ZA200603931B - Compositions for controlling parasites comprising a combination of abamectin and ivermectin - Google Patents
Compositions for controlling parasites comprising a combination of abamectin and ivermectin Download PDFInfo
- Publication number
- ZA200603931B ZA200603931B ZA200603931A ZA200603931A ZA200603931B ZA 200603931 B ZA200603931 B ZA 200603931B ZA 200603931 A ZA200603931 A ZA 200603931A ZA 200603931 A ZA200603931 A ZA 200603931A ZA 200603931 B ZA200603931 B ZA 200603931B
- Authority
- ZA
- South Africa
- Prior art keywords
- abamectin
- ivermectin
- oil
- composition
- formulation
- Prior art date
Links
- 239000000203 mixture Substances 0.000 title claims description 79
- 239000005660 Abamectin Substances 0.000 title claims description 41
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- 229960002418 ivermectin Drugs 0.000 title claims description 36
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Classifications
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- 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
- A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
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- A—HUMAN NECESSITIES
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- 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
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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Description
COMPOSITIONS FOR C ONTROLLING PARASITES COMPRISING A COMBINATION OF ABAMECTIN AND
MILBEMYCIN
The present L nvention relates to long acting compositiors for controlling parasites, comprising a combination of ivermectin and abamectin in a slow release vehicle, the use of such compositions in the preparation of a medicament for controlling parasites.
Avermectins are well known anthelmintic compounds, elonging to the class of macrocyclic Bactones. The avermectins are isolated frorm fermentation products of
Streptomyce s avemitilis and ivermectin is a compound which Is a semisynthetic chemical cornpound formed by modification of avermecztin. The basic structure of the avermectins is a 16-membered lactone ring to which are appended three main substituent groups: a hexahydrobenzofuran group, 2 di saccharide group (at C-13) and a spirok etal ring (C-17 to C-28). The avermectin series of compounds, including ivermectin, @abamectin, doramectin, eprinomectin and s elamectin, are potent anthelmintic and antiparasitic agents against internal amd external parasites (endectocidess). The natural product avermectins are di sclosed in US-A-4,310, 518 to
Albers Scho eberg st al., and the 22,23-dihydro avermesctin compounds are disclosed in Chabala eat al, US-A- 4,199, 568.
Endoparasitses cause widespread disease found in mary animals. The most frequently ercountered endoparasites are the group of worms referred to as nematodes. The nematodes are found in the Intestinal tract, heart, lungs, blood vessels and other body tissues of animals and are a primary cause of anemia, weight loss and malnutrition in the infected animals. The nematodes most commonly found to be the infecting agents of ruminants include Haemorchus and Ostertagia generally found in abcsmasum; Cooperia, Trichostrongylus and Ndematodirus generally found in the intestinal tract, and Dictyocaulus found in the lungs.
Ectoparasitess commonly infecting warm-blooded animaals are arthropods such as ticks (e.g. Beoophilus microplus), mites, lice, fleas, blowfly, and migrating dipterous larvae such as Hypoderma sp. in cattle.
Treatment osf animals to prevent infestation by any of tine above-mentioned parasites, or to reduce or control the proliferation of these parasites in animals is thus important.
Meanwhile the problem has arisen that some parasites develop a resistance to drugs like ivermec=tin. The resistance occurs when a strain of a parasite is able to tolerate
’ WOB 2005/037294 PCT/PEP2004/052554 doses of an active ingredient that i s efficacious against other populatiosns of parasites of the same species. This characteristic is inheritable.
After the use of macrocyclic lactormes for almost two decades in cattle fin Brazil the first reports on resistant parasites in cattle were published. In 2001 in Rio Grande do
Sul State, Martins & Furlong cbse wved low efficacy of doramectin, iver-mectin and moxidectin against a strain of Boo philus microplus.
In 2001 in Santa Catarina State, Souza et.al tested the efficacy of bowine anthelmintic on 7 farms (egg courting). Resistance to ivermectin was detected in 4 of them (3 to Cooperia and 1 to Haewsmonchus). in vitro trials demonstrated resistaance of H. placei and C. punctata to ivermectin in
Sao Paulo State. The resistance t 0 Cooperia and Haemonchus was a_lso shown in other trials (CARDOSC et al., 20092).
The endoparasites of the genus Cooperia and Haemonchus showed resistance to ivermectin in bovines in 11 farms of 12 evaluated in So Paulo State @SOUTELLO et al, 2003). These trials demonstra. ted that the problem of bovine parassites resistant to avermectins, particularly to ivermectin, might soon become as seriouss as itis in ovine species. 20% The discovery of novel anti-parasitics with equal or better qualities then macrocyclic lactones seems to be a distant reality in the veterinary pharmaceutical industry.
Therefore, the chemical groups awailable nowadays must be used in 2 rational way, with a view to achieving high percentages of efficacy against parasite s and delaying 55 the occurrence of resistant strainss (GEARY & THOMPSON, 2003).
The avermectins have similar moedss of action. Nevertheless, small diiflerences in their structures affect their therapeutic efficiency. Where ivermectin reasistant parasites will usually still be vulne=rable to abamectin, abamectin has “the 30> disadvantage that it cannot be used at higher concentrations since it &s toxic at higher concentrations. The use of low cosncentrations of abamectin however, has the disadvantage that the formulation s based on abamectin only are shor-tacting.
Many different concepts of prolon ged release of pharmaceutical compositions in animals have been described, e.g. use of low water soluble forms or ecomplexes of active ingredients, use of liposome. es, microspheres and lipospheres fomulations, polymer formulations, oil based fomulations, gel formulations etc. So=ms of them haves been proposed for the use with encllo and / or ectoparasitic compoundss. Several oil formulations have been suggested in gorior art for long acting formulations, e.g. ethy~1 oleate or sesam oil formulations.
A combination of ivermectin and abamecztin for antiparasitic use in bovines as been mer—tioned in Brazilian Patent Applicatiorn No. Pl 0104751-2, that was filed «on August 8, 28001 and published on August 12, 20C33. This document does not disclosse any specific amounts and ratio of the compomunds of the combination that alowss the conmposition to release ivermectin and awsermectin in a way to show the des ired effect eve in parasites that are resistant to ce rain macrocyclic lactone compouneds. it weould therefore be desirable to have aa long acting composition available that allo=ws the release of an effective amourat of the specific combination of ivermectin and® avermectin over a prolonged time p -eriod that are suitable to control pa rasites that show resistance to certain macrocysciic lactone compounds.
It heas now been found that the combination of ivermectin and abamectin in defined con. centration ranges in a long acting ve-hicle comprising castor oil resultin sucha bro=ad-spectrum antiparasitic compositio- n with long acting activity.
The= present invention concerns a long aacting composition for controlling parasites in ancd on animals, which comprises in a sl ow release vehicle a combination of iver-mectin and abamectin, characterizect in that the total percentage w/v of iver-mectin and abamectin equals or exc=eads 3% w/v and the concentratior of iver-mectin is higher than the concentrat®ion of abamectin,
In one embodiment the present inventio n provides a composition for controlling endo- and ecto- parasites in and on animals, v=vhich comprises as active ingrediert, an effeactive amount of a combination of ive=rmectin and abamectin in the followving corcentrations, 1.75-5% wiv ivermectin 5 0.5-2% w/v abamectin, the composition furtzher comprising 30-60 % w/v castor cil, a suitable amount of a solvent fosr the act ive ingredients, optionally other pharmaceutically acceptable ingredients, and up to 100 % v/v of a diluent.
By "w/V'is meant weight/volume, i.e." 9, wiv" means 1 g in 100 ml of the cormposition. ‘v/v’ means volume per volume, and 1% v/v means 1 ml, in aa total of 100 mil. .
Good results were obtained with a composition comprisirg 2.25% ivermectin and 1.25% abamectin, tocyether amounting to a total concentration of 3.5% wiv of active ingredient. When bermzyl alcohol is used as the solvent irm a composition comprising 2.25% wiv ivermectina and 1.25% w/v abamectin,
Preferably the composition comprises a long acting vehicle that employs castor oil.
Castor oil (ricinus oil, oleum ricini, ricinoleum, tangantanggan) is a triglyceride of fatty acids. The fatty acid scomposition is approximately ricinoBeic acid (87%); oleic acid (7%), linoleic acid (3%); palmitic acid (2%); stearic acid (1%) and trace amounts of dihydroxy stearic acied. Castor oil is the fixed oil obtained by cold-expression of the seeds of Ricinus cormnmunis Linn (Fam. Euphorbiaceae). (Rowe RC etal:
Handbook of Pharmaceutical Excipients, London, Pharmaceutical Press, GB, page 104-105).
The concentration of castor oil in the compositions acco rding to the invention is between 30 and 60 w/v. By raising or lowering the am ount of the castor oil in the formulation the viscosity of the formulation is adjusted a nd the slow release effect is influenced. For exanmple, by raising the concentration of castor oil, the viscosity is increased and the raate at which the active ingredients ame released from the depot is lowered. Good resul ts were obtained with concentratiore s of castor oil of 50.4% wiv (62.5 mi on a total o¥ 100 ml) and 33,6 %wi/v (35 ml on &x total of 100 mi).
As shown in a pharrmnacokinstics study in example 4 and 5, although both sesame and castor oil are pr-olonged action vehicles, the castor oil based formulation provides a better long acting gorofile for a macrocyclic lactone bassed formulation. Each oll promoted a different ivermectin and abamectin release pattern that is possible to verify by Tmax and ®&1/2 values, which are 229.70h and 261.70 for formulation using castor oil and 63.430 and 197.87h for formulation using sesame oll These results suggest that the casstor oil formulation has longer persisstency when compared to the sesame oil formulation what affects the residual efficacy of the product against parasites.
The novel composit ions according to the invention have proven long action and good efficacy against intesrnal and external parasites, especially in bovines. The novel compositions according to the invention result in a unig ue formulation which controls parasites resistant t-o ivermectin and doramectin, like, Ccoperia and Hasmonchus. it is worth mentiomning that these two nematode species account for approximately 80% of the parasites found in Brazilian cattle.
The diluent preferably is a vegetable oil. The vegetable oil used in the formulation 5 may be any sui table vegetable oil of a phamaceuticaxal grade, such as soy bean oil, sesame oil, oliwe oil, sunflower oil and/or corn oil. Such vegetable oils may be used alone or in combinations. Preferably corn oil and/or oslive oil is used, either alone or in combination.
The compositions according to the invention comprisse a solvent for the active ingredient. Suitable solvents are, for example, benzy~1 alcohol, or caprylic/ capric acid triglyceride. Trme amount of solvent used should be a_djusted to match the amount of active ingredie nts present in the composition. Preferably the solvent is benzyl alcohol. The concentration of benzyl alcohol preferakoly is 7.3 96 wiv.
An experiment conducted in cattle demonstrated thaat the association ivermectin + abamectin (3.5%) showed a higher anti-helminthic efficacy, when compared to a high concentration (3.15%) lvermectin commercial formu lation, against four species of endoparasites : Haemonchus placei, Cooperia punc-tata, C. spatulata and Trichuris discolor. Both formulations showed a 100% efficacy against the others four species on the 14th DEPT, 18 bovine hosts, divided into threes groups of six animals each that were necropsiied. Eight nematode species were identified.
Further pharmaceutically acceptable ingredients may be added such as an 55 antioxidant. A n antioxidant that is particularly useful for use in vegetable oils is tocopherol ac etate, but other suitable antioxidants known in the art may also be used.
The compositzions of the invention may be used for —the preparation of a medicament for controllingm parasites in and on host animals, particularly in bovines
The compositions according to the invention can be used in injectable formulations.
The composition of the invention may be delivered to the animal by injection, preferably su bcutaneously, for example in the neckc. The oily formulations of the invention will form a depot underneath the skin resulting in a slow release of the active ingredients.
The amount of the composition injected into a target animau! depends on the body weight of the animal. C=ood results were obtained when 1 rel of a composition was administered per 50 kc bodyweight. When a composition iss used comprising 2.25% wiv ivermectin and 1.2 5% wh abamectin, this results in 45 0 microgram/kg bodyweight for ivermectin and 250 microgram/kg bodyweight for abamectin.
Alternatively the comp-osition according to the invention can be used in pour-on formulations i.e. the p=arasiticidal active agents may be applied by a localised application to the oute r surface of an animal, whereby the active ingredient migrates as to protect the wholes external surface of the animal. By * “localised” application it Is meant that the active i ngredient is only applied to a minor portion of the outer surface of the animal, generailly as a line or spot on the animals back.
For such a pour on formulation a non-aqueous solvent as spreading agent may be added to the composiikion according to the invention in orcller to help dispersing the active ingredients so t-hat they reach all parasites of the arimal and control the level of skin penetration.
Suitable spreading ag ents are e.g. Crodamol® CAP and Crodamol PMP of Croda
Chemicals Europe, Est Yorkshire, United Kingdom whici is an oil soluble emollient comprising fatty acid esters, produced by the direct esterification of natural fatty acids and alcohols. }
Suitably pour on form ulations normally include a colouring agent to enable the user to visually monitor the application of the composition to th « animal. The nature of the coloring agent is unimportant and a wide variety of suitabEe dyes and pigments will be known to the skilled pmerson.
A suitable pour-on for-mulation is disclosed in Example 3.
EXAMPLE 1: Method tos produce formulation 1
FORMULATION 1
WERMECTIN 2.259
ABAMECTIN 1.259
BENZYL ALCOHOL 7.0mL
CASTOR OIL 52.5mL
TOCOPHEROL ACETATE 0.05g
CORN OIL up to 100mL
Method to manufactures formulation 1:
In a suitable recipient provided with stirrer and nitrogen bubbling system, add abamectin, ivermectin and benzy! alcohol. Heat until 50 o C uncer agitation and stirring until the solubilization of active ingredients occurs. Add «castor oil and mix during 30-60 minutes Linder heating (50 0 C).Turn off the heat 2nd diminish the temperature until 30-4€oC. Then, add acetate tocopherol and com oil and mix until to get homogeneous soliton (around 60-90 minutes)
Filter the solution through suitable filter cartridge and sterilized in 0.22 m cartridge to obtain sterile solution.
Alternative method to manufacture formulation 1:
PART 1: In a suitable recipient provided with stirrer and nitrogen bubbling system, add abamectin, iverm ectin and benzyl alcohol. Heat until 50 0 C under agitation and stirring until the solub ilization of active ingredients occurs.
PART 2: In another recipient add castor oil heat until 50 0 GC umder stirring.
Transfer the part 1 to part 2 and mix during 30-60 minutes and then turn off the heat and diminish the temgoerature until 30-400C. Then, add acetate tocopherol and corn oil and mix until to gext homogeneous solution {around 60-90 rminutes)
Filter the solution through suitable fitter cartridge and sterilizecd in 0.22 m cartridge to obtain sterile solut ion.
EXC AMPLE 2: Method to produce formulation 2
FORMULATION 2
IVERMECTIN 2.259
ABAMECTIN 1.259
BESNZYL ALCOHOL 7.0mL
CASTOR OIL 35mL
TCOCOPHEROL ACETATE 0.059
C «ORN OIL 35mL
O LIVE OIL up to 100mL
P ART 1: In a suitable recipient provided with stirrer and nitrogen bubblingg system, add abamectin, ivermectin and benzyl alcohol.
HE eat until 50 o C under agitation and sti ring until the solubilization of actzive irmgredient occurs.
P ART 2: In another recipient add castor- oil and corn cil, and mix during 330 minute u nder 50 o C.
Transfer the part 1 to part 2 and mix dusring 30-60 minutes and then turn off the heat and diminish the temperature until 30-4&0C. Then, add acetate tocopher—ot and olive o»iland mix until to get homogeneous solution (around one minute)
Filter the solution through suitable filter cartridge and sterilized in 0.22 m cartridge t« obtain sterile solution.
EXAMPLE 3: Pour-on formulation 1 VERMECTIN
ABAMECTIN w/ohicle: BENZYL ALCOHOL, CAPCIC./ CAPRYLIC ACID TRIGLYCERI DE, 1SOPROPYLALCOHOL, CASTOR Oil
VO 2005/037294 PCT/EP2004/052554
EXAMPLE 4: Comparison of Ilverrnectin plasma concentrations after administration in different long acting vehicles by sc administration to cattle
Material and Methods: The pharmacokinetic profile of an 1% ivermectin formulation comprising 35% (v/v) castor oil was assessed in this study by a parallel ¢ omparison with an 1% ivermectin formulation in 72.2% (w/w) sesame oil. The formulations were administered at a single dose subcutaneous (sc) into the neck of caattle.
Blood samples were collected by jugular venipuncture attimes 0, 0.5,1, 15,2,3,5, 7, 10, 15, 20, 30, and 40 days after drug administration. The concentration of
Ivermectin in the plasma samples was determined by HPLC.
Results: Figure 1 shows bovine plasma ivermectin concentrations (indivi«dual animals in ng/mL) after single sc administration of the formulations. The results o btained show that the castor oil based lon g acting formulation maintained therap «utic blood levels for 40 days compared to 20 days for the sesame oil based formulation.
EXAMPLE 5: Comparison of Abamectin plasma concentrations after ad ministration in different long acting vehicles bys sc administration to cattle
Material and Methods: The pharmacokinetic profile of an 1% abamectin formulation comprising 35% (v/v) castor oil was assessed in this study by a parallel ecomparison with an 1% abamectin formulation in 72.2% (w/w) sesame oil. The form ulations were administered at a single dose subcutaneous (sc) Into the neck of cattie. Blood samples were collected by jugular venipuncture at times 0, 0.5, 1, 1.5, 2, 3,5,7,10, 185, 20, 30, and 40 days after drug administration. The concentration of i vermectin in the plasma samples was determi ned by HPLC.
Results: Figure 2 shows bovine plasma abamectin concentrations (individual animals in ng/mL) after single sc administration of the formulations. The results obtained show that the castor oil based lorg acting formulation maintained theragoeutic blood levels for 30 days compared to 15 days for the sesame oil based formul ation.
Claims (10)
1. A long acting composition for controlling parasites in and on animals, which comprises in a slow release veahicle a combination of ivermectlin and abamectin, characterized in that the total percentage wiv of ivermectin ancd abamectin equals or exceeds 3% w/v and the concentration of ivermectin is higher than the concentration of abamectin
2. The composition according to claim 1 characterised in that —the slow release vehicle comprises 30 to 60% ‘wiv of castor oll, a solvent and u p to 100 % v/v ofa diluent.
3. The composition according to any of claims 1 or 2, characterised in that it comprises 1.75- 5% wiv ivermectin and 0.5- 2% w/v abamectin.
4. The composition accordingy to any of claims 1 to 3, charact erized in that it comprises 2.25% ivermectin and 1.25% abamectin.
5. The composition accordirk g to any of claims 1 to 4, charac=terised in that the diluent is a vegetable oil.
6. The composition according to any of claims 1 to 5, characterised in that the vegetable oil is selected fron corn oil or olive oil or a combin ation of corn oil and olive oil. o5
7. The composition accordin gto any of claims 1 to 6, charac=terised in that the solvent is benzyl alcohol.
8. Use of a composition according to any of claims 1 to 7 for the preparation of a medicament for controlling parasites in and on host animals —
9. Use according to claim 8 characterized in that the compossition is administered to the host animal by injection or as pour-on.
10. Use according to claim 8or 9, characterized in that the Bhost animal is bovine.
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AU (1) | AU2004281551B2 (en) |
BR (1) | BRPI0415366A (en) |
NZ (1) | NZ546340A (en) |
TR (1) | TR200601608T1 (en) |
WO (1) | WO2005037294A1 (en) |
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US20100022469A1 (en) * | 2008-06-24 | 2010-01-28 | Majid Razzak | Anthelminthic formulations |
US9616044B2 (en) | 2012-03-13 | 2017-04-11 | Bayer New Zealand Ltd | Long acting compositions |
CN104430394A (en) * | 2014-10-20 | 2015-03-25 | 广西大学 | Preparation method of ivermectin/emamectin benzoate compound microcapsule suspension |
CN109329077A (en) * | 2018-09-27 | 2019-02-15 | 江苏省协同医药生物工程有限责任公司 | A kind of anti parasitic experimental animal padding and preparation method thereof |
CN110721152B (en) * | 2018-12-29 | 2022-01-14 | 瑞普(天津)生物药业有限公司 | Sustained-release composition for treating animal skin parasite and fungus infection |
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BRPI0415366A (en) | 2006-12-12 |
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