NZ548938A - Topical macrocyclic lactone formulation - Google Patents

Abstract

Disclosed is a composition including: a macrocyclic lactone; and aromatic solvent; polybutene; a pharmacologically acceptable oil; and a spreading agent selected from the group consisting of isopropyl myristate, polydimethyl-cyclosiloxane, PEG-40 sorbitan peroleate, cyclomethicon, isopropyl palmitate, ethanol, or a mixture thereof; and wherein the macrocyclic lactone is moxidectin. Also disclosed are methods for the treatment, prevention or control of helminth, acarid or arthropod infection in non-human animals using the invention of claim 1.

Description

New Zealand Paient Spedficaiion for Paient Number 548938 / 04/08/2006 05:12 PM fraehills 12345678 36/47 004854003 4 8 9 3 8 *10052293782* 1 Topical formulation Field of the invention The present invention relates to topical macrolide compositions, and the use of such compositions for treating, controlling, preventing and protecting animals from infestation 5 and infection by internal and external parasites.

Background of the invention ^ Internal and external parasite (endectoparasite) infections and infestations in humans and animals frequently require a variety of medicaments or medical treatments for effective prevention or control. For example, helminthiasis is a widespread disease 10 found in many farm and companion animals and responsible for significant economic losses throughout the world. Among the helminths most frequently encountered are the group of worms referred to as nematodes. The nematodes are found in the intestinal tract, heart, lungs, blood vessels and other body tissues of animals and are a primary cause of anaemia, weight loss and malnutrition in the infected animals. They do serious 15 damage to the walls of the gastrointestinal tract and the tissue of the organs in which they reside and, if left untreated, may result in death to the infected animals.

Pour-on formulations are utilized by the animal industry as a means for administering certain anthelmintic agents and veterinary medicines to animals. In practice, the medicated formulation is applied directly to the external skin or hide of the animal. As 20 such, some practitioners have extended the term pour-on to include formulations which may be dispersed in water and applied as aqueous dips, baths or sprays. In the present specification, however, the term "pour-on" is not intended to suggest this type of application. Rather, the formulation of this invention is a non-aqueous formulation which is applied with the assistance of a suitable device such as a measuring cup, a squirt 25 bottle or an automatic microspray device which permits directed application of a small amount of formulation onto the skin of the animal being treated.

While a number of anthelmintic agents and veterinary medicines such as tetramisole, levamisole, trichlorphon and fenthion, have been successfully prepared as pour-on 04/08/2006 05:12 PM 004854003 f reehIlls 1 2345678 37/47 compositions, all veterinary medicines do not lend themselves to such formulation. Moreover, those medicines that have been so formulated generally have been found to be significantly less effective as pour-on formulations than they are when administered orally or parenterally.

For successful formulation as a pour-on, a drug must be active when dissolved, dispersed or emulsified in a suitable solvent which is well tolerated by the animal's skin. The drug must be readily absorbable through the animal's skin and the composition as a whole should disperse or spread well over the animal's body and be relatively non-| viscous when so spread. It is also advantageous that pour-on formulations are not 10 washed off during rainfall and retain efficacy on wet animals.

Summary of invention The present invention seeks to provide a non-aqueous, pour-on formulation which is effective on dry or wet skin or hide for the control of internal and external parasites in companion and farm animals.

This invention further seeks to provide an effective, non-aqueous, pour-on formulation which exhibits excellent skin or hide penetration and spreads rapidly over the animal's body.

It is a feature of this invention that the pour-on formulation contains as active ingredient a macrocyclic lactone, for example moxidectin, milbemycin D, avermectin, ivermectin, 20 abamectin, doramectin, or the like.

The present invention provides a topical composition including a macrocyclic lactone; an aromatic solvent; polybutene; a pharmacologically acceptable oil; and a spreading agent selected from the group consisting of isopropyl myristate; polydimethyl-cyclosiloxane; PEG-40 sorbitan peroleate; cyclomethicone; isopropyl palmitate; ethanol; 25 and a mixture thereof.

Advantageously, the composition of preferred embodiments of the invention is a nonaqueous, water-fast composition. 04/08/2006 05:12 PM fraehllls 12345678 38/47 004854003 3 Also provided is a method for the treatment, prevention and control of internal and external parasitic infection and infestation in an animal.

The present invention will now be described with reference to particular embodiments and examples. Nothing in the following discussion is intended to limit the scope of the 5 invention as claimed.

Detailed description of tine embodiments The compounds designated LL-F28249a-X are isolates from the fermentation broth of the microorganism Streptomyces cyaneogriseus subspecies noncyanogenus, deposited in the NRRL under deposit accession No. 15773. The method for preparation of the LL-F28249 compounds is disclosed in US 5,106,994. The 23-imino derivative of LL-F28249a, moxidectin, and a method for the preparation of moxidectin are disclosed in US 4,916,154. Pour-on formulations containing 23-oxo(keto)-LL-F28249a-^ and 23-imino-LL-F28249-a-X compounds are described in US 6,514,951, however these formulations require PPG-2 Myristyl ether propionate as an essential ingredient.

Accordingly, the present invention provides a topical composition including a macrocyclic lactone as active ingredient; an aromatic solvent; polybutene; a pharmacologically acceptable oil; and a spreading agent selected from the group ) consisting of isopropyl myristate; polydimethyl-cyclosiloxane (e.g. Silicone 344); PEG-40 sorbitan peroleate (e.g. Arlatone T); cyclomethicone; isopropyl palmitate; ethanol; 20 and a mixture thereof.

Advantageously, the formulations of preferred embodiments of the present invention are well tolerated by the host animal, are not malodorous, are capable of spreading well and rapidly over the animal's body and are readily absorbed through the hide or skin of the treated animal. A further benefit is that the formulations retain efficacy on wet skin or 25 hide and resist wash off.

Macrocyclic lactones suitable for use in the composition of the invention include moxidectin, milbemycin D, avermectin, ivermectin, abamectin, doramectin, or the like, preferably moxidectin. 04/08/2006 05:12 PM freehllls 12345678 39/47 004354003 4 Aromatic solvents suitable for use in the composition of the invention include C9-C12 aromatic solvent mixtures such as Aromatic 150® , Aromatic 100® (manufactured by Exxon-Mobil), or the like. A suitable aromatic solvent has a mixed aniline point in the range of 10°-19° C, a Kauri-Butanol value in the range of about 89 to about 96 minutes; 5 and a specific gravity at 15.6/15.6 °C in the range of about 0.8 to 1.0.

The polybutene suitable for use in the composition of the invention may be any suitable polybutene/polybutene mixture. An example of such a suitable polybutene is a mixture having an average molecular weight of about 320-3000 Daltons.

Pharmacologically acceptable oils suitable for use in the inventive composition may be any suitable oil known in the art to be safe for use on mammals. Such oils include, but are not limited to: plant oils such as soybean oil, groundnut oil, castor oil, corn oil, cottonseed oil, olive oil, grape seed oil, sunflower oil, sesame oil, safflower oil or the like; mineral oils such as petrolatum, paraffin, silicone, light mineral oil or the like; aliphatic or cyclic hydrocarbons, such as butoxyethoxyethanol or the like; medium-chain triglycerides such as capric/caprylic triglyceride, propylene glycol dicaprylate/dicaprate or the like. In a preferred embodiment, the pharmacologically acceptable oil is a vegetable oil, a mineral oil, a mixed capric/caprylic glyceryl triester oil or light mineral oil.

More preferably, the pharmacologically acceptable oil is a mixed capric/caprylic glyceryl triester oil.

Spreading agents suitable for use in the composition of the invention include isopropyl myristate; polydimethyl-cyclosiloxane (e.g. Silicone 344); PEG-40 sorbitan peroleate (e.g. Arlatone T); cyclomethicone; isopropyl palmitate; ethanol; or the like; or a mixture thereof. Preferably, the spreading agent is isopropyl myristate.

In one embodiment, the composition of the invention may further include 0-15% 25 surfactant. Suitable surfactants include, but are not limited to, one or more of the following: C8-Cio alkylphenol ethoxylates (e.g. Teric N9, Teric N20, Teric N100); Cg -C17 alcohol ethoxylates (e.g. Teric 9A2, Teric 16A16); C8-C2o aikyl amine ethoxylates (e.g Teric 13M15, Teric 18M20); castor oil ethoxylates (e.g. Cremophor EL, Acconon CA-5, Teric 380); hydrogenated castor oil ethoxylates (Cremophor RH 40, Cremophor 04/08/2008 05:12 PM f reahI I Is 12345878 40/47 004854003 RH 60); lanolin alcohol ethoxylates (e.g. Polycol 5, Polycol 40); sorbitan fatty acid ethoxylates (e.g. Polysorbate 20, Polysorbate 60, Potysorbate 80); sorbitan fatty acid esters (e.g. sorbitan monoisostearate, sorbitan monostearate, Hodag SML and Span 25); polyoxyethylenated alkyl ethers; polyethylene glycol stearate; polyglycerol esters; polyoxyethylenated fatty alcohols; polyoxyethylenated fatty acids, copolymers of ethylene oxide, copolymers of propylene oxide; or the like; preferably, Polysorbate 80.

Excipients such as dyes, antimicrobial agents, antioxidants or mixtures thereof may be included in the formulations of the present invention. The amounts of said excipients suitable for use in the invention range from about 0.0005% to 2.0% w/v. Dyes suitable 10 for use in the formulations of the present invention include anthroquinone dyes, azo dyes and the like. Examples of antimicrobial agents useful in the formulations of the present invention are benzoic acid, benzoic acid derivatives, methylparaben, propylparaben and the like. Antioxidants suitable for use in the formulations of the present invention according to the present invention include butylated hydroxytoluene, 15 butylated hyroxyanisoles, tertiary butylhydroxyquinolone, sodium bisulfite, sodium metabisulphite, propyl gallate and the like and mixtures thereof.

In another embodiment, the composition of the invention may further include an additional active agent for the treatment of infection or infestation by helminths (helminthiasis). Such active agents include, but are not limited to triclabendazole, closantel, praziquantel, levamisole, albendazole, or the like.

The effective amounts of macrocyclic lactone compounds may vary according to the potency of the compounds, the method of application, the host animal, the target parasite, the degree of infestation, or the like. In general, amounts of about 0.01-5.0% w/v, preferably 0.1-2.0 % w/v, of a macrocyclic lactone such as moxidectin may be suitable.

Aromatic solvents may be present in the inventive composition in amounts of about 2.5-20% w/v, preferably 5.0-20% w/v. Polybutene may be present in amounts of about 0-15% w/v, preferably about 5.0-15% w/v. The spreading agent may be present in the inventive composition in amounts of about 1.0-15% w/v, preferably about 5.0-15% w/v. 04/08/2006 05:12 PM 004854003 freahl I Is 12345678 41/47 6 As used herein, the term "w/w" designates weight/weight, the term "w/v" designates weight/volume, and the term "mg/kg" designates milligrams per kilogram of body weight.

The composition of the invention may be prepared by dissolving, dispersing or emulsifying about 0.01-5.0% w/v of the active ingredient such as moxidectin, in a mixture consisting essentially of 2.5.0-20% w/v of an aromatic solvent; about 1.0-15% w/v of a spreading agent such as isopropyl myristate; if present, about 1.0-15% w/v polybutene; and a quantity sufficient to total 100% w/v of a pharmacologically acceptable oil such as mineral oil, vegetable oil or mixed capric/caprylic glyceryl triester oil.

Beneficially, the composition of the invention is highly effective for protecting or treating farm and companion animals, such as cattle, sheep, deer, horses, swine, goats, dogs, cats or the like, against infection and infestation by helminths, nematodes, acarids and endo- and ectoparasites. Accordingly, the present invention provides a method for the treatment, prevention or control of helminth, acarid or arthropod endo- or ectoparasitic 15 infection or infestation in an animal includingtopically administering to said animal an effective amount of a composition includinga macrocyclic lactone as an active ingredient; an aromatic solvent; polybutene; a pharmacologically acceptable oil; and a spreading agent selected from the group consisting of isopropyl myristate; polydimethyl-cyclosiloxane (e.g. Silicone 344); PEG-40 sorbitan peroleate (e.g. Arlatone T); ™20 cyclomethicone; isopropyl palmitate; ethanol; and a mixture thereof.

Examples of topical administrations suitable for use in the method of the invention include pour-on, spray-on, spot-on, dip, or any of the conventional means of topically applying a liquid veterinary composition, preferably a pour-on.

Homeothermic animals suitable for treatment in the method of the invention include: 25 swine, cattle, sheep, horses, goats, camels, water buffalos, donkeys, fallow deer, reindeer, or the like, preferably swine, cattle, horses or sheep. Preferably, the animals treated with the method of the invention are cattle or sheep. 04/08/2006 05:12 PM 004854003 f r#«hIlls 1 2345678 42/47 7 Infections and infestations that may be treated, prevented or controlled by the method of the invention include, but are not limited to, Helminthiases caused by helminths such as Ostertagia circumcincta, Haemonchus contortus, Trichostrongylus colubriformis, or the like; nematode infections caused by, for example Haemonchus, Ostertagia, Cooperia, 5 Oesphagostomum, Nematodirus, or the like; acarid infestations such as biting lice, i.e. Damalinia ovis, Damalinia bovis, or the like; chorioptic, sarcoptic or demodectic mange caused by Chorioptes bovis Sarcoptes scabiei and Demodex, respectively, Psoroptic mange caused by Psoroptes ovis; arthropod endo- parasites such as cattle grubs; and the like.

The composition of the invention may be administered in dose rates of mg of active ingredient per kg of body weight of the host animal. Dose rates suitable for use in the method of invention will vary depending upon the mode of administration, the species and health of the host animal, the target parasite, the degree of infection or infestation, the breeding habitat, the potency of the active ingredient, or the like. In general, 15 amounts sufficient to provide about 0.1-5.0 mg/kg of active ingredient are suitable.

In order to facilitate a further understanding of the invention, the following examples are presented primarily for the purpose of illustrating more specific details thereof. .

EXAMPLE 1 Preparation of an Endo- and Ectoparasiticidal Topical Composition Component Description w/v% Moxidectin 0.100 Aromatic 100 15.00 Isopropyl myristate 10.00 Polybutene 10.00 Capric/caprylic triglyceride q.s. ad * •quantity sufficient to obtain a total of 100% w/v 04/08/2006 05:13 PM freehills 12345678 43/47 004854003 8 Method of Preparation Charge approximately 80 % of the required capric/caprylic triglyceride into a suitable vessel and heat to 60°C ± 5°C. Add polybutene and mix until dissolved. Cool to 40°C ± 5°C and hold until ready for use. Into a second vessel charge the 95 % of the Aromatic 5 100. Mix moxidectin and the remaining 5% Aromatic 100 into a slurry and add to the Aromatic 100 containing vessel. When the moxidectin is dissolved, add isopropyl myristate and mix until uniform. Then add the polybutene-capric/caprylic triglyceride mixture and mix until a uniform solution is obtained. Finally add the remaining | capric/caprylic triglyceride to bring to final volume. Mix until uniform and fill into bottles 10 of desired capacity.

EXAMPLES 2-4 Preparation of Endo- and Ectoparasiticidal Topical Compositions Using essentially the same procedure described in Example 1 hereinabove, the compositons shown below are prepared.

Ex. 2 Ex. 3 Ex. 4 Component Description w/v% w/w% w/w% moxidectin 0.100 0.100 0.100 Aromatic 100 15.00 15.00 15.00 isopropyl myristate 5.00 10.00 Polybutene 10.00 10.00 10.00 Cyclomethicone 5.00 Isopropyl palmitate 5.00 5.00 Ethanol 10.00 Capric/caprylic triglyceride q.s. q.s. ad q.s. ad ad * ^quantity sufficient to obtain a total of 100% w/v

Claims (13)

04/08/2006 05:13 PM fraahllls 12345678 44/47 004854003 9 EXAMPLE S Evaluation of the Plasma Levels of Test Compositions In this evaluation, test compositions prepared in Examples 1-4 and a conventional moxidectin-containing topical composition are administered to four calves per treatment 5 group by pouring the test composition down the midline of the back of the test animal at volumes providing a dose rate of 1mg/kg of moxidectin. Blood samples are drawn at intervals up to 96 h after treatment and are assayed for moxidectin. It will be understood that the invention disclosed and defined in this specification extends to all alternative combinations of two or more of the individual features 10 mentioned or evident from the text or drawings. All of these different combinations constitute various alternative aspects of the invention. Reference to any prior art in this specification is not, and should not be taken as, an acknowledgement, or any form of suggestion, that this prior art forms part of the common general knowledge in New Zealand or any other jurisdiction. 005104182 10 The claims defining the invention are as follows:

1. A composition including a macrocyclic lactone; an aromatic solvent; 5 polybutene; a pharmacologically acceptable oil; and a spreading agent selected from the group consisting of isopropyl myristate, polydimethyl-cyclosiloxane, PEG-40 sorbitan peroleate, cyclomethicone, isopropyl palmitate, ethanol, or a mixture thereof; and 10 wherein the macrocyclic lactone is moxidectin.

2. A composition according to claim 1 wherein said macrocyclic lactone is present at about 0.01-5.0% w/v.

3. A composition according to claim 1 or 2 wherein the pharmacologically acceptable oil is a vegetable oil, a mineral oil or a mixed capric/caprylic glyceryl triester 15 oil.

4. A composition according to any one of the preceding claims wherein said spreading agent is isopropyl myristate.

5. A composition according to any one of the preceding claims wherein said spreading agent is present at about 1.0-15% w/v. 20

6. A composition according to any one of the preceding claims being a pour-on. INTELLECTUAL PROPERTY OFFICE OF N.Z. i a MAR 2008 RECEIVED 005104182 11

7. A method for the treatment, prevention or control of helminth, acarid or arthropod endo- or ectoparasitic infection or infestation in a non-human animal including topically administering to said animal an effective amount of a composition including a macrocyclic lactone as an active ingredient; 5 an aromatic solvent; polybutene; a pharmacologically acceptable oil; and a spreading agent selected from the group consisting of isopropyl myristate, ^ polydimethyl-cyclosiloxane, PEG-40 sorbitan peroleate, cyclomethicone, isopropyl palmitate, ethanol, or a mixture thereof, and 10 wherein the macrocyclic lactone is moxidectin.

8. A method according to claim 7 wherein said composition is administered as a pour-on.

9. A method according to claim 7 or 8 wherein said animal is selected from the group consisting of: swine; cattle; horses; and sheep. ^15

10. A method according to claim 9 wherein said animal is cattle or sheep.

11. A method according to any one of claims 7 to 10 having a composition wherein said macrocyclic lactone is present at about 0.1-5.0% w/v.

12. A method according to any one of claims 7 to 11 having a composition wherein the effective amount of the composition is an amount sufficient to provide about 0.1-5.0 20 mg/kg of moxidectin.

13. A composition according to claim 1, substantially as described herein with reference to any one of the examples. INTELLECTUAL PROPERTY OFFICE OF N.Z. L i MAR 2008 RECEIVED