IE41448B1 - Sedative method and composition - Google Patents

Abstract

1504302 Topical sedative compositions FISONS Ltd 12 Aug 1975 [23 Aug 1974] 37079/74 Heading A5B A method of sedating a non-human animal comprises applying to the skin of the animal in an amount sufficient to exert a sedative effect one or more sedative compounds. Compositions containing 2-Acetyl-10-(3-dimethylaminopropyl) phenothiazine and pharmaceutically acceptable salts thereof; 2-Chloro-10-(3- dimethylaminopropyl) phenothiazine and pharmaceutically acceptable salts thereof; 10- (3-dimethylaminopropyl) phenothiazine and pharmaceutically acceptable salts thereof; 10- (3-Dimethylamino-2-methylpropyl) phenothiazine and pharmaceutically acceptable salts thereof; 4'-fluoro-4-[4-(o-methoxyphenyl)-1-piperazinyl] butyrophenone and pharmaceutically acceptable salts thereof; 4'-fluoro-4-[4-(2- pyridyl)-1-piperazinyl] butyrophenone and 5, 6-dihydro-2-(2, 6-xylidino)-4H-1, 3 triazine and pharmaceutically acceptable salts thereof are also claimed.

Description

This invention concerns sedative compositions and their method of use.

It is well known to sedate animals hy administering chemicals to the animals either orally or, more conventionally, by injection. For example, sedatives are often administered to sows before farrowing and to piglets before removing them from their mothers and mixing litters. We have now discovered a new, yet simple and advantageous method of treatment involving external application.

Accordingly, the invention provides a method of sedating non-human animals, which method comprises applying to the skin of the animal an amount of one or more sedative compounds sufficient to exert a sedating effect, whereby the compound(s) is/are absorbed by the animal through its skin.

Such compounds include: - Acetyl - 10 - (3 - dimethylaminopropyl)phenothiazine and pharmaceutically acceptable salts thereof: - Chloro - 10 - (3 - dimethylaminopropyl)phenothiazine and pharmaceutically acceptable salts thereof; - (3 - dimethylaminopropyl)phenothiazine and pharmaceutically acceptable salts thereof; - (3 - Dimethylamino - 2 - methylpropyl)phenothiazine and pharmaceutically acceptable salts thereof; 4’ - fluoro - [4 - (o - methoxyphenyl) - 1 - piperazinyl] butyrophenone and pharmaceutically acceptable salts thereof; 4' - fluoro - 4 - [4 - (2 - pyridyl) - 1 - piperazinyl]butyrophenone and pharmaceutically acceptable salts thereof, and ,6 - dihydro - 2 - (2,6 - xylidino) - 4H - 1,3 triazine and pharmaceutically acceptable salts thereof.

Where a salt is employed, it is, where appropriate, preferably a salt with a suitable mineral or organic acid.

The choice of a suitable salt is believed to be within the competence of those skilled in pharmacy.

Especially preferred are 4’ - fluoro - 4 - [4 - (2pyridyl) - 1 - piperazinyl]butyrophenone and pharmaceutically acceptable salts thereof.

The invention also provides a sedative composition for application to the skin of an animal, which composition comprises one or more of the above-specified sedative compounds in a carrier effective for passing the compound(s) through the skin of the animal to exert their sedative effect, the carrier, when liquid, comprising a mixture of two or more liquids.

The present technique makes it easier to ensure an accurate dose than when a sedative is added to the animal's food or water supply. It avoids the possibility of inhalation or subsequent explusion when a sedative is applied directly into the mouth of the animal. It is rapid and easy to use. It is, moreover, not necessary to sterilize materials, as is the case when a sedative is applied by injection. It also avoids any damage to tissue or local reaction which may be set up around the point of injection.

The present method is preferably applied to mammals, particularly those which are domestic or farm animals, such as sheep, pigs, cattle, horses, goats, dogs and cats. It may be applied also to animals used in laboratories, such as rats, mice and guinea pigs.

In the present method the animal absorbs the compound(s) through its skin. The compounds are usually applied in a composition containing a carrier, and especially in a composition as described and claimed herein. A wide range of appropriate carriers may be employed. The composition may be a cream. A liquid composition, however, is particularly convenient to use, e.g. facilitating measuring out doses, and facilitates absorption through the skin. Thus, a solution or suspension of the compound(s) in a liquid carrier is preferred. Solutions are especially good for transmitting the compound(s) through the skin and are therefore most preferred. The liquid carrier preferably comprises one or more liquids selected from hydrocarbons (e.g. aromatic hydrocarbons such as an aromatic hydrocarbon fraction of boiling point 130—25O°C e.g. 180—22O°C, xylene, benzene or toluene,or paraffins si’ch as those of 6—20 carbon atoms). - 4 414 4 8 halogenated aliphatic hydrocarbons (e.g. carbon tetrachloride), ketones (e.g. cyclohexanone or 2-butanone), esters (e.g. ethyl acetate, ethyl benzoate or triacetin) ethers (e.g. diisopropyl ether or tetrahydrofuran), alcohols (e.g. alkanols of 2—8 carbon atoms such as butyl alcohol, amyl alcohol or isopropyl alcohol, or glycols such as monopropylene glycol), amides (e.g. dimethylformamide), sulphones (e.g. dimethyl sulphone or sulpholane) and sulphoxide (e.g. dimethyl sulphoxide). In many cases a mixture of liquids Is desirable. Results vary depending on the particular carrier employed. Any envisaged carrier can of course readily be tested by routine experiment, usually initially on laboratory animals such as mice or rats, and generally a good degree of correlation has been found between results on such laboratory animals and results on farm animals such as sheep and cattle. Results on one species may not however be duplicated on another. Preferably the liquid carrier comprises one or more liquids selected from hydrocarbons (e.g. aromatic hydrocarbons), alcohols (e.g. isopropyl alcohol or amyl alcohol) and sulphoxides (e.g. dimethyl sulphoxide). The invention provides particularly a liquid sedative composition for use by external application to the animal, which composition comprises a solution or suspension of one or more of the above identified compounds in a carrier comprising at least one of dimethyl sulphoxide and amy? alcohol, preferably both.

Besides the compound(s) and the carrier which is effective for passing the compound through the skin of the animal, the composition may contain additives e.g. to facilitate use - 5 41448 on the animal. For example, the composition may contain additives to facilitate contact with the skin of the animal, to protect the skin from any undesirable action, e.g. undersirable irritation otherwise caused by the carrier, or to improve retention of the composition on the animal.

The viscosity of liquid compositions may be increased over what it would otherwise be, by including thickeners, which increase the viscosity. This may be desirable in order to retard or prevent the composition from running off the animal.

The additives may include for example a surface active k agent, an animal fat or wax, e.g. lanolin, a mineral oil,) e.g. liquid paraffih, a vegetable oil, e.g. peanut oil, olive oil, corn oil or caster oil, or a polymer, e.g. a hydrocarbon polymer such as polyisobutene.

The surface active agents may comprise anionic Compounds for example soaps, fatty sulphate esters such as dodecyl sodium sulphate, fatty aromatic sulphonates such as alkyl-benzene sulphonates or butyl-naphthalene sulphonates, more complex fatty sulphonates such as the amide condensation product of oleic acid and N-methyl taurine or the sodium sulphonate of dioctyl succinate.

The surface active agents may also comprise non-ionic surface active agents such as for example condensation products of fatty acids, fatty alcohols or fatty substituted phenols with ethylene oxide, or fatty esters and ethers of sugars or polyhydric alcohols, or the products obtained from the latter by condensation with ethylene oxide, or the products known as block copolymers of ethylene oxide and propylene oxide. The surface active agents may also comprise cationic agents such as for example cetyl trimethylammonium bromide.

The term surface active agent is used in the broad sense to cover materials variously called wetting agents, emulsifying agents, and dispersing agents.

The composition may contain substances whose taste deters other animals from licking the composition off the animal treated. An example of such a substance is bitter aloes.

A single material may function in more than one respect e.g. it may protect the skin and enhance retention.

The particular additives and their amounts which are employed depend on the particular compound and treatment. Generally, however, the composition may consist by weight of 1/2—95% of the compound(s), 5—99 1/2% of the carrier and 0—60% of additive, usually 1—15%, e.g. 1—10% of the compound(s), 45—99% of the carrier and 0—60%, e.g. 5—50%» of the additive.

Suitably the composition for use in the present method contains 1—10% by weight of the compound(s). A preferred embodiment comprises a method of sedating an animal especially a non-human mammalian animal, which method comprising applying to the skin of the animal a composition which is a solution or suspension of 1—1O% by weight of one or more of the above identified compounds in a carrier, in an amount sufficient to exert a sedative effect.

Usually the compound is applied just to the body of the animal, conveniently only to its back, and preferably only to a small portion of its back. Thus, when a liquid composition is employed, it can simply be poured on to the back of the animal. The volume of composition employed is generally 0.01—10 ml per kg body weight of the animal.

The dosage rate depends on such factors as the carrier employed, the desired effect and the animal treated. In general, however, the composition is applied at a rate of 1250, preferably 1—100, especially 1—50, mg of the compound(s) per kg body weight of the animal. For the larger mammals a suitable dose is 150—1,500 mg. A single dose may be sufficient, or it may be repeated if necessary.

The composition may be in unit dosage form, e.g. i jf individual capsules. It is desirably sterile. It may be) prepared by admixing the ingredients.

The invention is further described, though only by way of illustration, in the following Examples.

Example 1 - Fluoro - 4 - [4 - (2 - pyridyl) - 1 - piperazinyl]butyrophenone was formulated as a 5% w/v solution in 20% v/v dimethyl sulphoxide, 80% v/v Aromasol H (a proprietary hydrocarbon fraction? Aromasol is a Registered Trade Mark) and applied dermally to rats at 50 mg/kg and 100 mg/kg.

For these treatments, the appropriate volume of formulated material was applied to the shaven skin of the animals backs and covered immediately with the aluminium foil and an elastic plaster to prevent ingestion of the active compound by grooming. Rats were also treated with a 4% aqueous solution of the compound by intramuscular injection at the same dose rates so that the effects by dermal and intramuscular routes could be compared. Animals were closely - 8 41448 observed after treatment for signs of sedation, time of onset and recovery etc.

Within fifteen minutes of treatment at both dose rates dermally and by injection rats were markedly sedated but 5 responsive to stimuli. One hour and fifteen minutes after treatment all rats were still sedated though responsive. The animals were all normal the following day.

Example 2 Weanling pigs 8 weeks old were treated with a formula10 tion containing 4% w/v 4 - fluoro - 4 - [4 - (2 - pyridyl)1 - piperazinyl]butyrophenone, 20% v/v dimethyl sulphoxide, 80% v/v aromasol H. The sedative effects which occurred after treatment at 1 to 8 mg/kg dermally applied were simular to those occurring after intramuscular injection of similar dose rates.

Claims (16)

1. A sedative composition for application to the skin of an animal, which composition comprises one or more sedative compounds selected from: 2. - Acetyl - 10 - (3 - dimethylaminopropyUphenothiazine and pharmaceutically acceptable salts thereofj 2 - Chloro - 10 - (3 - dimethylaminopropyl)phenothiazine and pharmaceutically acceptable salts, thereof; 10 - (3 - dimethylaminopropyljphenothiazine and pharmaceutically acceptable salts thereof; 10 - (3 - Dimethylamino - 2 - methylpropyl)phenothiazine and pharmaceutically acceptable salts thereof,4' - fluoro - 4 - [4 - (o - methoxyphenyl) - 1piperazinyl]butyrophenone and pharmaceutically acceptable salts thereof; 4' - fluoro - 4 - [4 - (2 - pyridyl) - 1 - piperazinyl]butyrophenone and pharmaceutically acceptable salts thereof, and 5,6 - dihydro - 2 - (2,6 - xylidino) - 4H - 1,3 - triazine and pharmaceutically acceptable salts thereof, in a carrier effective for passing the compound(s) through the t skin to exert their sedative effect, the carrier, when liquid, comprising a mixture of two or more liquids.

2. A sedative composition as claimed in claim 1 wherein the carrier is a liquid carrier which comprises two or more liquids selected from hydrocarbons, halogenated aliphatic hydrocarbons, ketones, esters, ethers, alcohols, amides, sulphones and sulphoxides.

3. A sedative composition as ckimed in claim 2, 10 41448 wherein the liquid carrier comprises two or more liquids selected from aromatic hydrocarbon fractions, xylene, benzene, toluene, paraffins, carbon tetrachloride, cyclohexanone, 2-butanone, ethyl acetate, ethyl benzoate, triacetin, diisopropyl ether, tetrahydrofuran, alkanols of 2 to 8 carbon atoms, glycols, dimethylformamide, dimethylsulphone, sulpholane and dimethyl sulphoxide.

4. Ά sedative composition as claimed in claim 3, wherein the liquid carrier comprises a mixture of one or more aromatic hydrocarbons, one or more alcohols and one or more sulphoxides.

5. A sedative composition as claimed in any of claims 1 to 4, which contains from 1/2 to 95% by weight of the sedative compound(s) and from 5 to 99.5% by weight of the carrier.

6. A sedative composition as claimed in claim 5, which contains from 1 to 15% by weight of the sedative compound(s).

7. A sedative composition as claimed in claim 6, which contains from 1 to 10% by weight of the sedative compound(s).

8. A sedative composition as claimed in any of claims 1 to 7, and substantially as described herein with reference to any one of the Examples.

9. A method of sedating a non-human animal, which method comprises applying to the skin of the animal an amount sufficient to exert a sedative effect of one or more sedative compounds, whereby the compound(s) is/are absorbed by the animal through its skin.

10. A method as claimed in claim 9, wherein the compound (s) is/are applied in the form of a composition as claimed in any of claims 1 to 8.

11. A method as claimed in claim 9 or claim 10, i 5 wherein the animal to whose skin the compound(s) is/are applied is a domestic, farm or laboratory animal.

12. A method as claimed in any of claims 9 to 11, wherein the dose of the compound(s) applied is from 1 to 250 mg per kg body weight. 10

13. A method as claimed in claim 12, wherein the dose of the compound(s) applied is from 1 to 100 mg per kg body, weight. >,

14. A method as claimed in claim 13, wherein the dose of the compound(s) applied is from 1 to 50 mg per kg body 15. Weight.

15. A method as claimed in any of claims 10 to 14, wherein the composition applied is a liquid composition and is applied to the back of the animal.

16. A method as claimed in any of claims 9 to 15 and 20 substantially as described herein with reference to any one of the Examples. L