CA1112170A - Tetramisole and levamisole pour-on compositions and methods of use - Google Patents

Abstract

TETRAMISOLE AND LEVAMISOLE POUR-ON COMPOSITIONS
AND METHODS OF USE

Abstract of the Disclosure Pour-on veterinary compositions are prepared which comprise an anthelmintically effective amount of tetramisole, levamisole or an acid addition salt thereof in combination with a diluent suitable for pour-on formu-lations for use on animals. These compositions are used to treat helminthic infestations in animals by the pour-on method of application.

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Description

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The present invention~is concerned with pour- -on ~eterinary com~ositions and methods of treating hel-minthic infesta~ions in animals by the pour-on-application method wherein the active agent in said pour-on compositions is tetramisole, levam~sole or an acid addition salt thereof.
By "pour-on" veterinarycomposition is meant a composition that is applied directly to the external skin of the animal. This may be effected by pouring the compo-sition on or over the animal's external skin, by spraying the composition on all or a portion of the animal's external skin (as, for example, from a measuring vessel, a spray flask, an aerosol pack, or the like), or by drenching or otherwise immersing all or a part of the animal's external skln in the composition.
This "pour-on" method of application is known.
For example, phosphoric acid esters such as Ruelene (i.e., 4-tertiary -butyl-2-chlorophenyL N-methyl-0-methyl-phosphonamidate), Trichlorphon (i.e., dimethyl-[2,2,2-trichloro-l-hydroxyethyl~-phosphonate), Fenthion (i.e.
20 0,0-dimethyl-0-(4-methylmercapto-3-methylphenyL)-thiono-phosphate) and others, which in addition to an anthelmintic actlon also possess a very pronounced insecticidal action, are administered by pouring on. However, the anthelmin-tic action of Trichlorphon and Fenthion via pour-on ad-ministration is only slight, and dlstinctly less than that which is achieved via oral or subcutaneous adminis-tration. In the case of Fenthion it was also found that : 2 `

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the action against lung worm (Dictyocaulus) was only de-tectable in some of the cattle treated by pour-on applica-tion.

; The pour-on administration of Ruelene for use against infection with endoparasitic worms has also been attempted but the anthelmintic action thereby achieved is generally insufficiént for practical purposes.

As a rule, the anthelmintic action of a given preparation is substantially more pronounced when the pre-paration is orally or parenterally administered than whenit ls administered by pouring-on (Herlich et al., Veteri.-nary Medicine 56, 219-221 (1961); Hotson, Australian V~.
J. 39, 108-115 ~1963)).

However, the pour-on application o~ a suita~le composition can of~er distinct advantages in comparison to oral or parenteral administration, particularly in veter~nary prsctice. For example, the animals to be treated need not be held and, there~ore, there is less danger of injury to ~he animals ant to persons carrying out the treatmen~.
This method of application has particular vslue in the treatment of neats sincc these animals do not lend them-selves to oral or parenteral application. In addition, there is substantially less danger of transmission o~ in-fectious diseases, and there are substantially slighter

2; iocal non-toleration symptoms and less apparatus is re-quired than in the case of administration by injection.

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There is, ther'e~or'e',`a~'genuine need for a method'of combatting helminthic infestation which uses ' - the ';pour-on" method of administration. We have now dis-covered that this can be achieved while still affording an anthelmintic efect which is comparable to that ob-tained by oral or parenteral administration.

It is surprising that the pour-on veterinary compositions of the preseneion wherein the ac~ive ingre-; dient i8 tetramisole, levamisole, or an acid addition sa~t thereo~, exhibit good anthelmintic activity according to the pour-on application because other known antihelmintics such as Ruelene and~Trichlorphon exhibit a much stronger '- level of activity on oral and parenteral administration than they do when utilized in pour-on administrstion.

The present m~thod, therefore, reprcsents an ad-vance in veterinary medlc~ne ~nd has the distinct advantage o being simple and reliable. In contrast to injection or parenteral administration the animals need not be hcld. In ; general, it ls suf~icient if the animals, e.g. cattle, sheep or pigs, are herded into sheds, runs or a fenced-off grazing area or driven through a passage where the preparation is ad-ministered. The animals need not be tied up or held, as in the case of oral or parenteral administration.
It is obvious that such simple handling minimizcs the dang~r of inJ~ c-sv..s WhU c~rry ou~ the administra-tion. Li~ewise, there is no danger of injury to the ani~als as can be the case whcn a ne~dle is wrongly inserted as, ~or ,' ' .

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example, when the needle is inserted intramuscularly instead of subcutaneously or into the vicinity of a nerve, fasciae or bone. Even oral administration can result in injury to the animal as in the case of intratracheal administration or by injury to the palate.
An additional advantage to pour-on administration i8 that during treatment campaigns the danger of transmis-sion of infectious diseases, for example, swine plague, foot-and-mouth disease, bovine leucosis, symptomatic anthrax, swine erysipelas, brucellosis, infectious anaemia of horses, is sub-stantially eliminated.
The pour~on method of administration also elimin-ates the danger of forcing particles of dirt and germs under the skin during injection, which can occur when performed at inadequately disinfected parts of the skin and their sequelae.
Also, in comparison to subcutaneous or intramuscular in~ection there is very little danger wi~h pour-on administration of local intolerance caused by depositing a large quantity of preparation on a very limited area of tissue. In contrast to administration by injection,pouring and spraying on of the solution causes the animals no pain and does not provoke them into making defensive movements. As with injections or oral administration, the individual animal can be given an exact dose of the preparation when using pour-on administration.
This ensures that each treated animal receives an economic but r~eliably effective dosage in contrast to administration via the fodder or drinking water 5 , . ~

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Pour-on administration also has the advantage of requiring little apparatus. Sharp needles for injection or drench devices for oral treatment can be dispensed with and can be replaced, for example, by a measuring device which is emptied over the back of the animal or by devices with which the measured amount of preparation can be sprayed onto the animal.

The pour-on veterinary compositionso~ the pres-ent invention are prepared by dissolving, emulsifying or suspending tetramisole, levamisole, or an acid addition salt thereof, in a diluent suitable for pour-on applica-tion to animals. The compositions may, if desired, con-tain other pharmaceutically active compounds such as other ~nthelmintics.
The compositions of the present invention may be in any liquid or~ which is suitable ~or pour-on administration.
In particular said compositions may be in the ~orm o a solu-tion as, for example, where the active ingredient is dis-801ved in a suitable diluent, or it may be in the form of a suspension or emulsion as, for example, where the active in-; gredient is suspended or emulsified in a suitable diluent.
The term "diluent" refers to a nontoxic pharmacolo-gically acceptable carrier which, when mixed with the active ingredient, renders it suitable for pour-on administration.
The diluent must be sufficiently compatible with the active ingredient as to permit adequate concentrations of the B

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latter. In addition, the diluent must not inhibit ade-quate resorption of the active ingredient through the skin and, also, it must be sufficien~ly nontoxic as to avoid damaging the animal tissues with which it comes in contact.
Typical of the diluents which may be employed are ~or example:
water, mono- and polyhydric alcohols (e.g. e~hanol, isopro-panol, benzyl alcohol, propylene glycol, 1,3-butylene glycol, glycerol, tetrahydrofurfuryl alcohol, and polyethylene glycol), liquid esters (e.g. ethyl carbonate, ethyl acetate, isopropyl myristate, benzyl benzoate, caprylic and caproic acid triglycerides and ethyl lactate), natural oils (e.g.
cottonseed, groundnut, maize germ, olive, castor and sesame oils), waxy fatty acid esters (e.g. duck uropygeal gland fat), aliphatic and aromatic hydrocarbons (e.g. decahydronaphthal-end), ketones such as lower alkyl ketones, lower cycloal-kanones and N~lower alkyl pyrrolidones (e.g., acetone, methyl ethyl ketone, cyclohexanone and N-methyl-pyrrolidone), ethers (e.g., dioxane), amides (e.g., dimethylformamide), dimethylsulphoxide, and 2-dimethyl-4-hydroxymethyl-1,3-20 d~oxalane. Particularly suitable diluents include the t .
alcohols, for example, the lower alkanols such as ethanol and isopropanol, the glycols, for example, the lower alkyl-ene glycols such as ethylene glycolJ propylene glycol and butylene glycol, the lower cycloalkanones such as cyclo-~5 hexanone and tetrafurfuryl alcohol.

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The compositions used in this invention may also contain conventional adjuvants and modifiers such as adhesion promoters and surface-active agents. Typical o~ these are ~he following:
(a) adhesion promoters such as cellulose derivatives (e.g.
carboxymethyl cellulose and methylcellulose), starch derivatives, polyacrylates, alginates, gelatine, gum arabic, polyvinylpyrrolidone, polyvinyl alcohol, methyl vinyl ether and maleic anhydride copolymers, and poly-ethylene glycols; and t (b) surface-active agents, including emulsifiers and wetting agents and, frequently, substances which assist resorp-tion as, for example:
(1) anionic surface-active agents (e.g. sodium lauryl 8ulphate, fatty alcohol ether sulphates and mono-; or dialkylpolyglycol ether orthophosphoric acid e8ter monoethanolaminé salt);
(2) cntionic surface-active agents (e.g. cetyltri-methylammonium chloride);

(3) ampholytic surface-active agents (e.g. disodium-N-lauryl-~-iminodipropionate and lecithin); and

(4) nonionic surface-active agents (e.g. polyoxyethyl-ated castor oil, polyoxyethylated sorbitane mono-` oleate, sorbitane monostearate, ethyl alcohol, glycerine monostearate, polyoxyethylene stearate and alkylphenol poly~lycol ethers).

When the composition is intended for spraying as an aerosol it will generally contain one of the adhesion promo-ters mentioned under (a), suprat as well as one of the emulsl-fiers mentioned under (b), supra. Compositions for spray-ing can additionally contain the customary propellants as, for example, a chlorofluorohydrocarbon and/or butane.
Compositions used according to the invention which S are suspensions may contain a surface active agent as, for example, one or more of the surface-active agents indicated under item (b) above, a polyoxyethylene sorbitane ester, a glycerine monostearate and a thic~ener such as one or more of those recited above such as colloidal silica; methyl-cellulose, aluminium monostearate, polyacrylic acid deriva-tives and microcryst~lline cellulose.
The compositions of the present invention may be made up before use in unit dosage form. This means that the composition is ~ade up into physically discrete coherent portions suitable for pour-on administra-tion and that each portion contains a daily dose of the active ingredient or a multiple thereof o~ up ~o about our times the daily dose. Alternatively, the composition may be made up into a physically discrete portion containing a sub-multiple of a daily dose, down to about a fortieth of theda~ly dose. Whether the unit dosage form contains a daily dose or a half, a third or a quarter of said daily dosage will depend upon whether the composition is to be administered once, twice, three times or four times a day respectively.
TypLcal examples of unit dosage forms are sealed vials each containing a daily dose of the composition and which may be opened immediately before use and poured onto the animal's .
.. ~- , , , back. By this procedure, one can avoid having to measure out each dose of the composition to be administered at the situs and immediately ~efore administration.
The compositions of the present invention should contain from about 1.0% to 20.0% by weight of active in-gredient, and, preferably, from about 5.0% to 15.0% by weight of active ingredient.
In general, it has proved advantageous to ap-ply amounts of from flbout 1 mg to about 20 mg of the active ingredient per kg of body weight per day of the animal be-ing treated in order to achieve effective results.
For the animals of which the treatment is of principal interest, the following dosage rates have proved to be suitable.

; 15 mg of active ingredient A_imal per k~ of body wei~ht ; 8heep 5 ~ 10 neats S - 15 dogs 8 - 12 plgs 10 - 20 According to one embodiment of the present in-vention, a pour-on veterinary composition is produced which comprises 1% to 20%, especially 5% to 15%, by weight of tetramisole, levamisole, or an acid addition salt thereof, in combination with from 10% to 94%, especially from 60%
to 907O~ of an aliphatic alcohol preferably of 2 to 8 car-bon atoms, and especially alkanol of 2 to 8 carbon atoms, and from 5% to 89%, especially 5% to 30%, by weight of a : , .liquid paraffin, especially a light and purified spindle oil distillate. Alkanols of 2 to 4 carbon atoms have been found to be useful, especially because of their ready availability. Representative formulations include:
10 g levamisol, 63.3 g isopropanol, and lO g viscous paraf-fin; and 10% levamisole, 80% isopropanol and 10% light and purified spindle oil distillate.
Accoxding to another embodiment o~ the present invention, a pour-on veterinary composition is produced which comprises 1% to 20%, especially 5% to 15%, by wei~ht of tetramisole, levamisole, or an acid addition salt thereof.
in combina~ion with 10% to 94%, especially 60~/o to 90%, by weight o~ an ester of an aromatic acid, especially esters of phthalic acid, particularly the mono- and di-lower al~yL ~-esters, such as for example, an ester of phthalic flcid and from 5% to 50% b~ weight of a nonionic su~ce ~ctive agent, especially esters o~ sorbitan ~nd fatty acids wi~
and without polyoxyethylene.

The following examples illustrate the method by which the above-described compositions may be employed. In the said examples, the terms "Tetramisole", Levamisole" and "LPS" have the following definitions:
''Tetramisole" means D,L-(2,~,5,6)-tetrahydro-6-,phenyl-imidazo-(2,1-b)thiazole.
''Levamisole" means L-(2,3,5,6)-tetrahydro-6-phenyl-imidazo-~2,1-b)~hiazole.
"LPS" means light and purified spindle oil distilla~e.
11 ' ' -17~

Tables I - VIII-ln ~ res A, B and C which follow ^ indicate the anthelmintic compound empl~ed in ~he~o~owin-g~~-~
studies, the diluent used, the mode of applicàtion and the minimum dosage designated in mg of active ingredient/kg o~
S body weight which effected more than 90% of the worms to be expelled.
Example A

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Test animals infected with Stron~yloides ratti 10 were treated at the end of the prepatency period of the parasites. A solutio,~ of the active compound was applied by pouring-on.
The activity of the composition was determined by counting, after dissection o the animals, the worms remain-15 ing in the test animal1 comparing the result wi.th that ob-tained ~or untrèated control animals and calculating the per-centage action.
The results of this study are given in Table I and II below: 1 2 .
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Example B
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Nippostrongyl-ls m~ris/rats .
Test animals infected with Nippostron~ylus muris are treated at the end of the prepatency period of the para-sites. A solution o the active compound was applied by pouring-on. :
The activity of the formulation is determined by counting, after dissection of the animal, the wor~s remain-ing in the test animal, comparing the result to that obtained with untreated control animals, and calculating the percentage action.
The results of this study are indicated in Tables III and IV below: .
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i~Z17~) Example C
Ascaris suum larv~e/rats~

Test animals infected with Ascaris suum are treated 1 - 3 days after infection. A solution of the active compound was applied by pour-on administration.
The activity of the formulation is determined by dissection on the 7th day after infection, counting th~
worms remaining in the test animal, comparing the result to that obtained for untreated control animals, and c~lcu-lating ~he percentage action.
The results of this study are indicated in Tables V - VI below:

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The values given in the following tables VII and VIII relate to the local tolerance of some solvents used ln rat tests and not to the biological effectiveness o~ said compositions.

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Example D
Lun~ worm test in bov.ine cattIe `~
Neats infected experimentally or naturally with Dictyocaulus are treated by pouring the solution of active compound onto their backs or by subcutaneous injection.
The activity is determined by quantitatively counting the lung worm larvae expelled in the faeces before and after the treatment.
. A decrease in the larvae expelled after the treat-ment indicatcs that the worms have been killed or damaged so much that they cannot pr~duce any more larvae.
. The results of this study are indicated in Table IX
beiow:. .

TABLE IX ' . , .
~ . _ . .................................. .
`: 15 Preparation/application Dose Larvae (mg/kg)Reduction (%) 1: . . , .. , _ .
10% by weight of Levamisole) 10 100 . in isopropanol ~ ) 10% by weight o~ LPS ) 7.5 99 20 pour-on ) 5 99 , lOZ stren~th aqueous Leva-misole solution*, subcutaneous 5 98 . .
:~ * Known preparation for comparison :' , : 2 3 ':
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17~ ) Example E ~. -, _, _.:
Gastro-intestinal worm_test/controlled test against adults Neats e~perimentally infected with Haemonchus, : Cooperia and Oesophagostomum were treated by pouring the ; 5 solution of active compound onto their backs. -The activity of the preparation is determined by dissecting the animal, counting the worms remaining, com- :
paring the result with that of untreated con~rol animals, and calculating the percentage action.
The results of this study are indicated in Table X
below:

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, , Example F
Gastro-intestinal worm test in neats~controlled test against larval sta~es . . .
Neats experimentally infected with Haemonchus, ~ and Oeso~ha~ostomum are treated by pouring the solution of active compound onto their backs or by subcutan-eous injection.
The time at which the treatment was carried out was so chosen that the larvae were in the 4th stage of develop-i 10 ment.
The actiyity o the preparations is determined by dissecting the animal, counting the worms remaining, com-paring the result to that obtained with untreated control animals, and calculating ~he percentage action.
The results o this study are indicated in Table XI below:
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Gastro-int~stinal ~orm test in ncats/excretion of eggs Neats infect~d experimentally or naturally wqth various species of gastro-intestinal worms (Cooperia, Osterta~ia S Trichostron~Ylus, Bunostomum and Oesopha~,ostomum) were treated at the end of the prepatency period of the parasites by pour-, ing a solution of the active compound onto their backs.
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' The activity is determined by quantitatively count-ing the wonm eggs excreted with the faeces before and after the treatment.
A decrease in egg excretion after the treatment indicates that the worms have been expelled or are so severely , damaged that they cannot produce any more eggs.
The results of this study are indicated in Table ' XII below:
.
~ TABLE XII
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. .
Pxeparation/ Dose in Reduction in egg ; application mg/kg excretion in %
Tetramisole in 10 ' 87 '' ' 20 isopropanol, pour-on 5 ' 39 , Te~ramisole in i80propanol ~ LPS, 10 99, ; pour-on 5 76 .~ ,. .
' Levamisole in , 25 isopropanol ~ LPS, 10 ' 9S
pour-on 5 91 . . . _ ~ For comparison: *
', ,Levamisole oral 8 99 . . . ,_ .
' * Literature: Lyons et al., Am. J. Vet. Res.
Vol 33, No. 1, 65-71 (1972) , ,. : -. .

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Example H
Gastro-intestinal worm test in shee~
Sheep expe;imentally infected with Haemonchus or Cooperia were treated at the end of the prepatency period of the parasites by pouring the active substance solution onto their backs.
The activity is determined by quantitatively co~nt-~ng the worm eggs excreted with the faeces before and after the treatment.
A decrease in egg excretion after the treatment indicates that the worms have been expelled or are so severely damaged that they cannot produce any more eggs.
. The results of thi.s study are indicated in Table XIII below:

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L7~) Example I
Determination of level`i'n 'the b'I-o'o'd'~' . . . ~
The resorption of the anthelmintic agent can be estimated, with less trouble than with the method described above, by determining the level of the agent in the blood after administration. The blood levels in neats after treatment with 20 mg of Levamisole/kg were determined.
' The pour-on method (Levamisole in various solvents) ' was compared with peroral administration (2% strength aqueous Levamisole solution) and subcutaneous administration (10%
Levamisole in 0.9% strength aqueous NaCl solution).
Method . .
The active compound was isolated from the blood by the method of Holbrock and Scales (Analyt. Biochem. 18, 46-53 ]5 (1957)). The quantitative determination was carried out spectrophotometrically by measuring the extinction at a wave length of 215 nm.
, Using the pour-on method it is possible to achieve blood levels as high as, or higher than, those after peroral or subcutaneous administration. Only two hours aEter treat-ment does subcut:aneous administration give higher blood levels than the pour-on method. High blood levels, that is to say good resorption of the active compound, are the prerequisite for successful anthelmintic use of the active compound.
The following tables show the blood level of the active compound in~lg/ml at various times after administration in the stated manner of 20 mg/kg body weight.

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Claims (21)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A pour-on veterinary composition useful for the treatment of helminthic infestations in animals which comprises from 1% to 20% by weight of tetramisole, levamisole or a nontoxic acid addition salt thereof in combination with a pharmacologically acceptable nontoxic diluent suitable for pour-on therapy.

2. A composition as defined in claim 1 wherein the tetramisole, levamisole, or nontoxic acid addition salt thereof, is present in the amount of 5% to 15% by weight.

3. A composition as defined in claim 1 which comprises 1% to 20% by weight tetramisole or levamisole, 10% to 94% by weight of ethanol or isopropanol, and 5%
to 89% by weight of a liquid paraffin.

4. A composition as defined in claim 1 which comprises 5% to 15% by weight of tetramisole or levamisole, 60% to 90% by weight of said ethanol or isopropanol find 5% to 30% by weight of a liquid paraffin which is a light and purified spindle oil distillate.

5. A composition as defined in claim 1 which comprises 1% to 20% by weight of tetramisole or levamisole, 10% to 94% by weight of a mono- or di-lower alkyl ester of phthalic acid and 5% to 50% by weight of a nonionic surface active agent.

6. A composition as defined in claim 5 wherein the tetramisole or levamisole is present in the amount of 5% to 15% by weight and the ester is present in the amount of 60% to 90% by weight.

7. A composition as defined in claim 5 wherein the ester is the dibutyl ester of phthalic acid.

8. A composition as defined in claim 7 wherein the surface active agent is an ester of sorbitan and a fatty acid with polyoxyethylene or an ester or sorbitan and a fatty acid.

9. A pour-on veterinary composition useful for the treatment of helminthic infestations in animals which comprises 10% by weight levamisole, 80% by weight isopropanol and 10% by weight light and purified spindle oil distillate.

10. A pour-on veterinary composition useful for the treatment of helminthic infestations in animals which comprises 10% by weight levamisole, 75% by weight phthalic acid dibutyl ester and 15% sorbitan mono-oleate.

11. A composition as defined in claim 1 which comprises from 1% to 20% by weight of tetramisole or levami-sole.

12. A composition as defined in claim 1 which comprises from 5% to 15% by weight of tetramisole or levamisole.

13. A composition as defined in claim 1 which comprises 10% by weight of tetramisole or levamisole.

14. A composition as defined in claim 1 which comprises from 1% to 20% by weight of tetramisole or levamisole and wherein the pharmacologically-acceptable, nontoxic diluent is isopropanol.

15. A composition as defined in claim 1 which comprises from 5% to 15% by weight of tetramisole or levamisole and wherein the pharmacologically-acceptable, nontoxic diluent is isopropanol.

16. A composition as defined in claim 1 which additionally contains 5% to 50% by weight of a suitable surface active agent.

17. A composition as defined in claim 3 which comprises 10% to 94% by weight of ethanol.

18. A composition as defined in claim 3 which comprises 10% to 94% by weight of isopropanol.

19. A composition as defined in claim 4 which comprises 60% to 90% by weight of ethanol.

20. A composition as defined in claim 4 which compriese 60% to 90% by weight of isopropanol.

21. A composition as defined in claim 1 wherein the nontoxic acid addition salt is the hydrochloride salt.