C.

In the bitterness suppression method of the present invention, 1 mol or more, 2 mol or more, 3 mol or more, 4 mol or more, 5 mol or more, 10 mol or more, 20 mol or more, 21 mol or more, per 1 mol of atomoxetine hydrochloride, A mixture of 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 do. In the method for suppressing bitterness of the present invention, in one embodiment, the amount of cyclodextrin and/or its derivative can be 5 to 50 mol per 1 mol of atomoxetine hydrochloride. In another embodiment, the amount of cyclodextrin and/or its derivative may be 10 to 40 moles per mole of atomoxetine hydrochloride.

The type of cyclodextrin and/or its derivatives used in the bitter taste suppression method of the present invention is not particularly limited, but β-CD and/or its derivatives are particularly preferred. This is because β-CD and/or its derivatives are highly effective in suppressing the bitter taste of atomoxetine hydrochloride.

In the method for suppressing bitterness of the present invention, in a preferred embodiment, 5 to 50 mol of β-cyclodextrin and/or its derivative can be used per 1 mol of atomoxetine hydrochloride. By using 5 moles or more of β-cyclodextrin and/or its derivatives per 1 mole of atomoxetine hydrochloride, compared with using 5 moles or more of α- or γ-cyclodextrin and/or its derivatives. This is because the bitter taste of atomoxetine hydrochloride is significantly suppressed.

In another preferred embodiment of the method for suppressing bitterness of the present invention, 10 to 40 moles of β-cyclodextrin and/or its derivatives can be used per mole of atomoxetine hydrochloride. By using 10 moles or more of β-cyclodextrin and/or its derivatives for 1 mole of atomoxetine hydrochloride, compared with using 10 moles or more of α- or γ-cyclodextrin and/or its derivatives. This is because the bitter taste of atomoxetine hydrochloride is significantly suppressed.

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

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

According to the present invention, atomoxetine hydrochloride and β-cyclodextrin and/or its derivatives are mixed in a solvent to obtain an atomoxetine hydrochloride-containing solution with reduced bitterness. A method for producing a pharmaceutical composition containing atomoxetine hydrochloride is provided, in which the amount of the derivative is 1 mol or more per 1 mol of atomoxetine hydrochloride.

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 is a method similar to the above-mentioned method for suppressing the bitterness of atomoxetine hydrochloride. and similar solvents can be used.

In the method for producing a pharmaceutical composition provided by the present invention, atomoxetine hydrochloride and cyclodextrin and/or its derivatives can be used in the same molar ratio as in the method for suppressing the bitter taste of atomoxetine hydrochloride described above.

The atomoxetine hydrochloride-containing pharmaceutical composition produced by the production method of the present invention can contain a pharmaceutically acceptable additive in addition to CD, if necessary. Pharmaceutically acceptable additives may include excipients, disintegrating agents, binders, coating agents, swelling agents, glidants, lubricants, flavoring agents, sweeteners or solubilizing agents. , but not limited to. More specifically, pharmaceutically acceptable excipients such as magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, talc, lactalbumin, gelatin, starch, cellulose and its derivatives, animal and vegetable oils, and It is polyethylene glycol. The pharmaceutical composition produced by the production method of the present invention may be used in any form such as granules, powder, coated tablets, microcapsules, syrups, dry syrups, elixirs, suspensions, emulsions, or drops.

The atomoxetine hydrochloride-containing pharmaceutical composition produced by the production method of the present invention is a therapeutic or prophylactic agent for subjects suffering from or suspected of suffering from diseases for which atomoxetine hydrochloride has therapeutic and/or preventive effects. It can be used as an agent. Specifically, it can be used to treat attention deficit/hyperactivity disorder. The subject of administration is mammals including humans.

In one embodiment, the pharmaceutical composition produced by the production method of the present invention can be a liquid preparation for internal use. Although the present invention is not bound by any particular theory, in the production method of the present invention, it is thought that CD acts on the molecules of atomoxetine hydrochloride itself and masks the bitter taste, and even in liquid form, the bitter taste is suppressed and the internal Even when taken as a liquid preparation, patients are less likely to perceive bitterness. Liquid preparations for internal use also allow easy dosage adjustment. Therefore, according to one embodiment of the present invention, atomoxetine hydrochloride-containing drug that can be administered even to patients with reduced swallowing ability and is suitable for careful administration to the elderly because the dose can be easily adjusted. Liquid formulations for internal use can be provided. The clinical dose of atomoxetine hydrochloride is 40 mg to 120 mg per day (oral administration once a day or twice a day) in terms of atomoxetine. Since smaller doses are easier for elderly people and patients with swallowing disorders, the concentration of atomoxetine hydrochloride in liquid preparations for internal use should be at least 4.6 mg/mL (4 mg/mL in terms of atomoxetine). It is preferable to do so.

(Suppression of bitterness of donepezil hydrochloride)
Donepezil hydrochloride has the chemical name (2RS)-2-[(1-benzylpiperidin-4-yl)methyl]-5,6-dimethoxy-2,3-dihydro-1H-inden-1-one monohydrochloride. It is useful for suppressing the progression of dementia symptoms in Alzheimer's type dementia and Lewy body dementia. This is a compound represented by the following structural formula.

The present invention provides a bitter taste suppressant for donepezil hydrochloride, which contains cyclodextrin and/or a derivative thereof as an active ingredient.

When suppressing the bitterness of donepezil hydrochloride, the bitterness suppressor of the present invention can contain 0.1 mol or more, 0.2 mol or more, 0.5 mol or more, 1 mol or more, per 1 mol of donepezil hydrochloride. 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 As described above, 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 can be used.

In one embodiment of the bitter taste suppressor of the present invention, 1 to 50 moles of cyclodextrin and/or its derivatives are used per mole of donepezil hydrochloride. This is because the bitterness of donepezil hydrochloride is suppressed to an acceptable level by using 1 mole or more of cyclodextrin and/or its derivatives with respect to 1 mole of donepezil hydrochloride. In addition, if 50 moles or less of cyclodextrin and/or its derivatives are added to 1 mole of donepezil hydrochloride, the cost can be reduced, and the mixture of donepezil hydrochloride and cyclodextrin and/or its derivatives can be dried. This is because it is not too bulky.

In a preferred embodiment of the bitter taste suppressor of the present invention, 5 to 40 moles of β-cyclodextrin and/or its derivatives are used per mole of donepezil hydrochloride. By using 5 moles or more of β-cyclodextrin and/or its derivatives per 1 mole of donepezil hydrochloride, compared with using 5 moles or more of α- or γ-cyclodextrin and/or its derivatives. This is because the bitter taste of donepezil hydrochloride is significantly suppressed.

In another preferred embodiment of the bitter taste suppressor of the present invention, 10 to 40 moles of β-cyclodextrin and/or its derivatives are used per mole of donepezil hydrochloride. By using 10 moles or more of β-cyclodextrin and/or its derivatives for 1 mole of donepezil hydrochloride, compared with using 10 moles or more of α- or γ-cyclodextrin and/or its derivatives. This is because the bitter taste of donepezil hydrochloride is significantly suppressed. In addition, if 40 moles or less of cyclodextrin and/or its derivatives are added to 1 mole of donepezil hydrochloride, the cost can be reduced, and the mixture of donepezil hydrochloride and cyclodextrin and/or its derivatives can be used as a dry product. This is because it is not bulky.

The type of cyclodextrin and/or its derivatives that are the active ingredients of the bitter taste suppressor of the present invention is not limited, but β-CD and/or its derivatives are particularly preferred. This is because β-CD and/or its derivatives are highly effective in suppressing the bitter taste of donepezil hydrochloride. In one preferred embodiment, the cyclodextrin and/or its derivative which is the active ingredient of the bitter taste suppressor of the present invention is β-CD.

The bitterness suppressant of donepezil hydrochloride provided by the present invention can be mixed with donepezil hydrochloride in a solvent containing water. This is because the inclusion effect of CD or its derivative occurs in the state of an aqueous solution of CD or its derivative.

According to the present invention, the step includes a step of mixing donepezil hydrochloride and cyclodextrin and/or its derivative in a solvent, and the amount of cyclodextrin and/or its derivative is 0.1 mol or more per 1 mol of donepezil hydrochloride. A method for suppressing the bitter taste of donepezil hydrochloride is provided.

The step of mixing donepezil hydrochloride and cyclodextrin and/or its derivative in a solvent can be carried out by dissolving donepezil hydrochloride and cyclodextrin and/or its derivative in a solvent. and cyclodextrin and/or its derivatives may be added to the solvent first and dissolved therein, or may be added and dissolved at the same time. Alternatively, it can also be prepared by adding CD as a powder or solution to a donepezil hydrochloride solution in which donepezil hydrochloride is dissolved in a solvent, and stirring the mixture. The solvent can be selected from sterile or purified water, monohydric alcohols such as ethanol, polyhydric alcohols such as glycerol, and mixtures thereof. In order to increase the solubility of donepezil hydrochloride, donepezil hydrochloride can be first dissolved in an organic solvent such as polyethylene glycol, glycerin, etc., and then mixed with water. In order to increase the solubility of CD, the solvent to which donepezil hydrochloride and CD and/or its derivatives are added can be heated and stirred. When heating and stirring, the solvent can be heated, for example, to a temperature of 60 to 85°C.

In the bitterness suppression method of the present invention, 0.1 mol or more, 0.2 mol or more, 0.5 mol or more, 1 mol or more, 2 mol or more, 3 mol or more, 4 mol or more per 1 mol of donepezil hydrochloride. 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. In the method for suppressing bitterness of the present invention, in one embodiment, the amount of cyclodextrin and/or its derivative can be 3 to 50 mol per mol of donepezil hydrochloride. In another embodiment, the amount of cyclodextrin and/or its derivative may be 10 to 40 moles per mole of donepezil hydrochloride.

The type of cyclodextrin and/or its derivatives used in the bitter taste suppression method of the present invention is not particularly limited, but β-CD and/or its derivatives are particularly preferred. This is because β-CD and/or its derivatives are highly effective in suppressing the bitter taste of donepezil hydrochloride.

In the method for suppressing bitterness of the present invention, in a preferred embodiment, 5 to 50 mol of β-cyclodextrin and/or its derivative can be used per 1 mol of donepezil hydrochloride. By using 5 moles or more of β-cyclodextrin and/or its derivatives per 1 mole of donepezil hydrochloride, compared with using 5 moles or more of α- or γ-cyclodextrin and/or its derivatives. This is because the bitter taste of donepezil hydrochloride is significantly suppressed.

In another preferred embodiment of the method for suppressing bitterness of the present invention, 10 to 40 moles of β-cyclodextrin and/or its derivatives can be used per mole of donepezil hydrochloride. By using 10 moles or more of β-cyclodextrin and/or its derivatives for 1 mole of donepezil hydrochloride, compared with using 10 moles or more of α- or γ-cyclodextrin and/or its derivatives. This is because the bitter taste of donepezil hydrochloride is significantly suppressed.

The donepezil hydrochloride solution with suppressed bitterness according to the present invention can be powdered through a drying process such as freeze drying or spray drying.

Regarding the method for suppressing bitterness of donepezil 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 sensory tests and taste sensor output are highly correlated, indicating that taste sensors can detect bitterness masking (Ono et al. Journal of Pharmaceutical Sciences 100:1935-1943, 2011).

According to the present invention, the method includes a 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; A method for producing a pharmaceutical composition containing donepezil hydrochloride is provided, in which the amount of the derivative is 0.1 mol or more per 1 mol of donepezil hydrochloride.

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 is carried out by the same method as the above-mentioned method for suppressing the bitterness of donepezil hydrochloride. and similar solvents can be used.

In the method for producing a pharmaceutical composition provided by the present invention, donepezil hydrochloride and cyclodextrin and/or its derivatives can be used in the same molar ratio as in the method for suppressing the bitter taste of donepezil hydrochloride described above.

The donepezil hydrochloride-containing pharmaceutical composition produced by the production method of the present invention can contain, in addition to CD, a pharmaceutically acceptable additive if necessary. Pharmaceutically acceptable additives may include excipients, disintegrating agents, binders, coating agents, swelling agents, glidants, lubricants, flavoring agents, sweeteners or solubilizing agents. , but not limited to. More specifically, pharmaceutically acceptable excipients such as magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, talc, lactalbumin, gelatin, starch, cellulose and its derivatives, animal and vegetable oils, and It is polyethylene glycol. The pharmaceutical composition produced by the production method of the present invention may be used in any form such as granules, powder, coated tablets, microcapsules, syrups, dry syrups, elixirs, suspensions, emulsions, or drops.

The donepezil hydrochloride-containing pharmaceutical composition produced by the production method of the present invention is a therapeutic or prophylactic agent for subjects suffering from or suspected of suffering from diseases for which donepezil hydrochloride has therapeutic and/or preventive effects. It can be used as an agent. Specifically, it can be used to suppress the progression of dementia symptoms in Alzheimer's dementia and Lewy body dementia. The subject of administration is mammals including humans.

In one embodiment, the pharmaceutical composition produced by the production method of the present invention can be a liquid preparation for internal use. Although 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 molecules of donepezil hydrochloride itself and masks the bitter taste, and even in liquid form, the bitter taste is suppressed and the internal Even when taken as a liquid preparation, patients are less likely to perceive bitterness. Liquid preparations for internal use also allow easy dosage adjustment. Therefore, according to one embodiment of the present invention, a drug containing donepezil hydrochloride, which can be administered even to patients with reduced swallowing ability and is suitable for careful administration to the elderly because the dose can be easily adjusted, is provided. Liquid formulations for internal use can be provided. The clinical dose of donepezil hydrochloride is 3 mg to 10 mg of donepezil hydrochloride per day (oral administration once per day). Since smaller doses are easier for elderly people and patients with swallowing disorders, the concentration of donepezil hydrochloride in a liquid preparation for internal use is preferably at least 0.15 mg/mL.

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

The present invention provides a bitter taste suppressant of dorzolamide hydrochloride, which contains cyclodextrin and/or a derivative thereof as an active ingredient.

When suppressing the bitter taste of dorzolamide hydrochloride, the bitter taste suppressor of the present invention can be used in the following manner: 2 mol or more, 3 mol or more, 4 mol or more, 5 mol or more, 10 mol or more, 20 mol or more per 1 mol of dorzolamide hydrochloride. 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 Cyclodextrins and/or derivatives thereof can be used.

In one embodiment of the bitter taste suppressor of the present invention, 20 to 50 moles of cyclodextrin and/or its derivatives are used per mole of dorzolamide hydrochloride. This is because the bitterness of dorzolamide hydrochloride is suppressed to an acceptable level by using 20 moles or more of cyclodextrin and/or its derivatives for 1 mole of dorzolamide hydrochloride. In addition, if 50 moles or less of cyclodextrin and/or its derivatives are added to 1 mole of dorzolamide hydrochloride, the cost can be reduced, and the mixture of dorzolamide hydrochloride and cyclodextrin and/or its derivatives can be used as a dry product. This is because it is not too bulky.

In a preferred embodiment of the bitter taste suppressor of the present invention, 5 to 40 moles of γ-cyclodextrin and/or its derivatives are used per mole of dorzolamide hydrochloride. By using 5 moles or more of γ-cyclodextrin and/or its derivatives for 1 mole of dorzolamide hydrochloride, compared with using 5 moles or more of α- or β-cyclodextrin and/or its derivatives. This is because the bitter taste of dorzolamide hydrochloride is significantly suppressed.

In another preferred embodiment of the bitter taste suppressor of the present invention, 10 to 40 moles of γ-cyclodextrin and/or its derivatives are used per mole of dorzolamide hydrochloride. By using 10 moles or more of γ-cyclodextrin and/or its derivatives for 1 mole of dorzolamide hydrochloride, compared with using 10 moles or more of α- or β-cyclodextrin and/or its derivatives. This is because the bitter taste of dorzolamide hydrochloride is significantly suppressed. In addition, if 40 moles or less of cyclodextrin and/or its derivatives are added to 1 mole of dorzolamide hydrochloride, the cost can be reduced, and the mixture of dorzolamide hydrochloride and cyclodextrin and/or its derivatives can be used as a dry product. This is because it is not bulky.

The type of cyclodextrin and/or its derivatives which are the active ingredients of the bitter taste suppressor of the present invention is not limited, but γ-CD and/or its derivatives are particularly preferred. This is because γ-CD and/or its derivatives are highly effective in suppressing the bitter taste of dorzolamide hydrochloride. In one preferred embodiment, the cyclodextrin and/or its derivative which is the active ingredient of the bitter taste suppressor of the present invention is γ-CD.

The bitterness suppressant 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 derivative occurs in the state of an aqueous solution of CD or its derivative.

According to the present invention, dorzolamide hydrochloride includes a step of mixing dorzolamide hydrochloride and cyclodextrin and/or its derivative in a solvent, and the cyclodextrin and/or its derivative is 2 moles or more per 1 mole of dorzolamide hydrochloride. A method for suppressing the bitterness of salt is provided.

The step of mixing dorzolamide hydrochloride and cyclodextrin and/or its derivative in a solvent can be carried out by dissolving dorzolamide hydrochloride and cyclodextrin and/or its derivative in a solvent, and dorzolamide hydrochloride and cyclodextrin and/or its derivatives may be added to the solvent first and dissolved therein, or may be added and dissolved at the same time. Alternatively, it can also be prepared by adding CD in powder form or solution to a dorzolamide hydrochloride solution in which dorzolamide hydrochloride is dissolved in a solvent, and stirring the mixture. The solvent can be selected from sterile or 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, glycerin, etc., and then mixed with water. In order to increase the solubility of CD, the solvent to which dorzolamide hydrochloride and CD and/or its derivatives are added can be heated and stirred. When heating and stirring, the solvent can be heated, for example, to a temperature of 60 to 85°C.

In the bitterness suppression method of the present invention, 2 mol or more, 3 mol or more, 4 mol or more, 5 mol or more, 10 mol or more, 20 mol or more, 21 mol or more, 22 mol or more, per 1 mol of dorzolamide hydrochloride, 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. . In the method for suppressing bitterness of the present invention, in one embodiment, the amount of cyclodextrin and/or its derivative can be 3 to 50 mol per 1 mol of dorzolamide hydrochloride. In another embodiment, the amount of cyclodextrin and/or its derivative can be from 10 to 40 moles per mole of dorzolamide hydrochloride.

The type of cyclodextrin and/or its derivatives used in the bitter taste suppression method of the present invention is not particularly limited, but γ-CD and/or its derivatives are particularly preferred. This is because γ-CD and/or its derivatives are highly effective in suppressing the bitter taste of dorzolamide hydrochloride.

In the method for suppressing bitterness of the present invention, in a preferred embodiment, 5 to 50 moles of γ-cyclodextrin and/or its derivatives can be used per mole of dorzolamide hydrochloride. By using 5 moles or more of γ-cyclodextrin and/or its derivatives for 1 mole of dorzolamide hydrochloride, compared with using 5 moles or more of α- or β-cyclodextrin and/or its derivatives. This is because the bitter taste of dorzolamide hydrochloride is significantly suppressed.

In another preferred embodiment of the bitter taste 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. By using 10 moles or more of γ-cyclodextrin and/or its derivatives for 1 mole of dorzolamide hydrochloride, compared with using 10 moles or more of α- or β-cyclodextrin and/or its derivatives. This is because the bitter taste of dorzolamide hydrochloride is significantly suppressed.

Regarding the method for suppressing bitterness of dorzolamide hydrochloride provided by the present invention, evaluation of bitterness suppression can be performed by a sensory evaluation test by a panel and/or instrumental measurement (taste recognition device, taste sensor). Regarding bitterness masking, the results of sensory tests and taste sensor output are highly correlated, indicating that taste sensors can detect bitterness masking (Ono et al. Journal of Pharmaceutical Sciences 100:1935-1943, 2011).

According to the present invention, the method includes a 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; A method for producing a pharmaceutical composition containing dorzolamide hydrochloride is provided, in which the amount of the derivative is 2 mol or more per 1 mol of dorzolamide hydrochloride.

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 is carried out by the same method as the method for suppressing the bitterness of dorzolamide hydrochloride described above. and similar solvents can be used.

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

The dorzolamide hydrochloride-containing pharmaceutical composition produced by the production method of the present invention can contain pharmaceutically acceptable additives in addition to CD, if necessary. Pharmaceutically acceptable additives can include, but are not limited to, pH adjusting agents, thickening agents, or solubilizing agents.

The dorzolamide hydrochloride-containing pharmaceutical composition produced by the production method of the present invention is a therapeutic or prophylactic agent for subjects suffering from or suspected of suffering from diseases for which dorzolamide hydrochloride has therapeutic and/or preventive effects. It can be used as an agent. Specifically, it can be used to treat glaucoma and ocular hypertension. The subject of administration is mammals including humans.

In one embodiment, the pharmaceutical composition produced by the production method of the present invention can be an eye drop. Although 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 molecule itself of dorzolamide hydrochloride and masks the bitter taste, and the bitter taste is suppressed and the eye drops are Even if it flows from the nose to the throat, patients are unlikely to perceive bitterness. The clinical dose of dorzolamide hydrochloride is 1 drop of dorzolamide 0.5% solution at a time, three times a day. The concentration of dorzolamide hydrochloride is preferably at least 5.6 mg/mL (5 mg/mL in terms of dorzolamide).

The present invention will be specifically explained based on the following examples, but the present invention is not limited to these examples.

[Example 1: Suppression of 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 used as a duloxetine hydrochloride solution. To this, α-CD, β-CD, γ-CD, or hydroxypropylated β-CD (HP-β-CD) was added to a final concentration of 0.5 to 10 mM and completely dissolved.

The bitterness of duloxetine hydrochloride was determined by measuring the CPA (Change of Membrane Potential by Absorption) value (mV) using a taste recognition device "SA402B" (manufactured by Intelligent Sensor Technology Co., Ltd.) and a bitterness sensor AC0. The bitterness suppressing effect of duloxetine hydrochloride added with CD was evaluated by the CPA value. The CPA value is the average value of three measurement data. The higher the CPA value, the stronger the bitterness; therefore, the lower the CPA value, the higher the bitterness suppression effect due to CD addition.

In addition to the CPA value, the table below shows the relative CPA value at each CD addition concentration, assuming that the CPA value of a solution with a CD concentration of 0mM is 100%, and the CPA value of a solution containing only 10mM potassium chloride is 0%. .

As shown in the table above, when various CDs were added at 0.5 mM or more, a decrease in the CPA value of the duloxetine hydrochloride solution was observed. Suppression of bitter taste was observed by addition of various CDs, and the effect of β-CD was particularly remarkable.

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

It was revealed that the CPA value of duloxetine hydrochloride solution was reduced by the addition of β-CD, and the effect increased depending on the concentration of addition. From these results, it was confirmed that β-CD is effective in suppressing bitterness detected by a taste recognition device in a dose-dependent manner in the range of 0.5 to 40 mol per 1 mol of duloxetine hydrochloride. .

[Example 2: Production example of oral solution containing duloxetine hydrochloride]
Production example: Duloxetine hydrochloride 1.1mg/mL (1mg as duloxetine)
1. Dissolve 110 mg of duloxetine hydrochloride in 80 mL of purified water.
2. 1.9 g of β-CD is dissolved in a duloxetine hydrochloride aqueous solution.
3. Add fragrance to the above liquid mixture, and further add purified water to make 100 mL.
The oral liquid of this production example has suppressed bitterness and has an acceptable taste as a pharmaceutical.

[Example 3: Suppression of 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 at final concentrations of 10 mM, 0.5 mM, and 30 v/v, respectively. v % and 0.5 to 10 mM and completely dissolved.

The bitterness of aripiprazole was determined by measuring the CPA (Change of Membrane Potential by Absorption) value (mV) using a taste recognition device "SA402B" (manufactured by Intelligent Sensor Technology Co., Ltd.) and a bitterness sensor AC0. The bitterness suppressing effect of CD addition of aripiprazole was evaluated by the CPA value. The CPA value is the average value of three measurement data. The higher the CPA value, the stronger the bitterness; therefore, the lower the CPA value, the higher the bitterness suppression effect due to CD addition.

In addition to the CPA value, the table below shows the relative CPA value at each CD addition concentration, assuming that the CPA value of a solution with a CD concentration of 0mM is 100%, and the CPA value of a solution containing only 10mM potassium chloride is 0%. .

As shown in the table above, when various CDs were added at 0.5 mM or more, a decrease in the CPA value of the aripiprazole solution was observed. Suppression of bitter taste was observed by addition of various CDs, and the effect of β-CD was particularly remarkable.

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

It was revealed that the CPA value of the aripiprazole solution was reduced by the addition of β-CD, and the effect increased depending on the concentration of addition. From these results, it was confirmed that β-CD is effective in suppressing bitterness detected by taste enhancement in a dose-dependent manner in the range of 0.2 to 40 mol per 1 mol of aripiprazole.

[Example 4: Example of manufacturing oral liquid]
Production example: Aripiprazole 1.0mg/mL
1. Dissolve 100 mg of aripiprazole in 80 mL of purified water.
2. 2.5 g of β-CD is dissolved in the aqueous aripiprazole solution.
3. Add fragrance to the above liquid mixture, and further add purified water to make 100 mL.
The oral liquid of this production example has suppressed bitterness and has an acceptable taste as a pharmaceutical.

[Example 5: Suppression of 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 used as an atomoxetine hydrochloride solution. To this, α-CD, β-CD, γ-CD, or hydroxypropylated β-CD (HP-β-CD) was added to a final concentration of 0.5 to 5 mM and completely dissolved.

The bitterness of the atomoxetine hydrochloride solution was determined by measuring the CPA (Change of Membrane Potential by Absorption) value (mV) using a taste recognition device "SA402B" (manufactured by Intelligent Sensor Technology Co., Ltd.) and a bitterness sensor AC0. The bitterness suppressing effect of adding CD to the atomoxetine hydrochloride solution was evaluated by the CPA value. The CPA value is the average value of three measurement data. The higher the CPA value, the stronger the bitterness; therefore, the lower the CPA value, the higher the bitterness suppression effect due to CD addition.

In addition to the CPA value, the table below shows the relative CPA value at each CD addition concentration, assuming that the CPA value of a solution with a CD concentration of 0mM is 100%, and the CPA value of a solution containing only 10mM potassium chloride is 0%. .

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

Next, β-CD was dissolved in the atomoxetine hydrochloride solution to a final concentration of 10 mM or 20 mM, the CPA value was measured in the same manner as above, and the CPA relative value was calculated. The results are shown in the table below.
It was revealed that the CPA value of atomoxetine hydrochloride solution was reduced by the addition of β-CD, and the effect increased depending on the concentration of addition. From these results, it was confirmed that β-CD is effective in suppressing bitterness detected by a taste recognition device in a dose-dependent manner in a range of 1 to 40 mol per 1 mol of atomoxetine hydrochloride.

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

[Example 7: Suppression of 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 used as a donepezil hydrochloride solution. To this, α-CD, β-CD, γ-CD, or hydroxypropylated β-CD (HP-β-CD) was added to a final concentration of 0.5 to 10 mM and completely dissolved.

The bitterness of the donepezil hydrochloride solution was determined by measuring the CPA (Change of Membrane Potential by Absorption) value (mV) using a taste recognition device "SA402B" (manufactured by Intelligent Sensor Technology Co., Ltd.) and a bitterness sensor AC0. The bitterness suppressing effect of the addition of CD to the donepezil hydrochloride solution was evaluated by the CPA value. The CPA value is the average value of three measurement data. The higher the CPA value, the stronger the bitterness; therefore, the lower the CPA value, the higher the bitterness suppression effect due to CD addition.

In addition to the CPA value, the table below shows the relative CPA value at each CD addition concentration, assuming that the CPA value of a solution with a CD concentration of 0mM is 100%, and the CPA value of a solution containing only 10mM potassium chloride is 0%. .

As shown in the table above, when α-CD was added at 1mM or more, when β-CD was added at 0.5mM or more, when γ-CD was added at 1mM or more, and when HP-β-CD was added at 0. A decrease in the CPA value of donepezil hydrochloride solution was observed when added at .5 mM or higher.

Next, β-CD was dissolved in the donepezil hydrochloride solution to a final concentration of 0.1 mM or 20 mM, the CPA value was measured in the same manner as above, and the CPA relative value was calculated. The results are shown in the table below.
It was revealed that the CPA value of donepezil hydrochloride solution was reduced by the addition of γ-CD, and the effect increased depending on the concentration of addition. From these results, it was confirmed that β-CD is effective in suppressing bitterness detected by a taste recognition device in a dose-dependent manner in the range of 0.1 to 20 mol per 1 mol of donepezil hydrochloride. .

[Example 8: Example of manufacturing oral liquid]
Production example: Donepezil hydrochloride 0.15mg/mL
1. Dissolve 15 mg of donepezil hydrochloride in 80 mL of purified water.
2. 817.2 mg of β-CD is dissolved in an aqueous solution of donepezil hydrochloride.
3. Add fragrance to the above liquid mixture, and further add purified water to make 100 mL.
The oral liquid of this production example has suppressed bitterness and has an acceptable taste as a pharmaceutical.

[Example 9: Suppression of 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 used as a dorzolamide hydrochloride solution. To this, α-CD, β-CD, γ-CD, or hydroxypropylated β-CD (HP-β-CD) was added to a final concentration of 0.5 to 5 mM and completely dissolved.

The bitterness of dorzolamide hydrochloride was determined by measuring the CPA (Change of Membrane Potential by Absorption) value (mV) using a taste recognition device "SA402B" (manufactured by Intelligent Sensor Technology Co., Ltd.) and a bitterness sensor AC0. The bitterness suppressing effect of the addition of CD to the dorzolamide hydrochloride solution was evaluated by the CPA value. The CPA value is the average value of three measurement data. The higher the CPA value, the stronger the bitterness; therefore, the lower the CPA value, the higher the bitterness suppression effect due to CD addition.

In addition to the CPA value, the table below shows the relative CPA value at each CD addition concentration, assuming that the CPA value of a solution with a CD concentration of 0mM is 100%, and the CPA value of a solution containing only 10mM potassium chloride is 0%. .

In the above table, the CPA value of the dorzolamide hydrochloride solution is determined when α-CD is added at 10mM or more, when β-CD is added at 5mM or more, when γ-CD is added at 2.5mM or more, and when HP-CD is added at 2.5mM or more. A decrease in the CPA value of dorzolamide hydrochloride solution was observed when β-CD was added at 10 mM or more.

Next, γ-CD was dissolved in the dorzolamide hydrochloride solution to a final concentration of 1 mM or 20 mM, the CPA value was measured in the same manner as above, and the CPA relative value was calculated. The results are shown in the table below.
It was revealed that the CPA value of dorzolamide hydrochloride solution was reduced by the addition of γ-CD, and the effect increased depending on the concentration of addition. From these results, it was confirmed that γ-CD is effective in suppressing bitterness detected by a taste recognition device in a dose-dependent manner in a range of 2 to 40 mol per 1 mol of dorzolamide hydrochloride.

[Example 10: Production example of eye drops]
Production 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. 4.0 g of γ-CD is dissolved 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 suppressed bitterness and have an acceptable taste as a pharmaceutical.

Claims (9)

A bitter taste suppressor of a pharmaceutically active compound comprising cyclodextrin and/or a derivative thereof as an active ingredient, wherein the pharmaceutically active compound consists of duloxetine hydrochloride, aripiprazole, atomoxetine hydrochloride, donepezil hydrochloride, and dorzolamide hydrochloride. A bitter taste suppressor, which is any selected from the group. The bitter taste suppressor according to claim 1, wherein 0.5 mol or more of cyclodextrin and/or its derivative is used per 1 mol of the pharmaceutically active compound. The bitter taste suppressor according to claim 1 or 2, wherein 10 mol or more of cyclodextrin and/or its derivative is used per 1 mol of the pharmaceutically active compound. The bitter taste suppressor according to any one of claims 1 to 3, wherein the cyclodextrin and/or its derivative is β-cyclodextrin. A step of mixing a pharmaceutically active compound and a cyclodextrin and/or a derivative thereof in a solvent, wherein the amount of the cyclodextrin and/or its derivative is 0.5 mol or more per 1 mol of the pharmaceutically active compound, and the pharmaceutically active compound is , duloxetine hydrochloride, aripiprazole, atomoxetine hydrochloride, donepezil hydrochloride, and dorzolamide hydrochloride. The method for suppressing bitterness according to claim 5, wherein the cyclodextrin and/or its derivative is β-cyclodextrin. The step of mixing a pharmaceutically active compound and a cyclodextrin and/or its derivative in a solvent to obtain a pharmaceutically active compound-containing solution with reduced bitterness, wherein the cyclodextrin and/or its derivative is added to 1 mole of the pharmaceutically active compound. 0.5 mol or more, and the pharmaceutically active compound is any one selected from the group consisting of duloxetine hydrochloride, aripiprazole, atomoxetine hydrochloride, donepezil hydrochloride, and dorzolamide hydrochloride. Method for manufacturing the composition. The manufacturing method according to claim 7, wherein the cyclodextrin and/or its derivative is β-cyclodextrin. The manufacturing method according to claim 7 or 8, wherein the pharmaceutically active compound-containing composition is a liquid preparation for internal use.