WO2012085160A1 - Formulations of antiparasitic agents for topical administration to swine - Google Patents

Abstract

The present invention relates to an antiparasitic composition for use in the systemic treatment of parasitic infestations in pigs via topical administration, said composition comprising: an antiparasitic agent that comprises a macrocyclic lactone; a penetration enhancer; and a pharmaceutically or veterinarilly acceptable solvent; wherein the penetration enhancer is present in an amount of at least 10% w/v of the composition.

Description

FORMULATIONS OF ANTIPARASITIC AGENTS FOR TOPICAL ADMINISTARTION TO SWINE

The present invention relates to an antiparasitic composition for use in the systemic treatment of parasitic infestations in pigs via topical administration.

Drugs can be administered to animals in a variety of ways. In cattle, for example, parenteral, topical and oral compositions are commonly used. With pigs, however, transdermal methods of drug delivery are relatively rare because of the difficulty in achieving effective

concentrations of the active agent through porcine skin. In this regard, the stratum corneum of a pig is almost twice as thick as the stratum corneum of cattle in the area over the humeroscapular joint (see J. Invest Dermatol 95:582 - 586,

1990) . Generally speaking, therefore, few active agents can be delivered to pigs transdermally in effective

concentrations . The present inventors have developed a topical

composition that can be used to deliver antiparasitic agents based on macrocyclic lactones in effective concentrations transdermally to pigs. This is surprising as such agents are typically administered orally or parenterally to pigs.

According to the present invention, there is provided an antiparasitic composition for use in the systemic

treatment of parasitic infestations in pigs via topical administration, said composition comprising:

an antiparasitic agent that comprises a macrocyclic lactone ;

a penetration enhancer; and

a pharmaceutically or veterinarily acceptable solvent; wherein the penetration enhancer is present in an amount of at least 10% w/v of the composition.

The composition of the present invention is

advantageous because it delivers the active transdermally through the pig's skin. The composition is therefore conveniently administered, for example, as a pour-on, spot- on or spray-on composition. Pour-on compositions are preferred. Moreover, the composition is advantageous over known oral compositions in that it avoids the risk of irritation of the gastrointestinal tract and reduces stress associated with the necessary restraint for the

administration of an injection and drench formulations.

Furthermore, the risk of first-pass inactivation by the liver is eliminated.

The antiparasitic agent is preferably a macrocyclic lactone. The macrocyclic lactone may be an avermectin or a milbemycin. Avermectins are antiparasitic agents that are useful against a broad spectrum of endoparasites and

ectoparasites in mammals. The basic avermectin compound may be isolated from the fermentation broth of the soil microorganism, Streptomyces avermitilis (see US 4,310,519) .

Preferably, however, derivatives of this basic compound are used. Examples include ivermectin, emamectin, eprinomectin, latidectin, abamectin, doramectin, eprinomectin and

selamectin. Preferably, ivermectin is employed.

Milbemycins are antiparasitic agents that are useful against a broad spectrum of parasites in mammals. The basic milbemycin compound is the product of fermentation by

Streptomyces bacteria. Although this basic compound may be used, derivatives of this basic compound are preferred. Examples include milbemycin oxime, lepimectin and moxidectin .

The antiparasitic agent may be effective against a range of parasites, including worms, insects and mites. In this regard, the antiparasitic agent may be one or more of an anthelmintic, insecticidal or miticidal agent. The antiparasitic agent may be effective against parasitic infections caused by external and/or internal parasites. Examples of external parasites include arthropods, lice, fleas, ticks and mites. Examples of internal parasites include worms, such as Teladorsagia spp (including inhibited 0. Teladorsagia), Haemonchus placei, Trichuris spp ,

Trichostrongylus axei, Trichostrongylus colubriformis , Cooperia spp, Dictyocaulus viviparus, Ostertagia ostertagi (including inhibited 0. ostertagi), Dictyocaulus filaria, Oesophagostomum radiatum, Nematodirus helvetianus, N.

spathiger, N. battus, Dictyocaulus viviparus, Hypoderma bovis and H. lineatum, Psoroptes bovis, Sarcoptes scabiei var . bovis, Strongyloides papillosus, Linognathus vituli, Haematopinus eurysternus, Thelazia spp, Hypoderma bovis, Fasciola hepatica, Hypoderma lineatum, Haemonchus contortus, Trichostrongylus spp., Chabertia ovina, Bunostomum

phiebotomum .

The composition may be used for the treatment and control of a range of parasitic infestations in pigs. Such infestations may be caused by infestations of potentially harmful parasites, including adult parasites and larvae of parasites. Examples of such parasitic infestations include Ascaris suum, Hyostrongylus rubidus, Oesophagostomum spp, Strongyloides ransomi (adult and somatic larval stage), Metastrongylus spp. (adult), Haematopinus suis, Sarcoptes scabiei var . suis, and Stephanurus dentatus and Trichuris suis .

The composition comprises the antiparasitic agent in an amount of from 0.001% w/v to 15% w/v, preferably 0.1 to 8% w/v based on the total weight of the composition. More preferably, the composition comprises 0.5 to 5 % w/v, yet more preferably 1 to 4 % w/v of the antiparasitic agent based on the total weight of the composition.

Preferably, the composition comprises the macrocyclic lactone (e.g. avermectin and/or milbemycin) in an amount of 0.001% w/v to 15% w/v, preferably 0.1 to 8 % w/v based on the total weight of the composition. More preferably, the composition comprises 0.5 to 5 % w/v, yet more preferably 1 to 4 % w/v of the macrocyclic lactone (e.g. avermectin and/or milbemycin) based on the total weight of the

composition . In a preferred embodiment, the composition comprises the avermectin (e.g. ivermectin) and/or milbemycin in an amount of 0.001% w/v to 15% w/v, preferably 0.1 to 8 % w/v based on the total composition. More preferably, the composition comprises 0.5 to 5 % w/v, yet more preferably 1 to 4 % w/v of the avermectin (e.g. ivermectin) and/or milbemycin based on the total composition.

As mentioned above, the composition comprises a

penetration enhancer. This penetration enhancer facilitates the delivery of the antiparasitic agent through the pig's skin and, in particular, through the pig's stratum corneum. Any suitable penetration enhancer may be used. Suitable examples include azones, pyrrolidones , fatty acids and alcohols, fatty acid esters, essential oils and their derivatives, terpenes, terpenoids, oxazolidinones , DMSO and mixtures of two or more thereof. Examples of suitable fatty acid esters include butyl stearate, C12-C15 alkyl benzoate, cetearyl ethylhexanoate, isopropyl myristate, cetyl

palmiate, di-isopropyl adipate, di-ethylhexyl adipate, caprylic/capric triglyceride, isocetyl stearate, isopropyl palmitate, lauryl lactate, myristyl myristate, ethylhexyl cocoate, ethylhexyl hydroxystearate, ethylhexyl palmitate, ethylhexyl pelargonate, ethylhexyl stearate, di-ethylhexyl succinate, propylene glycol dicaprylate, propylene glycol dicaprate, PPG-2 myristyl ether propionate, pentaerythrityl tetraisostearate, pentaerythrityl tetracaprylate,

pentaerythrityl tetracaprate, cetyl esters, isotridecyl isononanoate, stearyl heptanoate, steryl caprylate, and/or mixture thereof.

Preferably, the penetration enhancer is selected from at least one of fatty acids, fatty acid esters, essential oils and their derivatives and terpenoids. Mixtures of such penetration enhancers may be used. In a preferred

embodiment, the penetration enhancer is cetearyl

ethylhexanoate and/or isopropyl myristate. In another preferred embodiment, the penetration enhancer is an

essential oil, such as menthol, or an essential oil

derivative, such as p-menthan-3 , 8-diol . In another

preferred embodiment, the penetration enhancer is a

terpenoid, such as camphor. The penetration enhancer is present in an amount of at least 10% w/v based on the total composition. Preferably, the penetration enhancer is present in an amount of at least 15% w/v, more preferably at least 20% w/v based on the total composition. The penetration enhancer may be present in an amount of less than 70% w/v, preferably less than 60% w/v, more preferably less than 50% w/v. In one embodiment, the penetration enhancer is present in an amount of 10 to 70 % w/v, preferably, 15 to 40 % w/v, more preferably 20 to 35 % w/v. For the avoidance of doubt, these amounts apply to any of the penetration enhancers mentioned above, including menthol, p-menthan-3 , 8-diol , camphor, isopropyl myristate and a combination of isopropyl myristate and cetearyl ethyl hexanoate.

The weight ratio of antiparasitic agent to the

penetration enhancer may be 0.001-15:10-70, preferably

0.5-5:10-50, more preferably 1-4:20-35.

The weight ratio of the macrocyclic lactone to the penetration enhancer may be 0.001-15:10-70, preferably

0.5-5: 10-50, more preferably 1-4:20-35. In one embodiment, the weight ratio of avermectin to penetration enhancer is 0.001-15:10-70, preferably 0.5-5:10- 50, more preferably 1-4:20-35.

The composition comprises a pharmaceutically or

veterinarily acceptable solvent. The solvent may be water or an alcohol. Suitable alcohols include Ci to C₁₂ alcohols, preferably Ci to C6 alcohols. The alcohols may be polyols, such as glycols, and/or monohydric alcohols and sugar alcohols. Suitable alcohols include benzyl alcohol, propylene glycol, polyethylene glycol, ethanol, glycerin and isopropyl alcohol. Isopropyl alcohol is preferred.

Accordingly, the solvent may consist essentially of

isopropyl alcohol. Other solvents include cyclomethicone and propylene carbonate. Mixtures of two or more solvents may be used. The solvent (and hence the composition) may or may not be anhydrous . The solvent may be present in an amount of at least 30% w/v.

Preferably, the solvent is present in an amount of at least 50% w/v, more preferably at least 60% w/v based on the total composition. The solvent may be present in an amount of less than 90% w/v, preferably less than 85% w/v. In one

embodiment, the solvent is present in an amount of 10 to 70 % w/v, preferably 20 to 35 % w/v.

As mentioned above, the composition of the present invention may be in the form of a pour-on, spot-on or spray- on composition. Preferably, the composition is a pour-on composition .

The composition may be applied to a pig at any suitable location. Suitable locations include the back of the ears and back (e.g. dorsal midline of the back. The composition may be packed as a single simple packaging or as a multipart kit

The composition is advantageous as it allows the antiparasitic compound to be absorbed steadily through the skin over a period of time. This avoids or reduces the risk of blood level peaks and troughs commonly encountered with oral dosage forms. The composition may be used to deliver the

antiparasitic active [such as avermectin (e.g. ivermectin) and/or milbemycin] in an amount of at least 0.25 mg per kg of body weight, preferably 0.5 to 15 mg per kg of body weight, more preferably 1 to 10 mg per kg of body weight, most preferably 2 to 6 mg per kg of body weight. In one embodiment, the dose is 2 mg per kg of body weight. In another embodiment, the dose is 3.75 mg/kg of body weight.

The composition of the present invention may optionally include an additional active agent. The additional active agent may be selected from at least one of phenyl pyrazoles, salicylanilide anthelmintics, other anthelmintics,

antinematodal agents, spinosads, non-steroidal antiinflammatory drugs (NSAIDs), steroidal anti-inflammatory drugs, other insect growth regulators, chitin synthesis inhibitors, spiroindoles , amino acetonitryl derivatives and RNA inhibitors.

When used, the additional active agent may be present in an amount of 0.001 to 30 % w/v, preferably 0.5 to 20% w/v based on the composition.

Other auxiliary agents may also be included in the composition. Examples include colouring agent (s), base(s), antioxidant ( s ) , preservative ( s ) , crystallisation inhibitor (s), additional active agent (s) and mixtures of two or more thereof .

The total amount of auxiliary agent (s) may be no more than 40 % w/v, preferably 1 to 30 % w/v of the composition, more preferably 5 to 20 % w/v.

In one embodiment, the composition comprises:

ivermectin,

a penetration enhancer comprising a fatty acid and/or a fatty acid ester, and an alcohol solvent.

Preferably, the penetration enhancer comprises/is isopropyl myristate or a combination of cetearyl

ethylhexanoate and isopropyl myristate. The alcohol solvent is preferably isopropyl alcohol.

In another embodiment, the composition comprises:

ivermectin,

a penetration enhancer comprising an essential oil and/or an essential oil derivative, and

an alcohol solvent.

Preferably, the penetration enhancer comprises/is menthol or p-menthan-3 , 8-diol . The alcohol solvent is preferably isopropyl alcohol.

In yet another embodiment, the composition comprises: ivermectin,

a penetration enhancer comprising a terpenoid, and an alcohol solvent.

Preferably, the penetration enhancer comprises/is camphor. The alcohol solvent is preferably isopropyl alcohol .

In a further aspect, the present invention provides a method of treating pigs by topically applying a composition to the pig, wherein the composition is defined above.

In a further aspect, the present invention provides a method of treating pigs infected with adult parasites by topically applying a composition comprising an antiparasitic agent that comprises a macrocyclic lactone; a penetration enhancer; and a pharmaceutically or veterinarily acceptable solvent; wherein the penetration enhancer is present in an amount of at least 10% w/v of the composition and wherein the macrocyclic lactone is administered at a dose of at least 0.25 mg/kg bodyweight.

In a further aspect, the present invention provides a method for treating pigs infected with larvae of parasites by topically applying a composition comprising an

antiparasitic agent that comprises a macrocyclic lactone; a penetration enhancer; and a pharmaceutically or veterinarily acceptable solvent; wherein the penetration enhancer is present in an amount of at least 10% w/v of the composition and wherein the macrocyclic lactone is administered at a dose of at least 0.25 mg/kg bodyweight.

Examples : Pour-on formulations according to the present invention were prepared having the compositions shown in I-IX below. The formulations were topically administered on the back of pigs at various dose rates. Table 1 represents

pharmacokinetic parameters after administering formulations of examples I-V at different dose rates.

[I]

Crodamol CAP is a mixture of cetearyl ethylhexanoate and isopropyl myristate.

[II] Ivermectin 2.5% w/v

Crodamol CAP 10% w/v

Isopropyl alcohol q.s. 100 ml

[III]

[IV]

[VI]

[VII]

[VIII]

Ivermectin 1.0% w/v

Camphor 35% w/v

Isopropyl alcohol q.s. 100 ml IX

Ivermectin 1.0% w/v

Isopropyl myristate 35% w/v

Isopropyl alcohol q.s. 100 ml

Table 1: Plasma pharmacokinetic parameters after topical administration of ivermectin pour on at various dose rates on pigs

* n = 4

The following formulation was tested on pigs to

determine the efficacy of the formulation against parasites:

The study was conducted to determine the efficacy of several different dose rates for pigs following topical administration of the above-identified formulation, measured by the reduction in the number of Oesophagostomum dentatum worms present post treatment. The study was conducted using an induced infection model. Three does rates were

investigated 1.0 mg ivermectin/kg, 2.0 mg invermect in/kg and 3.0 ivermectin/kg bodyweight. Thirty six pigs of either gender aged approximately 3-4 months old at the time of Oesophagostomum dentatum inoculation, were used for the study.

This study comprised 4 groups of 8 animals which had been confirmed as nematode free via the determination of faecal egg count examinations. Oesophagostomum dentatum was chosen for this study as the dose limiting internal parasite for pigs and is the most common parasite of the large intestine of pigs in the northern hemisphere. It is also found in the more temperate areas of the southern

hemisphere. The formulation, however, is not limited to the treatment of Oesophagostomum dentatum, rather it is directed to the treatment of other parasites, including those listed herein. On Day -45 all 32 animals were each administered approximately 7500 L₃ larvae of Oesophagostomum dentatum orally. On day -5 animals were faecal sampled and randomised into groups on the basis of faecal egg counts. On Day 0 the pigs were weighed to calculate the dose of ivermectin to be administered to each animal in the treatment groups. A, B and C respectively, group D animals received no treatment. Between days +14 and +17 the animals were slaughtered and the contents of the small and large intestine sampled. All samples were assayed for worm identification and counting, which was conducted blind relative to treatment group.

The total counts of Oesophagostomum dentatum from each animal were enumerated and summarised using the mean, geometric mean, minimum, maximum and sample size. Geometric means were used to calculate percentage efficacy of

treatment according to the following formula:

% efficacy = Geometric Mean of Controls-Geometric Mean of Treated X 100

Geometric Mean of Controls

On study days +14, +15, +16 and +17 animals in Groups A, B, C and D were slaughtered. Small and large intestines were processed and total worm counts determined. The results for the groups are summarized in the table below.

Group A Group B Group C Group D

Ivermectin 1.0 mg/kg 2.0 mg/kg 3.0 mg/kg N/A

Dose rate bodyweight bodyweight bodyweight

Mean 21.88 0 0 1471.00

Maximum 80 0 0 2585

Minimum 0 0 0 30

Geometric 3.24 0 0 937.22 mean

Number 8 8 8 8 The efficacy of each dose rate was determined by the use of the geometric mean of the worm counts for each treatment group compared to that of the control group and are outlined below.

A further study was conducted using the same

formulation, but with different dose rates of ivermectin. Specifically, three dose rates were investigated 0.25 mg ivermectin/kg, 0.75 mg ivermectin/kg and 1.0 mg

ivermectin/kg bodyweight.

Similar to the above-described study, this dose

determination study comprised 3 treatment groups of 8 animals plus one control group of 7 animals, confirmed as nematode free via the determination of faecal egg count examination. On Day -45 all animals were infected orally with approximately 7500 L3 larvae of Oesophagostomum

dentatum. On day -5 animals were faecal sampled and

randomised into groups on the basis of descending faecal egg counts. On Day 0 the pigs were weighed to calculate the dose of Ivermectin to be administered to each animal in the treatment groups A, B and C respectively, group D animals received no treatment. Between days +14 and +17 the animals were slaughtered and the contents of the small and large intestine sampled. All samples were assayed for worm identification and counting, which was conducted blind relative to treatment group.

On study days +14, +15, +16 and +17 animals in Groups A, B, C and D were slaughtered. Small and large intestines were processed and total worm counts determined. The results for the groups are summarized in the table below.

The efficacy of each dose rate was determined by the use of the geometric mean of the worm counts for each treatment group compared to that of the control group and are outlined below.

Another study was conducted to determine the efficacy in treating 1.4 Oesophagostomum dentatum infection in pigs. Specifically, this dose confirmation study comprised two treatment groups of 8 animals plus one control group of 8 animals, confirmed as nematode-free via the determination of faecal egg count examinations. On Day -9 all animals were infected orally with approximately 7500 L3 larvae of

Oesophagostomum dentatum. On day 0 animals were weighed and randomisation into groups was conducted on the basis of descending weights. The weight of the pigs was used to calculate the dose of ivermectin to be administered to each animal in the treatment groups (Groups A and B) . The control group (Group C) animals received no treatment.

On study days +52, +53, and +54 animals in Groups A, B and C, respectively were slaughtered. The small and large intestines from each animal were processed and worm counts were determined blind with regard to treatment group. The results for the groups are summarized in the table below, as is the efficacy of each dose rate relative to the untreated animals .

Group A Group B Group C 0.75 mg 1.0 mg No ivermectin/kg ivermectin/kg treatment

Geometric Mean 111.26 51.11 1980.88

% Efficacy 94.4 97.4 N/A relative to Group

C

Claims

Claims

1. An antiparasitic composition for use in the systemic treatment of parasitic infestations in pigs via topical administration, said composition comprising:

an antiparasitic agent that comprises a macrocyclic lactone ;

a penetration enhancer; and

a pharmaceutically or veterinarily acceptable solvent; wherein the penetration enhancer is present in an amount of at least 10% w/v of the composition.

2. The composition according to claim 1 or 2 wherein the composition comprises the active agent in an amount of from about 0.001% w/v to 10% w/v.

3. The composition according to any of the preceding claims wherein the antiparasitic agent is selected from avermectin, milbemycin, doramectin, emamectin, eprinomectin, ivermectin, latidectin, lepimectin, milbectin, moxidectin, selamectin and mixtures of two or more thereof and/or salt(s) thereof.

4. The composition according to claim 4 wherein the antiparasitic agent is ivermectin.

5. The composition according to any of the preceding claims wherein the composition comprises from 10% w/v to 70% w/v of penetration enhancer.

6. The composition according to of any of the preceding claims wherein the penetration enhancer is selected from azones, pyrrolidones , fatty acids, fatty acid esters, essential oils and their derivatives, terpenes, terpenoids, oxazolidinones , DMSO, and mixtures of two or more thereof.

7. The composition according to claim 6 wherein the penetration enhancer comprises fatty acids and/or fatty acid esters selected from at least one of butyl stearate, C12-C15 alkyl benzoate, cetearyl ethylhexanoate, isopropyl

myristate, cetyl palmiate, di-isopropyl adipate, di- ethylhexyl adipate, caprylic/capric triglyceride, isocetyl stearate, isopropyl palmitate, lauryl lactate, myristyl myristate, ethylhexyl cocoate, ethylhexyl hydroxystearate, ethylhexyl palmitate, ethylhexyl pelargonate, ethylhexyl stearate, di-ethylhexyl succinate, propylene glycol

dicaprylate, propylene glycol dicaprate, PPG-2 myristyl ether propionate, pentaerythrityl tetraisostearate,

pentaerythrityl tetracaprylate, pentaerythrityl

tetracaprate, cetyl esters, isotridecyl isononanoate, stearyl heptanoate, steryl caprylate, and/or mixtures thereof .

8. The composition according to claim 7, wherein the penetration enhancer is a cetearyl ethylhexanoate and/or isopropyl myristate.

9. The composition according to claim 6, wherein the penetration enhancer is selected from camphor, p-menthan-

3,8-diol, menthol, isopropyl myristate and a combination of cetearyl ethyl hexanoate and isopropyl myristate.

10. The composition according to any of the preceding claims wherein the pharmaceutically or veterinarily

acceptable solvent is selected from water, cyclomethicone, benzyl alcohol, propylene glycol, polyethylene glycol, propylene carbonate, ethanol, glycerin and isopropyl alcohol .

11. The composition according to claim 10 wherein the pharmaceutically or veterinarily acceptable solvent is isopropyl alcohol.

12. The composition according to any one of the preceding claims wherein the composition is in the form of a pour-on, spot-on or spray-on formulation.

13. The composition according to any one of the preceding claims, wherein the antiparasitic agent is an anthelmintic agent, an insecticide and/or a miticide.

14. The composition according to any one of the preceding claims for use in the treatment and control of parasites selected from at least one of Ascaris suum, Hyostrongylus rubidus, Oesophagostomum spp, Strongyloides ransomi (adult and somatic larval stage), Metastrongylus spp. (adult), Haematopinus suis, Sarcoptes scabiei var . suis

15. The composition according to any one of the preceding claims, which further comprises at least one additional active agent.

16. The composition according to any one of the preceding claims, wherein the weight ratio of the amount of antiparasitic agent to penetration enhancer in the

composition is 1-4:20-35.

17. A method of treating pigs by topically applying a composition to the pig, wherein the composition is defined in any one of claims 1 to 16.

18. Use of a fatty acid and/or a fatty acid ester as a penetration enhancer in an antiparasitic composition

according to any one of claims 1 to 16.

19. Use as claimed in claim 18, wherein the penetration enhancer is selected from camphor, p-menthan-3 , 8-diol , menthol, isopropyl myristate and a combination of cetearyl ethyl hexanoate and isopropyl myristate.

20. A method of treating pigs infected with adult parasites by topically applying a composition comprising an

antiparasitic agent that comprises a macrocyclic lactone; a penetration enhancer; and a pharmaceutically or veterinarily acceptable solvent; wherein the penetration enhancer is present in an amount of at least 10% w/v of the composition and wherein the macrocyclic lactone is administered at a dose of at least 0.25 mg/kg bodyweight.

21. A method for treating pigs infected with larvae of parasites by topically applying a composition comprising an antiparasitic agent that comprises a macrocyclic lactone; a penetration enhancer; and a pharmaceutically or veterinarily acceptable solvent; wherein the penetration enhancer is present in an amount of at least 10% w/v of the composition and wherein the macrocyclic lactone is administered at a dose of at least 0.25 mg/kg bodyweight.