GB2136293A - Antiinflammatory compositions - Google Patents

Abstract

Antiinflammatory compositions for veterinary use comprising tylosin or a salt thereof; a corticosteroid of formula (I), <IMAGE> wherein R1 is hydrogen or fluorine, R2 is hydrogen or hydroxyl, A is hydroxyl or N-methyl-piperazino and @@ is -CH2-CH2- or -CH=CH-, or a salt thereof; iodochlorooxyquinoline; and ethinyloestradiol, of particular use in the treatment of metritis and colpitis.

Description

SPECIFICATION Antiinflammatory compositions for veterinary use This invention relates to new antiinflammatory compositions for veterinary use and in particular for the treatment of metritis and colpitis in female animals.

The uterus of pregnant animals such as cows is practically sterile. Labour creates favourable conditions for the invasion of germs approaching the womb and makes an animal in labour more susceptible to infections. American authors have reported (JAVMA 172, 489 [1 978]) that 14 days after labour, uterine infection can be observed in about 85 to 93% of animals. According to our own statistics, in Hungary about 60% of the cows have subclinical metritis and in about 30% the symptoms are clinical. Such infections may lead to extension of the service period, infertility, early sorting out, emergency slaughter and/or the need for more fertilizations to achieve a subsequent pregnancy.

For the treatment of metritis and colpitis the present most frequently used veterinary compositions are METRIJET and OSTRILAN (the preparations of the firms Intervet and Ciba Geigy, respectively).

METRIJET contains oxytetracycline, furazolidone, iodochlorooxyquinoline and ethinyloestradione.

The use of this formulation, however, has the disadvantage that oxytetracycline has an undesired effect on the oestrus cycle (Seguin et al.: JAVMA 164, 609 [1974] and 168, 217 [1976].

The other composition widely used for this purpose, OSTRILAN contains sulfapyrazole, sulfachloropyridazine, iodochlorooxyquinoline and ethinyloestradiol. Due to its sulfonamide components, however, the use of OSTRILAN leads to the development of resistance, i.e. the composition has a decreasing activity. It is well known that a substantial resistance has to be faced even in the case of potentiated sulfonamides (Magyar Allatorvosok Lapja, 1 55 [1 976]].

We have surprisingly found that by using a particular combination of specific active ingredients, the above-mentioned disadvantages may be substantially reduced or avoided. Accordingly to the present invention we provide a veterinary composition comprising, in combination tylosin or a salt thereof; a corticosteroid of formula (I),

wherein R1 is hydrogen or fluorine, R2 is hydrogen or hydroxyl, A is hydroxyl or N-methyl-piperzino, and

ab is -CH2-CH2- or -CH=CH-, or a salt thereof; iodochlorooxyquinoline; and ethinyloestradiol.

Tyl osin (1 5-[[(6-desoxy-2,3-di-0-methyl-p-D-a llopyranosyl)-oxy]-methyl]-6-[[3,6-didesoxy-4-0- (2,6-didesoxy-3-C-methyl-a-L-ribo-hexapyra nosyl)-3-(dimethyla mino)-/3-D-glucopyranosyl]-oxy- 1 6 ethyl-4-hydroxy-5,0-dimethyl-2, 1 O-dioxo-oxacyclohexy-deca- 1,13-dien-7-acetaldehyde]) is a broad spectrum antibiotic whilst iodochlorooxyquinoline (5-chlorn-7-iod8-hydrnxyquinoline) is a disinfectant and ethinyloestradiol facilitates the regeneration of the endometrium. Tests carried out on a large number of animals in different farms have shown that about 80% of the treated animals were entirely cured using the compositions according to the invention.

Since iodochlorooxyquinoline is practically insoluble in water, rhe composition is generally administered in the form of a suspension, the dispersing medium being appropriately selected to obtain a satisfactory stability. Aqueous suspensions are thus particularly preferred forms for the compositions according to the invention.

According to a preferred embodiment of the invention there are provided compositions which contain 1.5 to 3% by weight of tylosin or a salt thereof; 0.003 to 0.01% by weight of corticosteroid of formula (I) or a salt thereof; 2.5 to 5% by weight of iodochlorooxyquinoline; and 0.002 to 0.003% by weight of ethinyloestradiol based on the total weight of the composition.

As a corticosteroid of formula (i) preferably mazipredone (1 1 P,1 7a-dihydroxy-2 1 -(4-methyl-l - piperazinyl)-1 ,4-pregna-1 ,4-diene-3,20-dione) is employed but other steroids, e.g. prednisolone, hydrocortisone, triamcinolone and dexamethasone may equally be used.

An anionic polyelectrolyte may usefully be added so as to increase the viscosity of the composition when in suspension form. Preferred anionic polyelectrolytes are carboxyvinyl polymers e.g. polyacrylic acid since they do not give use to incompatibility in the system and the rheological characteristics are very favourable and unchanged even after long storage. Taking into account the chemical stability of the active ingredients the preferred pH-range of compositions when in aqueous suspension form, is from 6.0 to 6.5. In this range polyacrylic acid shows a maximum viscosity, therefore, the desired viscosity can be achieved with a relatively small amount, i.e. 0.2 to 0.5% by weight, preferably 0.3% by weight of polyacrylic acid.

Ethinyloestradiol is preferably homogeneously dispersed in the system by means of a dispersant such as a polyethyleneglycol sorbitan fatty acid ester, more preferably polyethyleneglycol sorbitan monooleate. Such dispersants are preferably used in an amount of 1.5 to 3% by weight, more preferably about 2.25% by weight. With such amounts a rapid dissolution of ethyinyloestradiol is ensured without the need to heat the system. At the same time iodochlorooxyquinoline is also completely dispersed since its particles become imbedded in the monomolecular layer of dispersants such as polyethyleneglycol sorbitan monooleate, which prevents their aggregation. In this way the physical stability of the composition is increased.

The composition, when in aqueous suspension form, is preferably adjusted to pH 5.5 to 7.0, preferably 6.0 to 6.5. As a buffer sodium citrate/citric acid is preferably employed, since it has an excellent buffer capacity in the critical range, on the other hand, it alters the viscosity only slightly.

According to another aspect of the invention there is provided a process for the preparation of veterinary compositions which comprises admixing tylosin or a salt thereof; a compound of formula (I) as defined above or a salt thereof; ethinyloestradiol and odochiorooxyquinoline optionally together with conventional additives.

According to a preferred embodiment of the process according to the invention to an aqueous solution of a compound of formula (I) or salt thereof, preferably a salt of mazipredone with a mineral acid, most preferably mazipredone hydrochloride, ethinyloestradiol is added; the mixture obtained is treated with a dispersant, preferably a polyethyleneglycol sorbitan fatty acid ester; thereafter a tylosin salt, preferably tylosin tartarate is dissolved in the mixture; an aqueous gel containing a sodium citrate/citric acid buffer and polyacrylic acid is then added to the resultant solution; and finally, iodochlorooxyquinoline is suspended in the mixture, which is then diluted with distilled water and, if desired, homogenized.

The components of the composition may alternatively, if desired by dissolved in reverse order.

Thus, for example, tylosin can be dissolved in the mazipredone, ethinyloestradinol, polyethyleneglycol sorbitan oleate system even in high concentrations, thus it is not necessary to dissolve tylosin in a separate vessel to avoid coagulation. Polyacrylic acid gel and citrate buffer are generally prepared in the same pot since experiments have shown that the decrease in viscosity can be minimized in this manner.

The compositions according to the invention have the following major advantages: Using the composition according to the invention excellent results have been achieved in the treatment of acute and chronic infections of the genital tract. The best results have been obtained in the case of difficult parturition, abortion, infections of the endometrium if the foetal membrane is left behind, cervitis or vaginitis.

It has been found that by administering the compositions according to the invention into the lumen of the womb within 24 hours after fertilization, the number of animals getting pregnant can considerably be increased.

Using the compositions according to the invention infectious inflammations of other parts of the body can also successfully be treated, provided that the use of ethinyloestradiol is non contraindicated.

The antibiotic and iodochlorooxyquinoline components of the compositions according to the invention attack the bacterium and fungal flora of the uterus and inhibit the reproduction of bacteria and fungi. The corticosteroid is necessary (especially in acute cases) for spontaneous recovery; the undesired inflammatory reaction is locally reduced and does not affect the connective tissue surrounding the uterus, accordingly the danger or perimetritis and parametris which may result in temporary or permanent fertility disorders, is decreased. Ethinyloestradiol present in the composition, facilitates the regeneration of the endometrium and the normalization of the cycle and improves the blood supply and tone of the uterus. The carrier generally employed in these compositions will advantageously be a surfactant which inhibits the sedimentation of active ingredients during storage and, after injection, assists the distribution of the active ingredients over the whole surface of the endometrium.

The pH of the compositions when formulated as aqueous suspensions is preferably adjusted to the desired value as described above using a sodium citrate/citric acid buffer system. The pH range of 5.5 to 7.0, preferably 6.0 to 6.5, is not only advantageous with respect to stability but is also unfavourable for the development of microorganisms.

The process according to the invention can be performed without special equipment.

The invention is elucidated in detail by the aid of the following non-limiting Examples.

Example 1 The following composition is prepared: tylosin tartarate 40.0 g mazipredone hydrochloride 0.1 g iodochlorooxyquinoline 75.0 g eth inyloestradiol 0.05 g; citric acid 2.0 g sodium hydroxide 3.4 g polyacrylic acid 6.0 g polyethyleneglycol sorbitan monooleate 45.0 g distilled water ad 2000.0 ml A suspension of the above is prepared in three steps: I. 2.0 g of citric acid are dissolved in one liter of distilled water and 6.0 g of polyacrylic acid are added. After swelling a solution of 3.4 g of sodium hydroxide in 30 ml of distilled water is added.

II. 0.1 g of mazipredone hydrochloride are dissolved in 500 ml of distilled water, 0.05 g of ethinyloestradiol are added to the solution, followed by the gradual addition of 45.0 g of polyethyleneglycol sorbitan monooleate, which solubilizes ethinyloestradiol, under stirring. Thereafter, 40.0 g of tylosin tartarate are added to the mixture.

III. The solution II is added to the gel I and in this mixture 75.0 g of iodochlorooxyquinoline are suspended. The suspension is made up to 2000.0 ml with distilled water. A homogeneous, slightly beige, stable suspension of a pH between 6 and 6.5 is obtained. No deposition is observed. The suspension is then filled into plastic containers of 20 ml volume each.

EXAMPLE 2 The procedure described in Example 1 is essentially followed except that instead of mazipredone hydrochloride 0.05 g of prednisolone are employed. In Step II prednisolone and 0.05 g of ethinyloestradiol are employed.

EXAMPLE 3 The procedure described in Example 2 is followed except that instead of prednisolone 0.15 g of triamcinolone are employed.

EXAMPLE 4 The procedure described in Example 2 is followed except that instead of prednisolone 0.1 g of hydrocortisone are employed.

EXAMPLE 5 Essentially following the procedure described in Example 1 the following composition is prepared: tylosin tartarate 32.0 g mazipredone 0.06 g iodochlorooxyquinoline 55.0 g ethinyloestradiol 0.04 g polyacrylic acid 5.5 g polyethyleneglycol sorbitan monooleate 40.0 g citric acid/sodium citrate up to pH 6 distilled water ad 2000.0 ml EXAMPLE 6 Essentially following the procedure described in Example 1 the following composition is prepared: tylosin tartarate 55.0 g mazipredone hydrochloride 0.5 g iodochlorooxyquinoline 95.0 g ethinyloestradiol 0.06 g polyacrylic acid 6.0 g polyethyleneglycol sorbitan monooleate 50.0 g citric acid/sodium citrate up to pH 6 distilled water ad 2000.0 ml EXAMPLE 7 Comparative Example The tests were carried out on 60 speckled "Holstein friz F1 and R1,, cattle in milk suffering from chronic metritis.Groups of 1 5 were treated as follows: Group A: 20 ml of a suspension according to Example 1 intrauterinally, one to 3 times (as desired).

Group B: 1 injector of Metrijet suspension (Intervet) intrauterinally, one to 3 times (as desired).

Group C: 1 flask of Oestrilan suspension (Ciba Geigy) intrauterinally, one to 3 times (as desired) Group D: untreated control.

The animals were examined 10 to 90 days after parturition to determine the existence of acute or chronic metritis and the severity of inflammation. The treated groups were homogeneous as to age, severity of disease, etc. 2 to 6 days after treatment the examination was repeated and, if desired, the animals were subjected to further treatment.

The recovery ratio of the treated groups, the appearance of the first heat suitable for fertilization and the conception ratio were determined. The results are set forth in the following Table.

Pregnant at first Group No. of fertil treatments ization v6 Cured % no 15 29 8 53.5 12 80.0 n- 15 30 7 46.6 11 73.3 inc 15 33 5 33.3 9 60.0 n- 15 - 3 20.0 5 33.3 From the results it can be concluded that treatments carried out with the compositions according to the invention rapidly substantially improve the condition of animals suffering from metritis, most of the animals are entirely recovered after one to 3 treatments. The conception ratio is worst naturally in the control group, which received no treatment, while in the other groups it varies between 33 and 53%, depending on the composition employed. The results clearly show that the composition according to the invention is very effective in the treatment of metritis, and it has a significatly improved effect over the most widely used commercial compositions.

Claims (12)

1. A verterinary composition comprising, in combination tylosin or a salt thereof; a corticosteroid of formula (I),

wherein R1 is hydrogen or fluorine, R2 is hydrogen or hydroxyl, A is hydroxyl or N-methyl-piperzino, and

ab is -CH2-CH2- or -CH=CH-, or a salt thereof; iodochlorooxyquinoline; and ethinyloestradiol.

2. A composition as claimed in claim 1 wherein the compound of formula (I) is mazipredone.

3. A composition as claimed in claim 1 or claim 2, which contains 1.5 to 3% by weight of tylosin or a salt thereof; 0.003 to 0.01% by weight of a compound of formula (I) or a salt thereof; 2.5 to 5% by weight of iodochloroooxyquinoline; and 0.002 to 0.003% by weight of ethinyloestradiol based on the total weight of the suspension.

4. A composition as claimed in any preceding claim in the form of an aqueous suspension.

5. A composition as claimed in any preceding claim which additionally contains a carboxyvinyl polymer, a polyethyleneglycol sorbitan fatty acid ester and a sodium citrate/citric acid buffer.

6. A veterinary composition as claimed in claim 1 substantially as herein described.

7. A veterinary composition substantially as herein described in any one of Example 1 to 6.

8. A process for the preparation of veterinary compositions which comprises admixing tylosin or a salt thereof; a compound of formula (I) as defined in claim 1 or a salt thereof; ethinyloestradiol and iodochlorooxyquinoline optionally together with conventional additives.

9. A process as claimed in claim 8 substantially as herein described.

10. A process as claimed in claim 8 substantially as herein described in any one of Examples 1 to 6.

1 Veterinary compositions whenever prepared by a process as claimed in any one of claims 8 to 10.

12. Each and every novel method, process, composition and product herein disclosed.