JP-7857271-B2 - Bitterness inhibitor for pharmacoactive compounds and method for inhibiting bitterness

Inventors

• 相沢 萌子

Assignees

• 日本食品化工株式会社

Dates

Publication Date

20260512

Application Date

20231121

Claims (7)

1. A bitterness inhibitor for a pharmaceutically active compound , comprising a liquid composition or its dried product, 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 reduced 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 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 a solution containing a 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.

Description

This invention relates to a bitterness inhibitor for pharmaceutically active compounds, a method for inhibiting the bitterness of pharmaceutically active compounds, and a method for producing a composition containing a bitterness inhibitor for pharmaceutically active compounds. Medicinal active compounds are administered via various routes, including oral, nasal, and transdermal. Among these, oral administration is an easy, convenient, non-invasive, and well-known method of drug delivery. However, some medicinal active compounds have extremely unpleasant tastes, such as bitterness. While conventional solid forms (tablets or capsules, etc.) are usually swallowed immediately after ingestion, making the bitterness less noticeable, some patients may be unable to tolerate the extremely unpleasant bitter taste and may be unable to take the medication. For patients who have difficulty taking conventional solid forms orally due to reasons such as poor swallowing function (e.g., children and elderly patients), liquid forms (e.g., solutions, suspensions, syrups, emulsions, or dry syrups mixed with water, etc.) or formulations such as chewable tablets or orally disintegrating tablets are prescribed. However, these formulations have the problem of increasing the exposure of bitter substances to taste buds, making the bitterness more noticeable. Many prescription drugs commonly used in Japan, including those with sales exceeding 5 billion yen, contain bitter-tasting active ingredients. For example, atomoxetine hydrochloride (ADHD treatment), duloxetine hydrochloride (antidepressant), donepezil hydrochloride (Alzheimer's disease treatment), aripiprazole (antipsychotic), and dorzolamide hydrochloride (glaucoma/ocular hypertension treatment) are known to have a bitter taste. While it is crucial for patients to take their prescribed medications as directed, the bitter taste of these active ingredients can be a problem, potentially leading to decreased medication adherence and compliance. 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 using coatings or microencapsulation to contain the bitterness. However, these methods have problems, such as not being able to completely mask the bitterness, or the bitterness being perceived once the compound dissolves in the mouth. Patent Document 1 discloses a solid-state 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 dissolving film comprising one or more water-soluble polymers, one or more pharmaceutically active ingredients, a stevioside-based sweetener as an aftertaste improver, and one or more primary sweeteners as a taste blocker, and states that the pharmaceutically active ingredient may be aripiprazole, donepezil, etc. Special Publication No. 2007-517050Japanese Patent Publication No. 2013-147470Special Publication No. 2012-528854 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 indicated by "～" refer to a range that includes the numbers indicated before and after "～" as the lower and upper limits, respectively. 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. Cyclodextrin (sometimes referred to as "CD" in this specification) is also known as a cyclic oligosaccharide. It is a cyclic α-1,4-glucan produced by the intramolecular transfer reaction of cyclodextrin glucanotransferase to α-1,4-glucans such as starch. Its degrees of polymerization are mainly 6, 7, and 8, and these are called α-CD, β-CD, and γ-CD, respectively. In this 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 in