阅读说明：本技术 水难溶性成分增溶胶束及含有该胶束的液体制剂 (Sparingly water-soluble component-solubilizing micelle and liquid preparation containing the same ) 是由 冈城彻 于 2018-06-01 设计创作，主要内容包括：本发明的目的在于使水难溶性成分在液体制剂中增溶、提供一种含水难溶性成分的液体制剂、使水难溶性成分在水(例如,中性、弱酸性、弱碱性)中的溶解性增大、和/或使含水难溶性成分的液体制剂稳定至对作为药物实际使用而言充分的程度等。本发明提供一种胶束,其特征在于,阴离子胶束在其周围被保护剂保护,所述阴离子胶束将具有在碱性下阴离子化的官能团、并可形成阴离子胶束的成分作为构成单元；或者提供一种胶束,其特征在于,阳离子胶束在其周围被保护剂保护,所述阳离子胶束将具有在酸性下阳离子化的官能团、并可形成阳离子胶束的成分作为构成单元。(The purpose of the present invention is to solubilize a poorly water-soluble component in a liquid preparation, to provide a liquid preparation containing a poorly water-soluble component, to increase the solubility of a poorly water-soluble component in water (for example, neutral, weakly acidic, or weakly basic), to stabilize a liquid preparation containing a poorly water-soluble component to a degree sufficient for practical use as a drug, or the like. The present invention provides a micelle characterized in that an anionic micelle, which has a functional group anionized with basicity and is capable of forming an anionic micelle as a constituent unit, is protected around the anionic micelle by a protective agent; or a micelle characterized in that a cationic micelle having a functional group cationized under acidic conditions and a component capable of forming a cationic micelle as a constituent unit is protected around the cationic micelle by a protective agent.)

1. A micelle characterized in that an anionic micelle, which has a functional group anionizable under a basic condition and has a component capable of forming an anionic micelle as a constituent unit, is protected at the periphery thereof with a protective agent.

2. The micelle of claim 1, wherein the electron density of the atom of the protective agent bonded to the anionized functional group of the anionic micelle is less than the electron density of the anionized functional group of the anionic micelle.

3. The micelle according to claim 1 or 2, wherein the atom of the protective agent which bonds to the anionized functional group of the anionic micelle and the anionized functional group of the anionic micelle are bonded by hydrogen bonding.

4. Micelle according to any one of claims 1-3, wherein the protective agent has hydroxyl (-OH) groups in water.

5. The micelle according to any one of claims 1 to 4, wherein the protective agent is 1 or more selected from the group consisting of polyethylene glycol, glycerin, propylene glycol, sorbitol, mannitol, N-acetylglucosamine, chondroitin sulfate, glycyrrhizic acid, hydroxypropylmethylcellulose, methylcellulose, carboxymethylcellulose, povidone, polyoxyethylene hydrogenated castor oil, and polysorbate 80.

6. The micelle according to any one of claims 1 to 5, wherein the component has a low solubility in water in a neutral region having a pH of 6 to 8.

7. The micelle according to any one of claims 1 to 6, wherein the component is 1 or more selected from the group consisting of fexofenadine, rebamipide, indomethacin, L-carbocisteine, ibuprofen and ursodeoxycholic acid, and salts thereof.

8. A liquid preparation comprising the micelle according to any one of claims 1 to 7, wherein a component having a functional group that is anionized with a base is solubilized.

9. The liquid formulation of claim 8, wherein the concentration of the component is 0.01-5.0% (w/v).

10. The liquid preparation according to claim 8 or 9, which has a pH of 5 to 9 when stored for a long period of time.

11. The liquid preparation according to any one of claims 8 to 10, which is an eye drop or a nasal drop.

12. A method for producing a micelle in which an anionic micelle, which has a functional group that is anionized with a basic group and can form an anionic micelle, as a constituent unit, is protected with a protective agent, comprising the following steps (A) and (B):

(A) a step of making an aqueous suspension containing a component which has a functional group that is anionized with respect to alkalinity and can form an anionic micelle basic;

(B) and adding a protective agent.

13. A micelle produced by the method according to claim 12, wherein an anionic micelle is protected with a protective agent, and the anionic micelle has a functional group that is anionized at a basic site and can form an anionic micelle as a constituent unit.

14. A method for increasing the solubility of a component capable of forming an anionic micelle, which has a functional group that is anionized with a base, the method comprising a step of forming an anionic micelle from a component capable of forming an anionic micelle, which has a functional group that is anionized with a base.

15. A micelle characterized in that a cationic micelle, which has a functional group cationized under acidic conditions and can form a cationic micelle as a constituent unit, is protected at the periphery thereof with a protective agent.

16. The micelle of claim 15, wherein the electron density of the atom of the protectant that binds to the cationized functional group of the cationic micelle is greater than the electron density of the cationized functional group of the cationic micelle.

17. Micelle according to claim 15 or 16, wherein the atom of the protecting agent which is bonded to the cationized functional group of the cationic micelle and the cationized functional group of the cationic micelle are bonded by cation-pi interaction.

18. Micelle according to any one of claims 15-17, wherein the protecting agent has pi electrons.

19. Micelle according to any one of claims 15-18, wherein the protective agent is tyloxapol.

20. The micelle according to claims 15 to 19 further comprising a surfactant-containing layer, wherein the surfactant-containing layer is in close contact with the outer side of the protective agent-containing layer.

21. The micelle of any one of claims 15-20, wherein the component is at least 1 selected from the group consisting of brinzolamide, trimebutine, benzocaine, baclofen, metoclopramide, lidocaine, and salts thereof.

22. A liquid preparation comprising the micelle according to any one of claims 15 to 21, wherein a component having a functional group that is cationized under acidic conditions is solubilized.

23. The liquid formulation of claim 22, wherein the concentration of the component is 0.01-5.0% (w/v).

24. The liquid preparation according to claim 22 or 23, which has a pH of 5 to 9 when stored for a long period of time.

25. The liquid preparation according to any one of claims 22 to 24, which is an eye drop or a nasal drop.

26. A method for producing a micelle in which a cationic micelle having a component having a functional group that is cationized under acidic conditions as a constituent unit is protected with a protective agent, comprising the following steps (a) and (b):

(a) a step of making an aqueous suspension containing a component having a functional group that is cationized under acidic conditions into acidic conditions;

(b) and adding a protective agent.

27. A micelle produced by the method according to claim 26, wherein a cationic micelle having a component having a functional group that is cationized under acidic conditions as a constituent unit is protected with a protective agent.

28. A method for increasing the solubility of a component having a functional group that can be cationized under acidic conditions, comprising a step of forming a cationic micelle from a component having a functional group that can be cationized under acidic conditions.

Technical Field

The present invention relates to a poorly water-soluble component-solubilizing micelle and a liquid preparation containing the same.

Background

Fexofenadine as histamine H₁Receptor antagonists are used for treating pruritus associated with allergic rhinitis (pollinosis, etc.), urticaria and dermatosis, but they are poorly water-soluble (0.01% (w/v) or less at pH 7; non-patent document 1), and therefore have not been used in the form of liquid preparations (particularly eye drops, nasal drops, etc.). A suspension is known as a fexofenadine preparation (patent document 1). However, when the suspension is used, a user needs to shake the container with great effort to uniformly disperse the active ingredient and then use the suspension, which requires a complicated preparation process. In the formulation of a liquid preparation containing a poorly water-soluble component such as fexofenadine, a large equipment investment and a high production cost are required, and the suspension cannot be filtered by a membrane filter, and thus it is considered difficult to ensure sterility and quality.

On the other hand, a solubilizing technique based on fexofenadine included in cyclodextrin is known (patent document 2). However, according to the verification by the inventors of the present application, it was confirmed that fexofenadine is precipitated in a large amount at room temperature or at a pH of 6 to 7 in the fexofenadine-containing preparation prepared by the preparation method described in example 5 of patent document 2, and this technique has a fatal disadvantage when the fexofenadine-containing liquid preparation is used as a drug. In addition, the fexofenadine-containing solution prepared by this technique does not contain micelles in which anionic micelles having fexofenadine as constituent units are protected by a protecting agent. Other poorly water soluble ingredients are also the same as non-fexofenadine.

Therefore, a liquid preparation containing a water-insoluble component which has sufficient stability for practical use as a liquid preparation has been desired. The stability at this time includes: the water-insoluble component has excellent water solubility (the water-insoluble component is not easily precipitated) in a pH range applicable to human mucosa, namely, a pH of 5-9; stable at room temperature for a long time; and/or excellent preparation stability.

Disclosure of Invention

Technical problem to be solved by the invention

The present invention aims to solubilize a poorly water-soluble component in a liquid preparation, to provide a liquid preparation containing a poorly water-soluble component, to increase the solubility of a poorly water-soluble component in water (for example, neutral, weakly acidic, or weakly basic), and/or to solve the above-mentioned technical problems of stability.

Means for solving the problems

The present inventors have made intensive studies to solve the above-mentioned problems, and as a result, have found that a poorly water-soluble component can be solubilized by preparing a micelle in which an anionic micelle or a cationic micelle having the poorly water-soluble component as a constituent unit is protected with a protecting agent, and have further studied based on this finding, thereby completing the present invention.

That is, the present invention relates to the following inventions.

[1] A micelle characterized in that an anionic micelle, which has a functional group anionizable under a basic condition and has a component capable of forming an anionic micelle as a constituent unit, is protected at the periphery thereof with a protective agent.

[2] The micelle according to [1], wherein the electron density of an atom of the protective agent bonded to the anionized functional group of the anionic micelle is smaller than the electron density of the anionized functional group of the anionic micelle.

[3] The micelle according to the item [1] or [2], wherein the atom of the protective agent, which is bonded to the anionized functional group of the anionic micelle, and the anionized functional group of the anionic micelle are bonded to each other by a hydrogen bond.

[4] The micelle according to any one of [1] to [3], wherein the protective agent has a hydroxyl group (-OH) in water.

[5] The micelle according to any one of [1] to [4], wherein the protective agent is at least 1 selected from the group consisting of polyethylene glycol, glycerin, propylene glycol, sorbitol, mannitol, N-acetylglucosamine, chondroitin sulfate (コンドロイチン sulfuric acid エステ ル), glycyrrhizic acid, hydroxypropylmethylcellulose, methylcellulose, carboxymethylcellulose, povidone, polyoxyethylene hydrogenated castor oil, and polysorbate 80.

[6] The micelle according to any one of [1] to [5], wherein the component has low solubility in water in a neutral region having a pH of 6 to 8.

[7] The micelle according to any one of the above [1] to [6], wherein the component is 1 or more selected from the group consisting of fexofenadine, rebamipide, indomethacin, L-carbocisteine (L-carbocisteine), ibuprofen, ursodeoxycholic acid, and salts thereof.

[8] A liquid preparation comprising the micelle according to any one of [1] to [7], wherein a component having a functional group that is anionized with a basic group is solubilized.

[9] The liquid preparation according to [8], wherein the concentration of the component is 0.01 to 5.0% (w/v).

[10] The liquid preparation according to [8] or [9], which has a pH of 5 to 9 when stored for a long period of time.

[11] The liquid preparation according to any one of [8] to [10], which is an eye drop or a nasal drop.

[12] A method for producing a micelle in which an anionic micelle, which has a functional group that is anionized with a basic group and can form an anionic micelle, as a constituent unit, is protected with a protective agent, comprising the following steps (A) and (B):

(A) a step of making an aqueous suspension containing a component which has a functional group that is anionized with respect to alkalinity and can form an anionic micelle basic;

(B) and adding a protective agent.

[13] A micelle produced by the method according to [12], wherein an anionic micelle is protected with a protective agent, and the anionic micelle has a functional group that is anionized with a base and can form an anionic micelle as a constituent unit.

[14] A method for increasing the solubility of a component capable of forming an anionic micelle, which has a functional group that is anionized with a base, the method comprising a step of forming an anionic micelle from a component capable of forming an anionic micelle, which has a functional group that is anionized with a base.

[15] A micelle characterized in that a cationic micelle, which has a functional group cationized under acidic conditions and can form a cationic micelle as a constituent unit, is protected at the periphery thereof with a protective agent.

[16] The micelle according to [15], wherein the electron density of the atom of the protective agent bonded to the cationized functional group of the cationic micelle is larger than the electron density of the cationized functional group of the cationic micelle.

[17] The micelle according to [15] or [16], wherein the atom of the protective agent, which is bonded to the cationized functional group of the cationic micelle, and the cationized functional group of the cationic micelle are bonded by cation-pi interaction.

[18] The micelle according to any one of [15] to [17], wherein the protective agent has pi electrons.

[19] The micelle according to any one of [15] to [18], wherein the protective agent is tyloxapol (tyloxapol).

[20] The micelle according to any one of [15] to [19], further comprising a layer containing a surfactant, wherein the layer containing a surfactant is in close contact with the outside of the layer containing a protective agent.

[21] The micelle according to any one of [15] to [20], wherein the component is 1 or more selected from the group consisting of brinzolamide, trimebutine, benzocaine, baclofen, metoclopramide, lidocaine, and salts thereof.

[22] A liquid preparation comprising the micelle according to any one of [15] to [21], wherein a component having a functional group that is cationized under acidic conditions is solubilized.

[23] The liquid preparation according to [22], wherein the concentration of the component is 0.01 to 5.0% (w/v).

[24] The liquid preparation according to [22] or [23], which has a pH of 5 to 9 when stored for a long period of time.

[25] The liquid preparation according to any one of [22] to [24], which is an eye drop or a nasal drop.

[26] A method for producing a micelle in which a cationic micelle having a component having a functional group that is cationized under acidic conditions as a constituent unit is protected with a protective agent, comprising the following steps (a) and (b):

(a) a step of making an aqueous suspension containing a component having a functional group that is cationized under acidic conditions into acidic conditions;

(b) and adding a protective agent.

[27] A micelle produced by the method according to [26], wherein a cationic micelle having a component having a functional group that is cationized under acidic conditions as a constituent unit is protected with a protective agent.

[28] A method for increasing the solubility of a component having a functional group that can be cationized under acidic conditions, comprising a step of forming a cationic micelle from a component having a functional group that can be cationized under acidic conditions.

Effects of the invention

According to the present invention, a poorly water-soluble component can be solubilized in a liquid preparation, a liquid preparation containing a poorly water-soluble component can be provided, the solubility of a poorly water-soluble component in water (for example, neutral, weakly acidic, or weakly basic) can be increased, and/or the above-described technical problem of stability can be solved. The present invention is excellent in that, when the poorly water-soluble component is a physiologically active component or a pharmaceutically active component, the poorly water-soluble component can be solubilized while maintaining its physiological activity or medicinal effect. In addition, "stable" in the present specification does not mean that chemical decomposition of a component can be suppressed or that a component is bonded to another substance to be converted into another substance, but means that the solubilized component is maintained in a solubilized state in water and can be suppressed from being converted into an undissolved state.

Drawings

Fig. 1 is a two-dimensional schematic diagram (one example) showing an example of the micelle α or β.

Fig. 2 is a two-dimensional schematic diagram (one example) showing an example of the micelle α 2 or β 2.

Fig. 3 is a schematic diagram (an example) showing an anionic micelle.

Fig. 4 is a schematic diagram showing an example of the micelle α.

Fig. 5 is a schematic diagram showing an example of the micelle α.

Fig. 6 is a schematic diagram showing an example of the micelle α.

Fig. 7 is a schematic diagram (an example) showing a cationic micelle.

Fig. 8 is a schematic diagram showing an example of the micelle β.

FIG. 9 is a graph showing the results of measuring the absorbance at a wavelength of 268nm of samples 1 to 7.

Fig. 10 is a graph showing the results of measuring the ultraviolet absorption spectrum in the vicinity of the maximum absorption wavelength (λ max) of samples 1 to 7.

FIG. 11 is a graph showing the measurement results of the particle size distribution of the anionic micelles in preparation example 80.

FIG. 12 is a graph showing the measurement results of the particle size distribution of micelles in preparation example 81.

FIG. 13 is a graph showing the measurement results of the particle size distribution of micelles in preparation example 82.

Fig. 14 is a graph showing the results of a test for confirming the drug efficacy of fexofenadine.

Detailed Description

In the present invention, unless otherwise specified, "room temperature" means room temperature in the seventeenth modified japanese pharmacopoeia. Specifically, the temperature is 1 to 30 ℃. The "real-time room temperature" is a concept different from the "room temperature" and means a state in which the temperature and humidity are not controlled in a normal living room.

Micelle

The present invention provides a micelle characterized in that a negatively or positively charged micelle having a functional group which is negatively or positively charged in a pH region excluding pH7 as a constituent unit is protected with a protecting agent. Namely, the present invention provides: (α) a micelle (hereinafter, also referred to as micelle α) characterized in that an anionic micelle having a functional group anionized under a basic condition and capable of forming an anionic micelle is protected by a protective agent as a constituent unit; and/or (β) a micelle (hereinafter, also referred to as micelle β), characterized in that the cationic micelle is protected by a protective agent, and the cationic micelle has a component having a functional group that is cationized under acidic conditions as a constituent unit.

An example of each micelle is illustrated in two dimensions in fig. 1 or 2.

In fig. 1 or 2, the a core is an anionic micelle or a cationic micelle composed of the components, and the periphery thereof is surrounded by the protective agent to form the P layer, and the a core and the P layer form the micelle α or the micelle β as a whole.

In the case of the micelle α shown in fig. 1, the surface of the anionic micelle (hereinafter, also referred to as a core), that is, the anionic functional group of the anionic micelle is negatively charged. The electron density of atoms bonded to the a core surface, i.e., to the anionized functional group of the anionic micelle, is smaller than the electron density of the a core surface, i.e., to the anionized functional group of the anionic micelle, and the atoms form intermolecular interactions (e.g., hydrogen bonds) with the a core surface, i.e., the anionized functional group of the anionic micelle.

In the case of the micelle β shown in fig. 1, the cationic micelle (hereinafter, also referred to as a core) surface, that is, the cationized functional group of the cationic micelle is positively charged. The electron density of the atom bonded to the surface of the a core, that is, the cationized functional group of the cationic micelle is higher than the electron density of the cationized functional group of the surface of the a core, that is, the cationic micelle, and the atom forms an intermolecular interaction (for example, cation-pi interaction) with the surface of the a core, that is, the cationized functional group of the cationic micelle.

In the case where the functional group located on the outer side of the layer in which the protective agent is present is hydrophobic in a state where the anionic micelle or the cationic micelle is protected by the protective agent, the surfactant may further be in close contact with and attached to the outer side of the layer in which the protective agent is present. This surfactant corresponds to the S layer in fig. 2. The hydrophilicity of the micelle α or β can be further improved by bringing the surfactant into close contact with and attaching it to the outer side of the layer in which the protective agent is present. The surfactant is preferably a compound having a long-chain (for example, 7 or 8 or more carbon atoms) alkyl group. Specific examples of the surfactant include polysorbate 80(TO-10M), polyoxyethylene hydrogenated castor oil (HCO60), polyethylene glycol monostearate (MYS-40), polyethylene glycol (PEG400), polyethylene glycol (PEG4000) and polyethylene glycol (PEG 6000).

In other words, fig. 2 shows the micelle α 2 or β 2 in close contact with and attached to the outer side of the layer of the micelle α or β in which the protective agent is present.

In fig. 2, when the micelle α 2 is shown, the surface of the anionic micelle (hereinafter, also referred to as "a core"), that is, the anionic functional group of the anionic micelle is negatively charged. The electron density of atoms bonded to the a core surface, i.e., to the anionized functional group of the anionic micelle, is smaller than the electron density of the a core surface, i.e., to the anionized functional group of the anionic micelle, and the atoms form intermolecular interactions (e.g., hydrogen bonds) with the a core surface, i.e., the anionized functional group of the anionic micelle.

In fig. 2, an S layer composed of a surfactant is shown in close contact with the outer side of the P layer. The surfactant of the S layer is bonded to a substituent such as a hydrophobic substituent of the protecting agent present in the P layer by intermolecular interaction (for example, van der waals force), and a plurality of intermolecular interactions are generated on the outer surface of the P layer, whereby the S layer is formed in close contact with the outer side of the P layer and contains the surfactant.

In fig. 2, when the micelle β 2 is shown, the cationic micelle (hereinafter, also referred to as a core) surface, that is, the cationized functional group of the cationic micelle is positively charged. The electron density of the atom bonded to the surface of the a core, that is, the cationized functional group of the cationic micelle is higher than the electron density of the cationized functional group of the surface of the a core, that is, the cationic micelle, and the atom forms an intermolecular interaction (for example, cation-pi interaction) with the surface of the a core, that is, the cationized functional group of the cationic micelle.

In fig. 2, an S layer composed of a surfactant is shown in close contact with the outer side of the P layer. The surfactant of the S layer is bonded to a substituent such as a hydrophobic substituent of the protecting agent present in the P layer by intermolecular interaction (for example, van der waals force), and a plurality of intermolecular interactions are generated on the outer surface of the P layer, whereby the S layer is formed in close contact with the outer side of the P layer and contains the surfactant.

Micelle alpha

[ Components ]

The component in the micelle α has a functional group that is anionized under basicity, and can form an anionic micelle. The component in the micelle α preferably has a functional group that is anionized when the pH is greater than 7 and not greater than 14, the pH is 8 to 14, the pH is 9 to 14, the pH is 10 to 14, the pH is 11 to 14, the pH is 12 to 14, or the pH is 13 to 14, and more preferably has a functional group that is anionized when the pH is 12 to 14 or the pH is 13 to 14.

Examples of the functional group that is anionized with a base include a carboxyl group (-COOH) and a sulfo group (-SO)₃H) Phosphoryl (-O-PO (OH), hydroxyl (-OH), sulfonamide.

The functional group that is anionized with a base may be in an anionic state under acidic conditions (e.g., pH less than 7, pH 6 or less, pH5 or less, etc.).

In addition, the component in the micelle α may have a functional group that is cationized under acidic conditions or may not have a functional group that is cationized under acidic conditions, in addition to a functional group that is anionized under basic conditions.

One of the purposes of the present invention is to solubilize a water-insoluble component, and therefore, a component having low solubility in water can be usually selected as a component in the micelle α. In particular, when a drug such as a liquid preparation is produced by using the technique of the present invention, as described later, it is sometimes required that the pH of the liquid preparation is near neutrality during long-term storage or use from the viewpoint of irritation and the like, and therefore, it is preferable that the pH is a neutral region of pH 6 to 8 and the solubility in water is low because the effect of the present invention is further exerted. As the component having a low solubility in water in a neutral region of pH 6 to 8, a component having a solubility in water (for example, 20 ℃) of 1g/100gH in a neutral region of pH 6 to 8 is preferable₂O or less, more preferably 0.1g/100gH₂O or less, more preferably 0.001g/100gH₂O or less. The component having a neutral pH of 6 to 8 and a low solubility in water may be a component which is hardly soluble in water as described in the official gazette of the seventeenth revised Japanese pharmacopoeiaThe active ingredients of the medicine.

In the present disclosure, the long-term storage may mean 1 week, preferably 2 weeks, and more preferably 4 weeks from the preparation of the liquid preparation. The storage temperature during storage may be 40 ℃ or 25 ℃.

As components in the micelle α, the following compounds can be exemplified.

[ Table 1]

[ anionic micelle ]

Anionic micelles are micelles formed from a component having a functional group that is anionized with a base, and when micelles are formed, the functional groups constituting the surface layers of the micelles are negatively charged. The anionic micelles correspond to the A core in scheme 1 or 2.

Fig. 3 is a schematic diagram showing an example of an anionic micelle having a component having a functional group anionized under a basic condition as a constituent unit. The negative charge in fig. 3 indicates an anionized portion of the functional group that is anionized under alkalinity. The portion represented by the straight line bonding to negative charges in fig. 3 is a simplified representation: a portion of the component other than a portion anionized with a functional group anionized with a basic group. That is, one unit composed of a negative charge and a straight line bonded thereto in fig. 3 represents a component having a functional group that is anionized under a basic condition in one unit. In other words, in the anion micelle, a component having a functional group that is anionized with a base is a constituent unit. In addition, there may be a plurality of constituent units, a plurality of micelles composed of the same constituent unit, or one or more types of micelles composed of a plurality of constituent units.

As the association system of micelles, 2 types of H-type associations and J-type associations are generally known. The H-shaped associated body is formed by stacking the constituent units in parallel in the opposite directions, and the J-shaped associated body is formed by stacking the constituent units in the same orientation but displaced in an oblique direction. In the present invention, as shown in FIG. 3, it is preferable that the anionic micelles perform J-type association. When J-type association occurs, the absorption spectrum in the ultraviolet-visible light region shifts to the longer wavelength side, as compared with the case where each constituent unit is monodisperse, and thus evaluation can be performed.

[ protecting agent ]

When the anionic micelle is formed, solubility may be sufficiently improved depending on the components, and a stable anionic micelle may be formed. In particular, when the liquid preparation containing the anionic micelle of the present invention is stored for a long period of time after the pH is returned to near neutrality, the anionic micelle may disintegrate in this pH region. In such a case, by adding a protective agent, the disintegration of the anionic micelle can be prevented.

The protecting agent is bonded to the anionic micelle through some chemical bond and protects the anionic micelle. Specifically, the protecting agent preferably has a property of stabilizing the anionic micelle in water.

The protecting agent preferably has a hydroxyl group (-OH) in water. The number of hydroxyl groups (-OH) in water per 1 molecule is preferably 1 or more, more preferably 2,3, 4, 5, 6, 7 or 8 or more.

The protecting agent preferably has 2 or more hydroxyl groups (-OH) in water and has 1 or more molecular skeleton having a linear, branched or cyclic structure between 2 or more hydroxyl groups chemically bonded (for example, hydrogen bond) to an anionic functional group of the anionic micelle (for example, see fig. 4). The number of elements in the molecular skeleton between 2 or more hydroxyl groups chemically bonded (for example, hydrogen bond) to the anionic micelle is preferably 1 or more, and more preferably 2,3, 4, 5, 6, 7, or 8 or more. In the case of having 2 or more molecular skeletons, a protecting agent having 2 or more molecular skeletons between 2 or more hydroxyl groups chemically bonded (for example, hydrogen-bonded) to the anionized functional group of the anionic micelle may be present by bonding via a chemical bond (for example, hydrogen-bonding) (for example, see fig. 5 and 6).

Examples of such a protective agent include water-soluble polymers, polyhydric alcohols, sugar alcohols, and the like, and among them, water-soluble polymers are preferable.

Examples of the protective agent include polyethylene glycol, glycerin, propylene glycol, sorbitol (e.g., D-sorbitol), mannitol, N-acetylglucosamine, chondroitin sulfate, glycyrrhizic acid, dipotassium glycyrrhizinate, hydroxypropylmethylcellulose, methylcellulose (e.g., methylcellulose 15 or methylcellulose 400), carboxymethylcellulose, sodium carboxymethylcellulose, povidone (e.g., povidone K30), polyoxyethylene hydrogenated castor oil, polysorbate 80, polyethylene glycol (e.g., PEG400, PEG4000, or PEG6000), and any combination thereof.

[ relationship between protective agent and anionic micelle ]

Fig. 4 to 6 schematically show examples of the micelle α, but the micelle α is not limited thereto.

In fig. 4, the surface of the anion micelle shown in the inner frame is negatively charged. In the layer between the inner frame and the outer frame in which the protective agent is present, 1 molecule of the protective agent shown as a representative example has an electron density of a hydrogen atom bonded to the anionized functional group of the anionic micelle, which is chemically bonded (e.g., hydrogen bond) to the anionized functional group of the anionic micelle, which is lower than the electron density of the anionized functional group of the anionic micelle. That is, the dotted line in fig. 4 represents a chemical bond (e.g., hydrogen bond).

In fig. 5, the surface of the anion micelle shown in the inner frame is negatively charged. In the layer between the inner frame and the outer frame in which the protective agent is present, 2 molecules of the protective agent shown as a representative example have an electron density of hydrogen atoms bonded to the anionized functional group of the anionic micelle, which is chemically bonded (e.g., hydrogen bond) to the anionized functional group of the anionic micelle, lower than the electron density of the anionized functional group of the anionic micelle. In addition, 2 molecular protective agents are chemically bonded (e.g., hydrogen bonding) to each other. That is, the dotted line in fig. 5 represents a chemical bond (e.g., hydrogen bond).

Fig. 6 shows in detail the chemical bond of the protecting agent to the anionic micelle for the same micelle as the micelle α of fig. 5.

It is preferable that the electron density of the atom of the protecting agent bonded to the anionized functional group of the anionic micelle is smaller than the electron density of the anionized functional group of the anionic micelle.

The atom of the protective agent that bonds to the anionized functional group of the anionic micelle and the anionized functional group of the anionic micelle are preferably bonded to each other by a chemical bond such as a hydrogen bond, a covalent bond, a bond based on van der waals force, or an ionic bond, and more preferably by a hydrogen bond.

[ Properties "of micelle ]

The physical properties of the micelles can be confirmed by measuring the particle size distribution of the micelles by a known method. In the micelle α of the present invention, when the diameter of the anionic micelle and the diameter of the micelle α are measured, the diameter of the micelle α is larger than that of the anionic micelle. The diameter of the anionic micelle greatly varies depending on the molecular weight of the constituent components, the concentration of the components, and the like, and is usually 0.1nm or more and 100nm or less, and particularly preferably 1nm or more and 10nm or less. The diameter of the micelle α is usually 0.2nm or more and 150nm or less, and particularly preferably 1.5nm or more and 20nm or less.

Further, the presence of the micelle α can be confirmed by adding a large amount of counter ions (cations) (e.g., sodium chloride) to the aqueous solution containing the micelle α to eliminate the charge, or by adding an inorganic salt (e.g., sodium chloride) to lower the Critical Micelle Concentration (CMC) to confirm the component precipitation.

[ liquid preparation ]

The present invention provides a liquid preparation containing micelle alpha and solubilized with a component having a functional group that is anionized under alkaline conditions. The lower limit concentration of the micelle α in the liquid preparation of the present invention is not particularly limited, and is, for example, 0.01% (w/v) or more, 0.02% (w/v) or more, 0.03% (w/v) or more, 0.04% (w/v) or more, 0.05% (w/v) or more, 0.07% (w/v) or more, 0.09% (w/v) or more, 0.1% (w/v) or more, or 0.2% (w/v) or more in terms of the component (non-salt). The upper limit concentration of the micelle α in the liquid preparation of the present invention is not particularly limited, and is, for example, 5.0% (w/v) or less, 3.0% (w/v) or less, 1.0% (w/v) or less, 0.5% (w/v) or less, 0.3% (w/v) or less, 0.25% (w/v) or less, 0.2% (w/v) or less, 0.15% (w/v) or less, or 0.1% (w/v) or less in terms of the component (non-salt). All combinations of the lower and upper concentrations listed above are included in the invention. In addition, the concentration of the micelle α can be easily adjusted at any stage of the production method described below.

The pH of the liquid preparation of the present invention when stored for a long period of time is not particularly limited, and may be in the vicinity of neutral to the vicinity of acid, in the vicinity of neutral to the vicinity of alkali, in the vicinity of neutral to the vicinity of weakly acidic, in the vicinity of neutral to the vicinity of weakly alkaline, or the like, and preferably in the vicinity of neutral. The neutral vicinity in this case is, for example, pH5 to 9, 5.5 to 8.5, 6 to 8, 6.5 to 7.5, etc. The pH is adjusted by a known method (for example, a method of adding hydrochloric acid, sulfuric acid, nitric acid, or the like). The liquid preparation of the present invention can dissolve a water-insoluble component even in the vicinity of neutrality, and is therefore particularly useful as an eye drop, a nose drop or an oral liquid preparation. When used as eye drops, nose drops or oral liquid preparations, the daily dose of the composition (non-salt) for an adult may be 0.01 to 10000 mg. When used as an oral liquid preparation, the daily dose of the composition (non-salt) for an adult may be 1 to 10000mg, 0.1 to 1000mg, or 1 to 100 mg. The dose per day can be administered from 1 to several times.

In the liquid preparation of the present invention, when the component having a functional group that is anionized with a base is a physiologically active component or a pharmaceutical component, the activity or the pharmaceutical effect thereof can be exhibited. The liquid preparation of the present invention is useful for the prevention and/or treatment of itching accompanying allergic rhinitis, urticaria, skin diseases (eczematous dermatitis, cutaneous pruritus, atopic dermatitis) in the case where the ingredient is useful for the prevention and/or treatment of itching accompanying allergic rhinitis, urticaria, skin diseases (eczematous dermatitis, cutaneous pruritus, atopic dermatitis).

[ production method ]

The present invention provides a method for producing a micelle α in which an anionic micelle having a component having a functional group anionized with a basic group as a constituent unit is protected with a protective agent, the method comprising the following steps (a) and (B):

(A) a step of making an aqueous suspension containing a component having a functional group that is anionized with respect to alkalinity, the component having the functional group that is anionized with respect to alkalinity, alkaline, and alkaline;

(B) and adding a protective agent.

In the step (a) of making an aqueous suspension containing a component having a functional group that is anionized with respect to basicity basic properties to be basic, the aqueous suspension is made basic by, for example, mixing the component with water in a desired ratio, stirring the mixture by a conventional method, and adding a base to the resulting suspension. The concentration of the component in the suspension is preferably at least the Critical Micelle Concentration (CMC). The ratio of the component to water (the component (g): water (mL)) may be changed as appropriate depending on the component, and specifically may be (0.001:100) or more (5:100) or less, (0.01:100) or more (3:100) or less, (0.1:100) or more (1:100) or less. The basicity at this time may be appropriately changed depending on the component, but is preferably a pH at which a part (for example, 50% or more, 60% or more, 70% or more, 80% or more, or 90% or more) or all of the component is dissolved, and specifically, a pH of 9 or more and 14 or less, a pH of 10 or more and 13 or less, a pH of 11 or more and 13 or less, a pH of 11.5 or more and 13 or less, or a pH of 11.7 or more and 12.9 or less, and the like can be cited. When the component is fexofenadine, the pH is preferably 12 or more. The base used for pH adjustment may be any of strong bases (e.g., sodium hydroxide, potassium hydroxide, barium hydroxide, calcium hydroxide, etc.) and weak bases (e.g., ammonia, tromethamine, etc.), and is preferably a strong base.

In the method for producing micelle α, in the step of adding a protecting agent in (B), a desired amount of the protecting agent is added to the composition containing the component obtained in the step (a). The molar ratio of the component (component: protecting agent) to the protecting agent may be appropriately changed depending on the protecting agent, and may be, for example, (100:1) to (1: 100).

In the above-described steps (a) and (B), the micelle α has sufficient stability and can be used as it is, but when the present invention is applied to a drug, for example, if a solution containing the micelle α is applied to a human as it is at such a pH, the solution may be highly irritating and difficult to use. In such a case, the method for producing micelle α may further include a step (C) of adjusting the pH to a range suitable for human use after the step (B).

(C) In the step of adjusting the pH to a range suitable for human use, a pH adjuster, a pH buffer, or the like is added to the composition containing the component obtained in the step (B), thereby adjusting the pH of the composition to a range suitable for human use. Examples of the pH adjuster and the pH buffer include hydrochloric acid, citric acid, phosphoric acid, and salts thereof. The range applicable to humans means, for example, a range in which eye drop administration, nasal drop administration, oral administration as a liquid preparation, or the like can be performed to humans. In this case, the range applicable to human is, for example, pH5 to 9, preferably pH 6 to 8, more preferably pH 6 to 7, pH7 to 8, and the like.

Even if the pH is changed to a range suitable for human use in this way, the micelle α produced by the above-described steps (a) and (B) and the like is not easily disintegrated, and the effect of the present invention can be exhibited.

Micelle prepared by the above preparation method

The present invention provides a micelle (also referred to as micelle α) prepared by the above preparation method, in which an anionic micelle having a component having a functional group anionized under a basic condition as a constituent unit is protected with a protecting agent. For the micelle α, the description of the micelle α can be referred to.

[ method for increasing solubility of component ]

The present invention provides a method for increasing the solubility of a component having a functional group that is anionized with respect to a base, the method comprising a step of forming an anionic micelle from a component having a functional group that is anionized with respect to a base. The solubility of a component having a functional group that is anionized with a base is the solubility of the component when the pH is near neutral (e.g., pH 6 to 8, pH 6.5 to 7.5, etc.). The method for increasing the solubility of a component having a functional group that is anionized with a base preferably further comprises a step of protecting the formed anionic micelle with a protecting agent.

Applications of

The invention includes the use of micelle alpha for the preparation of a liquid formulation having a high concentration of dissolved components having functional groups that are anionized under basic conditions.

Micelle beta

[ Components ]

The component (A) has a functional group that is cationized under acidic conditions.

The components in the micelle β have functional groups that are cationized under acidity. The component in the micelle beta preferably has a functional group that is cationized at a pH of 1 or more and less than 7, at a pH of 1 to 6, at a pH of 1 to 5, at a pH of 1 to 4, at a pH of 1 to 3, at a pH of 1 to 2.5, or at a pH of 1 to 2, and more preferably has a functional group that is cationized at a pH of 1 to 2.5 or at a pH of 1 to 2, for example.

Examples of the functional group that can be cationized under acidic conditions include an amino group, a monomethylamino group, a dimethylamino group, a monoethylamino group, a diethylamino group, a morpholino group, and a piperidyl group.

The functional group that is cationized under acidic conditions may be in a cationized state under basic conditions (e.g., pH greater than 7, pH 8 or greater, pH 9 or greater, etc.).

In addition to the functional group that is cationic under acidic conditions, the component in the micelle β may have a functional group that is anionic under basic conditions, or may not have a functional group that is anionic under basic conditions. As the component having a low solubility in water in a neutral region of pH 6 to 8, a component having a solubility in water (for example, 20 ℃) of 1g/100gH in a neutral region of pH 6 to 8 is preferable₂O or less, more preferably 0.1g/100gH₂O or less, more preferably 0.001g/100gH₂O or less. The component having a neutral pH of 6 to 8 and a low solubility in water may be an active ingredient of a hardly water-soluble drug described in the seventeenth official gazette of the Japanese pharmacopoeia or the like.

In the present disclosure, the long-term storage may mean storage for 1 week, preferably storage for 2 weeks, and more preferably storage for 4 weeks from the preparation of the liquid preparation. The storage temperature during storage may be 40 ℃ or 25 ℃.

As components in the micelle β, the following compounds can be exemplified.

[ Table 2]

[ cationic micelle ]

Cationic micelles are micelles formed from components having functional groups that are cationized under acidic conditions, and when micelles are formed, the functional groups constituting the surface layers of the micelles are positively charged. The cation corresponds to the A nucleus in scheme 1 or 2.

Fig. 7 is a schematic diagram as an example of the cationic micelle β. The positive charge in fig. 7 indicates a cationized portion of the functional group that is cationized under acidic conditions. The portion represented by the straight line bonding with positive charge in fig. 7 is a simplified representation: the component (A) is a part other than a part cationized by a functional group cationized under acidic conditions. That is, one unit composed of a positive charge and a straight line bonded thereto in fig. 7 represents a component having a functional group that is cationized under acidic conditions in one unit. In other words, in the cationic micelle, a component having a functional group that is cationized under acidic conditions is a constituent unit. In this case, there may be a plurality of types of micelles composed of the same constituent unit, or there may be one or more types of micelles composed of a plurality of constituent units.

As the association system of micelles, 2 types of H-type associations and J-type associations are generally known. The H-shaped associated body is formed by stacking the constituent units in parallel in the opposite directions, and the J-shaped associated body is formed by stacking the constituent units in the same orientation but displaced in an oblique direction. In the present invention, as shown in FIG. 7, it is preferable that the cationic micelle performs J-type association. When J-type association occurs, the absorption spectrum in the ultraviolet-visible light region shifts to the longer wavelength side, as compared with the case where each constituent unit is monodisperse, and thus evaluation can be performed.

[ protecting agent ]

When the cationic micelle is formed, the solubility may be sufficiently improved depending on the components, and a stable cationic micelle may be formed. In particular, when the pH of a liquid preparation containing the cationic micelle of the present invention is returned to near neutral and stored for a long period of time, the cationic micelle may disintegrate in this pH region. In such a case, by adding a protective agent, the disintegration of the cationic micelle can be prevented.

The protecting agent may be any agent as long as it protects the cationic micelle, and specifically, it is preferable that the protecting agent has a property of allowing the cationic micelle to exist stably in water.

The protective agent preferably has pi electrons in water. Pi electrons refer to electrons associated with pi bonds and existing on the p orbital. Since the p-orbital is symmetrically present on the z-orbital, the dipole moments generated by the partial negative charges of the pi electrons originating from the p-orbital in the positive and negative directions of the z-axis cancel out, but a re-charged dipole moment induced by the partial negative charges is generated, as a result of which an electro-quadrupole moment is formed. The electric quadrupole moment is the driving force for intermolecular interactions with cations. The pi electrons and cations interact molecularly (cation-pi interactions) to exhibit non-covalent bonding intermolecular interactions, the bonds of which are comparable to hydrogen bonds. The protecting agent preferably exhibits intermolecular interaction (for example, cation-. pi. interaction) with the surface of the cationic micelle (see FIG. 8, for example).

As such a protective agent, for example, a compound in which pi electrons exist in a stable state is preferable, and specifically, a compound having a phenyl group as a substituent, a benzene derivative, or the like is preferable.

Examples of the protecting agent include compounds having 1 to 10 benzene rings which may be substituted (the substituents may be the same or different and are-O (C)₂H₄O) mH (m represents an integer of 8 to 10) or (C)_1～10) An alkyl group; here, (C)_1～10) Alkyl represents methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, tert-pentyl, neopentyl, 2, 3-dimethylpropyl, 1-ethylpropyl, 1-methylbutyl, 2-pentyl, neopentyl, or neopentyl,A straight-chain or branched alkyl group having 1 to 10 carbon atoms such as an n-hexyl group, an isohexyl group, a 2-hexyl group, a 3-hexyl group, a 2-methylpentyl group, a 3-methylpentyl group, a 1,1, 2-trimethylpropyl group, a 3, 3-dimethylbutyl group, an n-heptyl group, an n-octyl group, an n-nonyl group, and an n-decyl group).

Examples of the protective agent include tyloxapol represented by the following general formula (I) (wherein m represents an integer of 8 to 10 and n represents an integer of 1 to 5).

[ chemical formula 1]

[ relationship between protective agent and cationic micelle ]

Fig. 8 schematically shows an example of the micelle β, but the micelle β is not limited thereto.

In fig. 8, the surface of the cation micelle shown in the inner frame is positively charged. In the layer between the inner frame and the outer frame in which the protective agent is present, 1 molecule of the protective agent shown as a representative example has an electron density of a benzene ring bonded to the cationized functional group of the cationic micelle larger than that of the surface of the cationic micelle, and the benzene ring forms intermolecular interaction (for example, cation-pi interaction) with the surface of the cationic micelle. That is, an arrow (→) in fig. 8 indicates an intermolecular interaction (for example, cation-pi interaction).

[ Properties "of micelle ]

The physical properties of the micelles can be confirmed by measuring the particle size distribution of the micelles by a known method. In the micelle β of the present invention, the diameter of the micelle β is larger than the diameter of the cationic micelle when the diameter of the cationic micelle and the diameter of the micelle β are measured. The diameter of the cationic micelle greatly varies depending on the molecular weight of the constituent components, the concentration of the components, and the like, and is usually 0.1nm or more and 100nm or less, and particularly preferably 1nm or more and 10nm or less. The diameter of the micelle β is usually 0.2nm or more and 150nm or less, and particularly preferably 1.5nm or more and 20nm or less.

Further, the presence of the micelle β can be confirmed by adding a large amount of counter ions (anions) (e.g., sodium chloride) to the aqueous solution containing the micelle β to eliminate the charge, or by adding an inorganic salt (e.g., sodium chloride) to lower the Critical Micelle Concentration (CMC) to thereby confirm the component precipitation.

[ liquid preparation ]

Disclosed is a liquid preparation which contains a micelle beta and to which a component having a functional group that can be cationized under acidic conditions has been solubilized. The lower limit concentration of the micelle β in the liquid preparation of the present invention is not particularly limited, and is, for example, 0.01% (w/v) or more, 0.02% (w/v) or more, 0.03% (w/v) or more, 0.04% (w/v) or more, 0.05% (w/v) or more, 0.07% (w/v) or more, 0.09% (w/v) or more, 0.1% (w/v) or more, or 0.2% (w/v) or more in terms of the component (non-salt). The upper limit concentration of the micelle β in the liquid preparation of the present invention is not particularly limited, and is, for example, 5.0% (w/v) or less, 3.0% (w/v) or less, 1.0% (w/v) or less, 0.5% (w/v) or less, 0.3% (w/v) or less, 0.25% (w/v) or less, 0.2% (w/v) or less, 0.15% (w/v) or less, or 0.1% (w/v) or less in terms of the component (non-salt). All combinations of the lower and upper concentrations listed above are included in the invention. In addition, the concentration of the micelle β can be easily adjusted at any stage of the production method described below.

The pH of the liquid preparation of the present invention when stored for a long period of time is not particularly limited, and may be in the vicinity of neutral to the vicinity of acid, in the vicinity of neutral to the vicinity of alkali, in the vicinity of neutral to the vicinity of weakly acidic, in the vicinity of neutral to the vicinity of weakly alkaline, or the like, and preferably in the vicinity of neutral. The neutral vicinity in this case is, for example, pH5 to 9, 5.5 to 8.5, 6 to 8, 6.5 to 7.5, etc. The pH is adjusted by a known method (for example, a method of adding sodium hydroxide or potassium hydroxide). The liquid preparation of the present invention can dissolve a water-insoluble component even in the vicinity of neutrality, and is therefore particularly useful as an eye drop, a nose drop or an oral liquid preparation. When used as eye drops, nose drops or oral liquid preparations, the daily dose of the composition (non-salt) for an adult may be 0.01 to 10000 mg. When used as an oral liquid preparation, the daily dose of the composition (non-salt) for an adult may be 1 to 10000mg, 0.1 to 1000mg, or 1 to 100 mg. The dose per day can be administered from 1 to several times.

In the liquid preparation of the present invention, when the component having a functional group that is cationized under acidic conditions is a physiologically active ingredient or a pharmaceutical ingredient, the activity or the pharmaceutical effect thereof can be exhibited. The liquid preparation of the present invention is useful for the prevention and/or treatment of itching accompanying allergic rhinitis, urticaria, skin diseases (eczematous dermatitis, cutaneous pruritus, atopic dermatitis) in the case where the ingredient is useful for the prevention and/or treatment of itching accompanying allergic rhinitis, urticaria, skin diseases (eczematous dermatitis, cutaneous pruritus, atopic dermatitis).

[ production method ]

The present invention provides a method for producing a micelle β in which a cationic micelle having a component having a functional group that is cationized under acidic conditions as a constituent unit is protected with a protective agent, the method comprising the following steps (a) and (b):

(a) a step of making an aqueous suspension containing a component having a functional group that is cationized under acidic conditions acidic;

(b) and adding a protective agent.

In the step (a) of making an aqueous suspension containing a component having a functional group that is cationized under acidic conditions acidic, the micelle β is prepared by, for example, mixing the component with water in a desired ratio, stirring the mixture by a conventional method, and adding an acid to the resulting suspension to make the suspension acidic. The concentration of the component in the suspension is preferably equal to or higher than the Critical Micelle Concentration (CMC). The ratio of the component to water (the component (g): water (mL)) may be changed as appropriate depending on the component, and specifically may be (0.001:100) or more (5:100) or less, (0.01:100) or more (3:100) or less, (0.1:100) or more (1:100) or less. The acidity in this case may be appropriately changed depending on the component, but is preferably a pH at which a part (for example, 50% or more, 60% or more, 70% or more, 80% or more, or 90% or more) or all of the component is dissolved, and specifically, a pH of 1 or more and less than 7, a pH of 1 or more and 6 or less, a pH of 1 or more and 5 or less, a pH of 1 or more and 4 or less, a pH of 1 or more and 3 or less, a pH of 1 or more and 2.5 or less, a pH of 1 or more and 2.2 or less, or the like can be cited. When the component is brinzolamide, the pH that exhibits acidity is preferably 2 or less. The acid may be any of strong acids (e.g., hydrochloric acid, sulfuric acid, nitric acid, hydrogen iodide, perchloric acid, hydrogen bromide, etc.), weak acids (e.g., citric acid, acetic acid, formic acid, oxalic acid, hydrogen sulfide, etc.), and is preferably a strong acid.

In the method for producing micelle β, in the step of adding a protecting agent in step (b), a desired amount of the protecting agent is added to the composition containing the component obtained in step (a). The molar ratio of the component (component: protecting agent) to the protecting agent may be appropriately changed depending on the protecting agent, and may be, for example, (100:1) to (1: 1000).

Since the hydrophobic group is located on the outer side of the micelle β, the solubility of the micelle β may not be as high as desired depending on the kind of the protective agent. In such a case, the method for producing micelle β may further include, if necessary, a step of (c) adding a surfactant simultaneously with or after the step (b). (c) In the step (b), a surfactant is added in a desired amount to the composition containing the component obtained in the step (b). The molar ratio of the component (component: surfactant) to the surfactant may be appropriately changed depending on the surfactant, and may be, for example, (100:1) to (1: 1000).

In the above-mentioned steps (a) and (b) or, if necessary, the steps (a), (b) and (c), the micelle β can be used as it is with sufficient stability, but when the present invention is applied to a drug, for example, a liquid containing the micelle β is applied to a human as it is at such a pH, and thus, the application may be strong and difficult. In such a case, the method for producing micelle β may further include (d) a step of adjusting pH to a range suitable for human use after the step (b) or (c). In the method for producing micelle β, when step (d) is included after step (b), step (c) may be included after step (d).

(d) In the step of bringing the pH to a range applicable to humans, a pH adjuster, a pH buffer, or the like is added to the composition containing the component obtained in the step (b) or (c), thereby bringing the pH of the composition to a range applicable to humans. Examples of the pH adjuster and the pH buffer include hydrochloric acid, citric acid, phosphoric acid, and salts thereof. The range applicable to humans means, for example, a range in which eye drop administration, nasal drop administration, oral administration as a liquid preparation, or the like can be performed to humans. In this case, the range applicable to human is, for example, pH5 to 9, preferably pH 6 to 8, more preferably pH 6 to 7, pH7 to 8, and the like.

Micelle prepared by the above preparation method

The present invention provides a micelle (also referred to as micelle β) prepared by the above preparation method, in which a cationic micelle having a component having a functional group that is cationized under acidic conditions as a constituent unit is protected with a protecting agent. For the micelle β, the description of the micelle β can be referred to.

[ method for increasing solubility of component ]

The present invention provides a method for increasing the solubility of a component having a functional group that is cationized under acidic conditions, the method being characterized by comprising a step of forming a cationic micelle from a component having a functional group that is cationized under acidic conditions. The solubility of a component having a functional group that is cationized under acidic conditions means the solubility of the component when the pH value is near neutral (e.g., pH 6 to 8, pH 6.5 to 7.5, etc.), the solubility of the component when the pH value is near basic (e.g., pH 8 to 14, pH 8 to 10, pH 8 to 9, etc.), and the solubility of the component when the pH value is near acidic (e.g., pH 3 to 6, pH 4 to 6, pH5 to 6, etc.). The method for increasing the solubility of a component having a functional group that is cationized under acidic conditions preferably further comprises a step of protecting the formed cationic micelle with a protecting agent.

Applications of

The invention includes the use of micelle β for the preparation of a liquid formulation having a high concentration of dissolved components having functional groups that are cationized under acidic conditions.