CA2014157C - Antiparasitic formulation containing 25-cyclohexyl-avermectin b1 - Google Patents
Antiparasitic formulation containing 25-cyclohexyl-avermectin b1Info
- Publication number
- CA2014157C CA2014157C CA002014157A CA2014157A CA2014157C CA 2014157 C CA2014157 C CA 2014157C CA 002014157 A CA002014157 A CA 002014157A CA 2014157 A CA2014157 A CA 2014157A CA 2014157 C CA2014157 C CA 2014157C
- Authority
- CA
- Canada
- Prior art keywords
- avermectin
- cyclohexyl
- compound
- sesame oil
- solution according
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Saccharide Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
A solution of antiparasitic agent 25-cyclohexyl-avermectin B1 in a solvent consisting of 50-95% sesame oil with the remainder ethyl oleate is effective against parasites, well tolerated by animals and may be injected using standard injection equipment.
Description
~0 1 4 1 57 ANTIPARASITIC FORMULATIONS
This invention concerns the preparation of parenteral formulations of the compound known as 25-cyclohexyl-avermectin Bl of formula (I).
oc~, .
~o~ oc~, J~ 1' ~ Ct1~ ~ 2~C~
i~ "~ ~
10~ 0~0 C~, oH
(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.
P~C 496 Antiparasitic agents are most conveniently administered to animals by using parenteral, subcutaneous or intramuscular formulations. Water is generally a convenient liquid for injection, but avermectins have a very low solubility in water and simple aqueous solutions are too dilute to be useable. 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 on 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 inefficient and inconsistent antiparasitic efficacy.
Indeed, the commercially available antiparasitic agent, "Ivomec injectable for cattle", a co-solvent formulation of an avermectin known as ivermectin, is only suitable for subcutaneous use and may cause irritation and swelling at the injection site.
`: ~
3 2 ~ 1 4 1 5 7 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 1% 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 4C
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 2 0 1 4 t 57 compatible with conventional injection equipment.
According to the invention, there is provided a solution of 25-cyclohexyl-avermectin Bl, compound (1~, in a solvent consisting of from 50 to 95% by volume of sesame oil with the remainder ethyl oleate.
The preferred solvent mixture consists of from 75 to 90% 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, Capillaria, 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 Strongyloides 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 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 Bl in the oil formulations were made and tested by the methods given below.
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 10 mg Ethyl oleate 0.1 ml Sesame oil to 1.0 ml The ethyl oleate and sesame oil were mixed and heated to 80C, whilst purging with nitrogen. Compound I 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.
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 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 75/25 mixture of sesame oil and ethyl oleate:
Compound I 10 mg Ethyl oleate 0.25 ml Sesame oil to 1.0 ml 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 200~g/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 80 (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 -L 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 MicelleUntreated Formulation Untreated Day FormulationControlExample 1 Control Totals257 3454 30 4727 Treatment with formulation example 1 both delayed the production of adult female ticks and resulted in fewer ticks collected.
The toleration of avermectin formulations was assessed following injection into the s~ raneous 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.
O = Normal, no visible lesion 1 = Light scar 2 = Heavy scar 3 = Encapsulated debris<l.Ocm3 4 = Encapsulated debris>l.O<2.5cm 5 = Encapsulated debris>2.5cm3 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 200~g/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.
Table 2 Comparison of intramuscular injection site toleration scores Number of Average Treatment Day Animals Score 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.
This invention concerns the preparation of parenteral formulations of the compound known as 25-cyclohexyl-avermectin Bl of formula (I).
oc~, .
~o~ oc~, J~ 1' ~ Ct1~ ~ 2~C~
i~ "~ ~
10~ 0~0 C~, oH
(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.
P~C 496 Antiparasitic agents are most conveniently administered to animals by using parenteral, subcutaneous or intramuscular formulations. Water is generally a convenient liquid for injection, but avermectins have a very low solubility in water and simple aqueous solutions are too dilute to be useable. 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 on 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 inefficient and inconsistent antiparasitic efficacy.
Indeed, the commercially available antiparasitic agent, "Ivomec injectable for cattle", a co-solvent formulation of an avermectin known as ivermectin, is only suitable for subcutaneous use and may cause irritation and swelling at the injection site.
`: ~
3 2 ~ 1 4 1 5 7 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 1% 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 4C
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 2 0 1 4 t 57 compatible with conventional injection equipment.
According to the invention, there is provided a solution of 25-cyclohexyl-avermectin Bl, compound (1~, in a solvent consisting of from 50 to 95% by volume of sesame oil with the remainder ethyl oleate.
The preferred solvent mixture consists of from 75 to 90% 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, Capillaria, 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 Strongyloides 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 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 Bl in the oil formulations were made and tested by the methods given below.
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 10 mg Ethyl oleate 0.1 ml Sesame oil to 1.0 ml The ethyl oleate and sesame oil were mixed and heated to 80C, whilst purging with nitrogen. Compound I 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.
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 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 75/25 mixture of sesame oil and ethyl oleate:
Compound I 10 mg Ethyl oleate 0.25 ml Sesame oil to 1.0 ml 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 200~g/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 80 (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 -L 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 MicelleUntreated Formulation Untreated Day FormulationControlExample 1 Control Totals257 3454 30 4727 Treatment with formulation example 1 both delayed the production of adult female ticks and resulted in fewer ticks collected.
The toleration of avermectin formulations was assessed following injection into the s~ raneous 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.
O = Normal, no visible lesion 1 = Light scar 2 = Heavy scar 3 = Encapsulated debris<l.Ocm3 4 = Encapsulated debris>l.O<2.5cm 5 = Encapsulated debris>2.5cm3 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 200~g/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.
Table 2 Comparison of intramuscular injection site toleration scores Number of Average Treatment Day Animals Score 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 (9)
1. A solution of 25-cyclohexyl-avermectin B1 in a solvent consisting of from 50% to 95% by volume of sesame oil with the remainder ethyl oleate.
2. A solution according to claim 1, in which the solvent contains from 75% to 90% by volume of sesame oil with the remainder ethyl oleate.
3. A solution according to claim 1, containing from 1 to 30 mg/ml of 25-cyclohexyl-avermectin B1.
4. A solution according to claim 2, containing from 1 to 30 mg/ml of 25-cyclohexyl-avermectin B1.
5. A solution according to claim 1 containing about 10 mg/ml of 25-cyclohexyl-avermectin B1.
6. A solution according to claim 2 containing about 10 mg/ml of 25-cyclohexyl-avermectin B1.
7. The use of a solution according to any one of claims 1 to 6 for subcutaneous or intramuscular injection into animals.
8. The use of a solution according to any one of claims 1 to 6 for treating parasitic infections in animals.
9. A commercial package containing as active ingredient a solution according to any one of claims 1 to 6, together with instructions for the use thereof for treating parasitic infections in animals.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB8908071.7 | 1989-04-11 | ||
| GB898908071A GB8908071D0 (en) | 1989-04-11 | 1989-04-11 | Antiparasitic formulations |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2014157A1 CA2014157A1 (en) | 1990-10-11 |
| CA2014157C true CA2014157C (en) | 1996-05-07 |
Family
ID=10654763
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002014157A Expired - Lifetime CA2014157C (en) | 1989-04-11 | 1990-04-09 | Antiparasitic formulation containing 25-cyclohexyl-avermectin b1 |
Country Status (24)
| Country | Link |
|---|---|
| AR (1) | AR247096A1 (en) |
| AT (1) | ATE79263T1 (en) |
| BG (1) | BG60543B1 (en) |
| CA (1) | CA2014157C (en) |
| CZ (1) | CZ285736B6 (en) |
| DD (1) | DD293497A5 (en) |
| DE (1) | DE69000252T2 (en) |
| GB (1) | GB8908071D0 (en) |
| HU (2) | HU208252B (en) |
| IE (1) | IE62933B1 (en) |
| IL (1) | IL94006A0 (en) |
| IN (1) | IN173967B (en) |
| MA (1) | MA21803A1 (en) |
| MX (1) | MX20250A (en) |
| MY (1) | MY107092A (en) |
| NZ (1) | NZ233263A (en) |
| PE (1) | PE24891A1 (en) |
| PH (1) | PH26970A (en) |
| PT (1) | PT93697B (en) |
| RO (1) | RO105648B1 (en) |
| SK (1) | SK281618B6 (en) |
| UA (1) | UA18250A (en) |
| YU (1) | YU47912B (en) |
| ZA (1) | ZA902737B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE19826091A1 (en) * | 1998-06-12 | 1999-12-16 | Alcatel Sa | Method for securely changing data stored in a database, database system and network element equipped with it |
-
1989
- 1989-04-11 GB GB898908071A patent/GB8908071D0/en active Pending
-
1990
- 1990-04-02 PH PH40310A patent/PH26970A/en unknown
- 1990-04-04 IL IL94006A patent/IL94006A0/en not_active IP Right Cessation
- 1990-04-06 DE DE9090303716T patent/DE69000252T2/en not_active Expired - Fee Related
- 1990-04-06 RO RO144746A patent/RO105648B1/en unknown
- 1990-04-06 AT AT90303716T patent/ATE79263T1/en not_active IP Right Cessation
- 1990-04-09 PT PT93697A patent/PT93697B/en not_active IP Right Cessation
- 1990-04-09 MY MYPI90000572A patent/MY107092A/en unknown
- 1990-04-09 MX MX2025090A patent/MX20250A/en unknown
- 1990-04-09 IN IN353DE1990 patent/IN173967B/en unknown
- 1990-04-09 MA MA22062A patent/MA21803A1/en unknown
- 1990-04-09 BG BG91699A patent/BG60543B1/en unknown
- 1990-04-09 PE PE1990167632A patent/PE24891A1/en not_active Application Discontinuation
- 1990-04-09 CA CA002014157A patent/CA2014157C/en not_active Expired - Lifetime
- 1990-04-09 AR AR90316585A patent/AR247096A1/en active
- 1990-04-10 YU YU70490A patent/YU47912B/en unknown
- 1990-04-10 DD DD90339625A patent/DD293497A5/en unknown
- 1990-04-10 CZ CS901801A patent/CZ285736B6/en not_active IP Right Cessation
- 1990-04-10 ZA ZA902737A patent/ZA902737B/en unknown
- 1990-04-10 NZ NZ233263A patent/NZ233263A/en unknown
- 1990-04-10 IE IE128590A patent/IE62933B1/en not_active IP Right Cessation
- 1990-04-10 SK SK1801-90A patent/SK281618B6/en not_active IP Right Cessation
- 1990-04-11 HU HU902255A patent/HU208252B/en not_active IP Right Cessation
- 1990-04-11 UA UA4743681A patent/UA18250A/en unknown
-
1995
- 1995-05-19 HU HU95P/P00135P patent/HU211528A9/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| PE24891A1 (en) | 1991-08-17 |
| NZ233263A (en) | 1991-08-27 |
| HUT54272A (en) | 1991-02-28 |
| PT93697A (en) | 1990-11-20 |
| YU47912B (en) | 1996-05-20 |
| MX20250A (en) | 1993-11-01 |
| IN173967B (en) | 1994-08-13 |
| SK180190A3 (en) | 2001-05-10 |
| ATE79263T1 (en) | 1992-08-15 |
| AR247096A1 (en) | 1994-11-30 |
| MY107092A (en) | 1995-09-30 |
| MA21803A1 (en) | 1990-12-31 |
| IL94006A0 (en) | 1991-03-10 |
| CZ180190A3 (en) | 1999-10-13 |
| DE69000252D1 (en) | 1992-09-17 |
| DD293497A5 (en) | 1991-09-05 |
| HU211528A9 (en) | 1995-11-28 |
| CA2014157A1 (en) | 1990-10-11 |
| RO105648B1 (en) | 1992-11-30 |
| UA18250A (en) | 1997-12-25 |
| HU208252B (en) | 1993-09-28 |
| IE62933B1 (en) | 1995-03-08 |
| HU902255D0 (en) | 1990-08-28 |
| DE69000252T2 (en) | 1993-01-07 |
| GB8908071D0 (en) | 1989-05-24 |
| BG91699A (en) | 1993-12-24 |
| IE901285L (en) | 1990-10-11 |
| SK281618B6 (en) | 2001-05-10 |
| ZA902737B (en) | 1991-11-27 |
| PT93697B (en) | 1996-08-30 |
| BG60543B1 (en) | 1995-08-28 |
| YU70490A (en) | 1992-05-28 |
| CZ285736B6 (en) | 1999-10-13 |
| PH26970A (en) | 1992-12-28 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| MKLA | Lapsed | ||
| MKEC | Expiry (correction) |
Effective date: 20121202 |