CA2065093C - Remedies for bone diseases - Google Patents
Remedies for bone diseasesInfo
- Publication number
- CA2065093C CA2065093C CA002065093A CA2065093A CA2065093C CA 2065093 C CA2065093 C CA 2065093C CA 002065093 A CA002065093 A CA 002065093A CA 2065093 A CA2065093 A CA 2065093A CA 2065093 C CA2065093 C CA 2065093C
- Authority
- CA
- Canada
- Prior art keywords
- droloxifene
- bone diseases
- remedies
- bone
- salt
- 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 - Fee Related
Links
Classifications
-
- 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
- A61K31/02—Halogenated hydrocarbons
- A61K31/025—Halogenated hydrocarbons carbocyclic
- A61K31/03—Halogenated hydrocarbons carbocyclic aromatic
-
- 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
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/02—Nutrients, e.g. vitamins, minerals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
- A61P3/14—Drugs for disorders of the metabolism for electrolyte homeostasis for calcium homeostasis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
- A61P5/30—Oestrogens
Abstract
The use of drugs in which the active ingredient is droloxifene or a salt of droloxifene for the relief of bone diseases such as osteoporosis, Pagets' bone diseases, bone dissolution, malignant hypercalcemia and chronic articular rheumatism which are caused by deficiency of estrogen or the like is disclosed. Droloxifene has fewer side effects than tamoxifen and clomiprene which are known to increase uterine weight. Drugs according to the invention may be administered to animals or humans orally or parenterally.
Description
Remedies for Bone Diseases Detailed Description of the Invention ~ield of the Invention .
: This invention relates to remedies for bone diseases compri-sinq, as active inqredient, droloxifene havinq the chemical structure represented by the followinq formula, ~CH3 O-CH2CH2N~
~, or a salt thereof approved as a druq, which are to be used in the field of medical treatment.
Prior Art Droloxifene is a known compound disclosed in Japa~ese Patent Publication No. 39347/1985 and European Patent 0 054 168, in which it is described that this compound is useful as an anti-tumor agent, particularly as a remedy for tumors of the ~ st.
` - 2 - 2 0 6 5 3 9 3 However, it is not known that droloxifene is also useful for the relief of bone diseases caused by the deficiency of estro-~en or the like, which are often observed in women after meno-pause or those with the ovarium beinq excised.
On the other hand, it was disclosed in Japanese Patent Kokai No. 178917/1986 that tamoxifen and clomiprene, both havinq a chemical structure similar to that of droloxifene, are useful for the relief of osteoporosis.
O-CH 2CH2N~
~D
( TamoY.ifen ) (C~}i5)2~C~2CH20 ~ C=C
~.
(Clomiprene) Statement of Invention This invention relates to remedies for bone diseases which comprise, as an active ingredient, droloxifene or a salt thereof approved as a drug.
In particular, this invention pertains to a composition for the relief of bone diseases which comprises droloxifene or a pharmaceutically acceptable salt thereof and a pharmacologi-cally acceptable carrier.
A
-` 20650~3 Problems to be Solved by the Inventicr.
Thouqh useful as a remedy for osteoporosis, tamoxifen and clo-miprene are known to have a side effect of increasinq the ute-rine weiqht.
It is quite presumable that the increase in the uterine weiqht will be related to the qrowth of uterine cancers, because of the facts that administration of estroqen, which is a remedy for osteoporosis, is liable to cause uterine cancers ~Cancer, . _ _ _ _ _ 60, 1960-1964 ~1987)~, and that its administration also causes a marked increase in the uterine wei~ht.
Means to Solve the Problems This invention was accomplished under the circumstances descri-bed above, and provides remedies for bone diseases havinq lower side effects, such as the increase in the uterine weiqht.
The remedies for bone diseases of this invention comprise, as active inqredient, droloxifene or a salt thereof approved as a drug.
The salts of droloxifene approved as druqs are salts of non-toxic type commonly used, such as salts with or~anic acids (e.q., formic, acetic, trifluoroacetic, citric, maleic, tarta-ric, methanesulfonic, benzenesulfonic and toluenesulfonic acids), inor~anic acids (e.q., hydrochloric, hydrobromic, sul-furic and phosphoric acids), and amino acids (e.q., aspartic and qlutamic acids). These salts may be prepared by the methods commonly employed.
The remedies for bone diseases of this invention may be admini-stered to animals includinq humans orally or parenterally in the conventional for~ of preparations, such as capsules, micro-capsules, tablets, ~ranules, powder, troches, pills, supposito-ries, injections, suspensions and syrups.
The remedies for bone diseases of this invention can be prepa-red by the methods commonly employed usinq conventional, orqa-nic or inorqanic additives, such as an excipient ~e.q., sucro-se, starch, mannitol, sorbitol, lactose, qlucose, cellulose, talc, calcium phosphate and calcium carbonate), a binder (e.q., cellulose, methylcellulose, hydroxymethylcellulose, polypropyl-pyrroIidone, polyvinylpyrrolidone, qelatin, qum arabic, poly-ethyleneqlycol, sucrose and starch), a disinteqrator (e.q., starch, carboxymethylcellulose, hydroxypropylstarch, low sub-stituted hydroxypropylcellulose, sodium bicarbonate, calciumphosphate and calcium citrate), a lubricant (e.q., maqnesium stearate, light anhydrous silicic acid, talc and sodium lauryl sulfate), a flavorinq agent (e.q., citric acid, menthol, qly-cine and orange powder), a preservative (e.q., sodium benzoate, sodium bisulfite, methylparaben and propylparaben), a stabili-zer le.q. citric acid, sodium citrate and acetic acid), a sus-pendin~ a~ent (e.g., methylcellulose, polyvinylpyrrolidone and alminum stearate), a dispersin~ aqent (e.~., hydroxypropylme-thylcellulose), a diluent (e.~., water), and base wax ~e.~., cacao butter, white petrolatum and polyethylene ~lycol). The amount of the active inqredient in the medical composition may be at a level that will exercise the desired therapeutical effect; for example, about 1 m~ to 100 mg in unit dosaqe for both oral and parenteral administration.
The active in~redient may be usually administered once to four times a day with a unit dosa~e of 0.25 m~ to 1~0 m~, but the above dosa~e may be properly varied dependinq on the aqe, body weiqht and illness conditions of the patients and on the type of administration.
Effects Achieved by the Invention Described below is the result of a pharmacolo~ical test on dro-loxifene which is an active in~redient of the remedies for bone diseasec of this invention.
(Compounds Tested~
(1) Droloxifene (citrate) (2) Tamoxifen (citrate) (3) ~lomiprene (hydrochloride) (4) 17B-Estradiol 206~093 (Test Method) The ovaria on both sides are collected from each of the test animals (female, Wister rats 10 weeks old) under a qeneral anestetic, a test compound in the form of 0.5 % suspension in methylcellulose is orally administered on the next day in an amount of 5 ml/Kq, and this administration is continued over a period of four weeks once a day except Saturdays and Sundays.
Fastinq is then started in the eveninq, and the riqht femurs and the uterus are collected on the next day. These fe~urs are heated at 110C for six hours, and its lenqth is measured. In addition, its width and the amount of salts contained are measured at the position of 18/100 from its distal end by usinq sinqle photon absorptiometer and the bone density is calculated accordinq to the followinq formula. The uterine wei~ht is measured at sacrifice, and is divided by the body weiqht. The recovery rate of bone density and the rate of increase in the uterine weiqht are calculated bv lettinq the difference in data between the control qroup and the qroup to which no test compound is administered be 100 %.
Amount of Salts Bo~e Density ~
( Bone h7idth ) Test Result ) Table 1 ~est ~r~n~ ~ ~ e ~ itye(~o) Rautte~iof I~nc~x~e m 3.2 mg/~g ~1 26 110 mg/Kg 72 29 ;2 mg/Kg e4 32 21 mg/xg ~0 40 3.2 mg/~g 93 ~2 33.2 mg/Xg 62 43 10 mg/Kg 113 ~1 41 mg/~7 91 98 As may be seen from the test result shown above, droloxifene has an action of recoverin~ bone density, and is therefore use-ful as a remedy for bone diseases characterized by abnormali-ties of bone metabolism, such as osteoporosis, Pa~et's bone diseases, bone dissolution, maliqnant hypercalcemia, and chro-nic articular rheumatism.
Furthermore, droloxifene has lower side effect of increasinq the uterine weiqht compared with conventional remedies for bone diseases, such as tamoxifen, clomiprene and 17B-estradiol.
The followinq example will further illustrate the invention.
Example 1 Droloxifene citrate 100 q Lactose 1190 q low substituted hydroxypropylcellulose 250 q Polyvinylpyrrolidone 50 g Magnesium stearate 10 q The components listed above were mixed toqether by the usual method, and the mixture thus obtained was compressed into 1 o, ono tablets each containinq 10 mc of droloxifene citrate.
These tablets were then subiected to film coatinq by the usual method, thus civinq film-coated tab]ets.
: This invention relates to remedies for bone diseases compri-sinq, as active inqredient, droloxifene havinq the chemical structure represented by the followinq formula, ~CH3 O-CH2CH2N~
~, or a salt thereof approved as a druq, which are to be used in the field of medical treatment.
Prior Art Droloxifene is a known compound disclosed in Japa~ese Patent Publication No. 39347/1985 and European Patent 0 054 168, in which it is described that this compound is useful as an anti-tumor agent, particularly as a remedy for tumors of the ~ st.
` - 2 - 2 0 6 5 3 9 3 However, it is not known that droloxifene is also useful for the relief of bone diseases caused by the deficiency of estro-~en or the like, which are often observed in women after meno-pause or those with the ovarium beinq excised.
On the other hand, it was disclosed in Japanese Patent Kokai No. 178917/1986 that tamoxifen and clomiprene, both havinq a chemical structure similar to that of droloxifene, are useful for the relief of osteoporosis.
O-CH 2CH2N~
~D
( TamoY.ifen ) (C~}i5)2~C~2CH20 ~ C=C
~.
(Clomiprene) Statement of Invention This invention relates to remedies for bone diseases which comprise, as an active ingredient, droloxifene or a salt thereof approved as a drug.
In particular, this invention pertains to a composition for the relief of bone diseases which comprises droloxifene or a pharmaceutically acceptable salt thereof and a pharmacologi-cally acceptable carrier.
A
-` 20650~3 Problems to be Solved by the Inventicr.
Thouqh useful as a remedy for osteoporosis, tamoxifen and clo-miprene are known to have a side effect of increasinq the ute-rine weiqht.
It is quite presumable that the increase in the uterine weiqht will be related to the qrowth of uterine cancers, because of the facts that administration of estroqen, which is a remedy for osteoporosis, is liable to cause uterine cancers ~Cancer, . _ _ _ _ _ 60, 1960-1964 ~1987)~, and that its administration also causes a marked increase in the uterine wei~ht.
Means to Solve the Problems This invention was accomplished under the circumstances descri-bed above, and provides remedies for bone diseases havinq lower side effects, such as the increase in the uterine weiqht.
The remedies for bone diseases of this invention comprise, as active inqredient, droloxifene or a salt thereof approved as a drug.
The salts of droloxifene approved as druqs are salts of non-toxic type commonly used, such as salts with or~anic acids (e.q., formic, acetic, trifluoroacetic, citric, maleic, tarta-ric, methanesulfonic, benzenesulfonic and toluenesulfonic acids), inor~anic acids (e.q., hydrochloric, hydrobromic, sul-furic and phosphoric acids), and amino acids (e.q., aspartic and qlutamic acids). These salts may be prepared by the methods commonly employed.
The remedies for bone diseases of this invention may be admini-stered to animals includinq humans orally or parenterally in the conventional for~ of preparations, such as capsules, micro-capsules, tablets, ~ranules, powder, troches, pills, supposito-ries, injections, suspensions and syrups.
The remedies for bone diseases of this invention can be prepa-red by the methods commonly employed usinq conventional, orqa-nic or inorqanic additives, such as an excipient ~e.q., sucro-se, starch, mannitol, sorbitol, lactose, qlucose, cellulose, talc, calcium phosphate and calcium carbonate), a binder (e.q., cellulose, methylcellulose, hydroxymethylcellulose, polypropyl-pyrroIidone, polyvinylpyrrolidone, qelatin, qum arabic, poly-ethyleneqlycol, sucrose and starch), a disinteqrator (e.q., starch, carboxymethylcellulose, hydroxypropylstarch, low sub-stituted hydroxypropylcellulose, sodium bicarbonate, calciumphosphate and calcium citrate), a lubricant (e.q., maqnesium stearate, light anhydrous silicic acid, talc and sodium lauryl sulfate), a flavorinq agent (e.q., citric acid, menthol, qly-cine and orange powder), a preservative (e.q., sodium benzoate, sodium bisulfite, methylparaben and propylparaben), a stabili-zer le.q. citric acid, sodium citrate and acetic acid), a sus-pendin~ a~ent (e.g., methylcellulose, polyvinylpyrrolidone and alminum stearate), a dispersin~ aqent (e.~., hydroxypropylme-thylcellulose), a diluent (e.~., water), and base wax ~e.~., cacao butter, white petrolatum and polyethylene ~lycol). The amount of the active inqredient in the medical composition may be at a level that will exercise the desired therapeutical effect; for example, about 1 m~ to 100 mg in unit dosaqe for both oral and parenteral administration.
The active in~redient may be usually administered once to four times a day with a unit dosa~e of 0.25 m~ to 1~0 m~, but the above dosa~e may be properly varied dependinq on the aqe, body weiqht and illness conditions of the patients and on the type of administration.
Effects Achieved by the Invention Described below is the result of a pharmacolo~ical test on dro-loxifene which is an active in~redient of the remedies for bone diseasec of this invention.
(Compounds Tested~
(1) Droloxifene (citrate) (2) Tamoxifen (citrate) (3) ~lomiprene (hydrochloride) (4) 17B-Estradiol 206~093 (Test Method) The ovaria on both sides are collected from each of the test animals (female, Wister rats 10 weeks old) under a qeneral anestetic, a test compound in the form of 0.5 % suspension in methylcellulose is orally administered on the next day in an amount of 5 ml/Kq, and this administration is continued over a period of four weeks once a day except Saturdays and Sundays.
Fastinq is then started in the eveninq, and the riqht femurs and the uterus are collected on the next day. These fe~urs are heated at 110C for six hours, and its lenqth is measured. In addition, its width and the amount of salts contained are measured at the position of 18/100 from its distal end by usinq sinqle photon absorptiometer and the bone density is calculated accordinq to the followinq formula. The uterine wei~ht is measured at sacrifice, and is divided by the body weiqht. The recovery rate of bone density and the rate of increase in the uterine weiqht are calculated bv lettinq the difference in data between the control qroup and the qroup to which no test compound is administered be 100 %.
Amount of Salts Bo~e Density ~
( Bone h7idth ) Test Result ) Table 1 ~est ~r~n~ ~ ~ e ~ itye(~o) Rautte~iof I~nc~x~e m 3.2 mg/~g ~1 26 110 mg/Kg 72 29 ;2 mg/Kg e4 32 21 mg/xg ~0 40 3.2 mg/~g 93 ~2 33.2 mg/Xg 62 43 10 mg/Kg 113 ~1 41 mg/~7 91 98 As may be seen from the test result shown above, droloxifene has an action of recoverin~ bone density, and is therefore use-ful as a remedy for bone diseases characterized by abnormali-ties of bone metabolism, such as osteoporosis, Pa~et's bone diseases, bone dissolution, maliqnant hypercalcemia, and chro-nic articular rheumatism.
Furthermore, droloxifene has lower side effect of increasinq the uterine weiqht compared with conventional remedies for bone diseases, such as tamoxifen, clomiprene and 17B-estradiol.
The followinq example will further illustrate the invention.
Example 1 Droloxifene citrate 100 q Lactose 1190 q low substituted hydroxypropylcellulose 250 q Polyvinylpyrrolidone 50 g Magnesium stearate 10 q The components listed above were mixed toqether by the usual method, and the mixture thus obtained was compressed into 1 o, ono tablets each containinq 10 mc of droloxifene citrate.
These tablets were then subiected to film coatinq by the usual method, thus civinq film-coated tab]ets.
Claims (2)
1. Remedies for bone diseases comprising, as active ingredient, droloxifene or a salt thereof approved as a drug.
2. A composition for the relief of bone diseases which comprises droloxifene, or apharmaceutically acceptable salt thereof, and a pharmacologically acceptable carrier.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP3166944A JPH04312526A (en) | 1991-04-09 | 1991-04-09 | Remedy for osteopathy |
| JP166944/91 | 1991-04-09 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2065093A1 CA2065093A1 (en) | 1992-10-10 |
| CA2065093C true CA2065093C (en) | 1995-10-03 |
Family
ID=15840531
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002065093A Expired - Fee Related CA2065093C (en) | 1991-04-09 | 1992-04-03 | Remedies for bone diseases |
Country Status (14)
| Country | Link |
|---|---|
| US (1) | US5254594A (en) |
| EP (1) | EP0509317B1 (en) |
| JP (1) | JPH04312526A (en) |
| KR (1) | KR100196810B1 (en) |
| AT (1) | ATE114113T1 (en) |
| AU (1) | AU648154B2 (en) |
| CA (1) | CA2065093C (en) |
| DE (1) | DE69200675T2 (en) |
| DK (1) | DK0509317T3 (en) |
| EE (1) | EE02971B1 (en) |
| ES (1) | ES2064130T3 (en) |
| HK (1) | HK1004257A1 (en) |
| IE (1) | IE66900B1 (en) |
| ZA (1) | ZA922527B (en) |
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| US6663881B2 (en) * | 1993-01-28 | 2003-12-16 | Neorx Corporation | Therapeutic inhibitor of vascular smooth muscle cells |
| US6491938B2 (en) | 1993-05-13 | 2002-12-10 | Neorx Corporation | Therapeutic inhibitor of vascular smooth muscle cells |
| US5595722A (en) * | 1993-01-28 | 1997-01-21 | Neorx Corporation | Method for identifying an agent which increases TGF-beta levels |
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| US5482949A (en) * | 1993-03-19 | 1996-01-09 | Eli Lilly And Company | Sulfonate derivatives of 3-aroylbenzo[b]thiophenes |
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| DE69405491T2 (en) * | 1993-06-24 | 1998-02-19 | Lilly Co Eli | Anti-estrogens 2-phenyl-3-aroylbenzothiophenes as hypoglycemic agents |
| US5384332A (en) * | 1994-05-11 | 1995-01-24 | Eli Lilly And Company | Methods for inhibiting aortal smooth muscle cell proliferation and restenosis with 1,1,2-triphenylbut-1-ene derivatives |
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| US8497258B2 (en) | 2005-11-12 | 2013-07-30 | The Regents Of The University Of California | Viscous budesonide for the treatment of inflammatory diseases of the gastrointestinal tract |
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|---|---|---|---|---|
| US4206234A (en) * | 1977-08-22 | 1980-06-03 | Imperial Chemical Industries Limited | Triphenylbut-1-ene derivatives and pharmaceutical compositions and uses thereof |
| DE2860900D1 (en) * | 1977-08-22 | 1981-11-05 | Ici Plc | Triphenylalkene derivatives, process for their preparation and pharmaceutical compositions containing them |
| DE3046719C2 (en) * | 1980-12-11 | 1983-02-17 | Klinge Pharma GmbH, 8000 München | 1,1,2-Triphenyl-but-1-ene derivatives, processes for their preparation and pharmaceuticals |
| US4729999A (en) * | 1984-10-12 | 1988-03-08 | Bcm Technologies | Antiestrogen therapy for symptoms of estrogen deficiency |
-
1991
- 1991-04-09 JP JP3166944A patent/JPH04312526A/en active Pending
-
1992
- 1992-04-01 DE DE69200675T patent/DE69200675T2/en not_active Expired - Fee Related
- 1992-04-01 ES ES92105595T patent/ES2064130T3/en not_active Expired - Lifetime
- 1992-04-01 EP EP92105595A patent/EP0509317B1/en not_active Expired - Lifetime
- 1992-04-01 AT AT92105595T patent/ATE114113T1/en not_active IP Right Cessation
- 1992-04-01 DK DK92105595.0T patent/DK0509317T3/en active
- 1992-04-02 AU AU13994/92A patent/AU648154B2/en not_active Ceased
- 1992-04-03 CA CA002065093A patent/CA2065093C/en not_active Expired - Fee Related
- 1992-04-07 KR KR1019920005743A patent/KR100196810B1/en not_active IP Right Cessation
- 1992-04-08 IE IE921116A patent/IE66900B1/en not_active IP Right Cessation
- 1992-04-08 US US07/865,106 patent/US5254594A/en not_active Expired - Fee Related
- 1992-04-08 ZA ZA922527A patent/ZA922527B/en unknown
-
1994
- 1994-11-11 EE EE9400265A patent/EE02971B1/en unknown
-
1998
- 1998-04-24 HK HK98103450A patent/HK1004257A1/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| EE02971B1 (en) | 1997-04-15 |
| IE921116A1 (en) | 1992-10-21 |
| ATE114113T1 (en) | 1994-12-15 |
| EP0509317B1 (en) | 1994-11-17 |
| DK0509317T3 (en) | 1995-01-30 |
| AU648154B2 (en) | 1994-04-14 |
| CA2065093A1 (en) | 1992-10-10 |
| HK1004257A1 (en) | 1998-11-20 |
| US5254594A (en) | 1993-10-19 |
| JPH04312526A (en) | 1992-11-04 |
| ES2064130T3 (en) | 1995-01-16 |
| EP0509317A2 (en) | 1992-10-21 |
| AU1399492A (en) | 1992-10-15 |
| DE69200675D1 (en) | 1994-12-22 |
| DE69200675T2 (en) | 1995-03-16 |
| EP0509317A3 (en) | 1993-03-03 |
| KR920019342A (en) | 1992-11-19 |
| ZA922527B (en) | 1992-12-30 |
| IE66900B1 (en) | 1996-02-07 |
| KR100196810B1 (en) | 1999-06-15 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| MKLA | Lapsed |