as used herein avermectins refer to the most potent anthelmintic , insecticidal and acaricidal compounds known . several avermectins have been developed , including , ivermectin , abamectin , doramectin , eprinomectin and selamectin . ivermectin is preferably used in intradermic and / or subcutaneous compositions , such as implants and methods according to the present invention . “ conventional avermectin formulations ” refers to heartgard ® chewable tablets marketed by merial , heartgard ® 10 mg / ml and 2 . 7 mg / ml injectable form ; 0 . 153 percent and 1 . 87 percent paste form and 10 mg / ml liquid oral form . “ subject ” or “ animal subject ” refers to any non human animals able to develop pathologies related to heartworms such as , for example , pet animals . canines may be the preferred subjects of the present invention . the subject is typically a non - human mammal , and may be any such animal mentioned herein . “ heartworms ” generally may include roundworms that typically reside within the heart of a host during the final reproductive stages of its life cycle . some specific heartworms may include dirofilaria immitis and diroflaria repens and any other similar worms of the same class or subclass . “ combination ” as used herein may broadly include two or more elements or compounds physically , chemically , and / or otherwise suitably coupled with each other to produce a desired result . both components of the combination may be administered simultaneously or sequentially and may be separate dosage forms or may be part of same dosage form . “ controlling ” as used herein may broadly include the reduction , the treatment , the eradication and / or the prevention of dirofilaria immitis and dirofilaria repens and any other similar worms of the same class or subclass . the present invention thus aims at developing improved formulations of an avermectin , particularly ivermectin , that overcome the disadvantages and constrains of existing treatment and provides a method of controlling infestation and a dosage form that can be easily and safely administered to produce an efficacious response across many species susceptible to heartworm infestation / infection . currently approved dosages of ivermectin are about 6 mcg / kg orally or 200 mcg / kg subcutaneously . it is generally reported that ivermectin administered per se at 6 mcg / kg is able to kill efficiency one month aged dirofilaria larvae . cunningham cp et al ., ( am . j . vet , res ., 2006 , 67 ) brought evidence that this effective rate might be around 0 . 2 ng / ml of ivermectin in the plasma . the background art does not teach or suggest a method or formulation of ivermectin , providing a lower effective concentration of the active ivermectin drug relative to that resulting from the administration of conventional ivermectin formulations , whilst maintaining the efficacy and exhibiting improved safety profile . the present inventors have surprisingly established an effective rate at around 0 . 1 ng / ml of ivermectin in the plasma . also , the formulations according to the present invention provide a long term protection , e . g ., at least 6 months , 12 months , or 18 months up to 24 months against infections caused by parasites . accordingly in a preferred embodiment , the current invention provides a method of controlling heartworm infestation by administering an effective dose of ivermectin which achieves a reduction in dirofilaria immitis and / or dirofilaria repens in a subject , at a lower plasma concentration of ivermectin as compared to plasma ivermectin concentration obtained via conventional ivermectin formulations as defined by cunningham cp et al . ( am . j . vet . res ., 2006 , 67 ). in a preferred embodiment , said lower plasma ivermectin concentration is less than 0 . 2 ng / ml , or less to 0 . 15 ng / ml , ranges from 0 . 1 ng / ml to 0 . 15 ng / ml , around 0 . 09 ng / ml , 0 . 08 ng / ml , 0 . 07 ng / ml , 0 . 06 ng / ml , or about of 0 . 1 ng / ml . in a most preferred embodiment the said lower plasma ivermectin concentration is about 5 - 95 % of conventional ivermectin formulations , particularly preferred plasma concentration is about 50 % of conventional ivermectin formulations . in another preferred embodiment , the present invention provides a composition for controlling heartworm infestation in a subject or the use of a composition for controlling heartworm infestation , wherein the composition is effective at a lower plasma concentration of ivermectin as compared to conventional ivermectin formulations , and exhibits a reduced side effect profile as compared to a conventional formulation . in a preferred embodiment , said lower plasma ivermectin concentration is less than 0 . 2 ng / ml , or less to 0 . 15 ng / ml , ranges from 0 . 1 ng / ml to 0 . 15 ng / ml , around 0 . 09 ng / ml , 0 . 08 ng / ml , 0 . 07 ng / ml , 0 . 06 ng / ml , or is about of 0 . 1 ng / ml . in a most preferred embodiment the said lower plasma ivermectin concentration is about 5 - 95 % of conventional ivermectin formulations , particularly preferred plasma concentration is about 50 % of conventional ivermectin formulations . the present invention also provides novel active composition for controlling or eradicating dirofilaria immitis and / or dirofilaria repens infestation in subject , comprising a combination of an avermectin , preferably ivermectin and at least one other ectoparasitic or endoparasitic ( control ) agents . said composition may be administered and used in the manner described herein for other compositions , including the dosage , time period or ( implanted ) form . the formulations of the present invention are preferably administered for intradermic and / or subcutaneous application via shaped articles . most preferably shaped articles are implants . when compared to the existing treatment options , e . g ., chewables , spots on which are administered monthly , injectable suspensions which a long term action , i . e ., 6 - 12 months , the implant formulation does not contain any aggressive solvent ( contrary to the spot on product ), has a long duration of action . preferably , the implant formulation according to the present invention , comprises a therapeutically effective amount of ivermectin having a systemic action and / or an agent active against internal parasites and are administered to the animals at least once in 6 months , 12 months , or once in 18 months up to once every two years . the compositions of the present invention may be in the form of implants comprising an amount of ivermectin sufficient to achieve a plasma concentration of less than 0 . 2 ng / ml , or less to 0 . 15 ng / ml , ranges from 0 . 1 mg / ml to 0 . 15 ng / ml , around 0 . 09 ng / ml , 0 . 08 ng / ml , 0 . 07 ng / ml , 0 . 06 ng / ml , or is about of 0 . 1 ng / ml for a period of at least 6 months , 12 months , or at least 18 months and up to 24 months . implant formulation according to the present invention may be in the form of rods which have been extruded . alternatively , the implant may be formulated in a dispersed matrix structure . rod - like shape is preferred . such rod - like shape may be circular cylinders , prisms , and elliptical cylinders . when the implant is administered using an injector - type instrument , a circular cylinder device is preferred . such implant may be solid or hollow devices , may have various dimensions of a few mm 2 , and thus have a cross - sectional diameter of for example 0 . 2 mm to 4 mm , an axial length of about 0 . 2 to 30 mm , preferably 0 . 5 to 15 mm , and more preferably about 1 to 10 mm . the rod - shape implant may have various lengths and sizes for implantation in the animal subject , and may comprise a sufficient amount of ivermectin so as to achieve an ivermectin plasma concentration as described above for a period of at least 6 months , 12 months , or 18 months and up to 24 months . more than one rod can be implanted in each animal . also , they may be designed to provide extended or sustained or controlled release of an avermectin , preferably ivermectin , and effective at half the plasma concentration of conventional avermectin formulations for a period of at least 6 months , 12 months , or 18 months and up to 24 months . the matrix formulated implant may be injected or otherwise surgically implanted into the body , where it remains as a depot from which the compound slowly dissolves , or is released by diffusion . matrix formulations may comprise waxy semi - solids such as vegetable waxes and high molecular weight polyethylene glycols . very effective sustained action is obtained by introducing into the animal subject an implant containing the effective amount of ivermectin . such implants are now well known in the veterinary art and may be formed from a biocompatible or a biodegradable material . the biocompatible material may be polyesters , polyamine acids , silicones , cellulose , ethylene - vinyl acetate copolymers , polyvinylalcohols , and silicone material . such silicone material may be a porous silicon or biosilicon material . preferred implants are made of a silicon rubber or other polymerized plastic such as methacrylate . biodegradable material may be formed of water - soluble material . the water - soluble material may be for example synthetic polymers such as polyethylene glycol , polyethylene propylene glycol , or sugars , polysaccharides such as dextran , amino acids , mineral salts , organic salts , or proteins ( gelatin and collagen ). implants according to the present invention may include additional carriers or excipients , lubricants , fillers , plasticizers , binding agent , pigments , and stabilizing agents . suitable fillers may be for example talc , titanium dioxide , starch , kaolin , cellulose ( microcrystalline or powdered ) and / or a mixture thereof . binding agents may include polyvinyl pyrrolidine , hydroxypropyl cellulose and hydroxypropyl methyl cellulose and mixtures thereof . the active ingredient is dispersed through the solid implant or is contained inside a hollow implant . the active ingredient is dispersed by first dissolving or mixing with the polymer , or dissolved in , or mixed with a carrier , it is dispersed within the polymer . after implantation , the active ingredient diffuses or leaches out of the solid or hollow implant into the body fluids of the treated animal . the rate at which the ivermectin is released from an implant , and hence , the length of time during which the implant remains effective , is controlled with good accuracy by the proper adjustment of the concentration of ivermectin in the implant , the external area of and amount of carrier in the implant , the external area of the implant , the formulation of the polymer from which the implant is made , the thickness of the wall of hollow implants and the diffusion characteristics of the ivermectin through the wall of the implant or through specially designed end - plugs of polymer or other membrane forming one or more surfaces of the implant , or by being forced through a porous membrane or aperture by an osmotic pump activated by absorption of body water into an osmotically active component contained in a second compartment of a hollow implant . administration of ivermectin by means of an implant is a further particularly preferred embodiment . such administration is highly economical and efficacious because a properly designed implant maintains a constant concentration of the compound in the tissues of the host animal , and is easily inserted in the animal . no further handling of the animal or concern over the dosage is necessary after implant insertion . said implant may be erodible / soluble or biodegradable and thus may be left in the animal tissue , or it may be insoluble / non - erodible and suitable for surgical removal after exhaustion of ivermectin . the above dosage forms may be administered at a single time ( e . g ., as one dose ) or at separate time points ( e . g . divided doses ). according to the present invention , the formulation may be administered as implant dosage form at separate time points , the interval between the separate administrations being at least 6 months , 12 months , preferably every 18 months up to every 24 months . indeed , administration of ivermectin implant provides a long term protection against parasites for a period of at least 6 months , 12 months , at least 18 months to at least 24 months . in an additional , preferred embodiment , the compounds in these amounts may be combined with other ectoparasitic or endoparasitic control agents . in a particularly preferred embodiment , the present invention provides a kit useful in the control ( treatment and / or prophylaxis ) of heartworm infestation in a subject , which comprises a dose of ivermectin which achieves a reduction in or control of infestation of dirofilaria immitis and / or dirofilaria repens in subjects , at a lower plasma concentration of ivermectin as compared to plasma ivermectin concentration obtained via conventional ivermectin formulation , optionally in combination with ectoparasitic ( ticks , fleas . . . ) or endoparasitic ( ascaris , ancylostoma . . . ) agents , optionally a carrier , and instructions for the treatment or control of a parasitic infestation . the following ivermectin implant containing invermectin as listed in the following table 1 was prepared . for the tests , 2 adult dogs have received the 6 % ivermectin implant ( dogs a and b ), 1 adult dog have received the 4 . 5 % ivermectin implant ( dog c ), and 1 adult dogs have received the 3 % ivermectin implant ( dog d ). the concentrations of ivermectin ( ng / ml ) in the plasma , collected in the jugular vein at day 0 to day 429 , are presented in table 2 . for the tests , 7 adult dogs were divided into two groups : one group of 4 dogs have received an ivermectin implant as described in example 1 and the second control group of 3 dogs ( dogs x , y and z ) without any treatment . these 7 dogs have been challenged at d365 ( 365 days after the implantation of the ivermecti implant by a subcutaneous injection of 2 ml of 75 dirofilaria immitis l3 larvae ). the concentrations of ivermectin in the plasma , collected in the jugular vein , have been evaluated during 429 days for dogs a and 13 ( table 2 , example 1 ) or just dosed until d365 for dogs c and d . dirofilaria immitis infestations have been evaluated by serological tests done by elisa detection test of dirofilaria immitis ( canine heartworm antigen test kit , petchek ™ htwm pf - idexx ) 150 days ( d515 ), 195 clays ( d560 ) or 240 clays ( d605 ) after the d365 dirofilaria challenge . the serological tests have been realized on dogs a to d at d560 and d605 after the implant were removed at d515 . the 3 control dogs have been euthanasia at d515 to control definitively the serological data . the necropsy of the control dogs showed that half of the worms were in the lung artery , and half in the heart .
the present invention further relates to ivermectin , most preferably formulated as an implant for administration of pet and domestic animals . these formulations provide long term protection against dirofilaria parasites , without the risks for secondary adverse events of conventional formulations . preferred formulations are implants and are administered at least twice a year , once a year , or at least once in 18 months , up to 24 months .