JPS6340769B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to compositions useful as veterinary medicine, and more particularly to compositions useful in the treatment of bacterial and protozoal diseases of poultry. Coctidiosis is a common disease of poultry caused by protozoan parasitic species of the genus Eimeria . This infection commonly occurs in poultry between 2 and 14 weeks of age and can cause widespread damage if left untreated. The prevention and treatment of coctidia in the poultry industry is therefore of great economic importance. One of the drugs often used in therapeutics to treat coctidia is sulfaquinoxaline [N-(2-quinoxalyl)sulfanilamide], which is described in the reference book "Organic".
Organic Medicine and Pharmaceutical Chemistry
Pharmaceutical Chemistry), 4th edition [G.
B. Ritzpinkotsuto, Philadelphia (J.
Unfortunately, it is toxic at high doses. It has been found that by combining sulfonamides with certain groups of compounds, the efficacy of the sulfonamides as antibacterial agents is maintained and the required dosage is reduced. Some current drugs for the treatment of coccidiosis contain sulfaquinoxalines in combination with diaaveridine [2,4-diamino-5-(3,4-dimethoxybenzyl)pyrimidine] sulfonamide fortifiers. British Patent No. 1028204 and
No. 1108112 describes such agents. On the other hand, trimethoprim [2,4-diamino-5
-(3,4,5-trimethoxybenzyl)pyrimidine] is an antibacterial agent that is commonly used in humans and mammals as a compound of certain species such as sulfathiazole, sulfamethoxazole, sulfadiazine, sulfazimidine and sulfadoxin. Used in combination with sulfonamides. However, it has not previously been suggested that trimethoprim could be combined with sulfaquinoxaline for the treatment of coccidiosis in poultry. It has now been discovered that a drug containing trimethoprim and sulfaquinoxaline provides an effective and improved treatment of coccidial diseases, including coccidial diseases caused by sulfaquinoxaline-resistant species of protozoa of the genus Eimeria .
This combination is also unexpectedly effective against bacterial infections , including infections caused by certain sulfonamide-resistant species of Escherichia coli , and in the treatment of malaria in poultry. This suggests a combined potentiation between sulfonamides and trimethoprim.
It has been suggested that this does not occur in vitro if the infection is sulfonamide resistant [Lewis, et al.
Anderson and Racey (Lewis, Anderson)
and Lacey), J. Clin. path. (J.Clin.
Path.), 1974, 27 , 87-91]. Accordingly, the present invention provides veterinary pharmaceutical compositions containing an effective amount of trimethoprim in combination with an effective amount of sulfaquinoxaline, wherein the weight ratio of trimethoprim present to sulfaquinoxaline present is about 1:1 to 1:4. I will provide a. Preferably, trimethoprim is present as the free base and sulfaquinoxaline may be present as a salt with a veterinarily acceptable base. Trimethoprim can also be used with free sulfaquinoxaline as an acid addition salt, for example as a salt formed with a veterinarily acceptable acid, or both active ingredients can be used in their free, non-salt forming form. It can also exist. A preferred weight ratio of trimethoprim to sulfaquinoxaline is about 1:3. In a preferred embodiment, the invention comprises an effective amount of trimethoprim in combination with an effective amount of a veterinary acceptable salt of sulfaquinoxaline, wherein the weight ratio of trimethoprim present to sulfaquinoxaline present is as defined above. A veterinary pharmaceutical composition is provided. The veterinary pharmaceutical compositions of the invention are usually in the form of either a powder or a concentrated solution. In the powders of the invention it is preferred to use an alkali metal salt of sulfaquinoxaline, such as its sodium salt. Convenient water-soluble excipients such as lactose or sucrose can be incorporated into this powder to improve its physical properties, according to standard veterinary pharmaceutical composition practices. A particularly suitable powder according to the invention therefore contains 50 to 100% w/w, preferably 60 to 80% w/w, of a mixture of trimethoprim and an alkali metal salt of sulfaquinoxaline and 0 to 80% w/w of customary veterinary excipients. 50% w/w, preferably 20-40% w/w, and the ratio of trimethoprim present to sulfaquinoxaline present is as defined above. These powders can be used, for example, either added to the animal's feed in the manner of intermediate premixes or diluted in the animal's drinking water. The powder of this invention diluted with water to provide about 133 ppm of trimethoprim and sulfaquinoxaline as active ingredients is particularly effective for poultry use. An effective treatment for poultry is therefore obtained by adding 20 g of a powder containing 70% w/w of a mixture of trimethoprim and sodium sulfaquinoxaline to 100 g of drinking water. The concentrated solution of the present invention is suitably prepared by adding a solution of trimethoprim and sulfaquinoxaline to a water-soluble base.
In particular, a water-soluble veterinary acceptable salt of sulfaquinoxaline formed from mixing with an organic base such as ethanolamine or diethanolamine is contained in a veterinarily acceptable water-miscible solvent. Suitable solvents include polyethylene glycol, propylene glycol,
Includes glycerol, glycerol formal or mixtures of such solvents with up to 30% v/v ethanol. Polyethylene glycol is a particularly convenient solvent for use in the concentrates of the present invention. Suitably, the sulfaquinoxaline salt is formed in situ by presenting the sulfaquinoxaline in a concentrated solution with an organic base. Accordingly, in another preferred embodiment, the present invention provides 10 to 50% w/v of a mixture of trimethoprim and a salt of sulfaquinoxaline formed from a veterinarily acceptable water-soluble organic base, such as glycol, propylene glycol. , glycerol, and glycerol formal, and the weight ratio of trimethoprim to sulfaquinoxaline is as defined above. The concentrated solution of the invention is administered to animals, especially poultry, in their drinking water. They are particularly suitable for automatic addition to poultry drinking water by using a water dispenser. The veterinary pharmaceutical composition of the invention is particularly suitable for the treatment of coccidiosis in chickens. In another embodiment, the invention provides a method for treating bacterial diseases in poultry, comprising orally administering 1 to 100 mg/Kg of a veterinary pharmaceutical composition of the invention as described above. Suitably 5 to 70 mg/Kg of the composition of the invention,
Preferably 20 to 40 mg/Kg is administered orally daily by placing the composition in the feed or drinking water of poultry in the treatment of bacterial diseases. In yet another aspect, the present invention provides a method for treating coccidiosis in poultry, comprising daily oral administration of said dosage of a veterinary pharmaceutical composition as described above. The present invention also provides a method for treating malaria in poultry, comprising daily oral administration of said dosage of a veterinary pharmaceutical composition as described above. The following examples demonstrate the veterinary efficacy of the compositions of the invention and their preparations. The percentages used here, weight-to-volume concentrations, are g/100ml. Antibacterial and antiprotozoal activity of trimethoprim/sulfaquinoxaline compositions against sulfonamide-resistant E. Coli (E.Coli) species
Chickens infected with E. coli species 18EC were treated with a trimethoprim/sulfaquinoxaline composition at different dosage levels.
inducing a syndrome very similar to septicaemia; Piercy and West, J. component. path. (J.comp.
Path.), (1976) 86 , 203]. Similarly infected chickens were also treated with the drug trimethoprim and two commercially used drugs, sulfachlorpyridazine and oxytetracycline, for comparison purposes. Chickens were infected at 18 days of age and weighed.
Seven days after infection, the birds were sacrificed and weighed again, followed by a post-mortem examination. All chickens, apart from uninfected and infected/untreated controls, received drug-containing drinking water ad libitum for 24 hours prior to infection without receiving additional drug-free water until the end of treatment.
Dosages and treatment durations are shown in Table 1. This table also shows the observations recorded at the post-mortem examination. The degree of lesions observed at post-mortem examination was recorded on a scale of 0 to 4 based on the following: Score no lesions 0 Inflammatory reaction in the injected air sacs 1 Inflammation of both air sacs 2 Severe bilateral air saccharitis (airsacculitis) (inflammation, air sac enlargement, and E. coli septic symptoms) + pericarditis 3 All of the above symptoms + fibrin peritonitis or death 4 [Table] [Table] 5 groups of 1-week-old young male Wrangell chickens were treated with E. 50 000 sporulated oocysts of Ongar species of Acervulina , Weybridge of E. maxima
Oral infection was carried out with a mixture of 50,000 oocysts of E. brunetti and 50,000 oocysts of E. brunetti, Weybridge sp., respectively. This resulted in a 72% mortality rate in untreated chicks. Chicks were treated with a 3:1 sulfaquinoxaline/trimethoprim drug (132 ppm final concentration) in drinking water. The 5-day treatment began on the day of infection and on days 1 and 2 post-infection. The uninfected and uninfected groups served as controls, and the uninfected groups were given non-toxic water. Table 2 shows 0-4, 4-7, 7-14 and 0
The weight gain of chicks after −14 days (day 0 is the day of infection) is shown. This treatment completely controlled both mortality and bleeding/diarrhea. [Table] Five groups of 1-week-old young male Wrangell chickens were placed on Ei.
Oral infection was carried out with 50,000 sporulating oocysts of Tenella Weybridge sp. This results in a mortality rate of 73.5% in non-medicated chicks.
The chicks were treated with a 4:1 sulfaquinoxaline/diaveridine solution (96 ppm final concentration) and a 3:1 sulfaquinoxaline/trimethoprim solution (133 ppm final concentration). Treatment started on the day of infection;
Continued for 3 and 4 days. Table 3 shows the results of mortality control. Sulfaquinoxaline/diaveridine solution has a 95% mortality rate after 3 days of treatment
This resulted in the prevention of On the other hand, the sulfaquinoxaline/trimethoprim drug produced 100% inhibition at both 3-day and 4-day treatments. [Table] Toplim; 3:1
Each of the five groups of one-week-old young male Wrangell chickens was
Sulfaquinoxaline-resistant Dessord Mill species of E. acervulina
Oral infection with 250,000 sporulated oocysts. The chicks were treated with a 3:1 sulfaquinoxaline/trimethoprim drug in the drinking water (final concentration
132ppm). Treatment for 5 days began on the day of infection and 1 and 2 days thereafter. Controls included an uninfected and uninfected untreated group, and the uninfected untreated group received a dose of water by gavage as a sham infection. Table 3 shows 0-4, 4-7, 7-14 and 0
- Shows the weight gain of chicks after 14 days (day 0 is the day of infection). Over the entire 14 days, all treatment groups achieved significantly better weight gain compared to infected controls, which was approximately 97% overall of uninfected controls. The results are shown in Table 4. [Table] Example 1 Make a 24% solution of 3:1 sulfaquinoxaline/trimethoprim with the following composition: 6 g trimethoprim 18 g sulfaquinoxaline 4 g monoethanolamine Polyethylene glycol 200 Amount to make 100 ml Heat trimethoprim to 70-80°C. Dissolve in 70ml of polyethylene glycol 200. Add monoethanolamine and sulfaquinoxaline and stir the mixture until the contents are dissolved.
The solution is cooled to room temperature and made up to a constant volume with polyethylene glycol 200. Mix the resulting solution thoroughly to ensure its homogeneity. Example 2 Make a soluble powder containing a 3:1 drug of sulfaquinoxaline/trimethoprim with the following composition: Sodium sulfaquinoxaline 10.73g Trimethoprim 3.3g Sodium lauryl sulfate 0.1g Lactose 5.87g Lactose, trimethoprim and sodium sulfaquinoxaline Mix thoroughly together with a mixer. Dissolve the sodium lauryl sulfate in a small amount of water and use this solution to granulate the powder. The resulting granules are screened, dried and the dried granules are screened again. The sieved and dried granules are thoroughly mixed. The product is thus in a form suitable for administration to animal feed or animal drinking water.

Claims (1)

[Scope of Claims] 1. A bacterial strain containing an effective amount of trimethoprim in combination with an effective amount of sulfaquinoxaline, wherein the weight ratio of the amount of trimethoprim present to the amount of sulfaquinoxaline present is about 1:1 to 1:4. Veterinary drug composition for the treatment of protozoal diseases. 2. The veterinary pharmaceutical composition of claim 1, wherein the weight ratio of the amount of trimethoprim present to the amount of sulfaquinoxaline present is about 1:3. 3. A veterinary pharmaceutical composition according to either claim 1 or 2, wherein trimethoprim is present as a free base. 4. A veterinary pharmaceutical composition according to any one of claims 1 to 3, wherein the sulfaquinoxaline is present as a salt with a veterinarily acceptable base. 5 Claims 1 to 4 in powder form
Veterinary pharmaceutical compositions as described in Section. 6. Veterinary pharmaceutical composition according to claim 5, wherein the sulfaquinoxaline is present in the form of an alkali metal salt. 7. The veterinary pharmaceutical composition according to claim 6, wherein the alkali metal salt of sulfaquinoxaline is a sodium salt. 8. Any one of claims 5 to 7, wherein the powder contains 50 to 100% w/w of a mixture of trimethoprim and sulfaquinoxaline.
The veterinary drug composition described in . 9. Veterinary pharmaceutical composition according to any one of claims 5 to 8, wherein the powder contains 60 to 80% w/w of a mixture of trimethoprim and sulfaquinoxaline. 10. A veterinary pharmaceutical composition according to any one of claims 1 to 4, which is in the form of a concentrated solution. 11. A veterinary pharmaceutical composition according to claim 10, containing a water-soluble veterinary acceptable salt of trimethoprim and sulfaquinoxaline. 12. The veterinary pharmaceutical composition of claim 11, comprising a solution comprising sulfaquinoxaline and trimethoprim together with a water-soluble base in a water-miscible solvent that is acceptable for veterinary medicine. 13. The veterinary pharmaceutical composition according to claim 12, wherein the water-soluble base is an organic base. 14. The veterinary pharmaceutical composition according to claim 12 or 13, wherein the water-soluble base is ethanolamine or diethanolamine. 15. According to any one of claims 12 to 14, the water-miscible solvent is polyethylene glycol, propylene glycol, glycerol, glycerol formal or a mixture of such a solvent with up to 30% v/v ethanol. veterinary medicine composition. 16. Veterinary pharmaceutical composition according to any one of claims 10 to 15, containing 10 to 50% w/v of a mixture of trimethoprim and sulfaquinoxaline. 17. A veterinary pharmaceutical composition according to any one of claims 10 to 15, containing about 24% weight/volume of a mixture of trimethoprim and sulfaquinoxaline. 18. Administering a veterinary pharmaceutical composition comprising an effective amount of trimethoprim in combination with an effective amount of sulfaquinoxaline, wherein the weight ratio of trimethoprim present to sulfaquinoxaline present is about 1:1 to 1:4. A treatment method for protozoal diseases of birds. 19. The method of claim 18, wherein the protozoal disease is coccidiosis. 20. Administering a veterinary pharmaceutical composition comprising an effective amount of trimethoprim in combination with an effective amount of sulfaquinoxaline, wherein the weight ratio of trimethoprim present to sulfaquinoxaline present is about 1:1 to 1:4. How to treat bacterial diseases in birds.