JP2003176228A - Liquid medicine - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a liquid medicine having improved solubility of N-[4-[4-(1,2- benzisothiazol-3-yl)-1-piperazinyl]butyl]-1,2-cis-cyclohexanedicarboxylic imide or a salt thereof. <P>SOLUTION: This clear aqueous liquid medicine having improved solubility therein is provided by formulating the N-[4-[4-(1,2-benzisothiazol-3-yl)-1- piperazinyl]butyl]-1,2-cis-cyclohexanedicarboxylic imide or the salt thereof, in combination with at least one compound selected from the group consisting of a nonionic surfactant, a polyvinylpyrrolidone and a polyhydric alcohol. <P>COPYRIGHT: (C)2003,JPO

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to N- [4- [4
-(1,2-benzisothiazol-3-yl)-
The present invention relates to a liquid preparation having improved solubility of 1-piperazinyl] butyl] -1,2-cis-cyclohexanedicarboximide or a salt thereof.

[0002]

N- [4- [4- (1,2-Benzisothiazol-3-yl) -1-piperazinyl]]
Butyl] -1,2-cis-cyclohexanedicarboximide hydrochloride (perospirone hydrochloride) is a drug marketed as an antipsychotic drug indicated for schizophrenia. Since this drug is poorly soluble in water, it is orally administered in the form of tablets and used for medical purposes. And
Japanese Unexamined Patent Application Publication No. 8-193030 discloses N- [4- [4
-(1,2-benzisothiazol-3-yl)-
There are described gelatin capsules and tablet dosage forms containing 1-piperazinyl] butyl] -1,2-cis-cyclohexanedicarboximide or a salt thereof. A poorly water-soluble N- [4- [4- (1,2-benzisothiazol-3-yl) -1-piperazinyl] butyl] -1,2-cis-cyclohexanedicarboximide or a salt thereof is used as a liquid agent. No known medicine has been known so far. N- [4- [4- (1, 2, 2-
If benzisothiazol-3-yl) -1-piperazinyl] butyl] -1,2-cis-cyclohexanedicarboximide or a salt thereof can be administered,
Topical administration to the skin or mucous membranes is also possible, and a rapid-acting therapeutic effect can be expected as compared to oral oral preparations, and it is also useful from the viewpoint of bioavailability.

By the way, in eye drops, nasal drops and other liquids, as a solubilizing agent for dissolving a poorly soluble drug,
Nonionic surfactants, polyhydric alcohols, polyvinylpyrrolidone, etc. are known. However, although nonionic surfactants are expected to be applied to a wide range of poorly soluble drugs, their solubilizing action is relatively weak. Moreover, since it cannot be formulated at a high concentration due to irritation to the mucous membranes, etc., the drugs capable of obtaining a stable liquid formulation by the nonionic surfactant are limited. Polyhydric alcohol or polyvinylpyrrolidone has a relatively strong solubilizing action, but when it is blended at a high concentration, it causes a stickiness particularly in a formulation applied to mucous membranes or skin, which causes a problem of poor feeling in use. It was

As described above, there is no known method which can be applied to all poorly soluble drugs in eye drops, nasal drops and other liquids, and it dissolves or stabilizes each poorly soluble drug. We need to find the means.

[0005]

Accordingly, the object of the present invention is to provide N- [4- [4- (1,2-benzisothiazol-3-yl) -1-piperazinyl] butyl]-
It is to improve the solubility of 1,2-cis-cyclohexanedicarboximide or a salt thereof in a liquid agent.

[0006]

Means for Solving the Problems As a result of intensive studies to achieve the above object, the present inventors have found that a nonionic surfactant,
At least one compound selected from the group consisting of polyvinylpyrrolidone and polyhydric alcohol is N- [4- [4
-(1,2-benzisothiazol-3-yl)-
The inventors have found that coexistence with 1-piperazinyl] butyl] -1,2-cis-cyclohexanedicarboximide or a salt thereof improves the solubility and makes a stable liquid formulation, and has completed the present invention.

That is, the present invention is as follows (1) to (15)
(1) i) N- [4- [4-
(1,2-benzisothiazol-3-yl) -1
-Piperazinyl] butyl] -1,2-cis-cyclohexanedicarboximide or a salt thereof, ii) at least one compound selected from the group consisting of nonionic surfactants, polyvinylpyrrolidone and polyhydric alcohols (2) N-
[4- [4- (1,2-benzisothiazole-3
-Yl) -1-piperazinyl] butyl] -1,2-
The solution according to (1), wherein the concentration of cis-cyclohexanedicarboximide or a salt thereof is 0.1 w / v% or more, (3) the nonionic surfactant is a polyoxyethylene-polyoxypropylene block copolymer, poly At least one selected from oxyethylene sorbitan fatty acid esters, polyoxyethylene hydrogenated castor oil, polyoxyethylene alkyl ethers, polyoxyethylene-polyoxypropylene alkyl ethers, and polyoxyethylene alkylphenyl ethers (1 Or (2), the liquid agent according to any one of (1) to (3), wherein (4) the nonionic surfactant has an HLB of 10 or more, (5) a liquid agent containing a nonionic surfactant. Any of (1) to (4) in which the concentration is 0.001 to 10 w / v% Crab liquid agent, (6)
The concentration of polyvinylpyrrolidone in the liquid agent is 0.01 to 2
The liquid preparation according to any one of (1) to (5), which is 0 w / v%, (7) The polyhydric alcohol is at least one selected from polyethylene glycol, glycerin, and propylene glycol (1) to (6). (8) The liquid preparation according to any one of (1) to (7), wherein the concentration of the polyhydric alcohol in the liquid preparation is 0.01 to 20 w / v%, (8). The liquid preparation according to any one of (1) to (8), which contains a chelating agent, (1
0) The liquid agent according to any one of (1) to (9), wherein the chelating agent is at least one selected from the group consisting of ethylenediaminetetraacetic acid, citric acid and salts thereof.
(11) The concentration of the chelating agent in the liquid agent is 0.001 to 1
The solution according to any one of (1) to (10), which is 0 w / v%, (12) Furthermore, a borate buffer, a phosphate buffer, a carbonate buffer, an epsilon-aminocaproic acid buffer, and an aspartic acid buffer. (1) to (1) containing at least one buffer selected from the agents and Good's buffer
Liquid preparation according to any one of 1), (13) Liquid preparation according to any one of (1) to (12), which is aqueous, (14)
The liquid preparation according to any one of (1) to (13), which is clear, (15) the eye drop, the nasal drop, and the injection according to any one of (1) to (14).

In the present specification, unless otherwise specified,
% Shall mean w / v%.

[0009]

BEST MODE FOR CARRYING OUT THE INVENTION N- [4- [4- (1, 2
-Benzisothiazol-3-yl) -1-piperazinyl] butyl] -1,2-cis-cyclohexanedicarboximide (hereinafter also referred to as perospirone) or a salt thereof is disclosed in JP-A-62-123179, Japan. .
J. Pharmacol.53 pp321-329 (1990), JP-A-8-193
It is a known compound described in JP-A-033,
It can be produced according to the production method of No. 123179 or the method described in the literature, or can be produced by a known method according to the production method described in these literature.

Examples of salts of N- [4- [4- (1,2-benzisothiazol-3-yl) -1-piperazinyl] butyl] -1,2-cis-cyclohexanedicarboximide include organic compounds. Acid salts (eg, lactate, acetate, butyric acid, trifluoroacetate, fumarate,
Maleate, tartrate, citrate, succinate, malonate, methanesulfonate, toluenesulfonate, tosylate, palmitic acid, stearic acid, etc.),
Inorganic acid salts (eg, hydrochloride, sulfate, nitrate, hydrobromide, phosphate, etc.), salts with organic bases (eg, methylamine, triethylamine, triethanolamine,
Morpholine, piperazine, pyrrolidine, amino acids, salts with organic amines such as tripyridine and picoline), salts with inorganic bases (for example, ammonium salt, sodium,
Examples thereof include alkali metals such as potassium, alkaline earth metals such as calcium and magnesium, salts with metals such as aluminum, and the like, and N- [4- [4-
(1,2-benzisothiazol-3-yl) -1
Most preferred is -piperazinyl] butyl] -1,2-cis-cyclohexanedicarboximide hydrochloride. In addition, N- [4- [4- (1,2-benzisothiazol-3-yl) -1-piperazinyl] butyl] -1,2-cis-cyclohexanedicarboximide or a salt thereof of the present invention is hydrated. It may be used as a substance, and examples thereof include perospirone hydrochloride hydrate.

Concentration of N- [4- [4- (1,2-benzisothiazol-3-yl) -1-piperazinyl] butyl] -1,2-cis-cyclohexanedicarboximide or a salt thereof in a liquid agent. As 0.00
It can be used in the range of 01 to 10%, more preferably 0.001 to 3%, particularly preferably 0.001 to
1%. In the present invention, N- [4- [4- (1,
It is possible to improve the solubility of 2-benzisothiazol-3-yl) -1-piperazinyl] butyl] -1,2-cis-cyclohexanedicarboximide or a salt thereof, and N- [4- [4 The concentration of-(1,2-benzisothiazol-3-yl) -1-piperazinyl] butyl] -1,2-cis-cyclohexanedicarboximide or a salt thereof is 0.1% or more, further 0.3%. Even at the above concentrations, it can be used as a stable liquid agent. Then, N − [4 − [4 − (1, 2, −
Benzoisothiazol-3-yl) -1-piperazinyl] butyl] -1,2-cis-cyclohexanedicarboximide or a salt thereof and a nonionic surfactant, polyvinylpyrrolidone and a polyhydric alcohol. By containing a chelating agent in at least one compound described above, a stable liquid agent can be obtained even at a concentration of 1.0% or more.

In the liquid preparation of the present invention, N- [4- [4-
(1,2-benzisothiazol-3-yl) -1
-Piperazinyl] butyl] -1,2-cis-cyclohexanedicarboximide or a salt thereof for improving the solubility in an aqueous solution, selected from the group consisting of nonionic surfactants, polyvinylpyrrolidone, and polyhydric alcohols. It is characterized by containing at least one compound which is As the nonionic surfactant of the present invention, a known nonionic surfactant which is usually used for liquid medicines can be used, and N- [4- [4- (1,
From the viewpoint of solubility and safety of 2-benzisothiazol-3-yl) -1-piperazinyl] butyl] -1,2-cis-cyclohexanedicarboximide or a salt thereof, polyoxyethylene is preferable as a surfactant. -Polyoxypropylene block copolymers, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene hydrogenated castor oil, polyoxyethylene alkyl ethers, polyoxyethylene-polyoxypropylene alkyl ethers, polyoxyethylene alkylphenyl ethers . Specifically, polyoxyethylene (POE) -polyoxypropylene (PO
P) block copolymers (eg poloxamer 407,
Poloxamer 235, Poloxamer 188, etc.), POE (20) sorbitan monolaurate (polysorbate 20), POE (20) sorbitan monooleate (polysorbate 8)
0) etc. POE sorbitan fatty acid esters, POE
(60) POE such as hydrogenated castor oil, hydrogenated castor oil, POE
(9) POE alkyl ethers such as lauryl ether and polyoxyethylene monostearate, POE (20) P
Examples thereof include POE / POP alkyl ethers such as OP (4) cetyl ether and POE alkyl phenyl ethers such as POE (10) nonylphenyl ether.
The number in parentheses indicates the number of added moles, and is 1 or 2
You may use it in combination of 2 or more types. The amount of the nonionic surfactant used is, for example, 0.001 to 10%, 0.
It is about 01 to 5% and 0.01 to 3%. Further, the nonionic surfactant used in the present invention is preferably a surfactant having an HLB of 10 or more.

In the present invention, polyvinylpyrrolidone is
It is a water-soluble polymer compound containing a repeating unit of 1-vinyl-2-pyrrolidone monomer, and examples thereof include polyvinylpyrrolidone K25, polyvinylpyrrolidone K30, and polyvinylpyrrolidone K90. As polyvinylpyrrolidone, a commercially available product which is usually used for liquid medicines can be used, and polyvinylpyrrolidone having different molecular weights or grades may be used alone or in combination of two or more kinds. The concentration of polyvinylpyrrolidone is, for example, 0.
It can be used in an amount of 01 to 20%, preferably 0.01 to 10%, and particularly preferably 0.05 to 5%.

In the present invention, the polyhydric alcohol is an alcohol having two or more hydroxyl groups in its molecule, and examples thereof include polyethylene glycol, glycerin, propylene glycol, xylitol, diethylene glycol, mannitol, sorbitol and polyvinyl alcohol. Commercially available polyhydric alcohols commonly used in can be used. From the viewpoint of solubility and safety, polyethylene glycol, glycerin and propylene glycol are particularly preferable. The concentration of the polyhydric alcohol in the liquid agent is, for example, 0.01 to 20%, preferably 0.0
It can be used in an amount of 1 to 10%, particularly preferably 0.1 to 10%.

The polyhydric alcohol suitable for the present invention will be described in more detail. As the polyethylene glycol, a commercially available product which is usually used for liquid medicines can be used.
G-1000, PEG-1540, PEG-2000, PEG-4000, P
EG-6000, PEG-20000, PEG-50000, PEG-2000
00 or PEG-400000 (trade name of Wako Pure Chemical Industries, Ltd.), Macrogol-200, Macrogol-300, Macrogol-400, Macrogol-600, Macrogol-100
It is sold under trade names such as 0, Macrogol-1540, Macrogol-4000, Macrogol-6000, or Macrogol-20000 (trade name of NOF Corporation). The weight average molecular weight of polyethylene glycol used in the present invention is not particularly limited, but is preferably 500 to 100,000, particularly preferably 1000 to 50,000. These polyethylene glycols having different molecular weights may be used alone or in combination of two or more, and in this case, the weight average molecular weight can be adjusted.

As glycerin, commercially available glycerin which is usually used for liquid medicines can be used.

As propylene glycol, commercially available propylene glycol which is usually used for liquid medicines can be used. For example, propylene glycol (Asahi Glass Co., Ltd.), ADEKA propylene glycol (Asahi Denka Kogyo Co., Ltd.) It is also sold.

In the present invention, the solubility or stability can be improved by blending at least one member selected from the group consisting of nonionic surfactants, polyvinylpyrrolidone and polyhydric alcohols, but more excellent effects can be obtained. In the case of mixing two kinds in order to obtain, a combination of glycerin and polyethylene glycol selected from a nonionic surfactant and a polyhydric alcohol, a nonionic surfactant and polyvinylpyrrolidone or a polyhydric alcohol is preferable.

The solution of the present invention further has improved solubility or stability by further containing a chelating agent. Examples of the chelating agent include citric acid, ethylenediaminetetraacetic acid (also referred to as edetic acid), ethylenediaminediacetic acid, diethylenetriaminepentaacetic acid, N- (2-hydroxyethyl) ethylenediaminetriacetic acid, N- (2-hydroxyethyl). Examples thereof include iminodiacetic acid, trihydroxymethylaminomethane, nitrilotriacetic acid and 1-hydroxyethane-1,1-diphosphonic acid. These chelating agents may be used alone or in combination of two or more, and may be used as a pharmacologically or physiologically acceptable salt. Preferred are citric acid, ethylenediaminetetraacetic acid or salts thereof, for example, disodium ethylenediaminetetraacetate, disodium ethylenediaminetetraacetate dihydrate (also referred to as sodium edetate), trisodium citrate dihydrate and the like. Can be given. When containing a chelating agent, the concentration in the solution is
For example, 0.001 to 10%, 0.001 to 5%, 0.0
It is about 05 to 5%.

The solution of the present invention further contains the buffering agent to further improve the solubility or stability. Examples of the buffer include borate buffer, phosphate buffer, carbonate buffer, acetate buffer, epsilon-aminocaproic acid, aspartic acid buffer, tris buffer and the like. Preferred buffers are borate buffers, phosphate buffers, Good's buffers and carbonate buffers. Particularly preferred buffers are borate buffers, Good's buffers or phosphate buffers. Examples of the borate buffer include borate salts such as alkali metal borate and alkaline earth metal borate (sodium borate, potassium tetraborate, potassium metaborate, etc.). Examples of the phosphate buffer include phosphates such as alkali metal phosphates and alkaline earth metal phosphates (sodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, etc.),
It may be a hydrate. Good buffer is a general term for various aminoethanesulfonic acid and aminopropanesulfonic acid derivatives having a zwitterionic structure and buffering ability devised by Good et al., MES, MOPS, PIPES, HEPE.
S, BES, TES, etc. are mentioned. When it contains a buffering agent, the concentration in the solution is, for example, 0.0001 to 10
%, 0.001 to 5%, and 0.01 to 4%.

The liquid preparation of the present invention is useful in that a poorly soluble drug is dissolved or stably retained in an aqueous solution. The application is not particularly limited as long as it utilizes this effect, and it can be used in various fields such as pharmaceuticals, quasi drugs, and cosmetics. For example, it can be used as an eye drop, a nasal drop, an injection, an internal solution, a lotion, an external solution and the like. Since it can be made into a clear aqueous or oily solution by improving the solubility, it is particularly useful for use in eye drops, nasal drops and injections, which are desired to be clear aqueous solutions.

The liquid preparation of the present invention is N- [4- [4- (1,2-benzisothiazol-3-yl) -1-piperazinyl] butyl] unless the effects of the present invention are impaired.
-1,2-cis-cyclohexanedicarboximide or a salt thereof may be contained in combination with various components (including pharmacologically active ingredients and physiologically active ingredients). The type of such components is not particularly limited, and examples include decongestant components, anti-inflammatory drug components, antihistamine drug components or antiallergic drug components, astringent drug components, antibacterial or bactericidal drug components, antitumor drug components, vitamins. And amino acids.

In the present invention, various components and additives may be optionally selected or used in combination according to the conventional method according to the application and the form, if necessary, within a range that does not impair the effects of the invention. It is possible. For example, various additives such as carriers (oil-based solvents, aqueous solvents, etc.) generally used for preparing liquid agents, thickeners, preservatives, bactericides, antibacterial agents, isotonic agents, flavoring agents, flavors and the like. Can be mentioned.

The typical components used in the composition of the present invention are illustrated below, but the components are not limited to these.

Thickeners: For example, polysaccharides or derivatives thereof (hyaluronic acid, chondroitin sulfate, etc.), cellulose derivatives (methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, carboxyethyl cellulose, cellulose etc.) Such. Surfactants: amphoteric surfactants such as glycine type such as alkyldiaminoethylglycine, betaine acetate such as lauryldimethylaminoacetic acid betaine, and imidazoline type; POE (10) POE alkyl ether phosphorus such as sodium lauryl ether phosphate Acids and salts thereof, N-acyl amino acid salts such as sodium lauroylmethylalanine, alkyl ether carboxylates, N-acyl taurine salts such as N-cocoylmethyl taurine sodium, sulfonates such as sodium tetradecene sulfonate, lauryl sulfate Alkyl sulphates such as sodium,
POE (3) PO such as sodium lauryl ether sulfate
E Alkyl ether sulfate, anionic surfactant such as α-olefin sulfonate, etc. The numbers in parentheses indicate the number of added moles.

Preservatives or bactericides: alkyl quaternary ammonium salts (benzalkonium chloride, benzethonium chloride, etc.), chlorhexidine, biguanide compounds, parabens and the like. Isotonicity agents: for example, polyhydric alcohols such as glycerin and propylene glycol, sugars (sugar sugar, mannitol, sorbitol, etc.), inorganic salts and the like. Further, a flavoring agent or a cooling agent (eg, menthol, camphor, borneol, geraniol, eucalyptus oil, bergamot oil, fennel oil, peppermint oil, cinnamon oil, rose oil, peppermint oil, etc.) can be added if necessary. .

The liquid preparation of the present invention is preferably adjusted so as to stably hold a poorly soluble drug, and is preferably adjusted within a range acceptable to the living body. In the present invention, the suitable pH is 3.8 to 9.0, preferably 3.8 to 8.0, and more preferably 3.8 to 7.0.

The liquid preparation of the present invention needs to be adjusted to an osmotic pressure within a range that is acceptable to the living body, if necessary. The osmotic pressure is 100 to 1200 mOsm, preferably 100 to 6
00 mOsm, particularly preferably 150 to 400 mOsm
The osmotic pressure to saline ratio is usually
It is 0.3 to 4.1, preferably 0.3 to 2.1, and particularly preferably 0.5 to 1.4.

The liquid preparation of the present invention can be produced by a known method. Furthermore, if necessary, a filter sterilization treatment step, a container filling step, and the like can be added.

[0030]

INDUSTRIAL APPLICABILITY The present invention provides N- [4- [4- (1,
2-Benzisothiazol-3-yl) -1-piperazinyl] butyl] -1,2-cis-cyclohexanedicarboximide or a salt thereof is a liquid preparation having improved solubility. Such a liquid formulation is N- [4-
[4- (1,2-benzisothiazol-3-yl) -1-piperazinyl] butyl] -1,2-cis-cyclohexanedicarboximide or a salt thereof together with a nonionic surfactant, polyvinylpyrrolidone, polyvalent It can be obtained by containing together at least one compound selected from the group consisting of alcohols.

In the liquid preparation of the present invention, N- [4- [4-
(1,2-benzisothiazol-3-yl) -1
-Piperazinyl] butyl] -1,2-cis-cyclohexanedicarboximide or N in solution
-[4- [4- (1,2-benzisothiazole-
3-yl) -1-piperazinyl] butyl] -1,2
-Has the effect of significantly improving the solubility of cis-cyclohexanedicarboximide or a salt thereof. Therefore, N- [4- [4- (1,2-benzisothiazol-3-yl) -1-piperazinyl] butyl] -1,2-cis-cyclohexanedicarboximide or a salt thereof is used as a clear liquid agent. It becomes possible to do. And a stable liquid preparation containing N- [4- [4- (1,2-benzisothiazol-3-yl) -1-piperazinyl] butyl] -1,2-cis-cyclohexanedicarboximide or a salt thereof. Can be provided.

Such solutions are eye drops, nasal drops, injections,
It can be used as an internal liquid preparation and the like, and is a useful liquid preparation from the viewpoints of safety for living bodies, ease of production, rapid pharmacological effect expression, and bioavailability.

[0033]

EXAMPLES The present invention will be described in detail below based on examples, but the present invention is not limited to these examples.

[0034] Example 1 Eye drops Perospirone hydrochloride hydrate 0.3 g Polysorbate 80 0.5g Poloxamer 407 0.05g Polyethylene glycol 4000 5.0 g Glycerin 0.1g Anhydrous caffeine 1.5g Sodium ethylenediaminetetraacetate dihydrate 0.05 g Boric acid 1.0g pH adjusting agentPurified water Suitable amount 100 ml (pH = 6.0)

[0035] Example 2 Eye drops Perospirone hydrochloride hydrate 1.0 g Polo sorbate 80 0.5g Polyethylene glycol 6000 2.5g Propylene glycol 1.0g Glycerin 0.5g Citric acid 2.0g Anhydrous caffeine 0.5g Epsilon-aminocaproic acid 0.5 g Sodium hydroxide suitable amountPurified water Suitable amount Total volume 100 ml (pH = 5.5)

[0036] Example 3 Nasal drops Perospirone hydrochloride hydrate 2.0 g Polysorbate 80 0.5g Polyoxyethylene 60 hydrogenated castor oil 0.1g Polyethylene glycol 7.0 g Glycerin 0.3g Sodium ethylenediaminetetraacetate dihydrate 0.05 g Boric acid 1.0g Purified water Suitable amountpH adjusting agent 100 ml (pH = 4.5)

[0037] Example 4 Eye drops Perospirone hydrochloride hydrate 0.3 g Polysorbate 80 0.5g Poloxamer 407 0.05g Citric acid 2.0g Purified water Suitable amountSodium hydroxide suitable amount 100 ml (pH = 4.5)

[0038] Example 5 Injection Perospirone hydrochloride hydrate 0.1 g Polysorbate 80 0.5g Purified water Suitable amountpH adjusting agent Total volume 100 ml (pH = 6.8)

[0039] Example 6 Nasal drops Perospirone hydrochloride hydrate 1.0 g Polysorbate 80 0.5g Polyoxyethylene 60 hydrogenated castor oil 0.5g Polyethylene glycol 4000 3.0 g Glycerin 1.0g Citric acid 2.0g Purified water Suitable amountSodium hydroxide suitable amount 100 ml (pH = 4.5)

[0040]Test Example 1 Solubility test N- [4- [4- (1, 2 described in Table 1 and Table 2
-Benzisothiazol-3-yl) -1-piperazi
Nyl] butyl] -1,2-cis-cyclohexanedica
Preparation of 100 ml of liquid formulation containing ruboximide hydrochloride
Then, a solubility test was conducted. Each solution is placed in a transparent glass container.
After being stored at room temperature for 24 hours, the insoluble matter is visually precipitated.
Was observed. The results are shown in Table 1. In the table, insoluble matter
The sample that was not observed was ○, and the precipitation of insoluble matter was observed.
The ones that were taken were marked x.

[0041]

[Table 1]

[0042]

[Table 2]

As a result of the test, in the case of a liquid preparation containing perospirone hydrochloride and a polyhydric alcohol such as polyvinylpyrrolidone, polyethylene glycol, glycerin or propylene glycol together with a nonionic surfactant, an insoluble matter was obtained even in a perospirone hydrochloride liquid preparation having a concentration of 0.3%. No precipitation was observed, and it was confirmed that perospirone hydrochloride was dissolved and a stable liquid drug was obtained. Further, by combining a nonionic surfactant and a polyhydric alcohol in an acidic solution, the solubility is further improved to form a stable liquid agent. Furthermore, a nonionic surfactant, a polyhydric alcohol and a chelating agent are combined. Thus, it was confirmed that the solubility was remarkably improved.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61K 47/16 A61K 47/16 47/18 47/18 47/24 47/24 47/32 47/32 47 / 34 47/34 A61P 25/18 A61P 25/18 F term (reference) 4C076 AA12 BB11 BB24 BB25 CC01 DD09 DD22 DD25 DD26 DD30 DD38 DD43 DD49 DD51 DD60 EE16 EE23 EE48 FF15 4C086 AA01 BC80 GA10 GA12 MA03 MA59 MA17 MA58 NA10 ZA18

Claims (15)

[Claims] 1. i) N- [4- [4- (1,2-benzisothiazol-3-yl) -1-piperazinyl]]
Butyl] -1,2-cis-cyclohexanedicarboximide or a salt thereof, ii) at least one compound selected from the group consisting of nonionic surfactants, polyvinylpyrrolidone and polyhydric alcohols. Liquid agent to be. 2. N- [4- [4- (1,2-benzisothiazol-3-yl) -1-piperazinyl]]
The liquid preparation according to claim 1, wherein the concentration of butyl] -1,2-cis-cyclohexanedicarboximide or a salt thereof is 0.1 w / v% or more. 3. The nonionic surfactant is a polyoxyethylene-polyoxypropylene block copolymer, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene hydrogenated castor oil, polyoxyethylene alkyl ethers, polyoxyethylene-polyoxy. The liquid agent according to claim 1, which is at least one selected from propylene alkyl ethers and polyoxyethylene alkylphenyl ethers. 4. The liquid agent according to claim 1, wherein the nonionic surfactant has an HLB of 10 or more. 5. The liquid preparation according to claim 1, wherein the concentration of the nonionic surfactant in the liquid preparation is 0.001 to 10 w / v%. 6. The liquid preparation according to claim 1, wherein the concentration of polyvinylpyrrolidone in the liquid preparation is 0.01 to 20 w / v%. 7. The liquid preparation according to claim 1, wherein the polyhydric alcohol is at least one selected from polyethylene glycol, glycerin and propylene glycol. 8. The concentration of the polyhydric alcohol in the liquid agent is 0.0.
The liquid agent according to any one of claims 1 to 7, which is 1 to 20 w / v%. 9. The liquid agent according to claim 1, further comprising a chelating agent. 10. The liquid agent according to claim 1, wherein the chelating agent is at least one selected from the group consisting of ethylenediaminetetraacetic acid, citric acid and salts thereof. 11. The concentration of the chelating agent in the liquid agent is 0.00.
The liquid agent according to any one of claims 1 to 10, which is 1 to 10 w / v%. 12. The method further comprises at least one buffer selected from borate buffer, phosphate buffer, carbonate buffer, epsilon-aminocaproic acid buffer, aspartic acid buffer and Good's buffer. 1 to 1
The liquid agent according to any one of 1. 13. The liquid agent according to claim 1, which is aqueous. 14. The liquid agent according to claim 1, which is clear. 15. The liquid preparation according to claim 1, which is an eye drop, a nasal drop, or an injection.