JPH07109218A - Aqueous solution containing amide pressure - Google Patents

Abstract

PURPOSE:To obtain an aqueous preparation having excellent solubility of an amide derivative in an aqueous solution and excellent stability in an aqueous solution, not impairing pharmacodynamic effect. CONSTITUTION:This aqueous preparation is obtained by mixing an amide derivative of formula I [R<1> is lower alkoxyl or lower aloxycarbonyloxy; R<2> is lower alkoxycarbonyloxy; R<3> is H; (m) is 1 or 2; Y is group of formula II ((p) is 2-4)] with a nonionic surfactant having 10-16 HLB, preferably 13-16 HLB, preferably polyoxyethylene hardened castor oil or polyoxyethylene sorbitan monooleate and a pH adjustor containing an organic acid to adjust the solution into pH4-5. The amount of the nonionic surfactant to sufficiently dissolve the amide derivative required is >=10 times as much as that of the amide derivative. The concentration of the nonionic surfactant is preferably 0.1-5 (W/V) % in order to obtain a stable solution by forming micelle and suppressing hydrolysis of the amide derivative by protection action of the micelle.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to an aqueous liquid preparation containing a specific amide derivative.

[0002]

The present applicant has previously developed and applied for a patent for an amide derivative (I) represented by the following general formula (I) and an antiallergic agent containing the amide derivative (I).

[0003]

[Chemical 1]

(In the formula, R1 is a lower alkoxyl group or a lower alkoxycarbonyloxy group, R2 is a lower alkoxycarbonyloxy group, R3 is a hydrogen atom, m is an integer of 1 or 2, and Y is a compound represented by the formula (II). .)

[0005]

[Chemical 2]

(In the formula, P represents an integer of 2 to 4.)

The amide derivative represented by the general formula (I) is
It is a drug that has both antihistamine action and leukotriene synthesis inhibitory action, is effective as a powerful antiallergic agent, and is expected to be applied to nasal drops and eye drops as a therapeutic agent for pollinosis, etc., which is increasing in recent years. Has been done.

When the amide derivative is administered as a solution such as nasal drops or eye drops for the treatment of allergic rhinitis or allergic eye diseases, it is 0.005-0.5 (W / V).
% Concentration is required.

However, the amide derivative was extremely insoluble in water, and it was extremely difficult to prepare an aqueous solution having a desired concentration.

Further, since the amide derivative is susceptible to hydrolysis in an aqueous solution, there is a problem of how to stabilize the amide derivative.

[0011]

In view of the above-mentioned problems, the present invention provides an aqueous preparation which is excellent in solubility and stability in the aqueous solution of the above amide derivative, and which does not impair the drug efficacy. The purpose is to provide.

[0012]

The present inventors have found the following present invention as a result of a sharp study.

(1) H is added to the amide derivative of the following formula (I)
Nonionic surfactant of LB10-16 and pH of solution
An amide derivative-containing aqueous liquid formulation containing a pH adjuster containing an organic acid for adjusting the pH to 4 to 5.

[0014]

[Chemical 3]

(In the formula, R1 is a lower alkoxyl group or a lower alkoxycarbonyloxy group, R2 is a lower alkoxycarbonyloxy group, R3 is a hydrogen atom, m is an integer of 1 or 2, and Y is a compound represented by the formula (II). .)

[0016]

[Chemical 4]

(In the formula, P represents an integer of 2 to 4.)

(2) The aqueous liquid preparation according to (1) above, wherein the amount of the nonionic surfactant is 10 times or more the amount of the amide derivative.

(3) The aqueous liquid preparation according to (1) above, wherein the concentration of the nonionic surfactant is 0.1 (W / V) to 5 (W / V)%.

(4) The aqueous liquid preparation according to (1) above, wherein the nonionic surfactant is polyoxyethylene hydrogenated castor oil.

(5) The nonionic surfactant is polyoxyethylene sorbitan monooleate (1).
The aqueous liquid preparation according to 1.

(6) The aqueous liquid preparation according to (1) above, wherein the pH adjuster is an organic acid.

(7) The aqueous liquid preparation according to (1) above, wherein the pH adjuster is an organic acid buffer.

(8) The aqueous liquid preparation according to (1) above, wherein the pH adjuster is a lactate buffer.

As a result of various studies on the solubility of the amide derivative (I) in various aqueous solutions, the present inventors have found that HLB
A nonionic surfactant having a value of 10 to 16, preferably 13 to 16 is added as a solubilizer, and an organic acid and / or an organic acid buffer solution is added to adjust the pH to 4.0.
It was found that the solubility is dramatically improved by adjusting to 5.0. At this time, in order to sufficiently dissolve the amide derivative, the amount of the nonionic surfactant needs to be 10 times or more the amount of the amide derivative. Further, in order to form a micelle and obtain a stable liquid agent in which hydrolysis of the amide derivative is suppressed by a micelle protecting action, the amount of the nonionic surfactant must be 0.1 (W / V)% or more. is there. On the other hand, considering the use as eye drops and nasal drops, that is, irritation to the mucous membrane, 5 (W / V)% or less is desirable.

In the present invention, the nonionic surfactant used is polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan monooleate, polyoxyethylene nonylphenyl ether, polyoxyethylene cetyl ether, polyoxyethylene glycol. Examples include monostearate. Among them, polyoxyethylene hydrogenated castor oil (HCO-60) and polyoxyethylene sorbitan monooleate (T
most preferred is ween 80).

The aqueous liquid preparation of the present invention is used in the pH range of 4.0 to 5.0 in consideration of the solubility and stability of the amide derivative. An organic acid and / or various organic acid buffers are used for pH adjustment, specifically citric acid,
Tartaric acid, lactic acid, acetic acid and buffers containing them are used, but the lactic acid buffer is most preferable from the viewpoint of solubility and odor of the amide derivative.

The above-mentioned organic acid and / or various organic acid buffers are preferably used in the range of 0.05 to 1.0 mol / l, but when used as eye drops or nasal drops, considering irritation to mucous membranes, It is necessary to make the osmotic pressure ratio of the drug solution as close as possible to that of the living body, and more preferably 0.1 to 0.3.
mol / l.

The aqueous preparation of the present invention is used as a nasal drop, an eye drop, a coating agent, an inhalant, an internal medicine and an injection having an antiallergic effect.

In the present invention, the liquid carrier for dissolving the amide derivative, the nonionic surfactant and the organic acid is not particularly limited, and commonly used distilled water, purified water, physiological saline or the like can be used. .

In addition to the above-mentioned components, the aqueous liquid preparation of the present invention is a coloring agent, a flavoring agent, a bulking agent, a disintegrating agent, a lubricant, a pressure-sensitive adhesive, a preservative, an aromatic agent, which is usually used in an aqueous liquid preparation. A propellant and the like can be appropriately contained as needed.

The aqueous liquid preparation of the present invention can be produced according to a method generally used for preparing a liquid preparation. It is generally performed as follows.

It can be obtained by heating and dissolving the amide derivative in a nonionic surfactant and distilled water, and adding a buffer for pH adjustment to the solution to completely dissolve it.

[0034]

EXAMPLES The present invention will be described in more detail below with reference to examples.

In this example, 1-[{5 '-(3''-methoxy-4''-ethoxycarbonyloxyphenyl)-2', represented by the following formula (III), was used as the amide derivative.
4'-Pentadienoyl} aminoethyl] -4-diphenylmethoxypiperidine is used.

[0036]

[Chemical 5]

The above compound is a white or slightly yellow crystalline powder having a melting point of 100 ° C., which is easily dissolved in dichloroethane and acetone, slightly soluble in acetonitrile, slightly soluble in ethanol, and hardly soluble in water.

(Experimental Example 1) Solubility test In order to confirm the solubility of the above compound, an experiment was conducted in which conditions such as the presence or absence of a nonionic surfactant and the type were changed.

In Formulation 1, compound (III) was added to 0.0
5 g and polyoxyethylene hydrogenated castor oil (HCO-
60) was placed in a 0.5 g beaker and dissolved by heating at about 60 ° C., and lactic acid / sodium lactate buffer (pH 5.0) was gradually added as a pH buffer while stirring to dissolve.

In the other formulations, the compound was dissolved by the same operation, and the dissolved state was visually confirmed.
The results are shown in Table 1.

[0041]

[Table 1]

As is clear from Table 1, the formulations 1-1 to 1
Comparing -6 with Formulations 1-8 to 1-10, it can be seen that the combination of the nonionic surfactant of the present invention and the organic acid buffer shows excellent solubility. It was also found that if only the solubility is a problem, the solubilizer (propylene glycol) other than the nonionic surfactant can be used to dissolve it clearly (formulation 1-7).

(Experimental Example 2) Stability test An experiment was conducted on the difference in stability due to the difference in the solubilizer. The stability was confirmed by the residual rate (%) of the compound (III). Each sample was filled in a screw cap glass tube and stored at 60 ° C. for 10 days and 20 days, and the residual ratio of the compound (III) was measured by liquid chromatography to evaluate the stability. The results are shown in Table 2.

[0044]

[Table 2]

As is clear from Table 2, the aqueous preparations (formulations 2-1 to 2-8) of the present invention were stabilized by the protective effect of micelles, but other than the nonionic surfactant as the solubilizer ( When propylene glycol) is used, there is no problem in terms of solubility (from Experimental Example 1), but it is understood that sufficient results cannot be obtained regarding stability (formulations 2-9, 2).
-10).

Next, the influence of the concentration of the solubilizer on the stability was examined. An experiment was conducted with a formulation in which the concentration of the compound (III) was kept constant and the concentration of the nonionic surfactant was increased stepwise. Each sample at 60 ° C for 10 days and 20
After being stored for a day, the residual rate (%) of the compound (III) was measured by liquid chromatography to evaluate the stability. The results are shown in Table 3.

[0047]

[Table 3]

As is clear from Table 3, the stability is improved as the HCO-60 concentration increases, and when the HCO-60 concentration is 0.10 (W / V)% or more, the protective effect by the micelle formation is almost sufficient. Stability was obtained.

(2-3) Table 4 shows the measurement results of the micelle particle size by the light scattering method. The concentration of compound (III) is 0.
In the case of 005 (W / V)%, HCO-60 concentration is 0.1
It was confirmed that micelles having an average particle size of 16 to 20 nm were generated at 0 (W / V)% or more.

[0050]

[Table 4]

The following compounds (IV), (V), (VI), (VI
For I), the same solubility and stability tests were conducted. The results are shown in Table 5.

[0052]

[Chemical 6]

[0053]

[Chemical 7]

[0054]

[Chemical 8]

[0055]

[Chemical 9]

[0056]

[Table 5]

(Experimental Example 3) Experimental efficacy test against experimental allergic rhinitis Using a male Hartley guinea pig as an experimental animal, a clinical efficacy test was carried out by a dye leakage model. That is, guinea pigs were thoracotomized under anesthesia, and surgery for inserting a polyethylene tube into the trachea was performed to obtain dye (4% brilliant blue,
1 ml / kg) after intravenous administration, the aqueous formulations of the present invention (formulations 3-1 to 3-3) and comparative aqueous formulations (formulation 3-4,
3-5) was preadministered into the nasal cavity through a tube, and then a histamine solution was similarly administered to the nasal cavity, and the dye leaching from the blood vessels in the nasal cavity due to the allergic reaction was quantified by the absorbance measurement method. The results are shown in Table 6.

[0058]

[Table 6]

In Formulations 3-1 to 3-3, the amount of dye leakage was suppressed and significant medicinal effects were observed. In addition, the drug effect was not recognized in the solution (formulation 3-5) in which the compound (III) was simply suspended, and the effect of solubilization by HCO-60 and the pH buffer solution was clear.

(Formulation Example) An example of an embodiment of the amide derivative-containing aqueous preparation of the present invention is shown below.

(Nasal drops 1) Compounding formulation Compound (III) 0.5 g HCO-60 5.0 g Benzyl alcohol 9.0 g 0.1 mol Lactic acid / sodium lactate buffer (pH 5.0) Appropriate amount 1000 ml in total

Preparation method: Lactic acid is added to purified water to dissolve, and the pH is adjusted with sodium hydroxide.
To 5.0. Separately, compound (III) and HCO
-60 is weighed and dissolved by heating, and then benzyl alcohol and the lactate buffer solution prepared above are added and dissolved by stirring under heating. After cooling, it was filtered through a 0.45 μm membrane filter and then filled in a predetermined container to give a nasal drug solution.

(Nasal drops 2) Compounding formulation Compound (IV) 0.05 g Tween 80 2.0 g Methyl paraoxybenzoate 0.3 g Propyl paraoxybenzoate 0.1 g 0.2 mol Acetic acid / sodium acetate buffer (pH 5.0) Appropriate amount 1000ml in total

Preparation method Acetic acid is added to purified water to dissolve it, and the pH is adjusted with sodium hydroxide.
Adjust to 5.0. Separately Compound (IV) and Twee
Weigh n80 and dissolve by heating. After dissolution, methyl paraoxybenzoate, propyl paraoxybenzoate and the acetate buffer prepared above are added and dissolved by stirring under heating. After cooling, it was filtered through a 0.45 μm membrane filter and then filled in a predetermined container to give a nasal drug solution.

(Nasal drops 3) Compounding formulation Compound (V) 0.05 g HCO-60 1.0 g Benzalkonium chloride 0.1 g 0.3 mol Lactic acid / sodium lactate buffer (pH 4.0) Appropriate amount 1000 ml in total amount

Preparation method Lactic acid is added to purified water to dissolve it, and the pH is adjusted with sodium hydroxide.
Adjust to 4.0. Separately, compound (V) and HCO-6
Weigh 0 and dissolve by heating. After dissolution, phenylethyl alcohol and the lactate buffer solution prepared above are added and dissolved by stirring under heating. After cooling, it was filtered through a 0.45 μm membrane filter and then filled in a predetermined container to give a nasal drug solution.

(Eye drops) Compounding formulation Compound (III) 0.5 g HCO-60 5.0 g Sodium azulene sulfonate 0.2 g Benzalkonium chloride 0.1 g 0.15 mol Sodium tartrate / sodium tartrate buffer (pH 4.0) ) Appropriate amount 1000ml in total

Preparation method Tartaric acid is added to purified water to dissolve it, and the mixture is dissolved in sodium hydroxide to p.
Adjust H to 5.0. Separately, compound (III) and HCO
Weigh -60 and dissolve by heating. After dissolution, sodium azulene sulfonate, benzalkonium chloride and the tartrate buffer solution prepared above are added and dissolved by stirring under heating. After cooling, it was filtered through a 0.45 μm membrane filter and then filled in a predetermined container to obtain a liquid preparation for eye drops.

(Inhalant) -Compounding Formulation Compound (III) 0.05 g HCO-60 1.0 g Chlorobutanol 5.0 g 0.2 mol Lactic acid / sodium lactate buffer (pH 5.0) Proper amount 1000 ml in total

Preparation method: Lactic acid is added to purified water to dissolve it, and the pH is adjusted with sodium hydroxide.
Adjust to 5.0. Separately, compound (III) and HCO-
Weigh 60 and dissolve by heating. After dissolution, chlorobutanol and the lactate buffer solution prepared above are added and stirred under heating to dissolve. After cooling, it was filtered through a 0.45 μm membrane filter and then filled in a predetermined container to obtain a liquid agent for inhalation.

Each of the preparations shown in the above formulation examples showed excellent solubility, stability and antiallergic effect similar to the amide derivative-containing aqueous preparations of the present invention shown in each experimental example.

[0072]

The amide derivative-containing aqueous liquid preparation of the present invention comprises:
A nonionic surfactant having an HLB value of 10 to 16 and an organic acid are mixed and the pH of the amide derivative is adjusted to 4.0 to 5.0 to enhance the solubility of the amide derivative in water to a concentration sufficient for manifestation of a drug effect. Further, by adding a small amount of a surfactant, sufficient stability can be obtained due to the effect of protecting micelles.

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Claims (8)

[Claims] 1. HLB1 is added to an amide derivative of the following formula (I):
0 to 16 nonionic surfactant and pH of solution to 4 to
An amide derivative-containing aqueous liquid formulation containing a pH adjuster containing an organic acid adjusted to 5. [Chemical 1] (In the formula, R1 is a lower alkoxyl group or a lower alkoxycarbonyloxy group, R2 is a lower alkoxycarbonyloxy group, R3 is a hydrogen atom, m is an integer of 1 or 2,
Y is a compound represented by the formula (II). ) [Chemical 2] (In the formula, P represents an integer of 2 to 4.) 2. The aqueous liquid preparation according to claim 1, wherein the amount of the nonionic surfactant is 10 times or more the amount of the amide derivative. 3. The concentration of the nonionic surfactant is 0.1 (W
/ V) to 5 (W / V)%. The aqueous liquid preparation according to claim 1. 4. The aqueous liquid preparation according to claim 1, wherein the nonionic surfactant is polyoxyethylene hydrogenated castor oil. 5. The aqueous liquid preparation according to claim 1, wherein the nonionic surfactant is polyoxyethylene sorbitan monooleate. 6. The aqueous liquid preparation according to claim 1, wherein the pH adjuster is an organic acid. 7. The pH adjusting agent is an organic acid buffer solution.
The aqueous liquid preparation according to 1. 8. The aqueous liquid preparation according to claim 1, wherein the pH adjuster is a lactate buffer.