HK1114563B - Versatile high load concentrate compositions comprising metaflumizone for control of ecto-parasites - Google Patents

Description

This application claims priority from copending provisional Application Number 60/683,949, filed May 24, 2005 .

BACKGROUND OF THE INVENTION

Arthropod ectoparasites commonly infecting warm-blooded animals include ticks, mites, lice, fleas, blowfly, the ectoparasite Lucilia sp. of sheep, biting insects including keds (Melophagus ovinus) and migrating dipterous larvae such as Hypoderma sp.and Dermataobia in cattle, Gastrophilus in horses and Cuterebra sp. in rodents.

Metaflumizone is useful for the prevention and control of infestation by ectoparasites in warm-blooded animals. Topical administration of this active is a preferred method for administering this compound.

To provide useful protection against ectoparasitic infection or infestation in warm-blooded animals it is desirable to use formulations having a relatively high loading of active agent, but such formulations must be stable, both with respect to the physical formulation, and also, with respect to the chemical stability of the active. Metaflumizone is one of several useful insecticidal agents which have found particular application for the control of fleas and ticks on animals, particularly companion animals such as dogs, cats and horses, and livestock such as cattle, sheep and goats. It is particularly advantageous in that it can provide 4-6 weeks of protection from fleas and ticks in companion animals, but it would be potentially useful for many other species if suitable formulations could be developed. Nonetheless, formulation of metaflumizone is made difficult by its insolubility in many solvents, and its instability in the presence of primary alcohols.

EP1413201 discloses a method for the prevention, amelioration or control of ectoparasitic infection or infestation in a homoeothermic animal by administering a composition of a neuronal sodium channel antagonist in carrier. D1 carrier does not mention gamma-hexalactone and/or 1-methoxy-2-propyl acetate.

WO2006/042099 discloses topical, parasiticidal veterinary compositions containing amitraz, and at least one additional parasiticidal compound, which are stable, and which allow sufficiently high concentrations of each of the active ingredients. The carriers of these compositions do not contain one or more of a bridging agent, a surfactant and gamma-hexalactone.

WO2006/002984 discloses a stable concentrate formulation including metaflumizone having a water-solubility of not more than 5 g/I, at 25°C/1013 mbar. None of D3 compositions comprises gamma-hexalactone or 1-methoxy-2-propyl acetate.

it is an object of the present invention to provide a versatile composition for topical administration which comprises a relatively high loading of metaflumizone and which will provide protection from ectoparasitic infestation. Most advantageously, the formulation can function as a concentrate, which with simple modifications, can be extended to use for a wide variety of other animals. Thus, the concentrated formulation can be utilized as a small volume spot-on formulation, for instance, for protection of companion animals, while further dilutions can be utilized as conventional pour-on products for farm animals, with still further dilutions utilizable for emulsified sprays delivered through an aerosol spray or a pump spray with numerous volumes of dosage and/or application to the feed.

It is also an object of the present invention to provide a method for preventing or treating acarid or arthropod ectoparasitic infestation in animals, especially warm-blooded animals, using the compositions of the invention.

It is another object of this invention to reduce or control the proliferation of such insects in warm-blooded animals for prolonged periods of time by a topically applied active, with the formulation being mild and gentle enough to avoid adverse skin reactions upon administration, yet with the ability to be retained in the animal's skin and/or coat over the time needed for protection.

These and other objects of the present invention will become more apparent from the description thereof set forth below and the appended claims.

SUMMARY OF THE INVENTION

The present invention provides high-load concentrate compositions for topical administration as defined in the appended claims.

The present invention further provides a composition as defined in the appended claims for preventing or treating ectoparasitic infection or infestation in a warm-blooded animal.

The present invention further provides the use of a composition as defined in the appended claims for the manufacture of a medicament, said medicament for preventing or treating ectoparasitic infection or infestation in a warm-blooded animal.

DETAILED DESCRIPTION OF THE INVENTION

In accordance with the present invention, the high load concentrate compositions comprise metaflumizone; a bridging agent or penetration enhancer, a surfactant, and a carrier solvent. The invention also provides the use of such compositions for preventing or treating acarid or arthropod ectoparasitic infection or infestation in warm-blooded animals by topical application of the aforesaid formulations.

Preferred high load concentrate compositions of this invention comprise on a weight to volume basis:

• about 5% to about 25% of metaflumizone;
• about 2% to about 15% of a bridging agent;
• about 2 to about 15%, and especially about 2 to about 8%, of a surfactant and
• about 50% to about 80% of a carrier solvent.

In certain embodiments about 15% to about 25% metaflumizone is included in the composition, e.g. about 20%. In certain embodiments about 5% to about 15% bridging agent is included, e.g. about 10% is included. In certain embodiments about 50% to about 60% carrier solvent is included.

While not wishing to be bound by any particular theory, it is believed that the compositions of the present invention have the requisite stability by virtue of physical and/or chemical interactions between the surfactant and the metaflumizone. The exact nature of the interactions is unknown, but apparently the surfactant stabilizes the metaflumizone in solution so as to ensure that the resultant formulation retains the desired physical characteristics over time, without loss of potency of the active. Further, the formulation is sufficiently viscous to be retained upon or in the animal's skin and/or hair, and be released over the desired period of time.

Uniquely, it has been found these high load concentrate compositions can be further utilized to prepare more dilute compositions for application in various other manners, i.e., for use as a pour-on for large animals, as a spray for large animals or for outdoor use, and as a water-dilutable formulation for addition to the feed and/or water supply of animals under treatment. This has the dual advantage of providing a concentrated formulation that can be shipped to the end-user for dilution and use, or to an intermediate formulator to prepare the compositions. The high loading of metaflumizone in the formulation thus provides a small volume of formulation to use as a "spot-on" formulation, for instance, for companion animals, especially felines. The concentrate can then be diluted by an appropriate organic solvent for use as a pour-on or in a spray, or with water, to provide the feed/water additive.

Metaflumizone, as well as its use in veterinary applications, is described in U.S. Patent No. 5,543,573 , and U. S. Published Application 2004-0122075A1 , Chemically, it is known as (E Z)-2-[2-(4-cyanophenyl)-1-[3-(trifluoromethyl)phenyl]ethylidene]-N-[4-(trifluoromethoxy)phenyl] hydrazinecarboxamide.

Bridging agents or penetration enhancers suitable for use in the compositions of this invention include, but are not limited to, alkyl methyl sulfoxides (such as dimethyl sulfoxide, decylmethyl sulfoxide and tetradecylmethyl sulfoxide); pyrrolidones (such as 2-pyrrolidone, N-methyl-2-pyrrolidone and N-(2-hydroxyethyl) pyrrolidone); laurocapram; and miscellaneous solvents such as acetone, dimethyl acetamide, dimethyl formamide, and tetrahydrofurfuryl alcohol. Other bridging agents include amphiphiles such as L-amino acids, and fatty acids. Additional bridging agents are disclosed in Remington: The Science and Practice of Pharmacy, 19th Edition (1995) on page 1583. Typically, the bridging agents is used at a level of about 10% w/v of the formulation where the end use is for a topical application, but this may vary, especially when the end use of the composition is for oral administration.

The surfactant utilized in the present invention may be a single surfactant, or a mixture of two or more surfactants, again, in part dependent upon whether the end use of the composition is topical or oral. The surfactant should be non-irritating, and non-toxic. Preferred are non-ionic, low foaming surfactants, such as the alcohol alkoxylate surfactants, with those sold by Uniqema under the tradename Synperonic^® NCA 810, 830 and 850 being especially suitable. Other useful surfactants are the nonylphenol ethoxylates, with those sold under the tradename Tergitol^® NP by the Dow Chemical Company being preferred. Additional surfactants, including appropriately chosen anionic and cationic surfactants, can also be utilized in the formulations of the present invention. Especially useful properties are found in anionic surfactants, such as dioctylsulfosuccinate salts.

Typically, the surfactant is utilized at a level of about 2 to about 15% w/v, especially about 2 to about 8% w/v, of the composition, but this may vary somewhat depending upon the end use of the composition. In the case where the end use of the concentrate is as a spray formulation, or as a water-dispersible feed /water additive, it may be desirable to add a further surfactant to ensure that the diluted formulation will be a unitary phase. This ensures that the spray will not block the spray nozzle, and that the active will be dispersed equally throughout the diluted product. In such cases, the additional surfactant may be added to the concentrate formulation, or added to the end use formulation with the diluting solvent. Particularly useful surfactants for use with an organic solvent diluent are non-ionic surfactants such as polyoxyl 35 castor oil sold under the Cremophor^® tradename.

The carrier solvent for the compositions of the present invention may be a single solvent, or a mixture of solvents. Due to the instability of metaflumizone in the presence of primary alcohols, preferred solvents are non-hydroxyl-group-containing solvents, especially those such as γ-hexalactone (also known as γ- caprolactone; ethyl butyrolactone; γ-ethyl-n-butyrolactone; hexanolide-1, 4; 4-hydroxy hexanoic acid γ-lactone or tonkalide). Optionally, other such solvents such as N,N-diethyl-m-toluamide, eucalyptol, dimethyl isosorbide, diisopropyl adipate and/or 1-methoxy-2-propyl acetate can be utilized in combination with the γ-hexalactone to comprise the carrier solvent.

To manufacture the high load concentrate composition of the present invention, the metaflumizone is dissolved in the carrier solvent or solvents, and the surfactant and bridging agent, if desired added to the mixture. This composition can then be utilized as a high load spot-on, or further diluted for additional uses.

An especially preferred composition for topical administration to warm-blooded animals comprises, on a weight to volume basis, about 5% to about 25 % metaflumizone; about 10% of a bridging agent, especially dimethyl sulfoxide, about 2-about 8% of a non-ionic, low foam surfactant; and about 50-60% carrier solvent, especially γ-hexalactone.

The high load concentrate compositions of this invention may further comprise other agents known in the art, such as preservatives (e.g., methylparaben and propylparaben), colorants, antioxidants, and the like. Generally, these agents would be present in the compositions in an amount up to about 2% on a weight to volume basis.

When topically administered, the compositions of this invention are highly effective for preventing or treating ectoparasitic infection and infestation for prolonged periods of time in warm-blooded animals such as cows, sheep, horses, camels, deer, swine, goats, dogs, cats, birds, and the like. Representative dosages for application to companions are, for instance, 20 mg/kg for dogs, and 40 mg/kg for cats, but lower dosages down to 5 mg/kg show efficacy on large animals such as horses and cattle.

In order to facilitate a further understanding of the invention, the following examples are presented primarily for the purpose of illustrating specific embodiments thereof. The invention is not to be deemed limited thereby, except as defined in the claims.

EXAMPLE 1 PREPARATION OF METAFLUMIZONE HIGH LOAD CONCENTRATE, SUITABLE FOR USE AS A SPOT-ON

To 10 grams of DMSO is added to 40 grams of γ-hexalactone. To this solvent mixture is added 20 g. of metaflumizone. Mild heat (40°C) may be used to facilitate the process of dissolution. To the resulting solution, 6 grams of Synperonic® NCA 830 brand of alcohol alkoxylate surfactant is added with stirring. Bring to 100 ml with γ-hexalactone.

Thus formulated, the composition can be applied as a "spot-on" (topical small dose) treatment for cats.

The efficacy of such a formulation is given in the efficacy table below:

Days after treatment	2	15	29	57
Untreated Control group, number of fleas /cat	53.9	83.9	62.9	65.2
20% metaflumizone spot-on 40mg/kg % Efficacy	100.0	100.0	100.0	97.1

EXAMPLE 2 PREPARATION OF METAFLUMIZONE POUR-ON FROM HIGH LOAD CONCENTRATE OF EXAMPLE 1

To 25 ml of the high load concentrate prepared in Example 1 is added q.s. 100 ml γ-hexalactone. This provides a pour-on formulation having sufficient metaflumizone and volume to treat 5 head of cattle weighing 200 Kg each at 5 mg/kg dose rate.

EXAMPLE 3 PREPARATION OF HIGH LOAD CONCENTRATE FOR USE AS A CONCENTRATE TO PREPARE METAFLUMIZONE SPRAY OR FEED/WATER SUPPLEMENT

12.59 grams of metaflumizone is added to dimethyl isosorbide using mild heating (approximately 40°C). To this solution is added 109.92 grams Cremophor® EL (polyethoxylated castor oil, sold by Basf Aktiengesellschaft), with stirring, followed by q.s. 200 ml 1-methoxy-2-propyl acetate The resultant solution is stored until ready for use, whereupon it can be diluted with water for use as a spray (17 ml of concentrate diluted to 3500 ml with water), or with water for use as a feed/water additive (in approximately the same ratio).

This formulation was diluted with water to a metaflumizone concentration of 10 mg/kg bodyweight, and applied to sheep at 1500 ml/animal to test the effect of metaflumizone on biting lice

Days after treatment	7	17	21	28
Untreated Control group, number of lice/animal	140.2	293.2	542.2	824.8
10mg/kg metaflumizone dosed as a body spray % Efficacy	100	100	100	100

EXAMPLE 4 PREPARATION OF SPOT-ON FORMULATIONS USING VARIOUS SURFACTANT CHEMISTRIES AND SOLVENT SYSTEMS, % W/V

Claims (18)

1. A composition for topical administration which comprises on a weight to volume basis:

   5% to 25% of metaflumizone;

   5% to about 15% of a bridging agent;

   2% to about 15% of a surfactant which is an alcohol alkoxylate surfactant or polyoxyl 35 castor oil; and

   50% to 80% of a carrier solvent which is γ-hexalactone or 1-methoxy-2-propyl acetate.
2. The composition according to Claim 1 which comprises 15% to 25% metaflumizone.
3. The composition according to claim 1 wherein the surfactant is an alcohol alkoxylate surfactant.
4. The composition according to anyone of Claims 1 to 3 wherein the surfactant is present at a level of 2% to 8% w/v.
5. The composition according to anyone of Claims 1 to 4 wherein the bridging agent is dimethyl sulfoxide.
6. The composition according to anyone of Claims 1 to 5 wherein the carrier solvent is γ-hexalactone.
7. The composition according to anyone of Claims 1 to 5 wherein the carrier solvent is 1-methoxy-2-propyl acetate.
8. The composition according to anyone of Claims 1 to 7 which additionally contains up to 2% of one or more preservatives, colorants, antioxidants, or stabilizers.
9. The composition of claim 1, wherein metaflumizone is at 20% on a weight to volume basis.
10. The composition of claim 1, wherein said bridging agent is at 10% on a weight to volume basis.
11. The composition according to claim 1 which comprises on a weight to volume basis:

    5% to 25% of metaflumizone;

    5% to about 15% of a bridging agent which is dimethyl sulfoxide;

    2% to about 15 of a surfactant which is an alcohol alkoxylate surfactant; and

    50% to 80% of a carrier solvent which is γ-hexalactone.
12. A composition for topical administration according to anyone of Claims 1 to 11, for use in preventing or treating ectoparasitic infection or infestation in a warm-blooded animal
13. Use of a composition according to anyone of Claims 1 to 11 for the manufacture of a topical medicament, said medicament for preventing or treating ectoparasitic infection or infestation in a warm-blooded animal.
14. The use according to Claim 12 wherein the animal is selected from the group consisting of a cow, a sheep, a horse, a camel, a deer, a swine, a goat, a dog, a cat, and a bird.
15. The use according to anyone of Claims 13 to 14 wherein the composition comprises γ-hexalactone as the carrier solvent.
16. The use according to anyone of Claims 13 to 15 wherein the composition is further diluted for use as a pour-on composition.
17. The use according to anyone of Claims 13 to 14 wherein the composition comprises 1-methoxy-2-propyl acetate as the carrier solvent.
18. The use according to Claim 17 wherein the composition is further diluted for use as a spray or feed/water additive.