WO2000030449A1 - Antiparasitic formulations - Google Patents

Antiparasitic formulations Download PDF

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Publication number
WO2000030449A1
WO2000030449A1 PCT/IB1999/001715 IB9901715W WO0030449A1 WO 2000030449 A1 WO2000030449 A1 WO 2000030449A1 IB 9901715 W IB9901715 W IB 9901715W WO 0030449 A1 WO0030449 A1 WO 0030449A1
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WO
WIPO (PCT)
Prior art keywords
formulation according
formulation
dpgmme
monomethyl ether
glycol monomethyl
Prior art date
Application number
PCT/IB1999/001715
Other languages
French (fr)
Inventor
Timothy Michael Lukas
Stephen Richard Wicks
Original Assignee
Pfizer Limited
Pfizer Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=10842728&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=WO2000030449(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Priority to AU59959/99A priority Critical patent/AU5995999C1/en
Priority to CNB998134554A priority patent/CN1147232C/en
Priority to DE69923583T priority patent/DE69923583T3/en
Priority to AT99972494T priority patent/ATE288201T1/en
Priority to BRPI9915458-7A priority patent/BR9915458B1/en
Priority to EA200100458A priority patent/EA003959B1/en
Priority to PL348638A priority patent/PL204763B1/en
Priority to EP99972494A priority patent/EP1130966B2/en
Priority to CA002351730A priority patent/CA2351730C/en
Priority to DK99972494T priority patent/DK1130966T4/en
Priority to IL14210499A priority patent/IL142104A0/en
Application filed by Pfizer Limited, Pfizer Inc. filed Critical Pfizer Limited
Priority to SK662-2001A priority patent/SK287540B6/en
Priority to NZ510678A priority patent/NZ510678A/en
Priority to SI9930759T priority patent/SI1130966T2/en
Priority to HU0104235A priority patent/HU229493B1/en
Priority to JP2000583347A priority patent/JP3507799B2/en
Publication of WO2000030449A1 publication Critical patent/WO2000030449A1/en
Priority to IL142104A priority patent/IL142104A/en
Priority to IS5907A priority patent/IS5907A/en
Priority to NO20012389A priority patent/NO20012389L/en
Priority to HR20010368A priority patent/HRP20010368B1/en
Priority to BG105601A priority patent/BG65440B1/en
Priority to HK02102583.7A priority patent/HK1040593B/en
Priority to IL173567A priority patent/IL173567A0/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A61K9/0017—Non-human animal skin, e.g. pour-on, spot-on
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/90—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having two or more relevant hetero rings, condensed among themselves or with a common carbocyclic ring system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/14—Ectoparasiticides, e.g. scabicides

Definitions

  • This invention relates to antiparasitic formulations, particularly antiparasitic formulations containing avermectins or milbemycins, including derivatives thereof, suitable for topical application to mammals, including humans and domestic animals such as cats and dogs, and which are useful in the treatment of conditions caused by endo- and/or ectoparasites.
  • formulations of substances active against fleas and/or heartworms are especially of interest.
  • Antiparasitic avermectins, milbemycins and their derivatives have been described in numerous publications, see for example European Patent Applications publication nos. 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, 0 410 615, British Patent Application numbers 1 573 955, 1 390 336, International Patent Applications publication nos.
  • ivermectin IvomecTM
  • doramectin DectomaxTM
  • moxidectin moxidectin
  • abamectin AvomecTM
  • a long-acting antiparasitic formulation suitable for topical application including:
  • the formulations of the invention have a good cosmetic profile. For instance when applied topically to the fur of a domestic animal such as a cat or dog, they spread well giving good skin contact across a wide range of temperatures. They do not leave an unsightly oily patch, of the type associated with some commercial avermectin or milbemycin formulations in fatty excipients.
  • formulations according to the invention are effective enough to enable long periods, e.g. a several weeks or a month, between treatments.
  • the active compound has activity against both endo- and ectoparasites.
  • the active compound is selected from ivermectin, doramectin, abamectin, moxidectin, and the avermectin 13-monosaccharide 5-oximes generically and specifically disclosed in International Patent Application publication no. WO 94/15944.
  • the active compound is 5-oximino-22,23-dihydro-25- cyclohexylavermectin B 1 monosaccharide (selamectin).
  • the di(C,_, glycol) mono(C alkyl) ether is diethylene glycol monomethyl ether (DEGMME) or dipropylene glycol monomethyl ether (DPGMME). More preferably the glycol monomethyl ether is DPGMME.
  • any source of phamaceutical/veterinary quality di(C 2 _ 4 glycol) mono(C, .4 alkyl) ethers may be used.
  • an acceptable commercial source of DPGMME is Dow Corning, whose product "Dowanol DPMTM" has the following characteristics: B.pt. 74.6°C at 13mbar; freezing point -83°C, density 0.948g/cm 3 at 25°C, viscosity 3.72 Pas at 25°C and refractive index of 1.421 at 25°C.
  • the di(C 2 . 4 glycol) mono(C,_ 4 alkyl) ether is present in the formulation at a level of up to about 20% v/v, yet more preferably in the range about 2-16% v/v, further more preferably in the range about 4-12% v/v, and most preferably in the range about 6- 12% v/v.
  • the skin acceptable volatile solvent is present and is ethanol or isopropanol (IPA). More preferably the skin acceptable solvent is IPA.
  • the w/v to v/v ratio of active compound to the glycol monomethyl ether is in the range about (0.5 to 2) to 1.
  • the w/v to v/v ratio of active compound to the glycol monomethyl ether is about (0.7 to 1.4) to 1.
  • the w/v to v/v ratio of active compound to the glycol monomethyl ether is about (0.9 to 1.1) to 1.
  • the w/v to v/v ratio of active compound to the glycol monomethyl ether is about 1:1.
  • the level of active avermectin or milbemycin in the total formulation is in the range about 1% to about 16% w/v, more preferably about 4% to about 12% w/v, yet more preferably about 6 to about 12% w/v.
  • the formulation can further include an antioxidant, such as propylgallate,
  • BHA (2-t-butyl-4-methoxyphenol), or BHT (2,6-di-t-butyl-4-methylphenol).
  • the antioxidant if present, is BHT.
  • the antioxidant if present, is at a level of less than 0.2% w/v, more preferably less than 0.1% w/v.
  • the formulation consists of: (a) 5-oximino-22,23-dihydro-25-cyclohexylavermectin Bl monosaccharide (selamectin, at a level of 1% to 16% w/v);
  • the formulation consists of:
  • a preferred group of formulations consists of the formulations mentioned in the Examples below.
  • Another aspect of the invention is a method of treatment of a condition caused by an endo- or ectoparasite by administration of 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.
  • Formulations according to the invention can be made by standard methods, for example by dissolution of the avermectin and/or milbemycin and optional antioxidant in the solvent or solvents, in accordance with standard pharmaceutical or veterinary practice, e.g. by agitation of a mixture of the ingredients, if necessary with concurrent warming.
  • the invention is illustrated by the following examples, in which (i) the BHT antioxidant (if present) was dissolved in a mixture of DPGMME or DEGMME and IPA, (ii) the drug substance was added, and the mixture stirred until dissolution took place, (iii) any residue was filtered off prior to filling into appropriate containers.
  • a formulation consisting of (a) 5-oximino-22,23-dihydro-25-cyclohexylavermectin Bl monosaccharide at 6% w/v
  • a formulation consisting of (a) 5-oximino-22,23-dihydro-25-cyclohexylavermectin Bl monosaccharide at 8% w/v (b) DPGMME at 16% v/v (c) BHA 0.1 % w/v (d) IPA q.s. 100% v/v.
  • Example 8 A formulation consisting of
  • the amount of antiparasitic avermectin / milbemycin material in a unit dose of the formulation can of course vary depending on the efficacy of the avermectin / milbemycin in treating the condition of interest, the desired frequency of application, etc., according to standard veterinary and pharmaceutical practice.
  • formulations of the invention can be administered in a way appropriate to the specific use envisaged, the particular species and weight of host animal being treated, the parasite or parasites involved, degree of infestation, etc., according to standard medical and veterinary practice.
  • a dose of 5-oximino-22,23-dihydro-25- cyclohexylavermectin B 1 monosaccharide (selamectin) of between 4 mg/kg and 12 mg/kg, preferably about 9 mg/kg body weight of the host animal as a single dose once per month will be satisfactory for flea control and heartworm prophylaxis, but of course there will be instances where higher or lower dosage ranges are indicated and such are within the scope of this invention.
  • a typical dosage regime for a 6mg/kg dose, to a domestic animal such as a typical domestic cat or dog, would be 0.25ml to 2ml of the formulation of Example 1 per dose per month.
  • formulations according to the invention are especially suitable to be administered topically.
  • dip, spray, pour-on, spot-on, jetting fluid, shampoos, collar, tag or harness may be used.
  • Particularly preferred is a spot-on formulation.
  • reference to treatment includes prevention, alleviation and cure of the condition or conditions caused by the parasite or parasites.
  • the efficacy of the formulations according to the invention is illustrated by the following.
  • Three formulations of selamectin were administered as a single topical dose of 8 mg/kg, and evaluated over time against induced infestations of the flea (Ctenocephalides felis) on dogs.
  • the three formulations each contained 160 mg/mL of selamectin and, respectively, 16% w/v diethylene glycol monomethyl ether
  • Efficacy was assessed by comb counts of viable fleas present on each dog. Each dog was infested with approximately 100 unfed viable adult C. felis on days 1, 4, 11, 18, 23, 27, 32, and 39, and comb counts were conducted approximately 72 hours after each infestation, on days 4, 7, 14, 21, 26, 30, 35 and 42. There were no adverse drug reactions and no mortalities during the study. Geometric mean flea comb counts for each of the three selamectin formulations were significantly lower (P ⁇ 0.05) than those of the saline control on each post-treatment flea counting day. Efficacies (percentage reductions in geometric mean flea comb counts) on day 30 were 98.6%, 98.2% and 99.4% for T2, T3 and T4, respectively.
  • the efficacy of a selamectin formulation was evaluated against induced infestations of Ctenocephalides felis on dogs for the determination of an appropriate dose.
  • the formulation contained 12% (120 mg/mL) of selamectin and 11.26% w/v dipropylene glycol monomethyl ether (DPGMME) in isopropanol.
  • Forty-eight dogs 24 males and 24 females were allocated randomly by flea counts within sex to one of four groups: placebo (negative control, Tl) or selamectin at 3 mg/kg (T2), 6 mg/kg (T3) or 9 mg/kg (T4).

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Zoology (AREA)
  • Dermatology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Pest Control & Pesticides (AREA)
  • Plant Pathology (AREA)
  • Organic Chemistry (AREA)
  • Dentistry (AREA)
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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

ANTIPARASITIC FORMULATIONS
This invention relates to antiparasitic formulations, particularly antiparasitic formulations containing avermectins or milbemycins, including derivatives thereof, suitable for topical application to mammals, including humans and domestic animals such as cats and dogs, and which are useful in the treatment of conditions caused by endo- and/or ectoparasites. Especially of interest are formulations of substances active against fleas and/or heartworms.
Antiparasitic avermectins, milbemycins and their derivatives have been described in numerous publications, see for example European Patent Applications publication nos. 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, 0 410 615, British Patent Application numbers 1 573 955, 1 390 336, International Patent Applications publication nos. WO 94/15944 and WO 95/22552, "Ivermectin and Abamectin", WC Campbell, Springer Nerlag, New York (1989), and "Doramectin - a potent novel endectocide", AC Goudie et al, Vet.Parasitol. 49 (1993) 5.
A number of such substances have been developed for commercialisation, for example ivermectin (Ivomec™), doramectin (Dectomax™), moxidectin and abamectin (Avomec™).
International Patent Application publication no. WO 94/15944, the teaching of which is herein incorporated by reference in its entirety, describes a family of 5-oximino derivatives of avermectin 13-monosaccharides having activity in the treatment of a number of conditions caused by endo- and/or ectoparasites, including 5-oximino-22,23- dihydro-25-cyclohexylavermectin Bl monosaccharide (selamectin, Example 5).
We describe herein long-acting formulations suitable for topical application that are capable of delivering avermectins and milbemycins with activity against endo- and/or ecto-parasites. These formulations have good cosmetic profiles, stability on storage, cutaneous tolerability, and transdermal delivery characteristics. According to one aspect of the invention there is provided a long-acting antiparasitic formulation suitable for topical application including:
(a) about OJ-50% w/v an avermectin or milbemycin having activity against endo- and/or ectoparasites;
(b) about 1-50% v/v a di(C2^, glycol) mono(C alkyl) ether;
(c) an optional antioxidant; and
(d) an optional skin acceptable volatile solvent q.s. v/v.
[By "w/v" is meant weight/volume, i.e. "1% w/v" means Ig in 100ml of the formulation.]
The formulations of the invention have a good cosmetic profile. For instance when applied topically to the fur of a domestic animal such as a cat or dog, they spread well giving good skin contact across a wide range of temperatures. They do not leave an unsightly oily patch, of the type associated with some commercial avermectin or milbemycin formulations in fatty excipients.
Certain of the formulations according to the invention are effective enough to enable long periods, e.g. a several weeks or a month, between treatments.
Preferably the active compound has activity against both endo- and ectoparasites.
Preferably the active compound is selected from ivermectin, doramectin, abamectin, moxidectin, and the avermectin 13-monosaccharide 5-oximes generically and specifically disclosed in International Patent Application publication no. WO 94/15944.
Most preferably the active compound is 5-oximino-22,23-dihydro-25- cyclohexylavermectin B 1 monosaccharide (selamectin).
Preferably the di(C,_, glycol) mono(C alkyl) ether is diethylene glycol monomethyl ether (DEGMME) or dipropylene glycol monomethyl ether (DPGMME). More preferably the glycol monomethyl ether is DPGMME.
Any source of phamaceutical/veterinary quality di(C2_4 glycol) mono(C,.4 alkyl) ethers may be used. For instance, an acceptable commercial source of DPGMME is Dow Corning, whose product "Dowanol DPM™" has the following characteristics: B.pt. 74.6°C at 13mbar; freezing point -83°C, density 0.948g/cm3 at 25°C, viscosity 3.72 Pas at 25°C and refractive index of 1.421 at 25°C.
Preferably the di(C2.4 glycol) mono(C,_4 alkyl) ether is present in the formulation at a level of up to about 20% v/v, yet more preferably in the range about 2-16% v/v, further more preferably in the range about 4-12% v/v, and most preferably in the range about 6- 12% v/v.
Preferably the skin acceptable volatile solvent is present and is ethanol or isopropanol (IPA). More preferably the skin acceptable solvent is IPA.
Preferably the w/v to v/v ratio of active compound to the glycol monomethyl ether is in the range about (0.5 to 2) to 1.
More preferably the w/v to v/v ratio of active compound to the glycol monomethyl ether is about (0.7 to 1.4) to 1.
Yet more preferably the w/v to v/v ratio of active compound to the glycol monomethyl ether is about (0.9 to 1.1) to 1.
Most preferably the w/v to v/v ratio of active compound to the glycol monomethyl ether is about 1:1.
Preferably the level of active avermectin or milbemycin in the total formulation is in the range about 1% to about 16% w/v, more preferably about 4% to about 12% w/v, yet more preferably about 6 to about 12% w/v.
Optionally the formulation can further include an antioxidant, such as propylgallate,
BHA (2-t-butyl-4-methoxyphenol), or BHT (2,6-di-t-butyl-4-methylphenol). Preferably, the antioxidant, if present, is BHT. Preferably, the antioxidant, if present, is at a level of less than 0.2% w/v, more preferably less than 0.1% w/v.
Preferably the formulation consists of: (a) 5-oximino-22,23-dihydro-25-cyclohexylavermectin Bl monosaccharide (selamectin, at a level of 1% to 16% w/v);
(b) DEGMME or DPGMME at 1 to 16% v/v, and at a w/v to v/v ratio of active compound to DEGMME/DPGMME of about 1 :1;
(c) isopropanol q.s. 100% v/v; and, optionally (d) BHT (at less than 0.1 % w/v).
More preferably the formulation consists of:
(a) 5-oximino-22,23-dihydro-25-cyclohexylavermectin Bl monosaccharide (selamectin, at a level of 6% to 12% w/v); (b) DEGMME or DPGMME 6 to 12% v/v, and at a w/v to v/v ratio of active compound to or DEGMME/DPGMME of about 1:1; (c) isopropanol q.s. 100% v/v; and, optionally (d) BHT (at less than 0.1% w/v).
A preferred group of formulations consists of the formulations mentioned in the Examples below.
Another aspect of the invention is a method of treatment of a condition caused by an endo- or ectoparasite by administration of 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 conditions caused by endo- and/or ecto-parasites. Formulations according to the invention can be made by standard methods, for example by dissolution of the avermectin and/or milbemycin and optional antioxidant in the solvent or solvents, in accordance with standard pharmaceutical or veterinary practice, e.g. by agitation of a mixture of the ingredients, if necessary with concurrent warming.
The invention is illustrated by the following examples, in which (i) the BHT antioxidant (if present) was dissolved in a mixture of DPGMME or DEGMME and IPA, (ii) the drug substance was added, and the mixture stirred until dissolution took place, (iii) any residue was filtered off prior to filling into appropriate containers.
Example 1
A formulation consisting of (a) 5-oximino-22,23-dihydro-25-cyclohexylavermectin Bl monosaccharide at 6% w/v
(b) DPGMME at 6% v/v
(c) BHT at 0.08% w/v
(d) IPA q.s. 100% v/v.
Example 2
A formulation consisting of
(a) 5-oximino-22,23-dihydro-25-cyclohexylavermectin Bl monosaccharide at 6% w/v
(b) DPGMME at 6% v/v (c) IPA q.s. 100% v/v.
Example 3
A formulation consisting of (a) 5-oximino-22,23-dihydro-25-cyclohexylavermectin Bl monosaccharide at 8% w/v (b) DPGMME at 16% v/v (c) BHA 0.1 % w/v (d) IPA q.s. 100% v/v.
Example 4
A formulation consisting of
(a) 5-oximino-22,23-dihydro-25-cyclohexylavermectin Bl monosaccharide at 12% w/v
(b) DPGMME at 12% v/v
(c) BHT at 0.08% w/v
(d) IPA q.s. 100% v/v.
Example 5
A formulation consisting of
(a) 5-oximino-22,23-dihydro-25-cyclohexylavermectin Bl monosaccharide at 12% w/v (b) DPGMME at 12% v/v
(c) IPA q.s. 100% v/v.
Example 6
A formulation consisting of
(a) 5-oximino-22,23-dihydro-25-cyclohexylavermectin Bl monosaccharide at 16% w/v
(b) DPGMME at 16% v/v (c) BHA OJ % w/v
(d) IPA q.s. 100% v/v.
Example 7
A formulation consisting of
(a) 5-oximino-22,23-dihydro-25-cyclohexylavermectin Bl monosaccharide at 16% w/v
(b) DEGMME at 16% v/v (c) IPA q.s. 100% v/v.
Example 8 A formulation consisting of
(a) 5-oximino-22,23-dihydro-25-cyclohexylavermectin Bl monosaccharide at 16% w/v
(b) DPGMME at 8% v/v
(c) IPA q.s. 100% v/v.
Example 9
A formulation consisting of
(a) 5-oximino-22,23-dihydro-25-cyclohexylavermectin Bl monosaccharide at 16% w/v
(b) DPGMME at 16% v/v (c) IPA q.s. 100% v/v.
Example 10
A formulation consisting of
(a) 5-oximino-22,23-dihydro-25-cyclohexylavermectin Bl monosaccharide at 16% w/v (b) DEGMME at 8% v/v
(c) IPA q.s. 100% v/v.
Example 11
A formulation with the following ingredients (in mg/ml): (a) 5-oximino-22,23-dihydro-25-cyclohexylavermectin Bl monosaccharide (60);
(b) DPGMME (56.28);
(c) BHT (0.8); and
(d) IPA (697.92).
Example 12
A formulation with the following ingredients (in mg/ml):
(a) 5-oximino-22,23-dihydro-25-cyclohexylavermectin Bl monosaccharide (120);
(b) DPGMME (112.56);
(c) BHT (0.8); and (d) IPA (613.64).
The amount of antiparasitic avermectin / milbemycin material in a unit dose of the formulation can of course vary depending on the efficacy of the avermectin / milbemycin in treating the condition of interest, the desired frequency of application, etc., according to standard veterinary and pharmaceutical practice.
The formulations of the invention can be administered in a way appropriate to the specific use envisaged, the particular species and weight of host animal being treated, the parasite or parasites involved, degree of infestation, etc., according to standard medical and veterinary practice.
For example, for dogs and cats, a dose of 5-oximino-22,23-dihydro-25- cyclohexylavermectin B 1 monosaccharide (selamectin) of between 4 mg/kg and 12 mg/kg, preferably about 9 mg/kg body weight of the host animal as a single dose once per month will be satisfactory for flea control and heartworm prophylaxis, but of course there will be instances where higher or lower dosage ranges are indicated and such are within the scope of this invention. A typical dosage regime for a 6mg/kg dose, to a domestic animal such as a typical domestic cat or dog, would be 0.25ml to 2ml of the formulation of Example 1 per dose per month.
The formulations according to the invention are especially suitable to be administered topically. For topical application, dip, spray, pour-on, spot-on, jetting fluid, shampoos, collar, tag or harness may be used. Particularly preferred is a spot-on formulation.
It is to be understood that reference to treatment includes prevention, alleviation and cure of the condition or conditions caused by the parasite or parasites.
The efficacy of the formulations according to the invention is illustrated by the following. Three formulations of selamectin were administered as a single topical dose of 8 mg/kg, and evaluated over time against induced infestations of the flea (Ctenocephalides felis) on dogs. The three formulations each contained 160 mg/mL of selamectin and, respectively, 16% w/v diethylene glycol monomethyl ether
(DEGMME), 8% w/v dipropylene glycol monomethyl ether (DPGMME) or 16% w/v DPGMME, with isopropanol to volume. Thirty-six dogs (16 males and 20 females) previously infested with 100 unfed viable adult fleas were allocated randomly by flea count to one of four groups which subsequently received saline (negative control, Tl), selamectin in 16% w/v DEGMME (T2), selamectin in 8% w/v DPGMME (T3), and selamectin in 16% w/v DPGMME (T4). Treatment was administered topically at the base of the neck in front of the shoulder blades on day 0. Efficacy was assessed by comb counts of viable fleas present on each dog. Each dog was infested with approximately 100 unfed viable adult C. felis on days 1, 4, 11, 18, 23, 27, 32, and 39, and comb counts were conducted approximately 72 hours after each infestation, on days 4, 7, 14, 21, 26, 30, 35 and 42. There were no adverse drug reactions and no mortalities during the study. Geometric mean flea comb counts for each of the three selamectin formulations were significantly lower (P ≤ 0.05) than those of the saline control on each post-treatment flea counting day. Efficacies (percentage reductions in geometric mean flea comb counts) on day 30 were 98.6%, 98.2% and 99.4% for T2, T3 and T4, respectively. On day 35, efficacies for T2, T3 and T4 were 93.5%, 95.9% and 97.7%, respectively. Efficacies on day 42 were 67.3%, 82.3% and 88.1% for T2, T3, and T4, respectively.
The efficacy of a selamectin formulation, administered topically at dosages of 3 mg/kg, 6 mg/kg and 9 mg/kg, was evaluated against induced infestations of Ctenocephalides felis on dogs for the determination of an appropriate dose. The formulation contained 12% (120 mg/mL) of selamectin and 11.26% w/v dipropylene glycol monomethyl ether (DPGMME) in isopropanol. Forty-eight dogs (24 males and 24 females) were allocated randomly by flea counts within sex to one of four groups: placebo (negative control, Tl) or selamectin at 3 mg/kg (T2), 6 mg/kg (T3) or 9 mg/kg (T4). On day 0, treatments were administered topically on the animal's back at the base of the neck in front of the shoulder blades. Efficacy was assessed by comb counts of live fleas present on each dog. Each dog was infested with approximately 100 unfed viable adult C. felis on days 4, 11, 18 and 27, and comb counts were conducted approximately 72 hours after each infestation, on days 7, 14, 21 and 30, respectively. There were no adverse drug reactions and no mortalities during the study. Percentage reductions in geometric mean flea comb counts for the three selamectin treatments ranged from 94.6% to 100% on days 7, 14 and 21. On day 30, percentage reductions were 81.5%, 94.7%, and 90.8% for T2, T3, and T4, respectively. Analysis of variance showed that day 30 flea comb counts for the treated groups (T2, T3 and T4 combined) were significantly lower (P ≤ 0.05) than for placebo (Tl), and that counts for the 3 mg/kg treatment (T2) were significantly higher (P ≤ 0.05) than for the 6 mg/kg and 9 mg/kg treatments (T3 and T4 combined), which were not statistically different (P > 0J 0).

Claims

1. An antiparasitic formulation including:
(a) OJ-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(CM alkyl) ether;
(c) an optional antioxidant; and
(d) an optional skin acceptable volatile solvent q.s. v/v.
2. A formulation according to claim 1 wherein the amount of the di(C2.4 glycol) mono(C,_4 alkyl) ether is in the range of about 1-20% v/v.
3. A formulation according to any preceding claim wherein the avermectin or milbemycin has activity against both endo- and ectoparasites.
4. A formulation according to claim 1 wherein the avermectin or milbemycin is selected from ivermectin, doramectin, abamectin, moxidectin, or is an avermectin 13- monosaccharide 5-oxime.
5. A formulation according to any preceding claim wherein the avermectin or milbemycin is 5-oximino-22,23-dihydro-25-cyclohexylavermectin Bl monosaccharide (selamectin).
6. A formulation according to any preceding claim wherein the di(C2.4 glycol) mono(CM alkyl) ether is diethylene glycol monomethyl ether (DEGMME) or dipropylene glycol monomethyl ether (DPGMME).
7. A formulation according to any preceding claim wherein the glycol monomethyl ether is DPGMME.
8. A formulation according to any preceding claim wherein the skin-acceptable solvent is present and is ethanol or isopropanol.
9. A formulation according to any preceding claim wherein the skin-acceptable solvent is present and is isopropanol.
10. A formulation according to any preceding claim wherein the w/v to v/v ratio of active compound to the glycol monomethyl ether is in the range (0.5 to 2) to 1.
11. A formulation according to any preceding claim wherein the w/v to v/v ratio of active compound to the glycol monomethyl ether is (0.7 to 1.4) to 1.
12. A formulation according to any preceding claim wherein the w/v to v/v ratio of active compound to the glycol monomethyl ether is (0.9 to 1J) to 1.
13. A formulation according to any preceding claim wherein the w/v to v/v ratio of active compound to the glycol monomethyl ether is about 1:1.
14. A formulation according to any preceding claim wherein the level of active substance in the total formulation is in the range 1% to 16%.
15. A formulation according to any preceding claim wherein the level of active substance in the total formulation is in the range 4% to 12%.
16. A formulation according to any preceding claim wherein the level of active substance in the total formulation is in the range 6% to 12%.
17. A formulation according to any preceding claim wherein the antioxidant is present, and is selected from propylgallate, BHA (2-t-butyl-4-methoxyphenol), and BHT (2,6-di- t-butyl-4-methy lphenol) .
18. A formulation according to any preceding claim wherein the antioxidant is present and is BHT.
19. A formulation according to claim 1 wherein the formulation consists of:
(a) 5-oximino-22,23-dihydro-25-cyclohexylavermectin Bl monosaccharide (selamectin, at a level of 1% to 16% w/v);
(b) DEGMME or DPGMME at 1 to 16% v/v, and at a w/v to v/v ratio of active compound to DEGMME/DPGMME of about 1:1;
(c) isopropanol q.s. 100% v/v; and, optionally (d) BHT (at less than 0.1% w/v).
20. A formulation according to claim 19 which consists of: (a) 5-oximino-22,23-dihydro-25-cyclohexylavermectin Bl monosaccharide (selamectin, at a level of 6% to 12% w/v);
(b) DEGMME or DPGMME 6 to 12% v/v, and at a w/v to v/v ratio of active compound to DEGMME/DPGMME of about 1:1;
(c) isopropanol q.s. 100% v/v; and, optionally (d) BHT (at less than 0.1% w/v).
21. A method of treatment of a condition caused by an endo- or ectoparasite by administration of an effective amount of a formulation according to any one of claims 1 to 20.
22. A formulation according to any one of claims 1 to 20 for use in medicine.
23. The use of a formulation according to any one of claims 1 to 20 in the manufacture of a medicament for the treatment of a condition caused by an endo- or ectoparasite.
PCT/IB1999/001715 1998-11-19 1999-10-20 Antiparasitic formulations WO2000030449A1 (en)

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SK662-2001A SK287540B6 (en) 1998-11-19 1999-10-20 Antiparasitic formulation
AT99972494T ATE288201T1 (en) 1998-11-19 1999-10-20 ANTIPARASITIC FORMULATIONS
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EA200100458A EA003959B1 (en) 1998-11-19 1999-10-20 Antiparasitic formulations
PL348638A PL204763B1 (en) 1998-11-19 1999-10-20 Antiparasitic formulations
SI9930759T SI1130966T2 (en) 1998-11-19 1999-10-20 Antiparasitic formulations
CA002351730A CA2351730C (en) 1998-11-19 1999-10-20 Antiparasitic formulations containing avermectin 13-monosaccharide 5-oxime
DK99972494T DK1130966T4 (en) 1998-11-19 1999-10-20 Antiparasitic formulations
IL14210499A IL142104A0 (en) 1998-11-19 1999-10-20 Antiparasitic formulations
AU59959/99A AU5995999C1 (en) 1998-11-19 1999-10-20 Antiparasitic formulations
DE69923583T DE69923583T3 (en) 1998-11-19 1999-10-20 Antiparasitic formulations
BRPI9915458-7A BR9915458B1 (en) 1998-11-19 1999-10-20 topical antiparasitic formulation.
EP99972494A EP1130966B2 (en) 1998-11-19 1999-10-20 Antiparasitic formulations
HU0104235A HU229493B1 (en) 1998-11-19 1999-10-20 Antiparasitic formulations
IL142104A IL142104A (en) 1998-11-19 2001-03-19 Antiparasitic formulations
IS5907A IS5907A (en) 1998-11-19 2001-03-23 Combinations against parasites
NO20012389A NO20012389L (en) 1998-11-19 2001-05-15 Antiparasitic formulations
HR20010368A HRP20010368B1 (en) 1998-11-19 2001-05-17 Antiparasitic formulations
BG105601A BG65440B1 (en) 1998-11-19 2001-06-14 Antiparasitic formulations
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US6797701B2 (en) 2004-09-28
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JP2002530302A (en) 2002-09-17
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AP1210A (en) 2003-09-30
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AP9901697A0 (en) 1999-12-31
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