AP133A - Antiparasitical Formulations - Google Patents
Antiparasitical Formulations Download PDFInfo
- Publication number
- AP133A AP133A APAP/P/1990/000174A AP9000174A AP133A AP 133 A AP133 A AP 133A AP 9000174 A AP9000174 A AP 9000174A AP 133 A AP133 A AP 133A
- Authority
- AP
- ARIPO
- Prior art keywords
- avermectin
- ethyl oleate
- sesame oil
- compound
- animals
- Prior art date
Links
- 239000000203 mixture Substances 0.000 title description 35
- 238000009472 formulation Methods 0.000 title description 28
- 230000002141 anti-parasite Effects 0.000 title description 4
- 239000000243 solution Substances 0.000 claims abstract description 20
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 claims abstract description 17
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 claims abstract description 17
- 229940093471 ethyl oleate Drugs 0.000 claims abstract description 17
- 239000008159 sesame oil Substances 0.000 claims abstract description 17
- 235000011803 sesame oil Nutrition 0.000 claims abstract description 17
- 241001465754 Metazoa Species 0.000 claims abstract description 13
- 239000002904 solvent Substances 0.000 claims abstract description 11
- 239000005660 Abamectin Substances 0.000 claims description 22
- 238000002347 injection Methods 0.000 claims description 14
- 239000007924 injection Substances 0.000 claims description 14
- 238000010255 intramuscular injection Methods 0.000 claims description 7
- 239000007927 intramuscular injection Substances 0.000 claims description 7
- 238000000034 method Methods 0.000 claims description 6
- 238000010254 subcutaneous injection Methods 0.000 claims description 5
- 239000007929 subcutaneous injection Substances 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 208000030852 Parasitic disease Diseases 0.000 claims 2
- QLFZZSKTJWDQOS-YDBLARSUSA-N doramectin Chemical compound O1[C@@H](C)[C@H](O)[C@@H](OC)C[C@@H]1O[C@@H]1[C@@H](OC)C[C@H](O[C@@H]2C(=C/C[C@@H]3C[C@@H](C[C@@]4(O3)C=C[C@H](C)[C@@H](C3CCCCC3)O4)OC(=O)[C@@H]3C=C(C)[C@@H](O)[C@H]4OC\C([C@@]34O)=C/C=C/[C@@H]2C)/C)O[C@H]1C QLFZZSKTJWDQOS-YDBLARSUSA-N 0.000 claims 1
- 239000003096 antiparasitic agent Substances 0.000 abstract description 7
- 244000045947 parasite Species 0.000 abstract description 5
- 229940125687 antiparasitic agent Drugs 0.000 abstract description 4
- 239000012899 standard injection Substances 0.000 abstract 1
- 150000001875 compounds Chemical class 0.000 description 22
- RRZXIRBKKLTSOM-XPNPUAGNSA-N avermectin B1a Chemical compound C1=C[C@H](C)[C@@H]([C@@H](C)CC)O[C@]11O[C@H](C\C=C(C)\[C@@H](O[C@@H]2O[C@@H](C)[C@H](O[C@@H]3O[C@@H](C)[C@H](O)[C@@H](OC)C3)[C@@H](OC)C2)[C@@H](C)\C=C\C=C/2[C@]3([C@H](C(=O)O4)C=C(C)[C@@H](O)[C@H]3OC\2)O)C[C@H]4C1 RRZXIRBKKLTSOM-XPNPUAGNSA-N 0.000 description 11
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 9
- 241000283690 Bos taurus Species 0.000 description 7
- 239000003921 oil Substances 0.000 description 7
- 235000019198 oils Nutrition 0.000 description 7
- 241000238876 Acari Species 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- SPBDXSGPUHCETR-JFUDTMANSA-N 8883yp2r6d Chemical compound O1[C@@H](C)[C@H](O)[C@@H](OC)C[C@@H]1O[C@@H]1[C@@H](OC)C[C@H](O[C@@H]2C(=C/C[C@@H]3C[C@@H](C[C@@]4(O[C@@H]([C@@H](C)CC4)C(C)C)O3)OC(=O)[C@@H]3C=C(C)[C@@H](O)[C@H]4OC\C([C@@]34O)=C/C=C/[C@@H]2C)/C)O[C@H]1C.C1C[C@H](C)[C@@H]([C@@H](C)CC)O[C@@]21O[C@H](C\C=C(C)\[C@@H](O[C@@H]1O[C@@H](C)[C@H](O[C@@H]3O[C@@H](C)[C@H](O)[C@@H](OC)C3)[C@@H](OC)C1)[C@@H](C)\C=C\C=C/1[C@]3([C@H](C(=O)O4)C=C(C)[C@@H](O)[C@H]3OC\1)O)C[C@H]4C2 SPBDXSGPUHCETR-JFUDTMANSA-N 0.000 description 5
- 229940102223 injectable solution Drugs 0.000 description 4
- 244000105624 Arachis hypogaea Species 0.000 description 3
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- 239000006184 cosolvent Substances 0.000 description 3
- 244000078703 ectoparasite Species 0.000 description 3
- 239000004615 ingredient Substances 0.000 description 3
- 230000007794 irritation Effects 0.000 description 3
- 229940007210 ivomec Drugs 0.000 description 3
- 230000003902 lesion Effects 0.000 description 3
- 238000007920 subcutaneous administration Methods 0.000 description 3
- 210000001519 tissue Anatomy 0.000 description 3
- AZSNMRSAGSSBNP-UHFFFAOYSA-N 22,23-dihydroavermectin B1a Natural products C1CC(C)C(C(C)CC)OC21OC(CC=C(C)C(OC1OC(C)C(OC3OC(C)C(O)C(OC)C3)C(OC)C1)C(C)C=CC=C1C3(C(C(=O)O4)C=C(C)C(O)C3OC1)O)CC4C2 AZSNMRSAGSSBNP-UHFFFAOYSA-N 0.000 description 2
- 235000003911 Arachis Nutrition 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 241000283086 Equidae Species 0.000 description 2
- 241000244206 Nematoda Species 0.000 description 2
- 241000238680 Rhipicephalus microplus Species 0.000 description 2
- 241000243774 Trichinella Species 0.000 description 2
- 235000012343 cottonseed oil Nutrition 0.000 description 2
- 239000002385 cottonseed oil Substances 0.000 description 2
- 229940074076 glycerol formal Drugs 0.000 description 2
- 238000007918 intramuscular administration Methods 0.000 description 2
- 229960002418 ivermectin Drugs 0.000 description 2
- 239000000693 micelle Substances 0.000 description 2
- 231100000241 scar Toxicity 0.000 description 2
- 230000008961 swelling Effects 0.000 description 2
- 241001147657 Ancylostoma Species 0.000 description 1
- 235000017060 Arachis glabrata Nutrition 0.000 description 1
- 235000010777 Arachis hypogaea Nutrition 0.000 description 1
- 235000018262 Arachis monticola Nutrition 0.000 description 1
- 241000244186 Ascaris Species 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 241000243990 Dirofilaria Species 0.000 description 1
- 241000498256 Enterobius Species 0.000 description 1
- 208000006968 Helminthiasis Diseases 0.000 description 1
- 241000238631 Hexapoda Species 0.000 description 1
- 241000920471 Lucilia caesar Species 0.000 description 1
- 241000498271 Necator Species 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 241001674048 Phthiraptera Species 0.000 description 1
- 241000207961 Sesamum Species 0.000 description 1
- 235000003434 Sesamum indicum Nutrition 0.000 description 1
- 241000258242 Siphonaptera Species 0.000 description 1
- 241000244174 Strongyloides Species 0.000 description 1
- 241000282898 Sus scrofa Species 0.000 description 1
- 241001489151 Trichuris Species 0.000 description 1
- 230000000895 acaricidal effect Effects 0.000 description 1
- 239000000642 acaricide Substances 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000000507 anthelmentic effect Effects 0.000 description 1
- 229940124339 anthelmintic agent Drugs 0.000 description 1
- 239000000921 anthelmintic agent Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 239000013057 ectoparasiticide Substances 0.000 description 1
- 244000079386 endoparasite Species 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 244000000050 gastrointestinal parasite Species 0.000 description 1
- 244000000013 helminth Species 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 239000002917 insecticide Substances 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000005374 membrane filtration Methods 0.000 description 1
- FXWHFKOXMBTCMP-WMEDONTMSA-N milbemycin Natural products COC1C2OCC3=C/C=C/C(C)CC(=CCC4CC(CC5(O4)OC(C)C(C)C(OC(=O)C(C)CC(C)C)C5O)OC(=O)C(C=C1C)C23O)C FXWHFKOXMBTCMP-WMEDONTMSA-N 0.000 description 1
- ZLBGSRMUSVULIE-GSMJGMFJSA-N milbemycin A3 Chemical class O1[C@H](C)[C@@H](C)CC[C@@]11O[C@H](C\C=C(C)\C[C@@H](C)\C=C\C=C/2[C@]3([C@H](C(=O)O4)C=C(C)[C@@H](O)[C@H]3OC\2)O)C[C@H]4C1 ZLBGSRMUSVULIE-GSMJGMFJSA-N 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- SFMJNHNUOVADRW-UHFFFAOYSA-N n-[5-[9-[4-(methanesulfonamido)phenyl]-2-oxobenzo[h][1,6]naphthyridin-1-yl]-2-methylphenyl]prop-2-enamide Chemical compound C1=C(NC(=O)C=C)C(C)=CC=C1N1C(=O)C=CC2=C1C1=CC(C=3C=CC(NS(C)(=O)=O)=CC=3)=CC=C1N=C2 SFMJNHNUOVADRW-UHFFFAOYSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 208000014837 parasitic helminthiasis infectious disease Diseases 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 235000020232 peanut Nutrition 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 244000144977 poultry Species 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 238000010926 purge Methods 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
Classifications
-
- 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
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- 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
-
- 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
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
-
- 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
- A61K47/44—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
-
- 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
- A61K9/08—Solutions
-
- 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
- A61P33/10—Anthelmintics
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Tropical Medicine & Parasitology (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Molecular Biology (AREA)
- Dermatology (AREA)
- Engineering & Computer Science (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Saccharide Compounds (AREA)
Abstract
A solution of antiparasitic agent 25-cyclohexyl-avermectin b1 in a solvent consisting of 50 to 95 percent sesame oil with remainder ethyl oleate is effective against parasites, well tolerated by animals and may be injected using standard injection equipment.
Description
ANTIPARASITIC FORMULATIONS
I
This invention concerns the preparation of parenteral formulations of the compound known as 25-cyclohexv1-avermectin Bl of formula (I).
This compound is a member of the avermectin family, described and claimed in European Patent publication 0214731. The avermectins are highly active antiparasitic agents having particular utility as anthelmintics, ectoparasiticides, insecticides and acaricides.
AP 0 0 0 1 3 3
BAD ORIGINAL
PLC 496
Antiparasi t ic agents are nest conveniently administered to animals by using parenteral, subcutaneous or intramuscular formulations. Water is generally a convenient liquid for injection, but avermectins have a very lew solubility in water and simple aqueous solutions are too dilute to be usable. Certain avermectins can be solubilized in water using surface active agents as solubilisers and suitable organic co-solvents to form a micellar solution as described in US Patent 4389397. However, these formulations do not provide doses of active compounds sufficient to remove satisfactorily both internal and external parasites of animals.
European Patent publication 146414 describes co-solvent solutions of avermectins, in a mixture of glycerol formal and propylene glycol or in propylene glycol containing a minor amount of water, for parenteral use. However, propylene glycol is known to cause irritation cr. subcutaneous or intramuscular injection.
Additionally, minor amounts of water in these formulations may cause hydrolytic degradation of the avermectin.
Such formulations, which comprise water-miscible organic solvents for the avermectin, tend to produce unwanted local precipitation of the avermectin at the injection site. This may result in irritation and swelling at the injection site and in inerricient and inconsistent antiparasitic efficacy.
Trdeed, the commercially available antiparasitic agent, Tvomec injectable for cattle, a co-solvent formulation of an avermectin known as ivermectin, is only suitable for .subcutaneous use and may carre '· ·. : L<.i. and swelling at the injection site.
APO 0013 3
BAD ORIGINAL
PIC 496
An alternative method of providing an injectable solution of an avermectin is to dissolve the avermectin in a pharmaceutically acceptable oil. The use of arachis (peanut) and cottonseed oils, and also ethyl oleate, as solvents for certain avermectins is disclosed in British patent publication 2166436. However, arachis oil and cottonseed oil do not provide a solution having at least a IX w/v concentration of compound I, as is generally required for a veterinary product. Veterinary formulations are commonly used or stored on farms at low temperatures, down to 4eC or even lower, and even if the avermectin Is sufficiently soluble in the oil at normal room temperature it may precipitate or form a supersaturated solution, on exposure to cold conditions and thus become unusable. Pure ethyl oleate, and mixtures of oils containing a major proportion of ethyl oleate, attack certain plastics or rubber components of commonly used veterinary syringes to an unacceptable extent.
European Patent Application 285561 mentions pure sesame oil as a possible solvent for a different group of compounds, the milbemycins. In comparative viscosity and syringeability studies it has been found that pure sesame oil has a viscosity which is too high to allow its use as a solvent for injection using conventional veterinary syringe equipment. For this reason, pure sesame oil cannot be used as an injectable solvent under practical field conditions.
The present invention is intended to provide a parenteral formulation for compound (I) which is effective against both internal and external parasites, Is well tolerated by animals on both subcutaneous and intramuscular administration and is
PLC 496 compatible with conventional injection equipment.
According to the invention, there is provided a solution of 25-cyclohexyl-avermectin BI, compound (I), in a solvent consisting of from 50 to 952 by volume of sesame oil with the remainder ethyl oleate.
The preferred solvent mixture consists of from 75 to 902 of sesame oil by volume with the remainder ethyl oleate.
The preferred content of avermectin for subcutaneous or intramuscular injection is from 1 to 30 mg/ml, most preferably about 10 mg/ml.
The formulations according to the invention are monophase solutions and are effective in treating a variety of conditions caused by endoparasites including, in particular, helminthiasis which is most frequently caused by a group of parasitic worms described as nematodes and which can cause severe economic losses in swine, sheep, horses and cattle as well as affecting domestic animals and poultry. The compounds are also effective against other nematodes which affect various species of animals including, for example, Dirofilaria in dogs and various parasites which can infect humans including gastro-intestinal parasites such as Ancylostoma, Necator, Ascaris, Strongyloides, Trichinella, Caplllaria, Trichuris, Enterobius and parasites which are found in the blood or other tissues and organs such as filiarial worms and the extra intestinal stages of Strongyloldes and Trichinella.
The formulations of the invention are also of value in treating ectoparasite infections including in particular anthropod ectoparasites of animals and birds such as ticks, mites, lice, fleas, blowfly, biting insects and migrating dipterous larvae
AP 0 0 0 1 3 3
BAD ORIGINAL $
PLC 496 which can affect cattle and horses.
It has been found, unexpectedly, that formulations according the invention show properties which are superior to the prior art formulations mentioned above, in that they show little or no irritation at the injection site when administered to animals by subcutaneous or intramuscular injection, are suitable for use in commonly used standard syringes, and give consistent antiparasitic efficacy.
A further advantage of the solutions of the invention is that, as the formulation vehicle contains esters of unsaturated acids, the avermectin is protected from air oxidation during prolonged storage.
The solutions of the invention may be prepared simply by dissolving compound (I) in the sesame oil ethyl oleate mixture and sterilising and packaging for administration in a conventional manner.
Formulations according to the invention are described by way of illustration in the following Examples.
EXAMPLES
Solutions of 25-cyclohexyl-avermectin BI in the oil formulations were made and tested by the methods given below.
EXAMPLE 1
The following ingredients were used to prepare an injectable solution containing 10 mgs of compound I in 1 ml of a nominal 90/10 mixture of sesame oil and ethyl oleate:
Compound I Ethyl oleate
Sesame oil mg
0.1 ml to 1.0 ml
PLC 496
The ethyl oleate and sesame oil were mixed and heated to 80°C, whilst purging with nitrogen. Compound 1 is then added to the hot oils until dissolved and the resulting solution rapidly cooled and the volume adjusted to 1 ml with sesame oil, if required. This final solution was sterilised by membrane filtration and packaged aseptically.
EXAMPLE 2
Using the method of example 1, the following ingredients were used to prepare an injectable solution containing 10 mgs of compound I in 1 ml of a nominal 50/50 mixture of sesame oil and ethyl oleate:
| Compound I | 10 mg |
| Ethyl oleate | 0.5 ml |
| Sesame oil | to 1.0 ml |
EXAMPLE 3
Using the method of example 1, the following to prepare an injectable solution containing in 1 ml of a nominal 75/25 mixture of sesame
Compound I 10 mg
Ethyl oleate 0.25 ml
Sesame oil to 1.0 ml ingredients were used 10 mgs of compound I oil and ethyl oleate:
AP 0 0 0 1 3 3
EXAMPLE 4
The efficacy of compound I against ectoparasites was determined using a modification of the method described by L G Cramer et al., in Vet. Record, (1988), 122, 611-612.
Compound I was administered to two groups of cattle by subcutaneous injection at a dose of 200pg/kg on day 0. Group A received compound I in an aqueous micelle formulation according to US Patent 4389397 containing 2.5 mg of compound I, 120 mg of Tween
BAD ORIGINAL
PLC 496 (Registered Trade Mark), 200 mg of glycerol formal, about 10 mg of benzyl alcohol and the remainder water per ml of formulation. Group B were treated with compound I in the formulation of example
1. The treated groups, together with a control for each treatment were then seeded with Boophilus microplus larvae on days 0, 2 and 4 and the ticks allowed to develop into adults. Resulting engorged adult female ticks were collected between days 21 and 32 and the mean daily counts recorded as shown in Table 1.
Table 1
Mean Daily counts of female B.microplus ticks collected
| Micelle | Untreated | Formulation | Untreated | |
| Ρ2Σ | Formulation | Control | Example 1 | Control |
| 21 | 0 | 287 | 0 | 0 |
| 22 | 0 | 651 | 0 | 324 |
| 23 | 0 | 879 | 0 | 996 |
| 24 | 0 | 753 | 0 | 1507 |
| 25 | 16 | 554 | 0 | 663 |
| 26 | 76 | 267 | 0 | 852 |
| 27 | 85 | 48 | 0 | 329 |
| 28 | 36 | 10 | 8 | 35 |
| 29 | 28 | 5 | 15 | 19 |
| 30 | 16 | 0 | 3 | 1 |
| 31 | 0 | 0 | 3 | 1 |
| 32 | 0 | 0 | 1 | 0 |
Totals 257 3454 30 4727
PLC 496
Treatment with formulation example 1 both delayed the production of adult female ticks and resulted in fewer ticks collected.
EXAMPLE 5
The toleration of avermectin formulations was assessed following injection into the semimembraneous muscle of cattle. Animals were humanely sacrificed at 7 and 14 days post-treatment and the injection sites, with surrounding tissue, removed. Tissues were examined for gross pathology and injection site lesions were evaluated using the scoring system described below.
« Normal, no visible lesion = Light scar = Heavy scar » Encapsulated debris<1.0cm = Encapsulated debris>1.0<2.5cm =* Encapsulated debris>2.5cm
Scores 0, 1 and 2 are considered acceptable. Scores greater than 2 have encapsulated debris. Compound I in formulations of examples 1 and 2 was administered to cattle by intramuscular injection at a dose of 200pg/kg. Injection site toleration was compared with that of the co-solvent formulation of the antiparasitic agent, ivermectin (Trademark; Ivomec for cattle) given at the same dose and by the same route.
AP000133
BAD ORIGINAL 0
PLC 496
Table 2
Comparison of Intramuscular Injection site toleration scores
| Treatment | Number of | Average Score | |
| Pay | Animals | ||
| Formulation | 7 | 5 | 0.4 |
| example 1 | 14 | 10 | 0.0 |
| Formulation | 7 | 5 | 0.4 |
| example 2 | 14 | 10 | 0.0 |
| Ivomec | 7 | 4 | 3.75 |
| 14 | 8 | 2.75 |
Compound I in formulation examples 1 and 2, was well tolerated with only a few minor lesions at 7 days post-injection; resolving completely by 14 days. In contrast, Ivomec given by intramuscular injection was poorly tolerated at 7 days with encapsulated debris still visible 14 days post-injection.
Claims (8)
1. A solution of 25-cyclohexyl-avermectin Bl in a solvent consisting of from 50 to 952 by volume of sesame oil with the remainder ethyl oleate.
2. A solution according to claim 1, in which the solvent contains from 75Z to 902 by volume of sesame oil with the remainder ethyl oleate.
3. A solution according to claim 1 or 2, containing from 1 to 30 mg/ml of 25-cyclohexyl-avermectin Bl.
4. A solution according to claim 3, containing about 10 mg/ml of 25-cyclohexyl-avermectin Bl.
5. A solution according to any preceding claim, for subcutaneous or intramuscular injection into animals.
6. A solution according to any one of claims 1 to 4, for treating parasitic infections in animals.
7. A method of treating parasitic infections in animals, which comprises administering a solution according to any one of claims 1 to 4 by injection.
8. A method of making a solution of 25-cyclohexyl-avermectin B1 which comprises dissolving 25.cyclohexyl-avermectin
B1 in a solvent consisting of from 50 to 95% by volume of sesame oil with the remainder ethyl oleate.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB898908071A GB8908071D0 (en) | 1989-04-11 | 1989-04-11 | Antiparasitic formulations |
| SG27894A SG27894G (en) | 1989-04-11 | 1994-02-22 | Injectable compositions containing 25-cyclohexyl-avermectin B1 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| AP9000174A0 AP9000174A0 (en) | 1990-04-30 |
| AP133A true AP133A (en) | 1991-06-05 |
Family
ID=26295191
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| APAP/P/1990/000174A AP133A (en) | 1989-04-11 | 1990-04-09 | Antiparasitical Formulations |
Country Status (16)
| Country | Link |
|---|---|
| EP (1) | EP0393890B1 (en) |
| JP (1) | JPH0647548B2 (en) |
| CN (1) | CN1035356C (en) |
| AP (1) | AP133A (en) |
| AU (1) | AU609660B2 (en) |
| CY (1) | CY1777A (en) |
| DK (1) | DK0393890T3 (en) |
| EG (1) | EG18956A (en) |
| ES (1) | ES2052173T3 (en) |
| FI (1) | FI92015C (en) |
| GR (1) | GR3005794T3 (en) |
| HK (1) | HK39294A (en) |
| NO (1) | NO175882C (en) |
| OA (1) | OA09203A (en) |
| RU (1) | RU1836084C (en) |
| SG (1) | SG27894G (en) |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE19613972A1 (en) * | 1996-04-09 | 1997-10-16 | Bayer Ag | Injection formulations of avermectins and milbemycins based on castor oil |
| EP0928136B1 (en) * | 1996-06-05 | 2003-10-22 | Ashmont Holdings Limited | Injectable compositions |
| DE19638045A1 (en) * | 1996-09-18 | 1998-03-19 | Bayer Ag | Injection formulations of avermectins and milbemycins |
| KR20000025762A (en) * | 1998-10-14 | 2000-05-06 | 유충식 | Soluble composition of ivermectins |
| GB9827727D0 (en) | 1998-12-16 | 1999-02-10 | Pfizer Ltd | Antiparasitic formulations |
| NZ590141A (en) * | 2008-06-24 | 2012-05-25 | Merial Ltd | Anthelminthic formulations including castor oil and another vegetable oil |
| KR101326428B1 (en) | 2009-02-16 | 2013-11-20 | 조에티스 엘엘씨 | High dosage doramectin formulation |
| EP2485725A2 (en) * | 2009-10-07 | 2012-08-15 | Wyeth LLC | Compositions comprising adjuvant, macrolide and proteinaceous antigen and methods of use thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0316124A2 (en) * | 1987-11-09 | 1989-05-17 | Pfizer Inc. | Ethylated avermectins |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2166436B (en) * | 1984-09-14 | 1989-05-24 | Glaxo Group Ltd | Antibiotic compounds and their preparation |
| ES8802229A1 (en) * | 1985-04-30 | 1988-04-16 | Glaxo Group Ltd | Macrolide antibiotics and their preparation |
| US4707470A (en) * | 1985-05-17 | 1987-11-17 | Smithkline Beckman Corporation | Polyene antibiotic emulsion formulation |
| EP0285561A3 (en) * | 1987-03-27 | 1989-10-25 | Ciba-Geigy Ag | Milbemycin derivatives with a paraciticidal and insecticidal activity |
-
1990
- 1990-04-06 ES ES90303716T patent/ES2052173T3/en not_active Expired - Lifetime
- 1990-04-06 EP EP90303716A patent/EP0393890B1/en not_active Expired - Lifetime
- 1990-04-06 DK DK90303716.6T patent/DK0393890T3/en active
- 1990-04-09 AP APAP/P/1990/000174A patent/AP133A/en active
- 1990-04-10 FI FI901816A patent/FI92015C/en active IP Right Grant
- 1990-04-10 OA OA59772A patent/OA09203A/en unknown
- 1990-04-10 NO NO901637A patent/NO175882C/en not_active IP Right Cessation
- 1990-04-10 AU AU53119/90A patent/AU609660B2/en not_active Ceased
- 1990-04-10 RU SU904743681A patent/RU1836084C/en active
- 1990-04-11 JP JP2096150A patent/JPH0647548B2/en not_active Expired - Fee Related
- 1990-04-11 EG EG22590A patent/EG18956A/en active
- 1990-04-11 CN CN90102072A patent/CN1035356C/en not_active Expired - Lifetime
-
1992
- 1992-09-24 GR GR920402116T patent/GR3005794T3/el unknown
-
1994
- 1994-02-22 SG SG27894A patent/SG27894G/en unknown
- 1994-04-28 HK HK39294A patent/HK39294A/en not_active IP Right Cessation
-
1995
- 1995-10-20 CY CY177795A patent/CY1777A/en unknown
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0316124A2 (en) * | 1987-11-09 | 1989-05-17 | Pfizer Inc. | Ethylated avermectins |
Non-Patent Citations (1)
| Title |
|---|
| CHEMICAL ABSTRACTS, Vol. 102, 1985, 216821 * |
Also Published As
| Publication number | Publication date |
|---|---|
| AU5311990A (en) | 1990-11-08 |
| NO901637D0 (en) | 1990-04-10 |
| EG18956A (en) | 1994-04-30 |
| JPH02290820A (en) | 1990-11-30 |
| AU609660B2 (en) | 1991-05-02 |
| NO901637L (en) | 1990-10-12 |
| FI92015B (en) | 1994-06-15 |
| FI901816A0 (en) | 1990-04-10 |
| CN1035356C (en) | 1997-07-09 |
| ES2052173T3 (en) | 1994-07-01 |
| DK0393890T3 (en) | 1992-09-28 |
| HK39294A (en) | 1994-05-06 |
| GR3005794T3 (en) | 1993-06-07 |
| EP0393890A1 (en) | 1990-10-24 |
| CN1046282A (en) | 1990-10-24 |
| SG27894G (en) | 1995-03-17 |
| JPH0647548B2 (en) | 1994-06-22 |
| FI92015C (en) | 1994-09-26 |
| CY1777A (en) | 1995-10-20 |
| EP0393890B1 (en) | 1992-08-12 |
| NO175882C (en) | 1994-12-28 |
| NO175882B (en) | 1994-09-19 |
| RU1836084C (en) | 1993-08-23 |
| OA09203A (en) | 1992-06-30 |
| AP9000174A0 (en) | 1990-04-30 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP1136081B1 (en) | Sustained-release compositions for the parenteral administration of macrolides | |
| EP0535734B1 (en) | Long acting injectable formulations containing hydrogenated castor oil | |
| DE69432982T2 (en) | POUR-ON FORMULATION CONTAINING POLYMERIC MATERIAL, GLYCOLES AND GLYCERIDES | |
| EP0413538A1 (en) | Long active injectable formulations containing triacetin | |
| AP133A (en) | Antiparasitical Formulations | |
| US6001822A (en) | Antiparasitic formulations | |
| US6699847B2 (en) | Antiparasitic formulation | |
| CA2014157C (en) | Antiparasitic formulation containing 25-cyclohexyl-avermectin b1 | |
| KR920006913B1 (en) | Insect Repellent Formulations | |
| KR20020067781A (en) | Anthelmintic injectable composition containing ivermectin and process for preparation thereof | |
| MXPA01006175A (en) | Doramectin formulations | |
| BRPI0101090B1 (en) | COMPOSITION FOR PARENTERAL ADMINISTRATION UNDERSTANDING A MACROLIDE COMPOUND OF THE CLASS OF MILBEMICINES |