Antiparasitic formulations

Description of the invention

The subject of the invention is an antiparasitic preparation with activity against endoparasites and ectoparasites and the use of this preparation for the preparation of a suitable medicament.

The antiparasitic preparation of the invention belongs to the group of antiparasitic preparations containing avermectins and milbemycins, including their derivatives, suitable for topical administration to mammals, including humans and domestic animals such as cats and dogs, which are useful in the treatment of disease conditions caused by endoparasites and / or external. In particular, active compound formulations with activity against fleas and / or parasites of Dirofilaria immitis are of interest.

Avermectins, milbemycins and their antiparasitic derivatives have been described in many publications, see, for example, European Patent Application Publication Nos. 0214731, 0284176, 0317148, 0308145, 0340832, 0335541, 0350187, 0170006, 025364583, 0334484, 04106903, and British Patent Application Nos. , international patent application publications WO 94/15944 and WO 95122552, "Ivermectin and Abamectin, WC Campbell, Springer Verlag, New York (1989) and "Doramectin - a potent novel endectocide, AC Goudie et al., Vet. Parasitol. 49 (1993) 5.

Many such substances are marketed, for example ivermectin (Ivomec ™), doramectin (Dectomax ™), moxidectin and abamectin (Avomec ™).

In the international patent application WO 94/15944, a family of 5-oximine derivatives of the 13-mono-saccharides of avermectin is described showing activity in the treatment of many disease states caused by endocrine and / or ectoparasites, including monosaccharide B1 5-oxyimino-22,23 -dihydro-25-cyclohexylavermectin (selamectin, example 5).

The invention relates to an antiparasitic preparation with activity against endoparasites and ectoparasites, characterized in that it comprises:

(a) 12-16% w / v selamectin, (b) 8-16% w / v di (C2-4 glycol) mono (C1-4 alkyl) ether, (c) optionally an antioxidant, and (d) optionally acceptable for applying a volatile solvent to the skin in the required volume.

Preferably the formulation as mono (C1-4 alkyl) di (C2-4 glycol) ether comprises diethylene glycol monomethyl ether (DEGMME) or dipropylene glycol monomethyl ether (DPGMME).

More preferably the formulation comprises DPGMME as glycol monomethyl ether.

Preferably, the formulation comprises ethanol or isopropanol as a skin acceptable solvent.

More preferably, the formulation comprises isopropanol as a skin-acceptable solvent.

Preferably the ratio (w / v: v / v) of selamectin to glycol monomethyl ether is (0.7-1.4) to 1.

More preferably the ratio (w / v: v / v) of selamectin to glycol monomethyl ether is about 1: 1.

Preferably the formulation comprises an antioxidant selected from the group consisting of propyl gallate, 2-t-butyl-4-methoxyphenol (BHA) and 2,6-di-t-butyl-4-methylphenol (BHT).

More preferably the formulation comprises BHT as an antioxidant.

Preferably the formulation comprises:

(a) selamectin at 12% w / v;

(b) DEGMME or DPGMME in an amount of 8-16% v / v, wherein the ratio (w / v: v / v) of active ingredient to DEGMME / DPGMME is about 1: 1;

(c) BHT (less than 0.1% w / v);

(d) isopropanol needed up to 100% v / v.

In another preferred embodiment, the formulation comprises:

(a) selamectin at 16% w / v;

(b) DEGMME or DPGMME in an amount of 8-16% v / v, wherein the ratio (w / v: v / v) of the active ingredient to DEGMME or DPGMME is about 1: 1;

(c) BHT (less than 0.1% w / v);

(d) isopropanol needed up to 100% v / v.

The invention also relates to the use of a formulation as defined above for the manufacture of a medicament for the treatment of a condition caused by an endoparasite or an ectoparasite.

The term "w / v means weight / volume ratio, ie" 1% w / v means 1 g per 100 ml of preparation and the term v / v means the fraction by volume.

PL 204 763 B1

The formulations according to the invention have a long-lasting effect, are suitable for topical administration, and allow the delivery of the active ingredient with activity against endoparasites and / or ectoparasites. These formulations show a good cosmetic profile, good storage stability, skin tolerance and are suitable for percutaneous administration.

The formulations according to the invention show a good cosmetic profile. When applied topically to the hair coat of a domestic animal such as a cat or dog, the formulations spread well to ensure good skin contact over a wide temperature range. These preparations do not leave an unpleasant greasy mark on the eye, such as can be found in certain commercial preparations containing avermectin or milbemycin with fatty excipients.

The formulations according to the invention are effective over long periods between use, e.g. many weeks or a month.

It is also possible to use ivermectin, doramectin, abamectin, moxidectin and the 5-oximes of the avermectin 13-monosaccharide generally and specifically disclosed in WO 94/15944 as active ingredient.

Any source of pharmaceutically / veterinary mono (C1-4 alkyl) di (C2-4 glycol) ethers can be used. For example, a commercially acceptable source of DPGMME is from Dow Corning, whose product "Dowanol DPMT ™ has the following properties: boiling point 74.6 ° C at 1.3 kPa; pour point -83 ° C, density 0.948 g / cm³ at 25 ° C, a viscosity of 3.72 mPa · s at 25 ° C and a refractive index of 1.421 at 25 ° C.

A preferred group of preparations are those mentioned in the examples below.

The invention enables the implementation of a method of treating a condition caused by an endoparasite or an ectoparasite by administering an effective amount of a formulation according to the invention.

The formulations according to the invention can be prepared by known methods, e.g. by dissolving salamectin and optionally an antioxidant in a solvent or solvents according to standard procedures used in pharmaceutical or veterinary practice, e.g. by mixing the mixture of ingredients, if necessary with simultaneous heating.

The invention is illustrated by the following examples in which (i) the antioxidant BHT (if present) was dissolved in a mixture of DPGMME or DEGMME and IPA, (ii) the active substance of the drug was added and the mixture was stirred until the ingredients dissolved, (iii) the residue was filtered before filling with the formulation suitable containers.

Example 1

Preparation containing (a) monosaccharide B1 5-oxyimino-22,23-dihydro-25-cyclohexylavermectin: 6% w / v (b) DPGMME: 6% v / v (c) BHT: 0.08% w / v (d ) IPA - as much as needed up to 100% v / v.

Example 2

Preparation containing (a) monosaccharide B1 5-oxyimino-22,23-dihydro-25-cyclohexylavermectin: 6% w / v (b) DPGMME: 6% v / v (c) IPA - as much as needed up to 100% v / v .

Example 3

Preparation containing (a) monosaccharide B1 5-oxyimino-22,23-dihydro-25-cyclohexylavermectin: 8% w / v (b) DPGMME: 16% v / v (c) BHA: 0.1% w / v (d ) IPA - as much as needed up to 100% v / v.

Example 4

Preparation containing (a) monosaccharide B1 5-oxyimino-22,23-dihydro-25-cyclohexylavermectin: 12% w / v (b) DPGMME: 12% v / v (c) BHT: 0.08% w / v (d ) IPA - as much as needed up to 100% v / v.

Example 5

Preparation containing (a) monosaccharide B1 5-oxyimino-22,23-dihydro-25-cyclohexylavermectin: 12% w / v

(B) DPGMME: 12% v / v (c) IPA - as much as needed up to 100% v / v.

Example 6

Preparation containing (a) monosaccharide B1 5-oxyimino-22,23-dihydro-25-cyclohexylavermectin: 16% w / v (b) DPGMME: 16% v / v (c) BHA: 0.1% w / v (d ) IPA - as much as needed up to 100% v / v.

Example 7

Preparation containing (a) monosaccharide B1 5-oxyimino-22,23-dihydro-25-cyclohexylavermectin: 16% w / v (b) DEGMME: 16% v / v (c) IPA - as much as needed up to 100% v / v .

Example 8

Preparation containing (a) monosaccharide B1 5-oxyimino-22,23-dihydro-25-cyclohexylavermectin: 16% w / v (b) DPGMME: 8% v / v (c) IPA - as much as needed up to 100% v / v .

Example 9

Preparation containing (a) monosaccharide B1 5-oxyimino-22,23-dihydro-25-cyclohexylavermectin: 16% w / v (b) DPGMME: 16% v / v (c) IPA - as much as needed up to 100% v / v .

Example 10

Preparation containing (a) monosaccharide B1 5-oxyimino-22,23-dihydro-25-cyclohexylavermectin: 16% w / v (b) DEGMME: 8% v / v (c) IPA - as much as needed up to 100% v / v .

Example 11

Preparation containing the following ingredients (in mg / ml):

(a) 5-oxyimino-22,23-dihydro-25-cyclohexylavermectin monosaccharide (60);

(b) DPGMME (56.28);

(c) BHT (0.8); and (d) IPA (697.92).

Example 12

Preparation containing the following ingredients (in mg / ml):

(a) 5-oxyimino-22,23-dihydro-25-cyclohexylavermectin monosaccharide (120);

(b) DPGMME (112.56);

(c) BHT (0.8); and (d) IPA (613.64).

In accordance with standard pharmaceutical and veterinary practice, the amount of avermectin antiparasitic in a unit dose formulation may vary depending on the effectiveness of avermectin in treating a particular condition, frequency of administration desired, etc.

The formulations of the invention may be administered according to standard procedures used in pharmaceutical and veterinary practice in a manner suitable for the particular use envisaged, the particular species and weight of the host animal to be treated, the type of parasite or parasites, the degree of parasite infestation, etc.

For example, for dogs and cats, a single monthly dose of monosaccharide B1 5-oxyimino-22,23-dihydro-25-cyclohexylavermectin (selamectin) in an amount from 4 mg / kg to 12 mg / kg, preferably about 9 mg / kg of the animal's body weight -The host will be satisfactory in flea control and prophylaxis against the commonly known American heartworm (Dirofilaria immitis), but of course there will be cases where higher or lower dose ranges are indicated. A typical dosing regimen for a 6 mg / kg dose in a domestic animal such as a cat or dog would be from 0.25 ml to 2 ml of the formulation according to Example 1 per dose per month.

PL 204 763 B1

The formulations according to the invention are particularly suitable for topical administration. Topical administration may be by dipping, splashing, dipping, spotting, spraying a liquid, using shampoos, collars / collars, branding or harnesses. A spot-on formulation is particularly preferred.

It should be understood that the term treatment includes the prevention, amelioration and treatment of a condition or conditions caused by a parasite or parasite.

The effectiveness of the formulation according to the invention is illustrated as follows. The three preparations of selamectin were administered topically as a single dose of 8 mg / kg and their effect over time on induced parasite infestation, fleas (Ctenocephalides felis) in dogs was evaluated. Each of the three formulations contained 160 mg / ml selamectin and 16% w / v diethylene glycol monomethyl ether (DEGMME), 8% w / v dipropylene glycol monomethyl ether (DPGMME) or 16% w / v DPGMME, and isopropanol added to the complete formulation, respectively. volume. Thirty-six dogs (16 male and 20 female) previously infected with 100 non-fed live adult fleas were randomized for flea numbers into one of four groups that received saline (negative control, T1), selamectin each in 16 % w / v DEGMME (T2), selamectin in 8% w / v DPGMME (T3) and selamectin in 16% w / v DPGMME (T4). The treatment was topical at the base of the neck, opposite the shoulder blades on day 0. Efficacy was assessed by combing the live fleas present on each dog on a comb. Each dog was infected with approximately 100 unfed live C. felis adults on days 1, 4, 11, 18, 23, 27, 32, and 39, and comb flea counting was performed approximately 72 hours after each parasite infestation, on day 4, 7, 14, 21, 26, 30, 35 and 42. There were no adverse drug reactions or fatalities during the course of the study. The geometric mean of the flea comb counts for each of the three selamectin formulations was significantly lower (P <0.05) than that of the saline control on each post-treatment flea count day. The efficacy (percent reduction in geometric mean comb counts) on day 30 was 98.6%; 98.2% and 99.4% for T2, T3, and T4, respectively. On day 35, the efficacy for T2, T3, and T4 was 93.5%, respectively; 95.9% and 97.7%. Efficacy on day 42 was 67.3%; 82.3% and 88.1% for T2, T3, and T4, respectively.

To determine the appropriate dose, the efficacy of a topical selamectin formulation at doses of 3 mg / kg, 6 mg / kg and 9 mg / kg against the induced parasite infestation, Ctenocephalides felis, in dogs was evaluated. The formulation contained 12% (120 mg / ml) selamectin and 11.26% w / v dipropylene glycol monomethyl ether (DPGMME) in isopropanol. Forty-eight dogs (24 males and 24 females) were randomized for the number of fleas within sex into one of four groups: placebo (negative control, T1) and selamectin at a dose of 3 mg / kg (T2), 6 mg / kg ( T3) or 9 mg / kg (T4). On day 0, doses of the drug were applied topically to the animal's back at the base of the neck in front of the shoulder blades. Efficacy was assessed by counting the number of live fleas on the comb inhabited by each dog. Each dog was infected with approximately 100 unfed live C. felis adults on days 4, 11, 18, and 27, and comb counts were performed approximately 72 hours after each parasite infestation on days 7, 14, 21, and 30, respectively. the study found no adverse drug reactions or fatalities. The percent reduction in geometric mean flea comb scores for the three selamectin doses ranged from 94.6% to 100% on days 7, 14, and 21. On day 30, the percent reduction was 81.5%; 94.7% and 90.8% for T2, T3 and T4, respectively. Analysis of variance showed that the comb on day 30 for the treatment groups (T2, T3, and T4 combined) was significantly lower (P <0.05) than the placebo (T1) results, and that the counts for the 3 mg dose were / kg (T2) were significantly higher (P <0.05) than for the 6 mg / kg and 9 mg / kg doses (T3 and T4 combined), which were statistically consistent (P> 0.10).