HK1161087B - High dosage doramectin formulation - Google Patents

Description

High dose doramectin formulations

Technical Field

The present invention relates generally to the field of antiparasitic compositions. In particular, the present invention relates to high dose doramectin compositions that are effective in treated animals and provide short retention times.

Background

Broad spectrum macrolides such as avermectins and milbemycins are antiparasitics with anthelmintic, endoparasiticidal, ectoparasiticidal, miticidal and insecticidal utility. Parasites that can be controlled with these broad spectrum drugs include: gastrointestinal roundworms (e.g., Haemonchus spp.), Haemonchus spp (haemanthus spp.), Strongyloides spp (trichostrongylous spp.), Cooperia spp (Cooperia spp.),), tertagous nematode (bunostomium spp.), Strongyloides spp (Strongyloides spp.), oesophagostomium spp (oesophagostomium spp.), and Trichuris spp.); pulmonary worms (e.g., Dictyocaulus viviparous); filariasis oculi (e.g., pythagordonia (Thelaziaspp.)); parasitic stage maggots (e.g., dermatia bovis (Hypoderma spp.) and dermatia hominis (dermatia hominis)); rodentica and sucking lice (e.g., bovines (Damalinia bovis), bovines (haematoponus eurystenus), bovines (linoganthus vituli) and bovines (solenoptes capillatus)); ticks (e.g., Boophilus microplus (Rhipicephalus)); mites (e.g., Psoroptes bovis (Psoroptes bovis) and sarcoptes scabiei (Sarcoptesscabiei)); spirochetes (e.g., trypanosoma hominis (Cochliomyia hominivorax)); and horn flies (e.g., Haematobia irritans).

US 6,063,394, 6,699,847 and US 6,617,314 relate to injectable compositions containing avermectins and/or milbemycins among the following: triglyceride oils (sesame oil, castor oil, fractionated coconut oil), ethyl oleate; medium chain triglycerides or glycol esters or fatty acid esters; a co-solvent selected from mono-or polyhydric aliphatic or aromatic alcohols and derivatives thereof; and adjuvants such as antioxidants and preservatives.

Us patent 6,174,540 relates to a long acting injectable composition comprising: a therapeutic agent selected from the group consisting of insecticides, acaricides, parasiticides, growth enhancers and oil-soluble NSAIDS; hydrogenated castor oil; and a hydrophobic carrier comprising triacetin, benzyl benzoate, or ethyl oleate, or a combination thereof; acylated monoglycerides, various medium chain esters, or combinations thereof.

U.S. patent 5,089,480 relates to avermectins and compositions thereof. U.S. patent 6,001,822 relates to a pharmaceutical composition comprising a solution of avermectin in a solvent combination consisting of sesame oil and ethyl oleate. Pfizer tradenameAn injectable doramectin composition is sold containing 1% (w/v) doramectin (10mg/mL) in a combination of sesame oil and ethyl oleate for treating parasitic infections in cattle.

After treatment, residual macrolides can be found after the animal tissue for a long time. Thus, when animals are treated with macrolides, there is a retention time during which the animal cannot be slaughtered for human consumption. Specifically, when a single dose of doramectin is administered to beef cattle at the recommended dose of 200 μ g/Kg body weight (which is equivalent to 10mg/110 pounds body weight), the retention time is 35 days.

In addition, many parasites are known to be able to and have developed resistance to many commercial antiparasitic products today. In an effort to combat resistance, higher doses of antiparasitic agents have been formulated. As mentioned above, avermectins and milbemycins have been formulated with castor oil and ethyl oleate due to their increased solubility. Secondly, high solubility corresponds to high lipophilicity, which affects the rate of release of the drug from the oil. As the drug concentration increases, the release rate becomes slower, which correlates to a longer retention time. In some cases, high doses of avermectins and milbemycins will precipitate out of solution due to the low partition coefficient between oil and drug. If this occurs, the residual drug concentration at the injection site may be high. Thus, the absorption and release rates are slow and the retention time is extended. Thus, cattle that are fed higher concentrations of avermectins and/or milbemycins cannot be slaughtered in time, thereby increasing herd management costs and subsequently consumer costs. The compositions of the present invention provide high doses of avermectins and/or milbemycins, preferably doramectin, which provide increased antiparasitic efficacy with substantially shorter retention times.

All U.S. patents and publications cited above are incorporated herein by reference.

Disclosure of Invention

The present invention relates to a veterinarily acceptable antiparasitic high dose doramectin composition further comprising a long chain triglyceride, a co-solvent and optionally one or more preservatives and auxiliary excipients.

In another aspect of the invention, the composition comprises: (a) 3-6% w/v doramectin; (b)39-60 vol/vol% cottonseed oil; (c)30-50 vol/vol% benzyl benzoate; and optionally, one or more preservatives and auxiliary excipients.

In another aspect of the invention, the composition comprises 3-6% w/v doramectin. Preferably, the doramectin is 3-4 wt/vol%. More preferably, the doramectin is 3.5 wt/vol%.

In another aspect of the invention, the composition comprises 39-60% vol/vol cottonseed oil, preferably 50-60% vol/vol cottonseed oil, and more preferably 55% vol/vol cottonseed oil.

In another aspect of the invention, the composition comprises 30 to 50 vol/vol% benzyl benzoate. Preferably, the benzyl benzoate is 35-45 vol/vol% and more preferably 39 vol/vol%.

In another aspect of the invention, the composition comprises at least one preservative. Preferably, the preservative is tocopherol. More preferably, the preservative is tocopheryl acetate (tocophenol acetate).

In another aspect of the invention, the composition comprises at least one auxiliary excipient. Preferably, the auxiliary excipient is benzyl alcohol.

In another aspect of the invention, the composition comprises at least one of a preservative and an auxiliary excipient. Preferred and more preferred preservatives and preferred auxiliary excipients are as defined above.

In another aspect of the invention, the composition comprises: 3.5% doramectin, 55% cottonseed oil, 39% benzyl benzoate, 6% benzyl alcohol and 0.05% tocopherol acetate.

In another aspect of the invention, is a method for preventing, treating, or controlling parasites in animals comprising administering to an animal in need thereof an effective amount of a high dose doramectin veterinary composition. Preferably the animal is a domestic animal. The most preferred animal is bovine.

In another aspect of the invention, methods of parenterally administering high doses of doramectin antiparasitic compositions are provided. Preferably, the composition is administered intramuscularly or subcutaneously. More preferably, the high dose doramectin antiparasitic composition is administered subcutaneously.

In another aspect of the invention, it is a combination veterinary composition comprising: a) doramectin, b) one or more other antiparasitic agents, c) cottonseed oil, d) benzyl benzoate, and optionally, e) one or more preservatives and auxiliary excipients. Preferably, the doramectin is between 1 and 3 wt/vol% and the other antiparasitics, alone or in combination, are between about 1 and 3 wt/vol%.

In another aspect of the invention, it is a combination veterinary composition, wherein the preferred additional antiparasitic agent is selected from the group consisting of ivermectin, abamectin, eprinomectin and moxidectin.

In another aspect of the invention, it is a combination veterinary composition comprising doramectin and abamectin, doramectin and eprinomectin, doramectin and ivermectin, and doramectin and moxidectin.

In another aspect of the invention, it is a combination veterinary composition comprising doramectin and two other antiparasitics selected from abamectin, eprinomectin, ivermectin and moxidectin (e.g., doramectin, abamectin and ivermectin; doramectin, ivermectin and eprinomectin; doramectin, ivermectin and moxidectin; and the like).

In another aspect of the invention, it is a combination veterinary composition comprising a) 1-3% w/v doramectin, b) 1-3% w/v of one other antiparasitic agent or 1-3% combined w/v of one or more other antiparasitic agents, c) 39-75% v/v cottonseed oil, d) 25-50% v/v benzyl benzoate, and optionally, e) one or more preservatives and adjuvants. Preferred and most preferred additional antiparasitic agents, preservatives and adjuvants are as defined herein.

In another aspect of the invention is a method for preventing, treating or controlling parasites in an animal comprising administering to said animal in need thereof an effective amount of a combination veterinary composition. Preferably the animal is a domestic animal. The most preferred animal is bovine.

In another aspect of the invention, a method of parenterally administering the combination composition. Preferably, the combination composition is administered intramuscularly or subcutaneously. More preferably, the high dose combination composition is administered subcutaneously.

In another aspect of the invention, the veterinary or veterinary combination composition further comprises at least one or more fat-soluble vitamins, as described above. Preferred fat soluble vitamins are vitamins A, D and E. Preferred vitamins for use in the vitamin enriched composition are phenol, m-cresol, BHA and BHT. More preferred preservatives are BHA and BHT.

In another aspect of the invention is a method for preventing, treating or controlling parasites in an animal comprising administering to said animal in need thereof an effective amount of a veterinary or veterinary combination composition(s) containing fat-soluble vitamins. Preferably the animal is a domestic animal. The most preferred animal is bovine.

In another aspect of the invention is a method of parenterally administering a veterinary or veterinary combination composition containing at least one or more fat-soluble vitamins. Preferably, the composition is administered intramuscularly or subcutaneously. More preferably, the composition is administered subcutaneously.

Detailed Description

The present invention provides high dose doramectin compositions that are useful as effective antiparasitic agents and provide reduced retention time in animals following administration.

Drawings

Figure 1 depicts the efficacy of single high dose doramectin and high dose ivermectin in humans against human dermatophagoides pteronyssinus larvae.

Definition of

For purposes of the present invention, the following terms and phrases are defined as follows, as described and claimed herein:

as used herein, unless otherwise specified, "animal" refers to an individual animal that is a member of the taxonomic class mammalia. Non-limiting examples of animals include dogs, cats, horses, pigs, sheep, goats, and cattle.

As used herein, unless otherwise indicated, "parasites (parasites or parasites)" refers to endoparasites and ectoparasites, including mites, insects, worms and their respective larvae, pupae, maggots, nymphs and the like.

As used herein, unless otherwise specified, "Parenteral" refers to a form of administration, which refers to intramuscular (e.g., into muscle), subcutaneous (e.g., under the skin), intradermal (e.g., into the skin itself), and intravenous (e.g., into a blood vessel).

As used herein, unless otherwise specified, "preservative(s)" refers to a substance or substances added to the compositions of the present invention to protect them from microbial action and chemical reactions. The term includes antioxidants (radical scavengers) that prevent a composition from undergoing a chemical reaction by scavenging free radicals, thereby eliminating electron transfer from one compound or species to another.

As used herein, unless otherwise indicated, "treating" or "treating" refers to reversing, alleviating, or preventing a disease or disorder to which such terms apply. Thus, treatment may refer to administration of a composition of the invention to an animal that is not afflicted with the disease or disorder at the time of administration.

As used herein, unless otherwise specified, "veterinarily acceptable" means that the substance or composition must be compatible with the other ingredients, including the composition and/or the animal chemistry and/or toxicology with which it is being treated.

As used herein, unless otherwise specified, "hold time" refers to the period of time during which an animal cannot be slaughtered for human consumption after the last dose of drug has been administered.

Detailed description of the invention

The present invention relates to a high dose doramectin composition comprising 3-6% (weight/volume, w/v) doramectin, 39-60% (volume/volume, v/v) cottonseed oil, and 30-50% (volume/volume, v/v) benzyl benzoate. Optionally, the composition may contain one or more auxiliary excipients, including antioxidants, preservatives and co-solvents. A typical composition is prepared by mixing an amount of doramectin with cottonseed oil, benzyl benzoate, tocopherol acetate as an antioxidant, and benzyl alcohol as a co-solvent. Other common suitable antiparasitic agents, veterinarily acceptable vegetable or synthetic oils and esters, co-solvents, antioxidants and preservatives recognized by those skilled in the art as safe for administration to animals may also be used. However, developing parenteral compositions that utilize avermectins and/or milbemycins requires an understanding of the interactions between the drug and other carriers and excipients of the composition. Avermectins and milbemycins antiparasitics are highly soluble in castor oil, however, the drug is not easily released from the oil due to the binding affinity between the drug and the oil. Therefore, the residual concentration of the drug at the injection site is high. Second, avermectins have a lower solubility profile in other oils (e.g., ethyl oleate, fractionated coconut oil, sesame oil, and cottonseed oil). Lower solubility does not allow for high dose compositions. Therefore, additional co-solvents are needed to ensure high dose solubility while maintaining low binding affinity. Finally, depending on the aqueous nature of the composition, high doses of avermectins may precipitate due to partitioning of the drug into the aqueous phase.

An active antiparasitic of particular emphasis in this invention is doramectin (3-6 wt/vol%). Preferably doramectin is 3-4 wt/vol%, more preferably 3.5 wt/vol%.

Suitable vegetable oils include long chain triglycerides, such as, for example, cottonseed oil, sesame oil, soybean oil, corn oil, and the like. It is also possible to use C₈/C₁₀Medium chain triglycerides (e.g., Miglyol 810 or 812).

Suitable cosolvents include esters, such as benzyl benzoate, ethyl oleate, tributyl citrate, tributylacetyl citrate, and C₈/C₁₀Medium chain propylene glycol diesters (e.g., Miglyol 840). Benzyl benzoate is preferred because it is unique among these esters in that it provides excellent doramectin solubility as well as moderate binding affinity, unlike long chain triglyceride castor oil. In addition, because of the moderate affinity, the rate of doramectin clearance from the injection site is faster. Thus, the cottonseed oil and benzyl benzoate composition allows the doramectin to remain solubilized while controlling absorption, clearance at the injection site and ultimately reducing retention time.

Auxiliary excipients may also be used in the composition. These co-solvents are typically added to the composition in a volume in the range of about 2 to 8%. Suitable auxiliary excipients include benzyl alcohol, propylene glycol or other non-toxic polyols, including, for example, polyethylene glycols. Benzyl alcohol is used as a mild anesthetic for parenteral compositions, thereby reducing injection site pain and subsequently promoting injection site tolerance.

Preservatives may also be used to ensure the overall stability of the composition. The amount of each preservative may vary from about 0.01% to about 2% by weight/volume and/or volume/volume of the composition, depending on whether the preservative of the composition is added to control or prevent antimicrobial growth and/or to control or prevent chemical reactions as an antioxidant. For example, tocopherol acetate may be added in the range of about 0.01% to about 0.10% weight/volume; BHA and BHT may each be added to a single composition in the range of about 0.05 to 0.5%. Non-limiting examples of suitable preservatives include: phenyl ethanol, phenol, m-cresol, benzalkonium, parabens, Butylhydroxyanisole (BHA), Butylhydroxytoluene (BHT), propyl gallate, etc. Some non-limiting preservatives that are antioxidants include: vitamin a, carotenoids, ascorbic acid, flavonoids, polyphenols, isothiocyanates, lycopene, cysteine, tocopherols (which include alpha, beta, gamma, delta tocopherols, mixtures thereof, and esters of tocopherols (e.g., acetates and succinates)), and the like.

The compositions of the present invention may also include an amount of at least one or more fat soluble vitamins. Preferred fat-soluble vitamins are vitamin a, vitamin D and vitamin E. Recommended vitamin requirements on cattle range from about 2000 to 4000IU/kg (vitamin A), about 275IU/kg (vitamin D) and 15 to 60IU/kg (vitamin E). Because these fat-soluble vitamins are stored mainly in the liver and adipose tissue, higher doses can be administered. The stored vitamins are slowly excreted over time, thus providing long-term vitamin nutrition. The rapid perfusion dose of vitamins A, D and E may range from about 100,000 to 500,000IU/mL, 10,000 to 75,000IU/mL, and about 5 to 300IU/mL, respectively. Depending on the age of the animal, dosages may be administered to provide about 2000 to 5000IU/kg of vitamin A, about 200 to 600IU/kg of vitamin D, and about 0.5 to 7IU/kg of vitamin E. Over time, these doses provide about 50 to 125 IU/kg/day of vitamin A per day for 40 days, and about 33-83 IU/kg/day of vitamin A per day for 60 days; vitamin D is administered in a daily amount of about 5 to 22 IU/kg/day for 40 days, and about 3 to 15 IU/kg/day for 60 days; vitamin E is administered daily at about 0.02 to 0.15 IU/kg/day for 40 days, and about 0.01 to 0.10 IU/kg/day for 60 days.

The compositions of the present invention may be prepared to provide an easily controlled pharmaceutical dosage and an easily handled product using conventional dissolution and mixing procedures to prepare veterinary dosage forms.

The composition of the invention (example 1) was prepared using a typical manufacturing procedure for injectable solutions. Doramectin was dissolved in benzyl benzoate at about 55 ℃. Tocopherol acetate was dissolved in benzyl benzoate alone and then added to doramectin solution. Benzyl alcohol and cottonseed oil were dissolved by adding the excipients to the doramectin solution. The doramectin solution was mixed at about 55 ℃ for about 1-2 hours without nitrogen sparging or vacuum. The solution was then sparged with nitrogen under vacuum. The solution was cooled to about 25 ℃ and then filtered with a 1 micron prefilter and a 0.22 micron sterilizing filter. The filtered solution was then stored in a sterile brown glass bottle and capped.

Compositions within the scope of the present invention have been shown to have efficacy against economically important endoparasites and ectoparasites after a single injection with significantly reduced retention times. This presents a significant advantage for those working in the livestock animal field, as it provides effective high dose treatment with reduced retention time. If the retention time can be significantly reduced while effectively treating endo-and ectoparasites in an animal, the animal, preferably a bovine, can be slaughtered for human consumption much faster after dose application. Second, the costs to the cattle farm operator, feedlot manager or other entity, and the ultimate consumer, will be significantly reduced. In addition, if the animal can be slaughtered faster, the risk of re-infection is reduced, especially in animals with residual drug concentrations that prevent slaughter due to prolonged retention time but which are too low to be effective.

Among the parasites (adults and larvae) that can be controlled using the high dose compositions of the present invention are roundworms, pulmonary worms, filarial worms, reniform nematodes, maggots, sucking and biting lice, ticks and mange mites. Gastrointestinal roundworms include, for example, ostomata austenitalis (ostomata ostertagi) (including suppressed larvae), perostegia erecta (o.lyrata), Haemonchus parviensis (haemonus plani), Haemonchus contortus (h.similis), Haemonchus contortus (h.contortus), Trichostrongylus fortis (Trichostrongylus axeri), Trichostrongylus serpentine (t.colubriformis), Trichostrongylus longicorniculatus (t.longicorniculatis), Trichostrongylus punctatus (Cooperia onas), Trichostrongylus styloides (c.pettylenchus brasiliensis), Trichostrongylus colubria (c.petatus), Trichostrongylus punctatus (c.pettylus), trichosanthes mucronatus (c.mcdonatus), trichosanthes mucronatus (c.mcdongylus), Trichostrongylus ternatus, strongyllus ternatus, strongylus teres, strongylus sp.e, strongylus nipulus sp And the genus Trichuris (Trichuris spp.) and the like. Other parasites include lung worms (e.g., Dictyocaulus vivipatus and Metastrongylus spp)); filaria oculata (e.g., pytharia spp.); maggots in the parasite stage (e.g., dermatia bovis (hypodermatis), dermatia striata (h.linear), and dermatia hominis); renal bulge nematodes (e.g., crown nematodes); sucking lice and rodentica (e.g., blood lice of cattle (haemantounus eurysternus), blood lice of pigs (h. suis), cheek lice of cattle (linogaphvsvituli), water lice of buffalo (solenoptes carpillatus), Damalinia bovis); helicopters (e.g., trypanosoma hominis (Cochliomyia hominivorax) (larvae), ticks (Rhipicephalus Rhipicephalus (Rhipicephalus hydroplus), Rhipicephalus sanguineus (Rhipicephalus sanguineus), I.ricinus, I.hexagonus, Dermacentor variabilis, Dermacentor dermativus (D.), Dermacentor dermativus andersonii (D.), Dermacentor dermativus (D.marginosus), Amblyomma maculatum (Amblyomma maculatum), Amblyomma tristezatum, Amblyomma clavatum, Amblyomma caerum (Amblyomma cajennense), Amblyomma caerum, Amblyomma malabaricum (Amblyomma cayenense), Amblyomma obtusifolium, Amblyomma Agrimonium, Amyomma Agrocybe procymoides, Amblyomma Agrocybe procymphaeus, Amblyomma Agrocybe procymoides, etc.); sarcoptids mitis (e.g., Psoroptes bovis, (larcoptes scabies)); and horn flies (e.g., Haematobia irritans).

The compositions of the present invention may be administered in a manner appropriate to the particular use being faced, the particular host animal and the weight of the host animal being treated, the parasite or parasites involved, the extent of infestation, and the like, in accordance with standard veterinary practice. Preferably, the compositions of the present invention are formulated for parenteral administration. More preferably, the composition is formulated for intramuscular and subcutaneous injection. Injection of the composition may be accomplished using a suitable veterinary applicator, such as a syringe or gun of the type from suppliers such as NJ Phillips Injector, instruments supplies and Simcrotec. The choice of injection device will depend on a variety of factors such as the viscosity of the composition, the ability to deliver a unit dose of the active drug under field conditions, etc., and in accordance with standard veterinary practice.

A veterinarian or one skilled in the art can determine the dosage appropriate for a particular animal, which may vary with species, age, weight and response. Average doses are exemplary of the general case. Thus, higher or lower dosage ranges may be approved depending on the factors described above and are within the scope of the invention.

The compositions of the present invention may be applied alone or in combination with one or more other antiparasitic agents as described above for 2-6% combination pharmaceutical compositions to form multicomponent insecticides providing an even broader spectrum of veterinary applications. Thus, the present invention also contemplates combination veterinary compositions comprising an effective amount of doramectin and at least one other antiparasitic agent, a long chain triglyceride, a co-solvent and optionally one or more preservatives and auxiliary excipients, as defined above. Specific additional antiparasitic agents include ivermectin, eprinomectin, abamectin, moxidectin and milbemycin. For simultaneous administration, doramectin and other antiparasitic agent(s) may be combined into a single pharmaceutical composition. For example, the compositions may be formulated in cottonseed oil and benzyl benzoate, containing 1-3% doramectin in combination with 1-3% of one other antiparasitic agent, or containing 1-3% doramectin in combination with at least two other antiparasitic agents at a combined weight/volume of about 1-3%, optionally with one or more preservatives and auxiliary excipients. Non-limiting combination compositions include: 1% doramectin and 1% abamectin; 1.5% doramectin, 1% abamectin, and 1% ivermectin; 1% doramectin, 1% abamectin, 2% ivermectin, etc. The combination veterinary composition may be formulated as described above.

Since it may be desirable to administer a combination of active compounds in a single composition, for example, for the purpose of treating a particular disease or condition, it is within the scope of the present invention that two or more veterinary compositions, at least one of which contains a doramectin according to the invention, may conveniently be combined in a kit suitable for simultaneous administration of the compositions.

Accordingly, the present invention also relates to a kit comprising two or more separate veterinary compositions, at least one of which contains a doramectin according to the invention; and means for separately storing the composition, such as a container, divided bottle, sachet, ampoule or divided foil box. To aid compliance, the kit typically includes instructions for administration and may be provided with a so-called memory aid.

The veterinary compositions of the present application can be packaged in a variety of ways depending on the method used to administer the drug. Generally, the dispensing article comprises a container in which the veterinary composition is stored in a suitable form. Suitable containers are well known to those skilled in the art and include materials such as bottles (plastic and glass), sachets, ampoules, plastic bags, metal cylinders and the like. The container may also include a tamper-proof fit to prevent light access to the package contents. In addition, the container has a label disposed thereon that describes the contents of the container. The tag may also include appropriate warnings.

The compositions of the present invention are tolerable when used in cattle. Furthermore, the compositions of the present invention are stable for 6 months at accelerated temperature and relative humidity (40 ℃/75%).

Examples

Embodiments of the present invention are illustrated by the following examples. However, it is to be understood that the embodiments of this invention are not limited to the particular details of these examples, as other variations thereof will be apparent to those skilled in the art in light of this disclosure.

Example 1

Compositions containing 3.5% (weight/volume, w/v) doramectin (0.7mg/kg) were formulated in cottonseed oil, benzyl benzoate and benzyl alcohol as follows.

Doramectin	3.5g
		Benzyl alcohol	6.0mL
Tocopherol acetate	0.050g
		Cottonseed oil	55.0mL
Benzyl benzoate q.s.p.	100.0mL

Example 2 comparative composition

A composition was prepared containing 3.0% (weight/volume, w/v) doramectin (0.6mg/kg) in a vehicle comprising 40% (volume/volume, v/v) castor oil and 60% (volume/volume, v/v) ethyl oleate.

Example 3

A composition without auxiliary excipients or preservatives containing 3.5% (weight/volume, w/v) doramectin (0.7mg/kg) formulated in cottonseed oil and benzyl benzoate can be prepared as follows.

Doramectin	3.5g
		Cottonseed oil	55.0mL
Benzyl benzoate q.s.p.	100.0mL

Example 4

Combination compositions containing 1% (weight/volume, w/v) doramectin (0.2mg/kg), 1% ivermectin (0.2mg/kg) formulated in cottonseed oil, benzyl benzoate, benzyl alcohol and preservatives can be prepared as described below. Similar compositions can be prepared without preservatives and/or auxiliary excipients (benzyl alcohol).

Doramectin	1.0g
		Ivermectin	1.0g
Benzyl alcohol	6.0mL
		Cottonseed oil	55.0mL
Tocopherol acetate	0.050g
		Benzyl benzoate q.s.p.	100.0mL

Example 5

Combination compositions containing 1% (weight/volume, w/v) doramectin (0.2mg/kg), 1% ivermectin (0.2mg/kg) and 1% abamectin (0.2mg/g) formulated in cottonseed oil, benzyl benzoate, benzyl alcohol and tocopheryl acetate can be prepared as described below. Similar compositions can be prepared without tocopherol and/or benzyl alcohol.

Doramectin	1.0g
		Ivermectin	1.0g
Abamectin	1.0g
		Benzyl alcohol	6.0mL
Cottonseed oil	55.0mL
		Tocopherol acetate	0.050g
Benzyl benzoate q.s.p.	100.0mL

Example 6

Compositions containing 1% (weight/volume, w/v) doramectin (0.2mg/kg), 1% abamectin (0.2mg/kg), formulated in cottonseed oil, benzyl benzoate, benzyl alcohol, vitamins A, D and E, and containing the preservatives BHA and BHT can be prepared as described below. Similar compositions can be prepared without tocopherol and/or benzyl alcohol. Depending on the age, health, and duration of supplemental administration required of the animal, the amount of each vitamin (A, D and/or E) can be increased or decreased accordingly to provide a dose (e.g., IU/kg) of vitamin(s).

Drug/excipient		IU/mL
			Doramectin	1.0g	na
Abamectin	1.0g	na
			Retinyl palmitate (A)	8.8g	160000
Vitamin D3(D)	0.1125g	45000
			dl-alpha-tocopheryl acetate (E)	4.5g	45
BHA	0.2g	na
			BHT	0.2g	na
Benzyl benzoate q.s.p.	25mL	na
			Cottonseed oil	qs 100mL	na

Oil/water distribution

Various triglyceride oil-ester solution compositions containing doramectin alone and doramectin with other avermectins were prepared to evaluate the composition, water partition coefficient and degree of drug precipitation as a tool for determining drug retention time. For example, if the drug/oil affinity is strong, the drug is not easily released from the oil, and if the drug precipitates, systemic absorption and clearance is even slower. Slower removal rates correspond to longer retention times. A triglyceride oil to ester composition carrier was prepared at a 55:45 oil to ester v/v ratio. A solid anti-parasitic drug is added to the carrier and dissolved by heating the solution while stirring. After cooling to room temperature, 1mL of each composition was added to 10mL of water and the mixture was allowed to equilibrate for 72 hours at room temperature by gentle rotary mixing. The oily aqueous phase is separated by centrifugation and the aqueous phase is further clarified by filtration if necessary to remove the precipitated drug. For each composition, both phases and the initial composition were evaluated by HPLC. The results are shown in table 1 below.

TABLE 1 antiparasitic triglyceride oil ester composition-Water equilibrium partition coefficient and percent precipitation

¹log P_FW= calculated composition-water partition coefficient = log ([ mg/mL of solubles in oil phase)]/[ mg/mL of the dissolved substance in the aqueous phase])

²% remaining in solution = ([ mg dissolved in oil phase)]+ [ mg of dissolved substance in aqueous phase]) Mg 100 g in the initial composition

In general, the cottonseed oil/benzyl benzoate compositions provide acceptably high dose solubility and composition water logP values for doramectin and other avermectins, alone and in combination. Furthermore, the compositions show an excellent ability to maintain drug solubility after exposure to an aqueous environment (e.g.. gtoreq.94% retention in solution), which indicates a low tendency for injection site precipitation and thus reduced retention time, while providing a higher effective dose. Similarly, the castor oil composition showed the expected acceptable solubility, however, there was a significant increase in log P due to the strong affinity between the drug and the oil. This affinity is predicted to result in significantly prolonged injection site drug clearance. Cottonseed oil ethyl oleate compositions also exhibit excellent solubility, however, a slight decrease in water exposure tolerance results in a slight increase in drug precipitation.

Biological research

Study of1

55 cattle were castrated (15/group) and the castrated wounds were naturally exposed to infestation by spirochetes (trypanosoma hominis larvae). The control group received no treatment. The first treatment group received a single injection dose of the comparative composition (example 2) at 0.6 mg/kg. The second treatment group received a single injection dose of the composition of example 1, 0.7 mg/kg. For each treatment group, the anti-spirochete efficacy was calculated as follows on each assigned evaluation day, from day 3 to day 20 post-treatment.

The results of study 1 are shown in Table 2

TABLE 2 efficacy (%) of high dose doramectin compositions against Trypanosoma hominis larvae, Days Post Treatment (DPT)

Overall, the data show that the efficacy of the composition of the invention (example 1) against trypanosoma manophilum larvae started earlier.

Study 2

24 naturally infected cattle with an insect egg count (EPG) of greater than 500 per gram of feces were randomly assigned to three treatment groups based on the average of three EPG counts (days-3, -2, and-1). The control group received no treatment. The second treatment group was treated with a single dose of the comparative composition (example 2) at a dose of 0.6 mg/kg. The third treatment group was treated with a single dose of the composition of example 1, 0.7 mg/kg. Cattle were left in separate stalls until day 14 post-treatment, at which time animals were euthanized and subjected to physical scrutiny to assess worm load. Several worms were collected from each group and counted (haemonchus (H1), cooperia (H2), trichostrongylus (H3), oesophagostomus (H4) and trichuris (H5)). The number and arithmetic mean of each worm are shown in table 3. For each species recorded, except for strongyloides, in which case the comparative formulation is effective, the group of cattle treated with the composition of the invention (example 1) had the lowest number of worms. In general, the total number of worms (of all species) of the compositions of the invention is less than half of the comparative compositions.

TABLE 3 efficacy of high dose doramectin compositions against different species of helminths in cattle-arithmetic mean.

Study 3

The veterinary composition of the invention (example 1) was compared with commercial high dose products and evaluated for its efficacy against bovine maggot (bot larvae). Three high dose avermectin compositions were evaluated. Forty cattle were selected based on visual inspection for larval infestation. Animals were randomly assigned to treatment groups based on the average of two pretreatment counts (day-2 and day-1) of human dermomyia larvae. Four groups of 10 animals each were formed as follows: t01 was a control (saline), T02 received doramectin 3.5% (example 1), T03 received ivermectin 3.15% (Ivomec Gold, Merial), T04 received ivermectin 4.0% (Master LP, Ouro Fino). During the study, animals were maintained within the same pasture boundary in brazil. Water and mineral supplements were provided ad libitum. On day 0, cattle were given a 1mL/50Kg dose subcutaneously. Larval nodules were counted at-2, -1, 3, 7, 14 and weekly thereafter until 133 days post-treatment. The results are shown in FIG. 1. Doramectin 3.5% showed better therapeutic and long lasting efficacy against human dermatidae larvae compared to other high dose commercial ivermectin compositions. The doses of doramectin 3.5%, ivermectin 3.15% and ivermectin 4.0% reached efficacy (geometric mean) higher than 90% on days 14 to 105, 28 to 77 and 28 to 84 after treatment, respectively.

FIG. 1 efficacy of high-dose doramectin and high-dose commercial ivermectin in cattle against human Piromosophila larvae

Study 4

Retention times of commercial low dose doramectin, high dose ivermectin, and high dose combination formulations containing ivermectin and abamectin were evaluated in comparison with high dose doramectin (example 1). Retention times based on residual drug concentrations obtained from animal tissues (skeletal flesh, fat, kidney and liver) were reported by each company on their respective product label and registered in the brazilian department of agriculture (MAPA). The product label reports retention times in days and months. For consistency, the retention time is expressed in days, with 30 days for one month. The retention times are shown in table 4. The high dose doramectin composition provides a retention time that is half that of other high dose compounds. Thus, cattle can be slaughtered for meat consumption shortly after treatment with high doses of doramectin, as compared to the time that would be achieved from other high doses of avermectins.

TABLE 4 reported beef cattle retention time versus residual avermectin concentration in meat

Claims (13)

1. A veterinary antiparasitic composition comprising: (a)3-6 wt/vol% doramectin; (b)39-60 vol/vol% cottonseed oil; (c)30-50 vol/vol% benzyl benzoate; and optionally, (d) one or more preservatives, auxiliary excipients and fat-soluble vitamins.

2. The composition of claim 1, further comprising one or more preservatives.

3. The composition of claim 2, further comprising one or more auxiliary excipients.

4. The composition of claim 3, further comprising one or more fat soluble vitamins selected from the group consisting of vitamin A, vitamin D, and vitamin E.

5. The composition of claim 3, wherein the doramectin is 3.5% w/v, the cottonseed oil is 55% v/v, the benzyl benzoate is 39% v/v, the auxiliary excipient is benzyl alcohol and the preservative is tocopherol.

6. The composition of claim 5 wherein the benzyl alcohol is 6 v/v% and the tocopherol is 0.05 w/v% tocopherol acetate.

7. The composition of claim 1, wherein the doramectin is 3.5% w/v, the cottonseed oil is 55% v/v, and the benzyl benzoate is 39% v/v, further comprising an auxiliary excipient and a preservative, wherein the auxiliary excipient is 6% v/v benzyl alcohol and the preservative is 0.05% w/v tocopheryl acetate.

8. Use of a composition as claimed in any one of claims 1 to 7 for the manufacture of a medicament for the prevention, treatment or control of parasites in livestock animals, comprising parenterally administering the medicament to the animal.

9. A combined veterinary antiparasitic composition comprising: (a)1-3 wt/vol% doramectin; b) 1-3% w/v of an antiparasitic selected from abamectin, ivermectin, eprinomectin, moxidectin and milbemycin or 1-3% w/v of a combination of more than one antiparasitic selected from abamectin, ivermectin, eprinomectin, moxidectin and milbemycin; (c)39-75 vol/vol% cottonseed oil; (d)25-50 vol/vol% benzyl benzoate; and optionally, (E) one or more preservatives, auxiliary excipients and fat-soluble vitamins, wherein the vitamins are selected from vitamin a, vitamin D and vitamin E.

10. The composition of claim 9, further comprising one or more preservatives.

11. The composition of claim 10, further comprising one or more auxiliary excipients.

12. The composition of claim 11, further comprising one or more fat soluble vitamins selected from the group consisting of vitamin a, vitamin D, and vitamin E.

13. Use of a composition as claimed in any one of claims 9 to 12 for the manufacture of a medicament for the prevention, treatment or control of parasites in livestock animals, comprising parenterally administering the medicament to the animal.