JPH0529331B2 - - Google Patents

Description

[Detailed description of the invention]

[Technical Field] The present invention relates to novel oxolinic acid suspensions. [Prior art] Oxolinic acid is a quinolone-based synthetic antibacterial agent that has excellent antibacterial effects against various bacteria.
In the livestock industry such as broilers, pigs, and cattle, it can be used to treat or prevent avian typhoid fever, pasteurella pneumonia, bacterial diarrhea, etc.
It is used in the field of fisheries for eels and other fish to treat or prevent amberjack tuberculosis, aubibriovirus disease, eel paracolovirus disease, etc. Conventionally known oxolinic acid preparations include powders, alkaline solutions, and oil preparations, which are commercially available under the trade names of "Parazan,""Parazan D for Fisheries," and "Parazan Oil Preparation for Fisheries," respectively. [Problems to be Solved by the Invention] However, conventional oxolinic powder preparations have had various drawbacks because the main ingredient, oxolinic acid, is poorly soluble in water. For example, when powders are diluted in water, they do not dissolve and quickly precipitate, so they can only be used for dosing by adding them to feed.
It is difficult to use in simple ways such as diluting and administering to broilers' drinking water. In addition, alkaline solutions are diluted with water and used for fish medicinal baths, but these solutions are strongly alkaline with a pH of around 12, so care must be taken when handling them, and if left open and left unattended, they may be released into the atmosphere. When absorbing carbon dioxide gas, oxolinic acid crystallizes and becomes insolubilized. Furthermore, since conventional oxolinic acid preparations use oxolinic acid bulk powder with a relatively large particle size of about 5 to 12 μm, absorption of oxolinic acid into the body is not necessarily good when administered to animals or fish. [Structure and Effects of the Invention] As a result of various studies aimed at solving the above-mentioned problems, the present inventors have found that using fine particulate oxolinic acid with a particle size of about 4 μm or less, and a specific surfactant and propylene glycol. Oxolinic acid suspension prepared in combination with (or butylene glycol) is stable and easy to handle, allows for a highly practical administration method, and has good absorption of the main drug, oxolinic acid, into the body. The present inventors have discovered that the present invention has extremely excellent advantages such as the following, and have completed the present invention. That is, the present invention provides an aqueous solvent having a pH of about 2 to 8 containing at least one surfactant selected from polyoxyethylene sorbitan fatty acid ester and polyoxyethylene hydrogenated castor oil and propylene glycol or/and butylene glycol. Approximately 1 to 100% of fine particulate oxolinic acid with a particle size of approximately 4 μm or less
This invention relates to an oxolinic acid suspension suspended at a concentration of 10 w/v. The particulate oxolinic acid used in the present invention may be in the form of a fine powder or microcrystals as long as the particle size is about 4 μm or less. Preferably, about
A particle size of 0.2 to 3 μm, more preferably about 0.5 to 2 μm is used. The concentration of oxolinic acid in the suspension is about 1 to 10 w/v, preferably about 2 to 5 w/v. Specific examples of the polyoxyethylene sorbitan fatty acid ester used in the present invention include polyoxyethylene sorbitan monooleate, polyoxyethylene monopalmitate, polyoxyethylene monostearate, etc. A suitable example of the oil is polyoxyethylene hydrogenated castor oil, which is commercially available under the trade name Nikkol HCO-60. Preferred examples of the aqueous solvent include water, water-containing ethanol, and the like. The aqueous solvent must have a pH of about 2 to 8, and a pH lower than 2 is undesirable from the standpoint of irritation to livestock, fish, and the like. In addition, if the pH is higher than this, large crystals of oxolinic acid may precipitate in the aqueous phase during long-term storage, or suspended particles may stick, impairing redispersibility, which is not preferable. The content of polyoxyethylene sorbitan fatty acid ester and/or polyoxyethylene hydrogenated castor oil is approximately 1/20 to 1/5 of the finely divided oxolinic acid.
Double doses are preferred. Further, the content of propylene glycol and/or butylene glycol is preferably about 1/20 to 1/2 times, particularly about 1/10 to 1/4 times, the amount of fine particulate oxolinic acid. The oxolinic acid suspension of the present invention may optionally contain sodium carboxymethyl cellulose,
It is possible to contain polyvinylpyrrolidone, gum arabic, etc., and it is particularly preferable to contain sodium carboxymethyl cellulose in an amount of about 0.2 to 1 w/v% in the suspension. Furthermore, the oxolinic acid suspension of the present invention can also contain preservatives (eg, sodium benzoate, methyl p-oxybenzoate, etc.), colorants, flavoring agents, etc., if desired. The oxolinic acid suspension of the present invention comprises at least one surfactant selected from polyoxyethylene sorbitan fatty acid ester and polyoxyethylene hydrogenated castor oil, propylene glycol or/and butylene glycol, and other components as necessary in an aqueous medium. (e.g. water or 0.5% ethanol)
It can be prepared by dispersing and dissolving the oxolinic acid in the solution, adding fine particulate oxolinic acid therein, and stirring with a homomixer or the like. Furthermore, the oxolinic acid suspension of the present invention has a particle size of approximately
It can be prepared by simultaneously producing oxolinic acid with a size of 4 μm or less and suspending the oxolinic acid. For example, at least one surfactant selected from polyoxyethylene sorbitan fatty acid ester and polyoxyethylene hydrogenated castor oil, propylene glycol or/and butylene glycol, oxolinic acid, and other components as necessary are dissolved in an alkaline aqueous solution (for example, a sodium hydroxide aqueous solution). ) and stirring this solution well in the presence of an acid (e.g., hydrochloric acid) to reduce the particle size to approximately
It can be prepared by preparing a liquid in which oxolinic acid having a diameter of 4 μm or less is suspended. The thus obtained oxolinic acid suspension of the present invention can be easily and uniformly redispersed at the time of use even if the suspended particles settle during storage, and even when diluted with drinking water etc., it remains practically sufficient for several hours. It has the advantage of being able to maintain a stable dispersion state, being easier to handle than conventional strong alkaline solutions, and having no fear of absorbing carbon dioxide gas in the air and causing irreversible changes. Further, the oxolinic acid suspension of the present invention has the advantage that the main drug, oxolinic acid, is easily absorbed in the body. The particulate oxolinic acid with a particle size of about 4 μm or less used in the present invention can be obtained by pulverizing a normal oxolinic acid bulk powder with a particle size of 5 to 10 μm or more using an appropriate grinder, such as a power mill or a ball mill. Alternatively, it can be produced by a method such as precipitating microcrystalline oxolinic acid from an alkaline solution of oxolinic acid under appropriate crystallization conditions. Experimental Example 1 A preparation with the following formulation was placed in a 500 ml glass bottle, and after being left at room temperature for a certain period of time, the appearance was observed and the redispersibility after shaking for 20 seconds was examined. The results are shown in Tables 1 and 2 below. [Preparation of the present invention] (Formulation 1) 5 g of oxolinic acid with a particle size of 1.5 μm Polyoxyethylene hydrogenated castor oil (trade name:
Nikkol HCO-60) 0.4g Sodium carboxymethylcellulose 0.8g Propylene glycol 1.0g Water 95ml Stir the above formulation with a homomixer to make a suspension. [Control formulation] (Formulation 2) Parazan (trade name) (0.05 oxolinic acid in 1g)
(powder containing g) 60g water 40ml Mix the above formulation. (Formulation 3) Oxolinic acid with a particle size of 8.9 μm 5 g Polyoxyethylene hydrogenated castor oil (Product name:
Nikkol HCO-60) 0.4g Sodium carboxymethyl cellulose 0.8g Propylene glycol 1.0g Water 95ml Stir the above formulation with a homomixer to make a suspension. (Formulation 4) Parazan D (trade name) (0.05 oxolinic acid in 1ml)
(strong alkaline solution containing g) 100ml

【table】

[Table] Experimental Example 2 Goldfish (weighing approximately 8 g) were tested with the formulation of the present invention (a suspension containing 0.6 g of polyoxyethylene hydrogenated castor oil in Formulation 1 of Experimental Example 1) or the control formulation (fishery product). A suspension of oxolinic acid bulk powder used for commercial parazan in 0.2% carboxymethyl cellulose) was administered orally by force at 100 mg/kg as oxolinic acid. After administration, five test fish were taken over time, and the concentration of oxolinic acid in the kidneys and muscles was measured by bioassay method. The results are shown in Table 3 below.

[Table] As shown in Table 3 above, the formulation of the present invention was better absorbed and had a higher concentration of oxolinic acid in organs. Experimental Example 3 12,000 day-old chicks introduced from a hatchery to a poultry farm were found to have coliosis, so 1,236 chicks were randomly selected, 412 were placed in a medicated area, and the remaining 824 chicks were placed in an untreated area. This was used as a medicated group (control group). In the treatment group, the preparation of the present invention used in Experimental Example 2 was added to drinking water as oxolinic acid at a dose of 10 ml/Kg/day, and the administration was carried out for 3 days from 2 to 4 days of age. The results of investigating the number of dead birds and the number of culled birds up to 90 days of age are shown in Table 4 below.

[Table] From Table 4 above, it can be seen that the formulation of the present invention was able to be administered through drinking water, which was not possible with conventional oxolinic acid formulations, and therefore very effective therapeutic results were obtained. Experimental Example 4 The drug bath absorption in carp (body weight: 490 to 710 g) was compared between the formulation of the present invention used in Experimental Example 2 and the control formulation. That is, five carp were housed in rearing water containing each preparation at a concentration of 25 ppm as oxolinic acid, and blood was collected from each fish over time, and the concentration of oxolinic acid in the serum was measured. The results are shown in Table 5.

[Table] *: Average value of 5 fish As shown in Table 5 above, when the oxolinic acid preparation, which is poorly soluble in water, was used in the medicinal bath solution without being dissolved, the absorption of the control preparation was low. In comparison, the formulation of the invention was very well absorbed. Example 1 (Formulation) 25 g of oxolinic acid with a particle size of 1.5 μm Polyoxyethylene hydrogenated castor oil (trade name:
Nikkol HCO-60) 2g Sodium carboxymethylcellulose 4g Prepylene glycol 5g Water Appropriate amount Total volume 500ml (Preparation method) Disperse and dissolve polyoxyethylene hydrogenated castor oil, sodium carboxymethylcellulose, and propylene glycol in water. Add oxolinic acid to this, stir with a homomixer, and PH with hydrochloric acid.
After preparing the solution, the total volume is made up to 500 ml with water and filled into a polyethylene container to obtain an oxolinic acid suspension that can be uniformly redispersed before use. Example 2 (Formulation) Oxolinic acid 20g polyoxyethylene sorbitan monooleate with a particle size of 2μm
4g Butylene glycol 2g Water Appropriate amount Total amount 500ml (Preparation method) Disperse and dissolve polyoxyethylene sorbitan monooleate and butylene glycol in water. Oxolinic acid was added to this, and the following Example 1
By treating in the same manner as above, an oxolinic acid suspension that can be uniformly redispersed at the time of use is obtained. Example 3 (Formulation) 40 g of oxolinic acid with a particle size of 1.0 μm Polyoxyethylene hydrogenated castor oil (trade name:
Nikkol HCO-60) 2g Sodium carboxymethylcellulose 2g Propylene glycol 4g Methyl paraoxybenzoate 0.25g Water Appropriate amount Total volume 500ml (Preparation method) Disperse polyoxyethylene hydrogenated castor oil, sodium carboxymethylcellulose, propylene glycol, and methyl paraoxybenzoate in water. ,
Dissolve. Oxolinic acid is added to this and treated in the same manner as in Example 1 to obtain an oxolinic acid suspension that can be uniformly redispersed before use. Example 4 Oxolinic acid that can be uniformly redispersed at the time of use is produced in the same manner as in Example 1 except that oxolinic acid with a particle size of 0.5 μm is used instead of oxolinic acid with a particle size of 1.5 μm. Obtain a suspension. Example 5 Dissolve 4 g of sodium hydroxide, 4 g of polyoxyethylene sorbitan monooleate, 5 g of propylene glycol, and 20 g of oxolinic acid in about 450 ml of water, and adjust the pH to 5 with 2N hydrochloric acid while stirring well to determine the particle size. A suspension of approximately 1.5 μm of oxolinic acid is obtained. Add water to this to make the total liquid volume 500ml,
A suspension of oxolinic acid is obtained, which can be filled into a polyethylene container and redispersed uniformly. Example 6 5 g of sodium hydroxide, 2.5 g of polyoxyethylene hydrogenated castor oil, 2.5 g of sodium carboxymethyl cellulose, 5 g of propylene glycol, 0.5 g of methyl paraoxybenzoate and 25 g of oxolinic acid were dissolved in about 450 ml of water, and the mixture was dissolved with stirring thoroughly. Adjust the pH to 6 with specified hydrochloric acid to obtain a suspension of oxolinic acid with a particle size of approximately 1.1 μm. Water is added to make the total liquid volume 500 ml, and the mixture is filled into a polypropylene container to obtain an oxolinic acid suspension that can be uniformly redispersed before use.

[Claims]

1. A composition for treating cell proliferative diseases in animals, comprising an extract of Nerium species. 2. The composition of claim 1, wherein the Oleander species is Nerium oleander. 3. The composition according to claim 1, wherein the disease is a malignant tumor. 4. The composition according to claim 3, wherein the malignant tumor is adenocarcinoma. 5. The composition according to claim 1, wherein the disease is a non-malignant tumor. 6. The composition according to claim 5, wherein the non-malignant tumor is psoriasis. 7. The composition of claim 1, wherein the extract inhibits in vivo growth of syngeneic tumors in mice. 8. The composition of claim 1, wherein the extract inhibits phorbol ester- or thymosan-induced chemiluminescence in human monocytes, but not human neutrophils, in vitro. 9. The extract is subjected to the following steps: (a) dispersing the plant body of the Oleander species in a polar inorganic solvent;