MXPA01005045A - Antiparasitic formulations - Google Patents

Abstract

A long-acting antiparasitic formulation suitable for topical application including:(a) 0.1-50%w/v an avermectin or milbemycin having activity against endo- and/or ectoparasites;(b) 1-50%v/v a di(C2-4 glycol) mono(C1-4 alkyl) ether;(c) an optional antioxidant;and (d) an optional skin acceptable volatile solvent q.s. v/v.

Description

ANTI-PARASITIC FORMULATIONS DESCRIPTIVE MEMORY This invention relates to antiparasitic formulations and, in particular, to antiparasitic formulations containing avermectins or milbemycins, including derivatives thereof, which are suitable for topical application to mammals, persons and domestic animals such as dogs or cats included, and which are useful in the treatment of disorders caused by endoparasites or ectoparasites. Of special interest are the formulations of active substances against fleas and / or filarias. Avermectins and antiparasitic milbemichines, as well as derivatives thereof, have been described in numerous publications. See, for example, European patent applications with publication numbers 0 214 731, 0 284 176, 0 317 148, 0 308 145, 0 340 832, 0 335 541, 0 350 187, 0 170 006, 0 254 583, 0 334 484 and 0 410 615, the British patent applications with publication numbers 1 573 955 and 1 390 336, the international patent applications with publication numbers WO 94/15944 and WO 95/22552, "Ivermectin and Abamectin", WC Campbell, Springer Verlag, New York (1989), or "Doromectin a potent novel endectocide", AC Goudie et al., Vet. Parasite!. 49 (1993) 5.

A number of these substances have been developed for commercialization, such as: ivermectin (Ivomec ™), doramectin (Dectomax ™), moxidectin and abamectin (Avomec ™). The international patent application with publication number WO 94/15944, the disclosure of which is included herein in its entirety as a reference, describes a family of 5-oximino derivatives of avermectin 13-monosaccharide having activity in the treatment of various disorders caused by endoparasites. or ectoparasites, and including 5-oximino-22,23-dihydro-25-cyclohexylavermectin B1 monosaccharide (selamectin, example 5). We will describe here long-acting formulations that are suitable for topical application and that are capable of releasing avermectins and milbemycins that have activity against endoparasites and ectoparasites. These formulations have good cosmetic properties, good preservation during storage, good cutaneous tolerability, as well as excellent transdermal diffusion characteristics. According to one aspect of the invention, a long-acting antiparasitic formulation is provided which is suitable for topical application and which contains: (a) approximately 0.1-5% w / v of avermectin and / or milbemycin exhibiting activity against endoparasites or ectoparasites; (b) about 1-50% v / v of a monoalkyl ether (C-i-4) of a dialkylene (C2.4) glycol; (c) an optional antioxidant; and, optionally; (d) a volatile solvent q.s. v / v, tolerable by the skin. [The term "w / v" means weight / volume, ie "1% w / v" means 1 g in 100 ml of the formulation]. The formulations of the invention exhibit good cosmetic properties. For example, when applied topically to the fur of domestic animals such as dogs or cats, they are well distributed allowing good contact with the skin over a wide range of temperatures. In addition, they do not leave unsightly oily stains, of the type associated with some commercial formulations of avermectin or milbemycin in fatty excipients. Certain formulations according to the invention are effective enough to allow long periods, ie several weeks or a month, between treatments. It is meant that the active compound has activity against both the endoparasites and against the ectoparasites. It is preferred to select the active compound from: ivermectin, doramectin, abamectin, moxidectin and the 5-oxime 13-monosaccharide avermectins, set forth specifically and generically in the international patent application with publication number WO 94/15944.

The most preferred active compound is 5-oximino-22,23-dihydro-25-cyclohexylavermectin B1 monosaccharide (selamectin). It is meant that the monoalkyl ether (C1.4) of a dialkylene (C2-4) glycol is the monomethyl ether of diethylene glycol (DEGMME) or the monomethyl ether of dipropylene glycol (DPGMME). The most preferred monomethyl ether of glycol is DPGMME. Monoalkyl (C -? -) ethers of dialkylene (C2- ') glycol of pharmaceutical or veterinary grade quality can be used from any source. For example, an acceptable provider of DPGMME is Dow Corning, whose "Dowanol DPM ™" product has the following characteristics: boiling point 74.6 ° C at 1.3 mPa, melting point -83 ° C, density 0.948 g / cm3 a ° C, viscosity 3.72 mPa.s at 25 ° C and refractive index 1421 at 25 ° C. It is preferred that the monoalkyl ether (C -? -) of dialkylene (C2.) Glycol be present in the formulation at a level of up to about 20% v / v, although it is better to be within the range of 2. - about 16% v / v, and even better within the range 4-12% v / v, approximately, with the maximum preference being within the range 6-12% v / v, approximately. It is preferred that the volatile solvent tolerable by the skin is present and that it is ethanol or isopropanol (IPA). The solvent tolerable by the skin of most preference is the IPA: It is preferred that the ratio between the concentration of the active compound, in w / v, and that of the glycol monomethyl ether, in v / v, be within the approximate range of (0.5 to 2) to 1. It is preferred that the The ratio between the concentration of the active compound, in w / v, and that of the monomethyl ether of glycol, in v / v, lies within the approximate range of (0.7 to 1.4) to 1. And it refers even more than the relationship between The concentration of the active compound, in w / v, and that of the glycol monomethyl ether, in v / v, is within the approximate range of (0.9 to 1.1) to 1. Although the maximum preference is that the ratio between the concentration of the active compound, in w / v, and that of the monomeric ether of the glycol, in v / v, is approximately 1: 1. It is preferred that the level of avermectin or active milbemycin in the total formulation is in the range of about 1% to about 16% w / v, better if it is between about 4% and the 12% p / v, approximately, and even better if it is located between 6%, approximately, and 12% p / v, approximately. Optionally, the formulation may include an antioxidant, such as propyl gallate, BHA (2-t-butyl-4-methoxyphenol), or BHT (2,6-di-t-butyl-4-methylphenyl). It is preferred that the antioxidant, if included, be the BHT. It is preferred that the antioxidant, if included, be at a lower level than 0. 2% p / v, and even better at a level below 0.1% p / v. It is also preferred that the formulation be composed of: (a) 5-oximino-22,23-dihydro-25-cyclohexylavermectin B1 monosaccharide (selamectin, at a level of 1 to 16% w / v); (b) DEGMME or DPGMME at a level of 1 to 16% v / v, and with a relation between the concentration of the active compound, in p / v, and that of the DEGMME or that of the DPGMME, in v / v, of the order of 1: 1; (c) isopropanol q.s. at 100% v / v; and, optionally (d) BHT (at a level lower than 0.1% w / v). The most preferred formulation is composed of: (a) 5-oximino-22,23-dihydro-25-cyclohexylavermectin B1 monosaccharide (selamectin, at a level of 6 to 12% w / v); (b) DEGMME or DPGMME at a level of 6 to 12% v / v, and with a relation between the concentration of the active compound, in p / v, and that of the DEGMME or that of the DPGMME, in v / v, of the order of 1: 1; (c) isopropanoi q.s. 100% v / v; and, optionally (d) BHT (at a level lower than 0.1% w / v). A group of preferred formulations is that of the formulations mentioned in the examples set forth below. Another aspect of the invention is a method for the treatment of a disorder caused by an endoparasite or an ectoparasite by administering an effective amount of a formulation according to the invention. Another aspect of the invention is a formulation according to the invention for use in medicine.

Another aspect of the invention is the use of a formulation according to the invention in the manufacture of a medicament for the treatment of disorders caused by endoparasites or ectoparasites. The formulations according to the invention can be obtained by standard methods, such as, for example, the dissolution of avermectin or milbemycin, or both, as well as that of an optional antioxidant in the solvent or solvents provided, according to the invention. with standard veterinary or pharmaceutical practice, that is, by agitation of the mixture of components and heating simultaneously, if necessary. The invention is illustrated by the following examples, in which (i) the antioxidant BHT (if included) was dissolved in a mixture of DPGMME or DEGMME and IPA, (i) the active compound was added and stirred the mixture until its total dissolution occurred, (iii) any residue was filtered before proceeding to fill the appropriate containers.

EXAMPLE 1 A formulation composed of: (a) 5-oximino-22,23-dihydro-25-cyclohexylavermectin B1 monosaccharide at 6% w / v (b) DPGMME at 6% v / v (c) BHT at 0.08% w / v (d) IPA qs 100% v / v.

EXAMPLE 2 A formulation composed of: (a) 5-oximino-22,23-dihydro-25-cyclohexylavermectin B1 monosaccharide at 6% w / v (b) DPGMME a! 6% v / v (c) IPA q.s. 100% v / v.

EXAMPLE 3 A formulation composed of: (a) 5-oximino-22,23-dihydro-25-cyclohexylavermectin B1 8% monosaccharide w / v (b) 16% DPGMME v / v (c) BHA at 0.1% w / v (d) IPA q.s. 100% v / v.

EXAMPLE 4 A formulation composed of: (a) 5-oximino-22,23-dihydro-25-cyclohexyiavermectin B1 12% monosaccharide w / v (b) 12% v / v DPGMME (c) BHT 0.08% w / v ( d) IPA qs 100% v / v.

EXAMPLE 5 A formulation composed of: (a) 5-oximino-22,23-dihydro-25-cyclohexylvermectin B1 12% monosaccharide w / v (b) 12% v / v DPGMME (c) IPA q.s. 100% v / v.

EXAMPLE 6 A formulation composed of: . (a) 5-Oximino-22,23-dihydro-25-cyclohexylvermectin B1 monosaccharide 16% w / v (b) DPGMME 16% v / v (c) BHAal 0.1% w / v (d) IPAq .s.100% v / v.

EXAMPLE 7 A formulation composed of: (a) 5-oximino-22,23-dihydro-25-cyclohexylavermectin B1 monosaccharide at 16% w / v (b) DEGMME at 16% v / v (c) IPAq.s.100% v / v.

EXAMPLE 8 A formulation composed of: (a) 5-oximino-22,23-dihydro-25-cyclohexylavermectin B1 monosaccharide 16% w / v (b) 8% DPGMME v / v (c) IPAq.s.100% v / v.

EXAMPLE 9 A formulation composed of: (a) 5-oximino-22,23-dihydro-25-cyclohexylavermectin B1 monosaccharide 16% w / v (b) DPGMME 16% v / v (c) IPA q.s. 100% v / v.

EXAMPLE 10 A formulation composed of: (a) 5-oximino-22,23-dihydro-25-cyclohexylavermectin B1 monosaccharide 16% w / v (b) 8% DEGMME v / v (c) IPA q.s. 100% v / v.

EXAMPLE 11 A formulation composed of the following components (in mg / ml): (a) 5-oximino-22,23-dihydro-25-cyclohexylververctin B 1 monosaccharide (60); (b) DPGMME (56.28); (c) BHT (0.8); and (d) IPA q.s. (697.92).

EXAMPLE 12 A formulation with the following components (in mg / ml): (a) 5-oximino-22,23-dihydro-25-cyclohexylavermectin B1 monosaccharide (120); (b) DPGMME (112.56); (c) BHT (0.8); and (d) IPA (613.64). The amount of avermectin or milbemycin antiparasitic material in a unit dose of the formulation will vary, logically, depending on the efficacy of avermectin or milbemycin in the treatment of the disorder of interest, as well as the frequency of application desired, etc. ., in accordance with standard veterinary or pharmaceutical practice. The formulations of the invention can be administered in a manner that suits the specific intended use, the particular species and the weight of the host animal being treated, the parasite in question, the degree of infestation, etc., in accordance with standard veterinary or pharmaceutical practice. For dogs and cats, for example, a dose of 5-oximino-22,23-dihydro-25-cyclohexylavermectin B1 monosaccharide (selamectin) of between 4 mg / kg and 12 mg / kg body weight of the host animal, preferably 9 mg / kg, as an individual dose once a month will be adequate for flea control and for filarial prophylaxis, although, of course, there will be cases in which higher or lower dosage ranges will be more indicated, said cases being within the scope of this invention. A usual dosage regimen for a dose of 6 mg / kg and for a typical pet such as a dog or cat, should be 0.25 ml to 2 ml of the formulation of example 1 per dose and per month. The formulations according to the invention are especially suitable for topical administration. Topical applications of these formulations can be highlighted: the immersion bath, the spray, the "pour-on", the "spot-on", the liquid or jet, the shampoos, the collar, the ear tag or the harness. A "spot-on" formulation is particularly preferred. It is understood that the reference to treatment includes prevention, relief and cure of disorder or disorders caused by the parasite or parasites. The effectiveness of the formulations according to the invention is illustrated below. Three formulations of selamectin were administered in the form of individual topical doses of 8 mg / kg and their efficacy was evaluated over time against induced infestations of the flea Ctenocephalides feüs in dogs. Each of the formulations contained 160 mg / ml selamectin and 16% w / v diethylene glycol monomethyl ether (DEGMME), 8% w / v of dipropylene glycol monomethyl ether (DPGMME) or 16% w / v of DPGMME, respectively, in addition to the isopropanol needed to reach the final volume. We randomly assigned 36 dogs (16 males and 20 females), which had previously been infested with 100 adult fleas, alive and not fed, to each of the four groups for the flea count. These groups subsequently received saline (negative control, T1), selamectin in 16% w / v of DEGMME (T2), selamectin in 8% w / v of DPGMME (T3), and selamectin in 16% w / v of DPGMME (T4). On day 0, treatment was administered topically at the base of the neck between the shoulder blades of the animal. The effectiveness was determined by comb counting the live fleas present in each dog. Each dog had been infested with approximately 100 adult C. feüs, alive and without feeding on days 1, 4, 11, 18, 23, 27, 32 and 39, and the comb counts were made approximately 72 hours after each infestation, on days 4, 7, 14, 21, 26, 30, 35 and 42. No adverse drug reactions or mortalities were observed during the study. The geometric mean of the comb count of the fleas for each of the three formulations of selamectin was significantly lower (P <0.05) than that corresponding to the saline control on each day post-treatment of flea count. On day 30, the efficiencies (reductions in percent of the geometric mean of flea comb counts) were 98.6%, 98.2%, and 99.4% for T2, T3, and T4, respectively. On day 35, the efficiencies were 93.5%, 95.9% and 97.7%, for T2, T3 and T4, respectively. On day 42, efficiencies were 67.3%, 82.3% and 88.1%, for T2, T3 and T4, respectively. The efficacy of the selamectin formulation, administered topically in dosages of 3 mg / kg, 6 mg / kg and 9 mg / kg, was evaluated over time against induced infestations of Ctenocephalides felis in dogs in order to determine the adequate dose. The formulation contained 12% (120 mg / ml) of selamectin and 11.26% w / v of dipropylene glycol monomethyl ether (DPGMME) in sodium propane. We randomly assigned 48 dogs (24 males and 24 females) for the flea count by sex to each of the following four groups: placebo (negative control, T1), selamectin at 3 mg / kg (T2), selamectin a 6 mg / kg (T3), selamectin at 9 mg / kg (T4). On day 0, treatment was administered topically on the animal's back, at the base of the neck between the shoulder blades. The effectiveness was determined by comb counting the live fleas present in each dog. Each dog had been infested with approximately 100 adult C. felis, alive and without feeding on days 4, 11, 18, and 27, and the comb counts were made approximately 72 hours after each infestation, on days 7, 14, 21 and 30. There were no adverse drug reactions or mortalities during the study. The reductions in percent of the geometric mean of the comb-flea counts for the three selamectin treatments were 94.6% to 100% on days 7, 14, and 21. On day 30, the percent reductions were 81.5%. %, 94.7% and 90.8% for T2, T3 and T4, respectively. The analysis of the variance showed that, on day 30, the comb counts of the fleas for each of the treated groups (T2, T3 and T4 combined) were significantly lower (P <0.05) than those of the placebo (T1), and that the counts for the treatment of 3 mg / kg (T2) were significantly higher (P <0.05) than the counts for the treatments of 6 mg / kg and 9 mg / kg (T3 and T4 combined), which were not statistically very different ( P> 0.10).

Claims (20)

NOVELTY OF THE INVENTION REVIVALS

1. - An antiparasitic formulation containing: (a) 0.1-50% w / v of a 5-oxime 13-monosaccharide avermectin (b) a 1-50 v / v of a monoalkyl ether (C? -4) of a dialkylene (C2.) Glycol; (c) an optional antioxidant; and optionally (d) a volatile solvent q.s. v / v, tolerable by the skin.

2. The formulation according to claim 1, wherein the amount of (C1-4) monoalkyl ether of (C2-4) dialkylene glycol is in the range of about 1-20% v / v.

3. The formulation according to the preceding claim in which avermectin or milbemycin has activity against both endoparasites and ectoparasites.

4. The formulation according to any of the preceding claims wherein the 5-oxime 13-monosaccharide avermectin is a 5-oxime-22,23-dihydro-25-cyclohexylververchne B1 monosaccharide (selamectin).

5. The formulation according to any of the preceding claims wherein the monoalkyl ether (C -? - 4) of a dialkylene (C2-4) glycol is the monomethyl ether of diethylene glycol (DEGMME) or the monomethyl ether of dipropylene glycol ( DPGMME).

6. The formulation according to any of the preceding claims wherein the monomethyl ether of glycol is DPGMME.

7. - The formulation according to any of the preceding claims wherein the solvent tolerable by the skin is present and is ethanol or ispropane !.

8. The formulation according to any of the preceding claims wherein the solvent tolerable by the skin is present and is isopropanol.

9. The formulation according to any of the preceding claims wherein the ratio p / v to v / v; of an active compound to glycol monomethyl ether is within the range of (0.5 to 2) to 1.

10. The formulation according to any of the preceding claims wherein the ratio p / vav / v of an active compound to glycol monomethyl ether! is from (0.7 to 1.4) to 1 11.-.

The formulation according to any of the preceding claims wherein the ratio v / v to v / v of an active compound to glycol monomethyl ether is from (0.9 to 1.1) to 1 12.-.

The formulation according to any of the preceding claims wherein the ratio v / v to v / v of an active compound to monomethyl ether of glycol is 1: 1 13.-.

The formulation according to any of the preceding claims wherein the level of active substance in the total formulation is in the range of 1 to 16%.

14. - The formulation according to any of the preceding claims wherein the level of active substance in the total formulation is within the range of 4 to 12%.

15. The formulation according to any of the preceding claims wherein the level of active substance in the total formulation is within the range of 6 to 12%.

16. The formulation according to any of the preceding claims wherein the antioxidant is present and selected from propylgalate, BHA (2-t-butyl-4-methoxyphenol), and BHT (2,6-di). -t-butyl-4-methylphenol).

17. The formulation according to any of the preceding claims wherein the antioxidant is present and is BHT.

18. The formulation according to claim 1 wherein the formulation is composed of: (a) 5-oximino-22,23-dihydro-25-cyclohexylavermectin B1 monosaccharide (selamectin, at a level of 1 to 16% p / v); (b) DEGMME or DPGMME at a level of 1 to 16% v / v, and with a ratio v / v to v / v of the active compound to DEGMME / DPGMME, of about 1: 1; (c) sopropanol q.s. 100% v / v; and, optionally (d) BHT (at a level lower than 0.1% w / v).

19. The formulation according to claim 18 which consists of: (a) 5-oximino-22,23-dihydro-25-cyclohexylavermectin B1 monosaccharide (selamectin, at a level of 6 to 12% w / v); (b) DEGMME or DPGMME at a level from 6 to 12% v / v, and with a ratio v / v to v / v of the active compound to DEGMME / DPGMME, of approximately 1: 1; (c) sopropanol q.s. 100% v / v; and, optionally (d) BHT (at a level lower than 0.1% w / v).

20. The use of a formulation according to any of claims 1 to 19 in the manufacture of a medicament for the treatment of a disorder caused by an endoparasite or by an ectoparasite.