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
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)
- Oil, Petroleum & Natural Gas (AREA)
- Tropical Medicine & Parasitology (AREA)
- Molecular Biology (AREA)
- Engineering & Computer Science (AREA)
- Dermatology (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.
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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.
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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
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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
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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:
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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
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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
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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.
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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 |
US6214367B1 (en) * | 1996-06-05 | 2001-04-10 | 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 |
WO2010008891A2 (en) * | 2008-06-24 | 2010-01-21 | Merial Limited | Anthelminthic formulations |
EP2396006B1 (en) * | 2009-02-16 | 2012-12-19 | Pfizer Inc. | High dosage doramectin formulation |
MX2012004133A (en) * | 2009-10-07 | 2012-05-08 | 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 |
---|---|---|---|---|
FR2570390B1 (en) * | 1984-09-14 | 1987-11-27 | Glaxo Group Ltd | NOVEL ANTIBIOTIC COMPOUNDS AND PREPARATION METHOD |
AU596586B2 (en) * | 1985-04-30 | 1990-05-10 | American Cyanamid Company | Chemical derivatives of antibiotics S541 |
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 EP EP90303716A patent/EP0393890B1/en not_active Expired - Lifetime
- 1990-04-06 ES ES90303716T patent/ES2052173T3/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 RU SU904743681A patent/RU1836084C/en active
- 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 FI FI901816A patent/FI92015C/en active IP Right Grant
- 1990-04-10 AU AU53119/90A patent/AU609660B2/en not_active Ceased
- 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 |
---|---|
JPH02290820A (en) | 1990-11-30 |
CN1046282A (en) | 1990-10-24 |
AU609660B2 (en) | 1991-05-02 |
AU5311990A (en) | 1990-11-08 |
ES2052173T3 (en) | 1994-07-01 |
EP0393890A1 (en) | 1990-10-24 |
OA09203A (en) | 1992-06-30 |
NO175882B (en) | 1994-09-19 |
SG27894G (en) | 1995-03-17 |
NO901637L (en) | 1990-10-12 |
CN1035356C (en) | 1997-07-09 |
JPH0647548B2 (en) | 1994-06-22 |
AP9000174A0 (en) | 1990-04-30 |
FI92015B (en) | 1994-06-15 |
EG18956A (en) | 1994-04-30 |
GR3005794T3 (en) | 1993-06-07 |
FI92015C (en) | 1994-09-26 |
HK39294A (en) | 1994-05-06 |
NO901637D0 (en) | 1990-04-10 |
EP0393890B1 (en) | 1992-08-12 |
RU1836084C (en) | 1993-08-23 |
NO175882C (en) | 1994-12-28 |
FI901816A0 (en) | 1990-04-10 |
DK0393890T3 (en) | 1992-09-28 |
CY1777A (en) | 1995-10-20 |
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