JP2002241311A - Surfactant-containing pharmaceutical composition - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a pharmaceutical composition containing a small amount of a surfactant and another additive enhancing the hemolysis inhibitory activity inherent in the surfactant so as to inhibit the hemolytic action inherent in the medicinal ingredient as a component of the composition. SOLUTION: This pharmaceutical composition is characterized by comprising a medicinal ingredient having hemolytic action, a surfactant and another additive enhancing the hemolysis inhibitory activity inherent in the surfactant.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a pharmaceutical composition containing a medicinal ingredient having a hemolytic action, in order to suppress the hemolytic action of the ingredient, further enhances the surfactant and the hemolytic inhibitory action of the surfactant. It relates to a pharmaceutical composition characterized by containing other additives.

[0002]

2. Description of the Related Art Among compounds having various medicinal effects, for example, an amphiphilic compound acting as a medicinal component acting on the central nervous system, such as an amphipathic compound, has the same osmotic pressure as plasma and can be administered after administration. Those exhibiting a hemolytic action are known. Hemolysis after parenteral administration of a pharmaceutical formulation can cause localized tissue damage, irritation or anemia, and in extreme cases can result in organ damage, especially kidney damage. Therefore, hemolysis after administration of the pharmaceutical preparation must be avoided as much as possible. Therefore, for example, a method of adding a surfactant, particularly a nonionic surfactant to the above-mentioned amphiphilic compound to reduce the hemolytic action of the amphiphilic compound is already known (Japanese Patent Application Laid-Open No. Hei 10 (1998)). -511382, US
5,880,123). However, when the hemolytic effect of the medicinal component is suppressed only by the surfactant as described above,
Unless a large amount of surfactant is added, the hemolytic action may not be able to be suppressed. Here, the maximum amount of surfactant used per day is defined by the Pharmaceutical Excipients Dictionary (edited by the Japan Pharmaceutical Excipients Association), and the higher alcohol polyoxyethylene, a type of nonionic surfactant, is used. Polyoxyethylene adducts such as addition ether type nonionic surfactants have strong transdermal absorption power and have hemolytic properties themselves. Therefore, a new pharmaceutical composition which contains a small amount of a surfactant and is capable of suppressing the hemolytic action of a medicinal component is required.

[0003]

SUMMARY OF THE INVENTION An object of the present invention is to suppress the hemolytic action of a pharmaceutically active ingredient by coexisting a surfactant and another additive that enhances the hemolytic action of the surfactant. An object of the present invention is to provide a pharmaceutical composition which can be produced and has a low surfactant content. Another object of the present invention is to provide a pharmaceutical composition containing a medicinal ingredient having a hemolytic action, by adding a surfactant and another additive that enhances the haemolysis-suppressing action of the surfactant, whereby the medicinal ingredient can be obtained. An object of the present invention is to provide a method for suppressing the hemolytic action and reducing the content of the surfactant.

[0004]

Means for Solving the Problems The present inventors have added a new pharmaceutical additive as a third component to a pharmaceutical composition containing a pharmaceutically active ingredient having a hemolytic action and a surfactant. A composition was prepared, and the hemolytic action of the pharmaceutical composition was measured. As a result, for some additives such as magnesium chloride, by using in combination with a surfactant,
An unexpected finding was obtained that it exhibited a better hemolysis-inhibiting action than when the surfactant was used alone. In addition, the present inventors further studied the effect of suppressing the hemolytic action of an additive that is not usually combined with a surfactant when used in combination with a surfactant. For example, polyethylene glycol is an additive that is generally widely used as a solubilizing agent, so it is rarely used in combination with a surfactant that also has a solubilizing effect. It has also been found that the combined use of glycol exhibits a more excellent hemolysis-inhibiting action than the case where a surfactant is used alone. in this way,
Even if the content of the surfactant is reduced by adding another additive that enhances the hemolysis-suppressing action of the surfactant,
Since the hemolysis of the medicinal component can be suppressed, the above-mentioned conventional problems concerning the content of the surfactant can be solved.

[0005] That is, the present invention is characterized in that (1) it contains a medicinal component having a hemolytic action, a surfactant, and another additive that enhances the hemolytic action of the surfactant. The pharmaceutical composition, (2) the pharmaceutical composition according to (1), wherein the surfactant is a nonionic surfactant, and (3) the polyionic sorbent is a nonionic surfactant. (4) the pharmaceutical composition according to (3), wherein the polysorbate is polysorbate 80;
(5) Other additives are a sugar alcohol, a sugar, an amino acid and a pharmaceutically acceptable salt thereof, an acid and a pharmaceutically acceptable salt thereof, an amine and a pharmaceutically acceptable salt thereof, (1) to (4), which are one or a mixture of two or more selected from the group consisting of amides, polyethylene glycols, inorganic salts and hard proteins.
And (6) other additives are mannitol, lactose, glycine, arginine, lactic acid, tartaric acid, triethanolamine, tris (hydroxymethyl) aminomethane, urea, polyethylene glycol 40
0, polyethylene glycol 600, magnesium chloride, sodium chloride and purified gelatin, one or more selected from the group consisting of the pharmaceutical composition according to (5), (7) and others. Additives of arginine, lactic acid, tris (hydroxymethyl)
The pharmaceutical composition according to the above (5), which is one or a mixture of two or more selected from the group consisting of aminomethane, polyethylene glycol 400, magnesium chloride and sodium chloride, and (8) other additives. Thing is,
One or two selected from the group consisting of polyethylene glycol 400, magnesium chloride and sodium chloride
(5) The pharmaceutical composition according to (5), wherein the other additive is magnesium chloride, and the content of magnesium chloride is 0.15 to 0.5% of the whole preparation.
(3) The pharmaceutical composition according to any one of (1) to (4), wherein the other additive is sodium chloride, and the content of sodium chloride is a formulation. The pharmaceutical composition according to any one of (1) to (4), wherein the content is 0.07 to 0.9 (w / w)% based on the whole.
(11) The pharmaceutical composition according to the above (1) to (10), wherein the pharmaceutically active ingredient having a hemolytic action is an amphiphilic compound, and (12) the pharmaceutically active ingredient having a hemolytic action is represented by the following formula: [1]

Embedded image [Wherein, R ¹ and R ² are the same or different and are each a hydrogen atom, a lower alkyl group, an amino group, a lower alkylamino group or a di-lower alkylamino group which may be substituted by a hydroxyl group, and R ³ and R ⁴ Are the same or different and each is a hydrogen atom, a halogen atom or a lower alkyl group; ring A is an aryl group or a heterocyclic group; ring B is a phenyl group, thienyl group, furyl group, pyrrolyl group, pyrrolidinyl group, oxazolyl group Or a cyclohexenyl group, X is a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkenyl group, an amino group, a cyano group or a lower alkyl group which may be substituted by a lower alkoxy group.

Embedded image 中 wherein E is a single bond, —CH ＝ CR ⁶ — (wherein R ⁶ is a hydrogen atom or an aryl group), —O—, and —S.
—, —NR ⁷ — (wherein R ⁷ is a hydrogen atom, a lower alkyl group or a lower alkoxycarbonyl group), a carbonyl group, a sulfinyl group, or —NHCO—,
Ring G is an aryl group, a heterocyclic group, a cycloalkyl group or a fused aryl group, and R ⁵ is a halogen atom; a hydroxyl group;
A lower alkoxy group optionally substituted by a lower alkoxy group, a halogen atom, a hydroxyl group or a lower alkanoyloxy group; a lower alkoxy group optionally substituted by a lower alkoxy group; an amino group A lower alkylamino group; a di-lower alkylamino group; a nitro group; a cyano group; a lower alkanoyl group; a lower alkanoyloxy group;
A lower alkoxycarbonyl group; a lower alkylsulfonyl group or a phenyl group, t is an integer of 0 or 1 to 5 representing the number of substituents on ring G, and when t is an integer of 2 to 5, R ⁵ is M may be the same or different, m is 0 or an integer of 1 to 8, and n is 0 or 1 to 4
Is an integer. ｝. [1] or a pharmaceutically acceptable salt thereof.
The pharmaceutical composition according to 1), wherein (13) the pharmaceutically active ingredient having a hemolytic action is N- (4-amino-2-methyl-6-quinolyl) -2-[(4-ethylphenoxy) methyl] benzamide hydrochloride (14) The pharmaceutical composition according to (1) to (13), wherein the pharmaceutical composition is a composition for intravenous injection. A composition, (15) an agent for enhancing the hemolytic activity of a surfactant, which comprises the additive according to (6), and (16) a medicament containing a pharmaceutically active ingredient having a hemolytic activity. (1) a method of suppressing the hemolytic action of the medicinal component, comprising adding a surfactant and another additive that enhances the hemolytic action of the surfactant to the composition;
7) Addition of another surfactant that enhances the hemolysis-suppressing action of a surfactant to a pharmaceutical composition containing a pharmaceutically active ingredient having a hemolytic action and a surfactant. A method for reducing the amount.

[0006]

BEST MODE FOR CARRYING OUT THE INVENTION The pharmacologically active ingredient having a hemolytic action according to the present invention is not particularly limited, and may be known per se. For example, an amphiphilic compound having both a hydrophilic region and a hydrophobic region can be used. Since the hydrophobic region of the compound has a high affinity for lipids constituting a biological membrane,
Erythrocyte membranes can be destroyed by such amphiphilic compounds. The amphiphilic compound may be a compound known per se, for example, an amino group including a tertiary amino group such as a dimethylamino group, a polar group such as a carboxyl group or a sulfo group, or a hydrophilic region such as an ionic group. When,
For example, a compound having a hydrophobic region such as an alkyl group or an aryl group can be used. Specifically, the common names Famotidine, Chlorpheniramine maleate, Mitomycin C (Mitomycin C)
tomycin C), Fludarabine phosphate (Fludarabine phosp)
hate), pentostatin (Pentostatin), tegafur (Tegafur), gemcitabine hydrochloride (Gemcitabine hydroch)
loride), Hydralazine hydrochloride
ide), sodium acetazolam
ide), levodopa, ceftizoxime sodium, sulbenicillin sodium, piperacillin sodium, aspoxycillin (Aspox)
icillin), cefpirome sulfate, minocycline hydrochloride, sulfamonomethoxine, sulfadimethoxine, 5-[[(2R, 3S) -2-[(1R) ) -1-
[3,5-bis (trifluoromethyl) phenyl] ethoxy] -3
-(4-fluorophenyl) -4-morpholinyl] methyl]
-N, N-dimethyl-1H-1,2,3-Triazole-4
-Methanamine and the like.

[0007] Other amphiphilic compounds include, for example, active ingredients acting on the central nervous system. The components are often amphiphilic in order to penetrate the brain through the blood-brain barrier. Further, an amide derivative represented by the following general formula or a pharmaceutically acceptable salt thereof can be mentioned (Japanese Patent No. 3013989). The compound is selectively Opio
By acting on the id receptor like-1 receptor, it has an analgesic effect as a nociceptin antagonist, and is useful for treating pain, particularly severe pain or hyperalgesia and pain due to sensory nerve abnormalities such as allodynia.

The above amide derivative has the general formula [1]

Embedded image [Wherein, R ¹ and R ² are the same or different and are each a hydrogen atom, a lower alkyl group, an amino group, a lower alkylamino group or a di-lower alkylamino group which may be substituted by a hydroxyl group, and R ³ and R ⁴ Are the same or different and each is a hydrogen atom, a halogen atom or a lower alkyl group; ring A is an aryl group or a heterocyclic group; ring B is a phenyl group, thienyl group, furyl group, pyrrolyl group, pyrrolidinyl group, oxazolyl group Or a cyclohexenyl group, X is a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkenyl group, an amino group, a cyano group or a lower alkyl group which may be substituted by a lower alkoxy group.

Embedded image 中 wherein E is a single bond, —CH ＝ CR ⁶ — (wherein R ⁶ is a hydrogen atom or an aryl group), —O—, and —S.
—, —NR ⁷ — (wherein R ⁷ is a hydrogen atom, a lower alkyl group or a lower alkoxycarbonyl group), a carbonyl group, a sulfinyl group, or —NHCO—,
Ring G is an aryl group, a heterocyclic group, a cycloalkyl group or a fused aryl group, and R ⁵ is a halogen atom; a hydroxyl group;
A lower alkoxy group optionally substituted by a lower alkoxy group, a halogen atom, a hydroxyl group or a lower alkanoyloxy group; a lower alkoxy group optionally substituted by a lower alkoxy group; an amino group A lower alkylamino group; a di-lower alkylamino group; a nitro group; a cyano group; a lower alkanoyl group; a lower alkanoyloxy group;
A lower alkoxycarbonyl group; a lower alkylsulfonyl group or a phenyl group, t is an integer of 0 or 1 to 5 representing the number of substituents on ring G, and when t is an integer of 2 to 5, R ⁵ is M may be the same or different, m is 0 or an integer of 1 to 8, and n is 0 or 1 to 4
Is an integer. ｝. ].

(A) In the general formula [1], a compound in which ring A is a quinolyl group is preferably used. (B) In the above general formula [1], ring B is a phenyl group, and X is

Embedded image (Wherein E, ring G, R ⁵ , t, m and n are the same as defined above) are preferably used. Among them, ring A is

Embedded image (Wherein, R ⁸ is a lower alkylthio group) is more preferably used.

(C) Further, in the general formula [1], ring A is a quinolyl group, R ¹ is an amino group, R ³ and R ⁴ are hydrogen atoms, and X is

Embedded image (Wherein E, ring G, R ⁵ , t, m and n are the same as defined above), which is the following general formula [1 ′]

Embedded image (Wherein, R ² , ring B, E, ring G, R ⁵ , t, m and n
Is the same as defined above. The amide derivative represented by the formula (1) is also preferably used. Among them, the amide derivative in which ring B is a phenyl group and R ² is a lower alkyl group is more preferably used. Furthermore, the amino group on the quinoline skeleton are substituted at the 4-position, R ² are substituted at the 2-position on it and quinoline skeleton methyl, an E is -O-, and

Embedded image (Wherein, the ring G, R ⁵ , t, m and n are the same as defined above), and the amide derivative in which the substituent substituted on the 2-position of the phenyl group which is the ring B is particularly preferably used. .

As the amide derivative represented by the above general formula [1 '], more specifically, for example, N- (4-amino-2-methyl-6-quinolyl) -2-[(4-ethylphenoxy) ) Methyl] benzamide hydrochloride, N- (4-
Amino-2-methyl-6-quinolyl) -2-[(2,4
-Dichlorophenoxy) methyl] benzamide hydrochloride, N- (4-amino-2-methyl-6-quinolyl)-
2- (phenoxymethyl) benzamide hydrochloride, N-
(4-amino-2-methyl-6-quinolyl) -2-
[(4-methoxyphenoxy) methyl] benzamide
Hydrochloride, N- (4-amino-2-methyl-6-quinolyl) -2-[(3,5-dimethylphenoxy) methyl]
Benzamide hydrochloride, N- (4-amino-2-methyl-6-quinolyl) -2-[(3,4-dimethoxyphenoxy) methyl] benzamide hydrochloride, N- (4-amino-2-methyl-6- Quinolyl) -2-[(4-nitrophenoxy) methyl] benzamide, N- (4-amino-2-methyl-6-quinolyl) -2-[(2,3-dimethoxyphenoxy) methyl] benzamide hydrochloride, N
-(4-amino-2-methyl-6-quinolyl) -2-
[(3-methylphenoxy) methyl] benzamide, N
-(4-amino-2-methyl-6-quinolyl) -2-
[(3,5-dimethoxyphenoxy) methyl] benzamide hydrochloride, N- (4-amino-2-methyl-6-quinolyl) -2-[(4-chlorophenoxy) methyl] benzamide hydrochloride, N- (4 -Amino-2-methyl-
6-quinolyl) -2-[(4-acetylphenoxy) methyl] benzamide hydrochloride, N- (4-amino-2-
Methyl-6-quinolyl) -2-[(4-hydroxyphenoxy) methyl] benzamide hydrochloride, N- (4-amino-2-methyl-6-quinolyl) -2-[(4-methoxymethoxyphenoxy) methyl] Benzamide hydrochloride, N- (4-amino-2-methyl-6-quinolyl)-
2-[(3-methoxyphenoxy) methyl] benzamide hydrochloride,

N- (4-amino-2-methyl-6-quinolyl) -2-[(4-cyanophenoxy) methyl] benzamide hydrochloride, N- (4-amino-2-methyl-6)
-Quinolyl) -2-[(4-methylphenoxy) methyl] benzamide hydrochloride, N- (4-amino-2-methyl-6-quinolyl) -2-[(4-trifluoromethylphenoxy) methyl] benzamide hydrochloride Salt, N-
(4-amino-2-methyl-6-quinolyl) -2-
[(3-Nitrophenoxy) methyl] benzamide hydrochloride, N- (4-amino-2-methyl-6-quinolyl)
-2-[(2-Nitrophenoxy) methyl] benzamide hydrochloride, N- (4-amino-2-methyl-6-quinolyl) -2-[(4-acetoxyphenoxy) methyl]
Benzamide hydrochloride, N- (4-amino-2-methyl-6-quinolyl) -2-[(2-methoxyphenoxy)
Methyl] benzamide hydrochloride, N- (4-amino-2
-Methyl-6-quinolyl) -2-[(4-aminophenoxy) methyl] benzamide dihydrochloride, N- (4-amino-2-methyl-6-quinolyl) -2-[(3-chlorophenoxy) methyl ] Benzamide hydrochloride, N-
(4-amino-2-methyl-6-quinolyl) -2-
[(4-Fluorophenoxy) methyl] benzamide
Hydrochloride, N- (4-amino-2-methyl-6-quinolyl) -2-[(3,4-dichlorophenoxy) methyl]
Benzamide hydrochloride, N- (4-amino-2-methyl-6-quinolyl) -2-[(2-chlorophenoxy) methyl] benzamide hydrochloride, N- (4-amino-2-
Methyl-6-quinolyl) -2-[(4-dimethylaminophenoxy) methyl] benzamide dihydrochloride, N-
(4-amino-2-methyl-6-quinolyl) -2-
[(4-tert-butylphenoxy) methyl] benzamide hydrochloride, N- (4-amino-2-methyl-6-
Quinolyl) -2- (4-biphenylyloxymethyl) benzamide hydrochloride,

N- (4-amino-2-methyl-6-quinolyl) -2-[(4-isopropylphenoxy) methyl] benzamide hydrochloride, N- (4-amino-2-methyl-6-quinolyl)- 2-[(4-nitrophenoxy) methyl] benzamide hydrochloride, N- (4-amino-2-methyl-6-quinolyl) -2-[(4-bromophenoxy) methyl] benzamide hydrochloride, N- (4 −
Amino-2-methyl-6-quinolyl) -2-[(4-propylphenoxy) methyl] benzamide hydrochloride, N
-(4-amino-2-methyl-6-quinolyl) -2-
[(3-Fluorophenoxy) methyl] benzamide
Hydrochloride, N- (4-amino-2-methyl-6-quinolyl) -2-[(3-trifluoromethylphenoxy) methyl] benzamide hydrochloride, methyl 4- [2- {N-
(4-Amino-2-methyl-6-quinolyl) carbamoyl {benzyloxy] benzoic acid hydrochloride, N- (4-amino-2-methyl-6-quinolyl) -2-[(4-iodophenoxy) methyl] Benzamide, N- (4-amino-2-methyl-6-quinolyl) -2- (3-pyridyloxymethyl) benzamide hydrochloride, 4- [2-
{(4-amino-2-methyl-6-quinolyl) carbamoyl} benzyloxy] benzoic acid hydrochloride, N- (4-
Amino-2-methyl-6-quinolyl) -2-[(3-cyanophenoxy) methyl] benzamide hydrochloride, N-
(4-amino-2-methyl-6-quinolyl) -2-
[(4-Mesylphenoxy) methyl] benzamide hydrochloride, N- (4-amino-2-methyl-6-quinolyl)
-2-[(2-Chloro-4-ethylphenoxy) methyl] benzamide hydrochloride, N- (4-amino-2-methyl-6-quinolyl) -2-[(4-chloro-3-methylphenoxy) methyl ] Benzamide hydrochloride, N-
(4-amino-2-methyl-6-quinolyl) -2-
[(2-Chloro-4-methylphenoxy) methyl] benzamide hydrochloride, N- (4-amino-2-methyl-6)
-Quinolyl) -2-[(4-ethylphenoxy) methyl] benzamide, N- (4-amino-2-methyl-6)
-Quinolyl) -2-[(4-chloro-3-methylphenoxy) methyl] benzamide, 4- [2-{(4-amino-2-methyl-6-quinolyl) carbamoyl} benzyloxy] benzyl acetic acid hydrochloride, N- (4-amino-
2-methyl-6-quinolyl) -2-[(4-hydroxymethylphenoxy) methyl] benzamide hydrochloride and N- (4-amino-2-methyl-6-quinolyl) -2
-[(4-ethylphenoxy) methyl] benzamide
An amide derivative selected from the group consisting of hydrochloride monohydrate is mentioned, and is suitably used in the present invention. Among them, N- (4-amino-2-methyl-6-quinolyl)-
Most preferably, 2-[(4-ethylphenoxy) methyl] benzamide hydrochloride is used in the present invention.

(D) In the general formula [1], R ¹ is an amino group, R ³ and R ⁴ are hydrogen atoms, ring B is a phenyl group, and X is

Embedded image E is -O-, ring G is a phenyl group,
The following general formula [1 ″] wherein m is 1 and n is 0

Embedded image (Wherein, ring A, R ² , R ⁵ and t are the same as defined above) are also suitably used in the present invention.

Here, "lower" preferably has 1 to 6 carbon atoms. Further, the “heterocyclic group” means one or more of one or more of an oxygen atom, a nitrogen atom, and a sulfur atom as a hetero atom, and the ring has 5 to 20 atoms. It is a cyclic compound group. Specifically, pyridyl group, quinolyl group, isoquinolyl group, quinoxalyl group, 2,3-dihydrobenzofuranyl group, 5,6,7,
8-tetrahydroquinolyl group, 5,6,7,8-tetrahydroacridinyl group, 2,3-dihydro-1H-cyclopenta [b] quinolyl group, and the like. Further, the “condensed aryl group” is an “aryl group” in which a “cycloalkyl group” is condensed, and has 5 to 1 carbon atoms constituting a ring.
And 8 cyclic compound groups. Specifically, an indanyl group,
5,6,7,8-tetrahydro-2-naphthyl group, 5,
6,7,8-tetrahydro-2-anthryl group, 1,
2,3-trihydroazulenyl group and the like. It should be noted that, in order to explain an embodiment of the present invention, Patent No. 30
The detailed description of the invention of the '13989 patent specification is incorporated as part of the disclosure herein.

In the present invention, as the surfactant, those known per se may be used, and generally include molecules containing a hydrophobic portion (eg, an alkyl chain) and a hydrophilic portion (eg, a polar group or an ionic group). Surfactants can be divided into a number of groups, including anionic, cationic, amphoteric and non-ionic. In the present invention, any group of surfactants may be used. It is particularly preferred to use activators. Nonionic surfactants include fatty alcohols; glyceryl esters such as natural mono-, di- and triglycerides; fatty acid esters of fats and other alcohols such as propylene glycol, polyethylene glycol, sorbitan and cholesterol; polyoxyethylene sorbitan Fatty acid esters; or polyoxyethylene ethers. Among them, polyoxyl stearate 40, polyoxyethylene [105] polyoxypropylene [5] glycol, polysorbate, sodium lauryl sulfate and the like are preferably used. Further, polysorbate is more preferably used. Here, the polysorbate is a polyoxyethylene ether obtained by esterifying a part of hydroxyl groups of anhydrous sorbitol with a fatty acid. Among the polysorbates, polysorbate 40 whose fatty acid is palmitic acid, polysorbate 60 whose fatty acid is stearic acid, and polysorbate 8 whose fatty acid is oleic acid
0 is preferable, and polysorbate 80 is more preferable.

Although the content of the surfactant cannot be unconditionally determined because the physical properties vary depending on the surfactant, it is preferably within the range of the critical micelle concentration of the surfactant used. Specifically, about 0.05 to 5 with respect to the whole preparation.
(W / w)%, more preferably about 0.1 to 2.5.
(W / w)% is preferable. The content of the surfactant is preferably about 40 times by weight or less, more preferably about 20 times by weight or less, based on the active ingredient having a hemolytic action. As described above, the pharmaceutical composition according to the present invention has an advantage that the content of the surfactant can be smaller than when the surfactant is used alone.

As the other additives as the third component according to the present invention, those which are known per se may be used as long as they enhance the hemolysis inhibiting effect of the surfactant. More specifically, for example, sugar alcohols such as sorbitol, mannitol, xylitol, inositol or glycerol;
For example, sugars such as glucose, fructose, xylose, lactose or maltose; aspartic acid,
Amino acids such as sodium aspartate, magnesium aspartate, alanine, glycine, alginic acid, sodium alginate, glutamine, glutamic acid, potassium glutamate, sodium glutamate, histidine, methionine, arginine, cysteine, propionic acid, and pharmaceutically acceptable salts thereof For example, acetic acid, glacial acetic acid, calcium acetate, potassium acetate, phosphoric acid,
Thioglycolic acid, lactic acid, sodium lactate, calcium lactate, tartaric acid, sodium tartrate, citric acid, sodium citrate, disodium citrate, sodium dihydrogen citrate, calcium citrate, benzoic acid, sodium benzoate, sorbic acid, malic acid Acid such as adipic acid, sodium gluconate or a pharmaceutically acceptable salt thereof; amines such as diethanolamine, triethanolamine, triethanolamine hydrochloride, triisopropanolamine or tris (hydroxymethyl) aminomethane; nicotine Amides such as acid amide, N, N'-dimethylacetamide or urea; for example, polyethylene glycol 1000, 1500, 15
40, 200, 20000, 300, 400, 400
Polyethylene glycol such as 0, 600 or 6000; for example, inorganic salts such as zinc chloride, potassium chloride, calcium chloride, magnesium chloride or sodium chloride; and hard proteins such as purified gelatin. These may be used alone or in any combination of two or more. Here, the “pharmacologically acceptable salt of an acid” includes, for example, alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; ammonium salt; Organic amine salts such as salts, triethylamine salts, dicyclohexylamine salts, ethanolamine salts, diethanolamine salts, triethanolamine salts, procaine salts, and N, N'-dibenzylethylenediamine salts. Examples of the “pharmacologically acceptable salt of an amino acid” include salts of a base addition salt when the amino acid has an acidic group and salts of an acid addition salt when the amino acid has a basic group. Such base addition salts include the salts described above. Examples of the acid addition salts include inorganic salts such as hydrochloride, sulfate, nitrate, phosphate, and perchlorate; for example, maleate, fumarate, tartrate, and the like.
Organic acid salts such as citrate, ascorbate and trifluoroacetate; and sulfonates such as methanesulfonate, isethionate, benzenesulfonate and p-toluenesulfonate.

Among them, mannitol, lactose, glycine, arginine, lactic acid, tartaric acid, triethanolamine, tris (hydroxymethyl) aminomethane, urea,
It is preferable to use polyethylene glycol 400, polyethylene glycol 600, magnesium chloride, sodium chloride or purified gelatin. In addition, arginine, lactic acid, tris (hydroxymethyl) aminomethane,
More preferably, polyethylene glycol 400, magnesium chloride or sodium chloride is used. In particular, it is more preferable to use polyethylene glycol 400, magnesium chloride or sodium chloride, and it is most preferable to use sodium chloride.

The content of other additives that enhance the hemolysis-suppressing action of the above-mentioned surfactants is such that these additives are generally used in the art, such as the doses described in the Pharmaceutical Excipients Dictionary. If it is an amount, it is not particularly limited. For example, when the additive is magnesium chloride, its content is about 0.15 to 0.43 (v /
v)% is preferable. When the other additive is sodium chloride, its content is about 0.07 with respect to the whole preparation.
About 0.9 (w / w)%, preferably about 0.08 to
About 0.2 (w / w)% is more preferable.

The pharmaceutical composition of the present invention can be processed into solid preparations such as capsules, tablets, powders or granules or liquid preparations according to methods well known or commonly used in the field of pharmaceuticals. For example, among preparations suitable for parenteral administration, preparations for intravascular administration such as injections and drops can be prepared preferably using an aqueous medium isotonic with human blood. More specifically, for example, an injection is prepared as a solution, suspension or dispersion with a suitable auxiliary agent according to a conventional method using an aqueous medium selected from a salt solution, a glucose solution or a mixture of a salt solution and a glucose solution. Can be prepared. The form of the medicament of the present invention and the method for producing the same are not limited to those specifically described above. However, in the present invention, it is preferable to use the pharmaceutical composition according to the present invention as a pharmaceutical composition for intravenous injection. When used as a composition for intravenous injection, the pharmaceutical composition according to the present invention contains other additives to suppress local irritation such as pain response, thrombosis, hyperemia, ileum or hot sensation. There is an advantage that can be.

The pharmaceutical composition according to the present invention is characterized in that it contains a pharmaceutically active ingredient having a hemolytic action, a surfactant, and other additives which enhance the hemolytic action of the surfactant. In addition, other pharmaceutical additives generally used in the art and known per se may be included. Such pharmaceutical additives vary depending on the final dosage form of the pharmaceutical. Specifically, when the pharmaceutical composition of the present invention is made into a liquid formulation suitable for parenteral administration, for example, isotonic such as sorbitol Agents: Pharmaceutical additives such as pH adjusters such as glacial acetic acid are used. When the pharmaceutical composition of the present invention is used as a liquid preparation suitable for oral administration, for example, an isotonic agent such as sorbitol; a pH adjusting agent such as glacial acetic acid;
Pharmaceutical additives such as oils such as olive oil and soybean oil; and preservatives such as p-hydroxybenzoic acid esters are used. Further, the pharmaceutical composition according to the present invention is a capsule,
When a solid preparation such as a tablet, powder or granule is used, for example, disintegrants such as starch and sodium alginate; lubricants such as magnesium stearate and talc; binders such as polyvinyl alcohol and hydroxypropyl cellulose; Pharmaceutical additives such as plasticizers such as glycerin are used. Also, when the components in the formulation are oxidized,
Sodium nitrite, sodium sulfite, dried sodium sulfite, sodium bisulfite, ascorbic acid, L-
Ascorbic acid, stearic acid ester, ascorbyl palmitate, alpha thioglycerin, sodium edetate, erythorbic acid, citric acid, cysteine hydrochloride,
Tocopherol, tocopherol acetate, d-δ-tocopherol, natural vitamin E, potassium dichloroisocyanurate, dibutylhydroxytoluene, 2,6-di-
t-butyl-4-methylphenol, soy lecithin, sodium thioglycolate, sodium thiomalate,
Tenox 2, sodium pyrosulfite, butylhydroxyanisole, 1,3-butylene glycol, pentaerythrityl-tetrabis [3- (3,5-di-t-butyl-4-hydroxyphenyl)] propionate, propyl gallate, -Antioxidants such as mercaptobenzimidazole and oxyquinoline sulfate can also be used.

The route of administration, dose and frequency of administration of the medicament comprising the pharmaceutical composition according to the present invention are not particularly limited, and include types of medicinal components having a hemolytic effect, types of conditions to be treated, age and weight of the patient, It can be appropriately selected according to various conditions such as the severity of symptoms and diseases.

The pharmaceutical composition according to the present invention is characterized in that a surfactant and another additive that enhances the hemolytic activity of the surfactant suppress the hemolytic activity of the pharmaceutically active ingredient contained in the pharmaceutical composition. The feature is that it can be done. Therefore, the pharmaceutical composition according to the present invention preferably has a measured value of hemolysis of preferably 5% or less, more preferably 2% or less, and still more preferably 1% or less. In addition, hemolysis can be easily measured by the method described in Test Example 1 of the following Examples.

[0025]

EXAMPLES Example 1 N- (4-Amino-2-methyl-6-quinolyl) -2-[(4-ethylphenoxy) methyl] benzamide hydrochloride as a pharmaceutically active ingredient having a hemolytic effect in water for injection 25 mg, Polysorbate 80 (trade name: Tween, manufactured by NOF CORPORATION) as a surfactant
80), and polyethylene glycol 4 as another additive to enhance the hemolytic action of the surfactant.
00 (manufactured by NOF CORPORATION, Macrogol 40)
0) was added in an amount of 3200 mg. Furthermore, sorbitol 2500 mg as an isotonic agent and glacial acetic acid 2
5 mg was added. The aqueous solution was adjusted to pH 5 with 1N NaOH. Further, water for injection was added to bring the total weight to 50 g. Thus, the pharmaceutical composition according to the present invention was produced.

Example 2 Polyethylene glycol 4 was used as another additive to enhance the hemolysis-suppressing action of a surfactant.
Except that 120 mg of lactic acid was added instead of 00,
A pharmaceutical composition according to the present invention was produced in the same manner as in Example 1.

Comparative Examples 1 and 2 A pharmaceutical composition was produced in the same manner as in Example 1 or 2, except that polysorbate 80 as a surfactant was not added.

[Comparative Example 3] N- (4-amino-2-methyl-6-yl-6) was used as an active ingredient having a hemolytic action in water for injection.
Quinolyl) -2-[(4-ethylphenoxy) methyl]
0.5 mg of benzamide hydrochloride, and polysorbate 80 (trade name Twe manufactured by NOF Corporation) as a surfactant
en80) was added. At this time, the ratio of the content of the pharmaceutically active ingredient to the content of the surfactant was 1:50, and the content of the surfactant was larger than the ratio of 1:20 in Examples. Further, 50 mg of sorbitol as an isotonic agent,
About 0.5 mg of glacial acetic acid was added as a pH adjuster. The aqueous solution was adjusted to pH 5 with 1N NaOH. Further, water for injection was added to bring the total weight to 1 g.

[Comparative Example 4] 10 m of polysorbate 80
Except for adding g, a pharmaceutical composition was produced in the same manner as Comparative Example 3. At this time, the ratio between the content of the pharmaceutically active ingredient and the content of the surfactant was 1:20, which was the same as the ratio in the examples.

[Test Example 1] The hemolytic properties of each of the pharmaceutical compositions produced in Examples 1 to 3 and Comparative Examples 1 and 2 were measured as follows. 1 ml of human whole blood is added to 10 ml of the sample to be measured and mixed. This at 37 ° C for 3
After leaving still for 0 minutes, centrifugation is performed at 3000 rpm for 5 minutes to separate into a supernatant and a sediment (blood cells). Add 3 more supernatants
Centrifuge at 000 rpm for 25 minutes to obtain a clear supernatant. The absorbance (Ai) of the supernatant is measured at a wavelength of 540 nm. When the absorbance (Ai) of the supernatant is large, the supernatant is diluted with water for injection as necessary and measured. Absorbances As and A when physiological saline and water for injection were used as the sample to be measured
The hemolytic property (%) of the measurement sample is calculated by the following formula, using the value of w as the standard for hemolytic property of 0% and 100%. Hemolytic (%) = 100 × (Ai-As) / (Aw-A
s) The results are shown in Table 1.

[0031]

[Table 1] In the table, the content of the content indicates the content (mg) in 1 g of the pharmaceutical composition.

From Comparative Examples 1 and 2, when polyethylene glycol 400 or lactic acid alone is used as another additive to enhance the hemolytic action of the surfactant, the hemolytic action of the pharmaceutically active ingredient can hardly be suppressed. On the other hand, when the surfactant was used alone, as apparent from Comparative Example 4,
The amount of the surfactant that is about 20 times the weight of the medicinal component is not sufficient to suppress the hemolytic effect of the medicinal component, and as is apparent from Comparative Example 3, it is necessary to effectively suppress the hemolytic effect of the medicinal component. It is understood that about 50 times by weight of the surfactant is required for the medicinal ingredient. However, Examples 1 and 2
As is apparent from the above, by coexisting a surfactant and polyethylene glycol 400 or lactic acid,
The hemolytic action of the medicinal component can be sufficiently suppressed by using the surfactant in an amount of about 20 times the weight of the medicinal component. Therefore, it was found that by adding other additives such as polyethylene glycol 400 or lactic acid, the effect of suppressing the hemolysis of the surfactant was enhanced, and as a result, the content of the surfactant could be reduced. In addition, sorbitol and glacial acetic acid also have a role of enhancing the hemolytic inhibitory action of the surfactant. However, in the above Examples and Comparative Examples, these compounds are added only to the extent that they are effective as isotonic agents or pH adjusters, and their content is small, so that the surfactant has an effect on inhibiting the hemolysis. Has little effect.

Example 3 N- (4-Amino-2-methyl-6-yl-6) was used as an active ingredient having a hemolytic action in water for injection.
Quinolyl) -2-[(4-ethylphenoxy) methyl]
25 mg of benzamide hydrochloride, Polysorbate 80 (Twee trade name, manufactured by NOF CORPORATION) as a surfactant
n80) was 500 mg, and each of the additives shown in Table 2 below was added as other additives for enhancing the hemolysis suppressing effect of the surfactant, as shown in Table 2. Further, 2500 mg of sorbitol as an isotonic agent and 25 mg of glacial acetic acid as a pH adjuster were added. PH of the aqueous solution with 1M NaOH
5 was prepared. Further, water for injection was added to bring the total weight to 50 g. Thus, the pharmaceutical composition according to the present invention was produced. The hemolytic property of each of the manufactured pharmaceutical compositions was measured in the same manner as in Test Example 1.
Table 2 shows the results.

[0034]

[Table 2] In the table, Macrogol 600 represents polyethylene glycol 600 manufactured by NOF Corporation.

Therefore, polyethylene glycol 40
Not only 0 or lactic acid, but also the above compounds were found to be useful as other additives that enhance the hemolysis-suppressing action of the surfactant.

Example 4 N- (4-Amino-2-methyl-6-yl-6) was used as an active ingredient having a hemolytic action in water for injection.
Quinolyl) -2-[(4-ethylphenoxy) methyl]
25 mg of benzamide hydrochloride, Polysorbate 80 (Twee trade name, manufactured by NOF CORPORATION) as a surfactant
n80), and the content of sodium chloride as shown in Table 3 was added as another additive for enhancing the hemolysis-suppressing action of the surfactant. Further, 2500 mg of sorbitol as an isotonic agent and 20 mg of glacial acetic acid as a pH adjuster were added. The aqueous solution was adjusted to pH 5 with 1 M NaOH. Further, water for injection was added to bring the total weight to 50 g. Thus, the pharmaceutical composition according to the present invention was produced. The hemolytic property of each of the manufactured pharmaceutical compositions was measured in the same manner as in Test Example 1. Table 3 shows the results.

[0037]

[Table 3]

Therefore, when sodium chloride is used as another additive to enhance the hemolytic effect of the surfactant, its content is about 0.07 to 0.9 with respect to the whole preparation.
(W / w)% is preferable, and about 0.08 to 0.2 (w
/ W)% was found to be more preferable.

[0039]

According to the pharmaceutical composition of the present invention, the hemolytic action of the pharmaceutically active ingredient contained in the pharmaceutical composition can be suppressed. Therefore, a compound that has pharmacological action but has not been used because it causes hemolysis after administration can be used as a medicine. In addition, by having other additives such as polyethylene glycol, magnesium chloride or sodium chloride coexist with the surfactant, there is an advantage that the hemolysis suppressing effect of the surfactant can be enhanced and local irritation can be reduced. . Furthermore, in the present invention, the content of the surfactant in the pharmaceutical composition can be reduced by using another additive that enhances the hemolysis-suppressing action of the surfactant. Thus, when administering an effective amount of a medicinal component for treating or preventing a disease or the like, if a sufficient amount of the surfactant is used to suppress the hemolytic action of the medicinal component, the administration of the surfactant is permitted. The conventional problem of exceeding the capacity can be solved.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61K 47/18 A61K 47/18 47/26 47/26 47/30 47/30 47/34 47/34 47 / 42 47/42 A61P 7/00 A61P 7/00 (72) Inventor Yoshinori Negishi 1-1-1 Muramachi, Takatsuki City, Osaka Prefecture F-term in Japan Tobacco Inc. Pharmaceutical Research Institute 4C076 AA12 BB13 CC14 DD23 DD43 DD50 DD51 DD54 DD67 DD68 EE06 EE42 FF11 FF67 FF68 4C084 AA17 AA27 BA44 CA59 MA05 MA17 MA66 NA06 NA07 ZA512 4C086 AA01 AA02 BC28 MA03 MA05 MA17 MA66 NA06 NA07 ZA51

Claims (17)

[Claims] 1. A pharmaceutical composition comprising a pharmaceutically active ingredient having a hemolytic action, a surfactant, and another additive that enhances the hemolytic action of the surfactant. 2. The pharmaceutical composition according to claim 1, wherein the surfactant is a non-ionic surfactant. 3. The pharmaceutical composition according to claim 2, wherein the nonionic surfactant is polysorbate. 4. The pharmaceutical composition according to claim 3, wherein the polysorbate is polysorbate 80. 5. Other additives include sugar alcohols, sugars, amino acids and pharmaceutically acceptable salts thereof, acids and pharmaceutically acceptable salts thereof, amines and pharmaceutically acceptable salts thereof. It is one or a mixture of two or more selected from the group consisting of salts, amides, polyethylene glycols, inorganic salts and hard proteins.
5. The pharmaceutical composition according to 4. 6. Other additives are mannitol, lactose, glycine, arginine, lactic acid, tartaric acid, triethanolamine, tris (hydroxymethyl) aminomethane, urea, polyethylene glycol 400, polyethylene glycol 600, magnesium chloride, sodium chloride. 6. The pharmaceutical composition according to claim 5, which is one or a mixture of two or more kinds selected from the group consisting of purified gelatin. 7. The method according to claim 1, wherein the other additive is one or a mixture of two or more selected from the group consisting of arginine, lactic acid, tris (hydroxymethyl) aminomethane, polyethylene glycol 400, magnesium chloride and sodium chloride. The pharmaceutical composition according to claim 5, characterized in that: 8. The pharmaceutical composition according to claim 5, wherein the other additive is one or a mixture of two or more selected from the group consisting of polyethylene glycol 400, magnesium chloride and sodium chloride. . 9. The other additive is magnesium chloride, wherein the content of magnesium chloride is 0.15 to the whole preparation.
2. The method according to claim 1, wherein the ratio is 0.43 (v / v)%.
The pharmaceutical composition according to any one of claims 1 to 4. 10. The other additive is sodium chloride, wherein the content of sodium chloride is 0.07 to 0.5% based on the whole preparation.
The pharmaceutical composition according to any one of claims 1 to 4, wherein the content is 9 (w / w)%. 11. The pharmaceutical composition according to claim 1, wherein the pharmaceutically active ingredient having a hemolytic action is an amphipathic compound. 12. The pharmaceutical component having a hemolytic action is represented by the following formula [1]: [Wherein, R ¹ and R ² are the same or different and are each a hydrogen atom, a lower alkyl group, an amino group, a lower alkylamino group or a di-lower alkylamino group which may be substituted by a hydroxyl group, and R ³ and R ⁴ Are the same or different and each is a hydrogen atom, a halogen atom or a lower alkyl group; ring A is an aryl group or a heterocyclic group; ring B is a phenyl group, thienyl group, furyl group, pyrrolyl group, pyrrolidinyl group, oxazolyl group Or X is a cyclohexenyl group, and X is a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkenyl group, an amino group, a cyano group or a lower alkyl group which may be substituted by a lower alkoxy group. 中 wherein E is a single bond, —CH ＝ CR ⁶ — (wherein R ⁶ is a hydrogen atom or an aryl group), —O—, and —S.
—, —NR ⁷ — (wherein R ⁷ is a hydrogen atom, a lower alkyl group or a lower alkoxycarbonyl group), a carbonyl group, a sulfinyl group, or —NHCO—,
Ring G is an aryl group, a heterocyclic group, a cycloalkyl group or a fused aryl group, and R ⁵ is a halogen atom; a hydroxyl group;
A lower alkoxy group optionally substituted by a lower alkoxy group, a halogen atom, a hydroxyl group or a lower alkanoyloxy group; a lower alkoxy group optionally substituted by a lower alkoxy group; an amino group A lower alkylamino group; a di-lower alkylamino group; a nitro group; a cyano group; a lower alkanoyl group; a lower alkanoyloxy group;
A lower alkoxycarbonyl group; a lower alkylsulfonyl group or a phenyl group, t is an integer of 0 or 1 to 5 representing the number of substituents on ring G, and when t is an integer of 2 to 5, R ⁵ is M may be the same or different, m is 0 or an integer of 1 to 8, and n is 0 or 1 to 4
Is an integer. ｝. Or a pharmaceutically acceptable salt thereof.
2. The pharmaceutical composition according to 1. 13. The drug component having a hemolytic action is N-
(4-amino-2-methyl-6-quinolyl) -2-
The pharmaceutical composition according to claim 12, which is [(4-ethylphenoxy) methyl] benzamide hydrochloride. 14. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is a composition for intravenous injection. 15. An agent for enhancing the effect of inhibiting the hemolysis of a surfactant, which comprises the additive according to claim 6. 16. A medicinal composition comprising a medicinal ingredient having a hemolytic action, comprising adding a surfactant and another additive which enhances the hemolytic action of the surfactant. A method for suppressing the hemolytic action of. 17. The surfactant, characterized in that a pharmaceutical composition containing a pharmaceutically active ingredient having a hemolytic action and a surfactant is further added with another additive which enhances the hemolysis-suppressing action of the surfactant. A method for reducing the content of an agent.