JPH041133A - Stable oxophosphoric acid emulsion and production thereof - Google Patents

Abstract

PURPOSE:To obtain a stable oxophosphoric acid emulsion exhibiting excellent stability in storage and in water-diluted state and producible without foaming by dispersing fine particles of recrystallized oxophosphoric acid in the form of emulsion in an aqueous solution of a water-soluble polymeric compound. CONSTITUTION:The objective emulsion can be produced by neutralizing an aqueous solution of an oxophosphoric acid alkali metal salt and a water-soluble polymeric compound such as water-soluble hydroxypropyl cellulose or hydroxyethyl cellulose with an acid such as hydrochloric acid, thereby recrystallizing oxophosphoric acid and emulsifying in stable fine particles in the aqueous solution of the water-soluble polymeric compound. The oxophosphoric acid is a quinolone-type synthetic antibacterial agent having excellent antibacterial activity against various bacteria and is used as a remedy and preventive for fowl paratyphoid, pasteurella pneumonia, bacterial diarrhea of broiler, pig, cattle, etc., in livestock industry and for yellowtail nodositas, sweetfish vibriosis, etc., of yellowtail, sweetfish, eel, etc., in pisciculture.

Description

Detailed Description of the Invention [Field of Industrial Application] The present invention provides a stable oxolinic acid milk, which is an emulsion in which recrystallized oxolinic acid is emulsified as fine particles in an aqueous solution of a water-soluble polymer compound. This invention relates to a suspension and a method for producing the same.

[Prior Art] Oxolinic acid is a quinolone-based synthetic antibacterial agent that has excellent antibacterial effects against various fungi. It is used for the treatment or prevention of diarrheal diseases, etc., and in the field of fisheries for yellowtail, sweetfish, eel, etc., for the treatment or prevention of yellowtail nodule disease, ayuvibrio disease, eel paracoro disease, etc. Conventionally known oxolinic acid preparations include powders, alkaline solutions, and oil preparations, each of which is commercially available. Furthermore, as a suspending agent for oxolinic acid, an oxolinic acid suspending agent was proposed in JP-A-64-18 in which a specific surfactant was used in a water-soluble solvent and oxolinic acid was suspended in an aqueous solvent. There is.

[Problems to be Solved by the Invention] Oxolinic acid preparations are used as powders, alkaline solutions, oils, etc. because oxolinic acid is insoluble in water. If it is a water-based liquid drug, it will be easy to handle and high efficacy can be expected from administration. The above-mentioned proposal of JP-A-64-18 can be said to be one of the concrete manifestations of this idea, and the problems in making oxolinic acid into a water-based liquid drug include stability on storage as a water-based liquid drug, stability when diluted with water, and Watoki's foaming properties, etc. Standing stability refers to the stability of an aqueous liquid drug of oxolinic acid when it is left to stand, and means that even if it is temporarily stabilized, oxolinic acid will precipitate if left to stand. In addition, water dilution stability refers to the stability when an aqueous liquid drug of oxolinic acid is diluted with water.If the water dilution stability is poor, stability may be lost due to dilution of water during use, and oxolinic acid will precipitate. If sedimentation occurs, an effective concentration cannot be maintained, which poses a practical problem.

As a result of the research conducted by the present inventors, it has been found that good water dilution stability cannot be obtained simply by suspending oxolinic acid in an aqueous solvent with a surfactant; that is, when diluted with water during use, the surfactant also diluted to the minimum micelle-forming concentration (C, M, C,
), micelles are destroyed and oxolinic acid precipitates. Therefore, it was found that the water dilution stability cannot be fundamentally solved by using a surfactant.

In addition to this, there is the problem of foaming during neutralization caused by the use of surfactants. Stirring is necessary for uniform neutralization during acid neutralization, but if a surfactant is used at this time, a large amount of foam will be generated, which will inhibit the uniform neutralization reaction.
Due to the increase in surface area due to the foam, there is a serious drawback that coagulation occurs at the end of the foam and coarse particles are produced.

Furthermore, even in terms of stability, surfactants cannot sufficiently stabilize particles, and recrystallization of oxolinic acid and fixation of particles that occur during standing are also problems.

[Means for Solving the Problems and Effects] As a result of repeated research in order to solve the problems in aqueous liquid medicines containing oxolinic acid, the present inventors have discovered that fine recrystallization of oxolinic acid can be carried out in an aqueous solution of a water-soluble polymer compound. The emulsion, which is formed as particles, has excellent water dilution stability and storage stability.Also, it is possible to neutralize the aqueous solution by adding an acid to an aqueous solution in which an alkali oxolinic acid salt and a water-soluble polymer compound are dissolved. By recrystallizing oxolinic acid and emulsifying it as stable fine particles in an aqueous solution of a water-soluble polymer compound, the above-mentioned stable emulsion can be produced without foaming. Obtain new knowledge and complete the present invention.

The present invention is characterized by: 1. A stable oxolinic acid emulsion in which recrystallized oxolinic acid is emulsified as fine particles in an aqueous solution of a water-soluble polymer compound.

2. The oxolinic acid emulsion according to claim 1, wherein the water-soluble polymer compound is a water-soluble cellulose derivative.

3. The oxolinic acid emulsion according to claim 1 or 2, wherein the water-soluble polymer compound is water-soluble hydroxypropyl cellulose and/or hydroxyethyl cellulose.

4. Add acid to an aqueous solution in which an alkali salt of oxolinic acid and a water-soluble polymer compound are dissolved, and recrystallize the oxolinic acid by neutralizing the aqueous solution to form stable fine particles in the aqueous solution of the water-soluble polymer compound. A method for producing a stable oxolinic acid emulsion, characterized by emulsifying it as particles.

5. The method for producing a stable oxolinic acid emulsion according to claim 4, wherein the water-soluble polymer compound is a water-soluble cellulose derivative.

6. 6. The method for producing a stable oxolinic acid emulsion according to claim 4 or 5, wherein the water-soluble polymer compound is water-soluble hydroxypropyl cellulose and/or hydroxyethyl cellulose.

Examples of the water-soluble polymer compound used in the present invention include gum arabic, water-soluble modified starch, water-soluble cellulose derivatives, polyvinyl alcohol, polyvinylpyrrolidone, etc., and these may be used alone or in combination. As can be understood from the fact that the oxolinic acid emulsion of the present invention is mainly applied to organisms in the fields of livestock and fisheries, it is a water-soluble polymer that is approved for use in foods as a water-soluble polymer compound. It goes without saying that the choice of compounds is preferred.

Among water-soluble polymer compounds, water-soluble cellulose derivatives having good storage stability are preferred. Examples of water-soluble cellulose derivatives include methylcellulose, ethylcellulose,
Carboxymethyl cellulose, carboxyethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, etc. are used, and these can be used alone or in combination.

In the present invention, oxolinic acid is recrystallized by neutralizing the oxolinic acid aqueous solution with acid, so among these water-soluble polymers, those whose water solubility and viscosity are not affected by acid are preferred.

In particular, hydroxypropylcellulose and hydroxyethylcellulose exhibit good action and effects.

On the other hand, since carboxymethyl cellulose and the like are affected by acids, their use alone does not give very favorable results.

In addition, the acids used in the present invention include non-acids, I!
Any acid that can neutralize an alkali, such as la, can be used, and two or more types can be used in combination. Among these, hydrochloric acid is particularly preferred.

A stable oxolinic acid emulsion is produced by adding an acid to an aqueous solution containing an alkali salt of oxolinic acid and a water-soluble polymer compound, and recrystallizing the oxolinic acid by neutralizing the aqueous solution. It is obtained by emulsifying stable fine particles in an aqueous solution.

Although it is still not completely clear theoretically why the oxolinic acid emulsion of the present invention has excellent storage stability and water dilution stability, the present inventors believe that the oxolinic acid emulsion of the present invention It is believed that the suspension, which is simply a suspension of oxolinic acid powder in an aqueous solvent using a surfactant, is due to the fact that the state of fine particles of oxolinic acid has clearly developed.

In other words, the oxolinic acid emulsion of the present invention is produced by recrystallizing oxolinic acid as fine particles in a dispersion system, and is immediately stabilized by a water-soluble polymer at the time of production. This is considered to be one of the reasons for its excellent storage stability and water dilution stability.

The water-soluble polymer attached to the surface of the oxolinic acid fine particles recrystallized by neutralization acts like a protective colloid, exists on the surface of the recrystallized particle by adsorption, is not affected by dilution, and is not affected by post-addition. This is thought to be due to the fact that it shows a certain performance. Therefore, unlike surfactants, sedimentation due to destruction of micelles during dilution does not occur.

On the other hand, stabilization by surfactants has a large effect on the amount of surfactant, and as mentioned above, when diluted with water, the minimum micelle formation concentration (C, M, C) is reached.

) or below, the micelles are destroyed, the stability provided by the surfactant is lost, and oxolinic acid is thought to precipitate.

Furthermore, regarding storage stability, a suspension of oxolinic acid powder suspended in an aqueous solvent using a surfactant has no
It is not possible to completely stabilize the particles of oxolinic acid,
Therefore, it is thought that recrystallization of oxolinic acid and fixation of particles occur, making it impossible to obtain excellent storage stability.

The present inventor conducted experiments using various surfactants and various water-soluble compounds instead of water-soluble polymer compounds, but it was not possible to recrystallize oxolinic acid by neutralizing the aqueous solution. Also, the crystals precipitated and could not be stabilized, or the recrystallization could not be stabilized as fine particles and precipitated as large crystals. However, a stable oxolinic acid emulsion was obtained only when neutralized in an aqueous solution of a water-soluble polymer compound.

In the present invention, the amount of the water-soluble polymer compound to be used depends on the amount of oxolinic acid in the obtained oxolinic acid emulsion and is not particularly limited. 0.5-5% by weight in suspension
It is preferable that

In the present invention, the amount of oxolinic acid in the emulsion is between 1 and 10
Preferably, it is % by weight.

Since it is customary for this type of drug to be diluted appropriately before use, it is desirable that the concentration be as high as possible, but on the other hand, there is also the problem of stability, so the above range is optimal.

The oxolinic acid emulsion of the present invention may contain preservatives such as sodium benzoate and methyl paraoxybenzoate, coloring agents, fragrances, and the like, if desired.

Next, the present invention will be explained with reference to Examples and Comparative Examples.

Example 1 6 parts by weight of hydroxypropylcellulose was gradually added and dissolved in 94 parts by weight of water while stirring to obtain a 6% aqueous hydroxypropylcellulose solution.

6% hydroxypropylcellulose aqueous solution 42 in the mixing tank
5 parts by weight of powdered oxolinic acid were added and stirred to uniformly disperse the mixture.

Adding 9 parts by weight of a 10% by weight aqueous solution of sodium hydroxide,
The mixture was stirred to completely dissolve 5 parts by weight of oxolinic acid.

While vigorously stirring an aqueous solution containing hydroxypropylcellulose and sodium oxolinate, the salt fi1.9
11% aqueous solution 44f! The EIH was adjusted to about 7 by gradually dropping a certain amount to obtain a stable oxolinic acid emulsion.

The concentration of oxolinic acid in the obtained oxolinic acid emulsion was approximately 5% by weight, and the concentration of droxypropyl cellulose was approximately 2% by weight.
．． It was 5% by weight.

Example 2 8 parts by weight of hydroxyethyl cellulose were gradually added and dissolved in 94 parts by weight of water while stirring to obtain an 8% aqueous hydroxyethyl cellulose solution.

A mixing tank was charged with 42 parts by weight of an 8% hydroxyethyl cellulose aqueous solution, and 5 parts by weight of powdered oxolinic acid, and stirred to uniformly disperse the mixture.

Knowing that 9 parts by weight of a 10% by weight aqueous solution of sodium hydroxide,
With stirring, 5 parts by weight of the oxoline was completely dissolved.

44 parts by weight of a 1.9% by weight aqueous solution of hydrochloric acid was gradually added dropwise to an aqueous solution in which hydroxyethylcellulose and sodium oxolinate were dissolved with strong stirring to adjust the ElM to about 7 to obtain a stable oxolinic acid emulsion. .

The concentration of oxolinic acid in the obtained oxolinic acid emulsion was about 5% by weight, and the concentration of hydroxyethylcellulose was about 3.5% by weight.
It was 4% by weight.

Example 3 5 parts by weight of powdered oxolinic acid was added to 40 parts by weight of water with stirring and uniformly dispersed. Sodium hydroxide 10j
iJ 1% aqueous solution 9f! 51 parts of oxolinic acid was added and stirred to completely dissolve 51 parts of oxolinic acid.

While stirring 54 parts by weight of an aqueous solution in which sodium oxophosphate was dissolved, 21 parts of hydroxypropyl cellulose powder was added.
jL parts were added gradually. After the addition was completed, the mixture was stirred for 1 hour for dispersion and dissolution, and then continued for another day to completely dissolve the hydroxypropyl cellulose.

While strongly stirring an aqueous solution in which hydroxypropyl cellulose and oxolinic acid sodium salt were dissolved, 44 parts by weight of a 61.9% salt aqueous solution was gradually added dropwise to adjust the pH to about 7 to obtain a stable oxolinic acid emulsion. Ta.

The concentration of oxolinic acid in the obtained oxolinic acid emulsion was approximately 5% by weight, and the concentration of hydroxypropyl cellulose was approximately 2% by weight.
, 5% by weight.

Comparative Example 1 An oxolinic acid suspension was obtained in the same manner as in Example 1, except that polyoxyethylene hardened mustard oil was used instead of the hydroxybutylene cellulose used in Example 1.

Comparative Example 2 In Example 1, 5 parts by weight of powdered oxolinic acid was stirred and uniformly dispersed in 42 parts by weight of a 6% hydroxypropylcellulose aqueous solution, which was then suspended for 24 hours using a ball mill and pulverized to obtain an oxolinic acid suspension. A cloudy liquid was obtained.

Comparative Example 3 A commercially available oxolinic acid suspension containing a surfactant was used.

Comparative Example 4 5 parts by weight of powdered oxolinic acid was added to 40 parts by weight of water with stirring and uniformly dispersed. 9 parts by weight of a 10% by weight aqueous solution of sodium hydroxide was added and stirred to completely dissolve 5 parts by weight of oxolinic acid.

While strongly stirring the aqueous solution in which the sodium oxolinic acid salt was dissolved, 44 parts by weight of a 1.9% by weight aqueous solution of salt a was gradually added dropwise to adjust I)H to about 7, and a fine powder of recrystallized oxolinic acid was suspended. A cloudy liquid was obtained. When stirring of this suspension was stopped, fine powder of oxolinic acid precipitated.

While vigorously stirring the above suspension, 2 parts by weight of hydroxyglopyl cellulose powder was gradually added.

After the addition was completed, stirring was continued for 1 hour to further disperse and dissolve. Furthermore-
The hydroxypropylcellulose was completely dissolved in a day-long apparatus to obtain an oxolinic acid suspension.

Test Example 1 The following storage stability test and water dilution stability test were conducted on the oxolinic acid emulsion obtained in the example and the oxolinic acid suspension obtained in the comparative example.

The test results were as shown in Table 1.

Storage stability test 100 ml of the sample was placed in a 100 ml measuring cylinder, the top was sealed, and the cylinder was left to stand for 3 months and the sample was observed.

Add 10sr of water dilution stability test sample to 3000cc of water with stirring,
00 times diluted with water, 100ml of water diluted with 100ml
Pour into a graduated cylinder and seal the top for 1 day! The subsequent stability was observed.

(Margins below) [Note] Regarding the storage stability test, the sample after being left for 3 months was stirred and compared with the sample immediately after production (1 day before release).

Regarding the water dilution stability test, the sample after being left for one day was stirred and compared with the sample immediately after being diluted with water (before being left to stand).

Good: After simple stirring, the sample became in the same condition as before being left.

Fair: By stirring strongly, the state became the same as the sample before being left.

杆：Even if the sample was stirred strongly, a precipitate was observed when the stirring was stopped, and the sample was not in the same state as before it was left standing.

Supernatant ((DI): The upper transparent layer resulting from the settling of the oxolinic acid particles after the stability test is expressed in graduated cylinder volume.

Sediment (ml): The thicker part of the lower suspension resulting from the settling of the oxolinic acid particles after the stability test is expressed as the volume of the graduated cylinder.

Evaluation: The oxolinic acid suspension of the example of the present invention does not change even after long-term storage, and the oxolinic acid suspension of the example of the present invention does not change even after long-term storage.
It can be used even after a day. However, the oxolinic acid suspension of the comparative example cannot be stored for a long period of time, and especially those diluted with water for administration cannot be used after one day, and the oxolinic acid will precipitate, making it difficult to administer the correct amount. Therefore, it is necessary to dilute the amount to be used with water and administer it within a short period of time, and if it remains after use, the oxolinic acid will precipitate, so it cannot be left unattended, making it inconvenient to use. be.

Test Example 2 The oxolinic acid emulsion obtained in Example 1 and the oxolinic acid suspension obtained in Comparative Example 2 were forcibly administered orally to egg-laying hens (3 birds) in an amount equivalent to 1011 g of oxolinic acid per 1 body weight. .

Blood was collected at 2.4.6.10 hours after administration, and the oxolinic acid concentration in plasma was measured.

The test results were as shown in Table 2.

! -2 = - Strong evaluation> It is understood that the examples of the present invention have good sustainability of high concentration of oxolinic acid in blood and excellent antibacterial effect.

Comparative Example 5 Oxolinic acid suspension was prepared in the same manner as in Example 1 except that the amount of hydroxypropyl cellulose used in Example 1 was 3 parts by weight and 3 parts by weight of polyoxyethylene sorbitan fatty acid ester as a surfactant was used in combination. I got the liquid. This comparative example is an example in which a water-soluble cellulose derivative and a surfactant were used together.

Test Example 3 Example 1 and Comparative Example 5 were compared in terms of foam generation during neutralization.

(1) Stirring of an aqueous solution of oxolinic acid sodium salt before neutralization with an aqueous hydrochloric acid solution In Example 1, only traces of bubbles were observed around the stirring shaft; It was possible to drip directly onto the liquid surface.

In Comparative Example 5, a large amount of foam was generated, and the liquid surface was covered with foam.

(2) Regarding the foam of the oxolinic acid emulsion The traces of foam immediately after the production of the oxolinic acid emulsion of Example 1 completely disappeared after being left for one day.

In Comparative Example 5, 7.5C11-10 from the liquid level immediately after production.
Bubbles of 2 were formed, and even after being left for one day, the bubbles remained at 7.5 .

[Effects] As mentioned above, the oxolinic acid emulsion of the present invention exhibits excellent storage stability effects, water dilution stabilization effects, and non-foaming effects during manufacture.

Claims (1)

[Claims] 1. A stable oxolinic acid emulsion in which recrystallized oxolinic acid is emulsified as fine particles in an aqueous solution of a water-soluble polymer compound. 2. The oxolinic acid emulsion according to claim 1, wherein the water-soluble polymer compound is a water-soluble cellulose derivative. 3. The oxolinic acid emulsion according to claim 1 or 2, wherein the water-soluble polymer compound is water-soluble hydroxypropyl cellulose and/or hydroxyethyl cellulose. 4. Add acid to an aqueous solution in which an alkali salt of oxolinic acid and a water-soluble polymer compound are dissolved, and recrystallize the oxolinic acid by neutralizing the aqueous solution to form stable fine particles in the aqueous solution of the water-soluble polymer compound. A method for producing a stable oxolinic acid emulsion, characterized by emulsifying it as particles. 5. The method for producing a stable oxolinic acid emulsion according to claim 4, wherein the water-soluble polymer compound is a water-soluble cellulose derivative. 6. The method for producing a stable oxolinic acid emulsion according to claim 4 or 5, wherein the water-soluble polymer compound is water-soluble hydroxypropyl cellulose and/or hydroxyethyl cellulose.