WO1998047503A1

WO1998047503A1 - Ibuprofen suspension preparations

Info

Publication number: WO1998047503A1
Application number: PCT/JP1998/001821
Authority: WO
Inventors: Kiyotaka Obata; Michio Yamagishi; Mayumi Naito
Original assignee: Taisho Pharmaceutical Co., Ltd.
Priority date: 1997-04-21
Filing date: 1998-04-21
Publication date: 1998-10-29
Also published as: AU6855198A

Abstract

A method for sterilizing ibuprofen suspension preparations characterized by sterilizing suspensions containing ibuprofen by applying pressure thereto at a temperature lower than the melting point of ibuprofen; and effectively sterilized ibuprofen suspension preparations containing from 100 to 5,000 mg/100 ml of ibuprofen and from 1 to 150 mg/100 ml of antiseptics and having a pH value of from 2.0 to 5.0.

Description

Description Ibuprofen suspension Technical field

The present invention relates to a method for sterilizing an effectively sterilized ibuprofen suspension and an ibuprofen suspension. Background art

Ibuprofen is known as a nonsteroidal anti-inflammatory, analgesic and antipyretic, and is widely used in the form of powders, fine granules, granules, capsules and the like. However, only syrups are known as liquids, and drinks such as suspensions and suspensions are not known. This is because syrups do not require sterilization because they can ensure safety by blending a high concentration of sugar and a large amount of preservatives, but sterilization is safe and high quality for suspensions. Despite the fact that it is an indispensable treatment to assure sterilization, sterilization technology has not been established due to the unique properties of ibuprofen.

Conventionally, sterilization of liquids has been carried out by heat treatment represented by a plate-type sterilizer. However, the melting point of ibuprofen is as low as around 75-77 ° C, so that sterilization of suspension containing ibuprofen by conventional heat treatment results in stable properties (such as expansion of particle damage due to recondensation after melting, In addition, there were problems such as the appearance of bitterness at the time of taking.

Sterilization technology under low temperature and pressure is mainly used in the food field, for example, to improve the flavor of jam. However, the bactericidal effect is secondary, and bacteria such as Bacillus are not actually killed. In the pharmaceutical field, particularly in ibuprofen, there is no known low-temperature pressurization sterilization technique for sterilization. Disclosure of the invention An object of the present invention is to provide an ibuprofen suspension which has been effectively sterilized without causing problems such as the appearance of property stability and irritation, and a sterilization method for obtaining the liquid.

The inventors of the present invention have conducted intensive studies to solve the above-mentioned problems, and as a result, by subjecting a suspension containing ibuprofen to pressure treatment at a low temperature equal to or lower than the melting point of ibuprofen, the problems were solved. This led to the completion of the present invention.

That is, the present invention includes the following inventions.

(1) A method of sterilizing an ibuprofen suspension, which comprises sterilizing a suspension containing ibuprofen by subjecting it to a pressure treatment at a temperature lower than the melting point of ibuprofen.

(2) 25-60. The method according to the above (1), wherein the treatment is carried out in C under a pressure of 3,000 to 10,000 kg / cm ² .

(3) An effectively sterilized ibuprofen suspension containing 100 to 5,000 mg / 100 ml of ibuprofen and a preservative of 1 to 15 OmgZl 0 Om1 and having a pH of 2.0 to 5.0 °.

The ibuprofen-containing suspension used in the method for sterilizing an ibuprofen suspension of the present invention is a liquid in which ibuprofen is finely and uniformly suspended in a liquid. This suspension is prepared by adding a suspension stabilizer or other suitable additives and purified water to an active ingredient such as ibuprofinin, suspending by an appropriate method, and uniformly dispersing the whole substance. be able to.

In the present invention, the concentration of ibuprofen in the suspension is usually from 100 to 5,000 Omg / 10 OmK, preferably from 200 to 4,000 mg / 100 ml, more preferably from 300 to 3,000 OmggZ10Om1. It is.

The pH of the ibuprofen suspension of the present invention is usually 2.0 to 5.0, preferably 2.5 to 4.0. To adjust the pH, organic acids such as citric acid, DL-malic acid, tartaric acid, lactic acid, gluconic acid, adipic acid, succinic acid, fumaric acid, and acetic acid, and salts thereof, and inorganic acids such as phosphoric acid are usually used. Acids and salts thereof can be used, but it is preferable to use organic acids such as citric acid, DL-malic acid, tartaric acid and lactic acid. When an organic acid is used to adjust the pH, its addition concentration is usually 500 to 30,000 mg / 100mi, preferably 1,000 to 15,000 mgZ 100 ml, more preferably 3,000 to 8.0 omgOmZZlOmi.

In the present invention, a suspension stabilizer such as a surfactant, a water-soluble polyhydric alcohol, or a polymer compound can be blended for improving the sedimentation stability of the suspended particles. As the surfactant, a polyglycerin fatty acid ester is preferable, and polyoxyethylene sorbitan monooleate surfactant (polysorbate 8 °, etc.) and polyoxyethylene hardened castor oil surfactant (HC060, etc.) are ibupro. This is not preferred because it increases the solubility of fen and generates suspended solids S over time. As the polyglycerin fatty acid ester, those having a glycerin polymerization degree of 1 to 7 and a final HLB of 4 or more are preferable. Among these polyglycerin fatty acid esters, preferred are decaglycerin monostearate, decaglycerin distearate, heptaglycerin monostearate, decaglycerin and hepnate, and these are used alone. Alternatively, two or more kinds can be used in combination. The amount of the polyglycerin fatty acid ester is usually 1-1, OOOmg / l O Oml, preferably 2-500 mgZZ 100ml in terms of the final preparation. At less than 1 mgZ 100 m1, the dispersibility of the suspended particles is insufficient, and at more than 1,000 mgZZ 100 ml, the solubility of the drug increases and the irritation increases.

Examples of the water-soluble polyhydric alcohol include glycerin, ethylene glycol, propylene glycol, 1,3-butylene glycol, diglycerin, polyglycerin, diethylene glycol, polyethylene glycol, dipropylene glycol, polypropylene glycol, sorbitan, sorbitol, mannitol, Xylitol, erythritol, trehalose and the like. Among these water-soluble polyhydric alcohols, for example, glycerin, diglycerin and polyglycerin are preferred. The compounding amount of the water-soluble polyhydric alcohol is usually 10 to 20,000 mgZ 100 ml, preferably 100 to 10,000 m100 ml in terms of the final preparation. If the amount is less than lOOmgZlOOml, the dispersibility and redispersibility of the suspension are poor, and if it exceeds 2OmgZlOOm1, the viscosity is high and the ingestibility is poor.

Examples of the polymer compound include xanthan gum, crystalline cellulose, carboxy Examples include vinyl polymer, ethyl cellulose, hydroxyethyl cellulose, polyvinyl alcohol, polyvinyl pyrrolidone, alginic acid, dextrin, sodium hyaluronate, chondroitin sulfate and the like. These polymer compounds can be used alone or in combination of two or more. Among these high molecular compounds, those having low solubilizing ability, for example, xanthan gum and crystalline cellulose are preferred.

In addition, substances generally used in pharmaceutical technology such as pharmaceutically acceptable preservatives, sweeteners, flavors, coloring agents and the like can be blended.

Examples of the preservative include parabens such as methyl P-oxybenzoate, ethyl P-oxybenzoate, propyl P-oxybenzoate and butyl P-oxybenzoate, and benzoic acid or salts thereof. it can. The added amount is usually 1 to 15 Omg / 100mK, preferably 5 to 100m10 ° m1, more preferably lOSOmgZlOOml.

The method of suspension is not particularly limited, and examples thereof include a method of uniformly dispersing using a general pulverizing and dispersing apparatus such as a disperser, a homomixer, and micros.

In the present invention, the suspension containing ibuprofen is sterilized by applying pressure at a temperature equal to or lower than the melting point of ibuprofen. The melting point of ibuprofen varies depending on the purity and other factors. It is usually 75-77 ° C.

If the processing temperature exceeds the melting point of ibuprofen, melting will occur, with concomitant irritation. The processing temperature is preferably 25-60, more preferably 40-60 ° C.

The pressure treatment is for sterilization, and the means preferably includes a pressure treatment by hydrostatic pressure or the like. To occupy become sterile effect sufficient, 3, 000-10, preferably be treated under a pressure of ^{000 k gZcm 2, 3, 000~6} , treating under pressure 0◦ 0 kg / cm ² Is more preferred. Therefore, in the present invention, it is particularly preferable to perform the treatment at 40 to 60 ° C. under a pressure of 3,000 to 6,000 kg / cm ² .

The processing time varies depending on the temperature and pressurizing conditions, but is usually 3 to 60 minutes, and is preferably Or i 0-40 minutes.

Remaining number of bacteria in Ibupurofen suspension of the present invention that is sterilized as described above, usually 1 0 ³ cfu / m less than 1, Ru preferably 1 0 ² cfu / m 1 below der. In addition, recrystallization of the ibuprofen suspension of the present invention is not observed by visual observation. BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, the present invention will be specifically described with reference to Preparation Examples, Examples, and Test Examples, which do not limit the scope of the present invention. In the following preparation examples, the “appropriate amount” for the amount of preservative added means 3 to 24 mgZ30 ml (10 to 80 mgZ100 ml). To adjust the pH, citric acid, sodium citrate, tartaric acid and Z or phosphoric acid were added as organic acids at 150 to 9000 Omg / 3 Om 1 (500 to 30,00 OmgZl 0 Om 1). .

(Preparation Example 1)

An ibuprofen suspension having the following composition was prepared.

(In 30 ml, pH 3.5)

Ibuprofen 144 mg

Decaglycerin monomyristate 30 mg

Glycerin 1 500 mg

52 5 mg

Sweetener appropriate amount

Preservative appropriate amount

A mixture of 48 g of ibuprofen, 10 g of decaglycerin monomyristate, 100 g of glycerin and 200 g of purified water is ground at 1000 rpm for 30 minutes with Micros MIC-0 (Nara Machinery Co., Ltd.), and then purified water is used. At the time of 50-fold dilution, 17.5 g of xanthan gum, 400 g of glycerin, a sweetener and a preservative were mixed to prepare a pH 3.5 ibuprofen suspension.

(Preparation Example 2)-A ibuprofen suspension having the following composition was prepared in the same manner as in Preparation Example 1. (In 30 ml, pH 3.5)

Ivbrofen 144 mg

Anhydrous caffeine 16 bmg

Decaglycerin monomyristate 30 mg

52 5 mg

Sweetener

Preservative

(Preparation Example 3)

The following composition (Lofyun suspension was prepared in the same manner as in Preparation Example 1 (in 30 ml, pH 3.5)

Ibuprofen 1 50 mg

Dihidrocodine phosphate 8 mg

Decaglycerin monomyristate 30 mg

52.5 mg

Sweetener

Preservative

(Preparation Example 4)

The following composition (Lofun suspension was prepared in the same manner as in Preparation Example 1 (in 3 Om1, pH 3.5)

Ibuprofen 1〇 0 mg

Acetaminophen 200 mg

Chlorpheniramine maleate 25 mg

d 1 Methyl efhydrochloride 20 mg

Decaglycerin monomyristate 30 mg

52 5 mg

Sweetener

Preservative

(Preparation Example 5)

The following composition Lofyun suspension was prepared in the same manner as in Preparation Example 1. (In 30 ml, pH 3.5)

200 mg of ibubrofen

Dihidrocodine phosphate mg

Chlorpheniramine maleate 25 mg

d 1 Methyl efhydrochloride 20 mg

Lysozyme chloride 30 mg

Decaglycerin monomyristate 30 mg

52 5 mg

Sweetener

Preservative

(Preparation Example 6)

In the same manner as in Preparation Example 1, the following composition was prepared. (In 30 ml, pH 3.5)

Ibubroun 200 mg

Dihidrocodine phosphate 8 mg

Bromhexine hydrochloride 1 2 mg

Chlorpheniramine maleate 2.5 mg

d 1 Methylefedrine monohydrochloride 20 mg

Salted lysozyme 30 mg

Decaglycerin monomyristate 30 mg

Xanthan gum 52.5 mg

Sweetener

Preservative appropriate amount

(Example 1)

(1) Strain used and preparation method of spore solution

The bacterium used was Bacillus subtilis ATCC 6633 (hereinafter referred to as “g. Sub.”). The spore solution was obtained by inoculating SCD medium (manufactured by Eiken Chemical) and culturing at 32.5 ° C for about 1 week. After heat treatment at 20 ° C for 20 minutes and centrifugation, the spores were washed with sterile physiological saline and suspended. (2) Sample preparation method

A spore solution was added to 1 L of the ibuprofen suspension obtained in Preparation Examples 1 to 6 so that the B. sub. Spore concentration became 10 cfuZm1, and the mixture was thoroughly stirred. Next, 2 Om1 of the suspension was added to a plastic bag, and the bag was sealed with a hot punch or the like while paying attention to air mixing. This was used as a sample.

(3) Test method

Insert the sample into a high-pressure processing device (using a small tester (Frescal MFP-7000) manufactured by Mitsubishi Heavy Industries, Ltd.) and pressurize it under the conditions of 6000 kg gZcm ² and a vessel temperature of 40 ° C. Each treatment was for 40 minutes. Next, the sample was appropriately diluted with an LP diluent (manufactured by Nippon Yakuhin), and 1001 was spread on SCDL P agar medium (manufactured by Eiken Chemical Co., Ltd.) and cultured at 32.5 ° C for about 24 hours. The number of spores remaining in the sample was calculated from the number of colonies that appeared.

(4) Result

The results are shown in Table 1. Similarly, for all samples, it was found that the spore count of §1. Decreased by a logarithmic value of 85.85 after 10 minutes of treatment, and decreased by 1.30 after another 4 minutes of treatment. As a result, it was verified that the treatment at 6000 kg / cm ² and 40 for 10 minutes had a sufficient sterilizing effect.

Table 1 Treatment time (min) Degree of bacterial count reduction (logarithmic value)

1〇 0.85

20 0.85

40 1.30

(Test Example 1)

6000 kg / cm ² , Container temperature 40 ° (Pressurizing treatment for 10 minutes and conventional heat treatment (90 ° C or more, 1 minute), stimulation during drinking (expression of bitterness'), bactericidal effect, The test was performed in the same manner as in Example 1. As the ibuprofen suspension, the suspension obtained in Preparation Example 1′6 was used ₍ judgment criteria are as follows).

(Stimulation during drinking (expression of bitterness))

Sensory evaluation 1: No irritation in the throat

2: almost no irritation in the throat

3: Irritation in the throat is weak

4: Feel the irritation in the throat

5: I feel strong irritation in the throat

(Bactericidal effect)

Yes: Β · sub. Spores are reduced by 0.2 or more in logarithmic value

None: B. sub. Spores decreased by less than 0.2 in logarithmic value

(Appearance change by visual observation)

Yes: with recrystallization

None: No recrystallization

The results are shown in Table 2.

Table 2 Heat treatment Pressure treatment Stimulation during drinking (sensory evaluation) 5 2

Sterilizing effect Yes Yes

Appearance change Yes No As is clear from Table 2, it was found that the method of the present invention can effectively sterilize the ibuprofen suspension without causing any problems such as irritation and recrystallization of components. .

(Test Example 2)

The effects of the treatment temperature, pressure and treatment time on the disinfection effect were examined. The test method was the same as in Example 1. Those obtained in 1 to 6 were used.

Table 3 shows the results.

Table 3 Treatment temperature (° C) Pressure (kg / cm ² ) Treatment time (min) Degree of bacterial count reduction (logarithmic value)

25 6000 40 0.2 1

40 3000 20 0.20

40 3000 40 0.28

4〇 1000 4〇 0.09

Industrial applicability

ADVANTAGE OF THE INVENTION According to this invention, the ibuprofen suspension agent which was effectively sterilized, without mix | blending a large amount of preservatives conventionally, can be provided. Further, according to the present invention, it is possible to provide a suspension of ibuprofen which does not cause problems such as manifestation of property stability and irritation, and which is easy to take.

Claims

The scope of the claims

1. A method for sterilizing an ibuprofen suspension, which comprises sterilizing a suspension containing ibuprofen by pressurizing the suspension at a temperature equal to or lower than the melting point of ibuprofen.

2. The method according to claim 1, wherein the treatment is performed under a pressure of 3,000 to 10,000 kg / cm ² at 25 to 60 ° C.

3. An effectively sterilized ibuprofen suspension containing 100 to 5,000 Omg / 10 Om1 of ibuprofen and a preservative of 1-150 mgZl0 Om1, and having a pH of 2.0 to 5.0.