NZ286752A - Stable injectable composition of endecticides - Google Patents

Description

New Zealand Paient Spedficaiion for Paient Number £86752 QU&S! ft'"** 6 7 9 0 0 .<* 3*«M y U 1 &1 ^ Patents Form # 5 NEW ZEALAND Patents Act 1953 COMPLETE SPECIFICATION AFTER PROVISIONAL #: DATED: TITLE: 286752/299093 June 1996/30 July 1996 Injectable Compositions We, Ashmoiit Holdings Limited Address: 48 Diana Drive, Glenfield, Auckland, New Zealand Nationality: New Zealand do hereby declare the invention for which we pray that a patent may be granted to us and the method by which it is to be performed, to be particularly described in and by the following statement: PF05.JWP FEE CODE 1050 or on TECHNICAL FIELD OF THE INVENTION This invention relates to novel compositions of macrolide avermectin and milbemycin endecticides with an immunising agent and in particular it relates to a stable injectable composition for use with warm-blooded animals, in particular ruminants.

The use of a combination of an parasitic agent and immunising agent as a single injectable formulation offers advantages both in time and cost saving to the farmer.

BACKGROUND New Zealand Patent Nos. 191413 and 193807 of ICI Tasman Limited disclose water based formulations of D, L-tetramisole and clostridial vaccine in the treatment of helminthiasis and 10 clostridial diseases in warm-blooded animals. Both D, L-tetramisole and the clostridial vaccine are water soluble hence a combination of the two is straight forward. What was surprising was that the clostridial vaccine remained effective at a pH lower than 6.0 and that the combination improved the immune response in ruminants, though not '~i other animals.

These aqueous formulations commonly used an adjuvant such as alum or alum hydroxide to 15 enhance the effect of the antigen. Such adjuvants are usually included in the formulation as an aqueous suspensions. The vaccines can then be readily mixed with water based anthelmintic formulations.

Since the use of D, L-tetramisole and more particularly the L-isomer levamisole, there have been a number of other potent antiparasitic macrocyclic lactone compounds such as the 20 avermectins, ivermectin, doramectin, abamectin, milbemycin, moxidectin used in the 8462scsl.696//S treatment of diseases in warm blooded animals. These later parasiticides are insoluble in water which creates difficulties in formulating stable injectable compositions. However, the compounds have the advantage that they are active against internal and external parasites in domestic animals.

Formulations are therefore based on co-solvent systems or aqueous solvent systems utilising a water-soluble solvent with one or more wetting agents. Water soluble solvents mix readily with traditional aqueous adjuvant systems to form combinations of anthelmintics and vaccines. This is not the case with oil based (non-aqueous) systems.

It is an object of the invention to provide an improved injectable composition combining a parasitic agent and an antigen or at least one that provides the public with a useful choice.

STATEMENT OF INVENTION It has been surprisingly discovered that non-aqueous anthelmintics can be combined with an antigen using a liquid such as an oil as an adjuvant and carrier to give a stable formulation 15 that can be safely injected into warm blooded animals including cattle and sheep.

In one aspect the invention comprises a stable injectable composition comprising a nonaqueous parasitic agent in a therapeutically effect amount and an antigen in combination with a liquid carrier that also acts as an adjuvant for use with warm blooded animals.

OBJECT 8462SCS2.897//S 752 n a & Preferably the non-aqueous parasitic agent is a macrolide compound selected from group comprising avermectin, ivermectin, doramectin, abamectin, milbemycin and moxidectin, present in from 0.05 to 10% w/v.

More preferably the non-aqueous parasitic agent is chosen from the group comprising 5 abamectin, ivermectin, moxidectin and doramectin.

Preferably, the carrier is an oil, either a vegetable oil such as sesame oil, saponine oil, soya bean oil, and corn oil or a mineral adjuvant oil, such as paraffin oil, or purified derivatives of vegetable or mineral oils, such as quiala, which is suitable for injection into animals or a mixture thereof. The oil acts as an adjuvant for the immunising agent and may also act as a 10 solvent for the anthelmintic. The oil also extends the action of the parasitic agent.

Additionally, the composition may further contain an oil soluble solvent. The oil soluble solvent is chosen from the group comprising alcohols having four or more carbon atoms for example benzyl alcohol, ethylbenzyl alcohol, phenethyl alcohol and other aromatic monohydric alcohols.

Preferably the alcohol is present in the range from 10-50 wlv%.

The antigen is incorporated into the composition by emulsifying it in a suitable emulsion agent, for example sorbiten oleate (Span 80™ or Liposorb 80™). Other suitable emulsion agents may also be used. The emulsifier is present in the range of from 5-50 w/v%. 8462scsl.696//S Antigens suitable to be used in the compositions include antigens derived from bacterial and viral pathogens of warm-blooded animals. Preferably the antigen is chosen from the group comprising antigens derived from and toxins of clostridial diseases including Clostridium septicum, Clostridium tetani, Clostridium chauvoei, Clostridium novyi, Clostridium sordelli and Clostridium haemolytica. Other possible antigens include Pasteurella, Pasteurella maltocida and Corynebacterium pseudotuberculosis and viral antigens for Infectious Bovine Rhinotracheitis, Bovine Viral Diarrhoea and Parainfluenza In another aspect, the invention comprises a method of treating parasitic diseases and preventing viral and bacterial diseases in warm blooded animals by administration to an animal of a composition as described above.

Preferably the composition is administered to the animal by injecting the animal.

Preferably the composition is administered at the rate of 0.5-5mL/50kg bodyweight of the animal.

PREFERRED EMBODIMENTS The present invention will be described by way of example only with reference to the following examples. 8462scsl.696//S 2£ -s_ Formulation lfoil based) Part A w/v% Abamectin 1.00 Benzyl Alcohol .0 Sesame oil 40.0.

Paraffin Oil to volume Part B v/v% Part A (1% abamectin) 50.0mls Span 80 lOgm Vaccine to volume 100% Formulation 2 foil based) Part A w/v% Abamectin (or ivermectin) 1.13 Benzyl Alcohol .0 Sesame Oil to volume Part B v/v% Ivermectin Benzyl Alcohol Saponin Oil 8462scsl .696//S v.J Part A (1% abamectin) 50.0mls Span 80 gm Vaccine to volume 100% Formulation 3 foii based) Part A w/v% 1.00 10.0 to volume 9H -Q Part B v/v% Part A 50.0mls Span 80 20 gm Vaccine to volume 100% Formulation 4 foil based) Part A w/v% Doramectin 1.13 Benzyl Alcohol 20.0 Sesame Oil to volume PartB v/v% Part A (1 % abamectin) 50.0mls Liposorb 80 10 gm Vaccine to volume 100% Formulation 5 foil based) Part A w/v% Abamectin 1.13 Benzyl Alcohol 20.0 Sesame Oil to volume PartB v/v% Part A 50.0ml Sorbitan Oleate lOgm Antigen 1 4.555ml Antigen 2 0.135ml Antigen 3 0.870ml 8462scsl.696//S 2990 Antigen 4 Antigen 5 Benzyl Alcohol 0.933ml 4.258ml to volume 100% Dosage rates for these formulations range from 0.5 - 5ml/50kg bodyweight of the animal.

These preparations have been shown to be stable and do not cause injury when injected to warm blooded animals. The parasitic agent and the antigen retain their activity. The formulations have a shelf life of approximately two years.

We have found that a formulation of a parasitic agent and an antigen, such as a closr idial 10 antigen, containing an oil such as sesame oil as the solvent is effective in the treatment of helminthiasis and clostridial diseases in warm blooded animals. Suprisingly, the oil also acts as an adjuvant in the composition, enhancing the activity of the vaccine and extending the parasiticide activity of the anthelmintic. Compositions that contained a traditional adjuvant such as alum and the oil stimulated the working of the vaccine to such a level that an adverse 15 reaction was produced in the animal.

ADVANTAGES The compositions of the invention are stable and be stored for long periods of time without loss of either parasitic agent or antigen potency. 8462scsl.696//S

Claims (10)

o 286/52 I _ / _ 29^033 -9- VARIATIONS Although the above examples use abamectin, ivermectin or doramectin, it is possible to use the other anthelmintics of the macrolide group. Although the use of a clostridial vaccine as the antigen is preferred a variety of other antigens 5 effective against other bacterial or viral pathogens could be incorporated. Although sesame oil is preferred as the solubilising agent, other oils such as soya bean oil, corn oil or mineral adjuvant oils, such as paraffin oils, or suitable mixtures thereof, may be used. Finally, it will be appreciated a that a variety of other alterations and modifications may be 10 made to the forgoing without departing from the scope of the invention. 8462SCS2.897//S 2 7 MS 1997 - 10- CLAIMS:

1. A stable injectable composition comprising a non-aqueous parasitic agent in a therapeutically effect amount, chosen from the macrolide group of compounds comprising avermectin, ivermectin, doramectin, abamectin, milbemycin and moxidectin, and an antigen in combination with a liquid carrier that also acts as an adjuvant for use with warm blooded animals.

2. A composition as claimed in claim 1 wherein the non-aqueous parasitic agent is present in from 0.05-10 w/v%.

3. A composition as claimed in claim 1 or claim 2 wherein the non-aqueous parasitic agent is chosen from the group comprising abamectin, ivermectin, moxidectin and doramectin.

4. A composition as claimed in any preceding claim wherein the carrier is an oil or mixture of oils which is suitable for injection into animals and is chosen from the group comprising sesame oil, saponine oil, soya bean oil, corn oil, paraffin oils, purified derivatives of vegetable oils and mineral adjuvant oils and mixtures thereof, and wherein the carrier extends the potency of the parasitic agent

5. A composition as claimed in any preceding claim further containing an oil soluble solvent chosen from the group comprising alcohols having four or more carbon atoms and the oil soluble solvent is present in a range from 10-50 w/v%. 8462SCS2.897//S COGWATEfMJ -11 - 5S6T5Z 299033

6. A composition as claimed in any preceding claim further containing an emulsifier and the . emulsifier is present in the range of from 5-50 w/v%.

7. A composition as claimed in any preceding claim wherein the antigen is chosen from the group comprising antigens and toxins for the prevention of clostridial diseases in warm- 5 blooded animals.

8. A method of treating parasitic diseases and treating bacterial and viral diseases in non-human warm blooded animals by administration to an animal of a composition as described in any preceding claim.

9. A method as claimed in claim 8 wherein the composition is administered to the animal by 10 injecting the animal.

10. A method as claimed in claims 8 or 9 wherein the composition is administered at the rate of 0.5-5mL/50kg bodyweight of the animal. JAMES W. PIPER & CO. (NORTH SHORE) gtyD OF CLAIMS Attorneys for 15 Ashmont Holdings Limited END OF CLAIMS 8462SCS2.897//S