CA2165446C - Use of ropivacaine in the manufacture of a pharmaceutical with analgetic effect with minimal motor blockade - Google Patents
Use of ropivacaine in the manufacture of a pharmaceutical with analgetic effect with minimal motor blockade Download PDFInfo
- Publication number
- CA2165446C CA2165446C CA002165446A CA2165446A CA2165446C CA 2165446 C CA2165446 C CA 2165446C CA 002165446 A CA002165446 A CA 002165446A CA 2165446 A CA2165446 A CA 2165446A CA 2165446 C CA2165446 C CA 2165446C
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- Prior art keywords
- ropivacaine
- weight
- concentration
- pain relief
- manufacture
- Prior art date
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- Expired - Fee Related
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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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P23/00—Anaesthetics
- A61P23/02—Local anaesthetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pain & Pain Management (AREA)
- Epidemiology (AREA)
- Anesthesiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Rheumatology (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Insulation, Fastening Of Motor, Generator Windings (AREA)
- Hydrogenated Pyridines (AREA)
- Medicinal Preparation (AREA)
- Steroid Compounds (AREA)
- Particle Accelerators (AREA)
- Air Conditioning Control Device (AREA)
- Investigating Or Analysing Biological Materials (AREA)
- Electromechanical Clocks (AREA)
Abstract
Use of a pharmaceutically acceptable salt of ropivacaine for the manufacture of a pharmaceutical preparation with sensoric block and minimal motor blockade.
Description
21 b5~46 Use of ropivacaine in the manufacture of a pharmaceutical with analgetic effect with minimal motor blockade Field of the invention The present invention is related to the use of a low concentration of a pharmaceutically acceptable salt of ropivacaine in the manufacture of pharmaceutical preparations for pain relief post operatively and in labour.
Background of the invention Post operative pain relief is still a problem within modern surgery. According to a newly published study about 70% of all patients treated surgically felt moderate to severe pain after the surgical treatment.
The need for qualified pain relief is greatest during the first 24 hours after the surgical treatment. The traditional method to treat the patients is to give narcotics intramuscularly or intravenously. Such treatment is often insufficient as narcotic analgetics have many negative effects. One disadvantage is depression of the breathing, which may occur even after treatment. This means that the patient must be intensively looked after by specialists.
A patient, who has been treated with morfine is tired, apathetic and is often feeling sick. The patient thus has no interest in things around him. It is thus difficult to take care of the patient and make him participate in respitatory exercises and prophylaxis for thromboses.
One method is administration epidurally, by infusion or ~'~~46 2~
intermittent injections of local anaesthetics. Such treatments can only be carried out on patients with epidural catheters being taken care of at an intensive care or post surgical unit by specially trained persons.
There has been a long felt need at ward leval to be able to give a greater group of patients qualified pain relief by epidural infusion of e.g. local anaesthetics instead of opiates. -Normally, with local anaesthetics a good blockade of the pain is obtained. The draw back is the motor blockade in the legs, which is disturbing to the patients, who wants to give up the pain relief treatment in advance. Among other effects the motor blockade means that the patient cannot leave his bed without assistance as the legs will not bear.
Outline of the invention According to the present invention it has surprisingly been found that the local anaesthetic agent ropivacaine, described e.g. in WO/85/00599, in form of its hydrochloride can be given to the patient in a dosage which gives pain relief with minimal effect on motor function. This is at a dosage of lower than 0.5% by weight, especially from 0.01% to 0.45% by weight. Such low dosages are normally considered to be ineffective.
The normal dosage is from 0.5-2% by weight.
The local anaesthetic compound used according to the invention is in the form of its pharmaceutically acceptable salts. It is especially preferred to use ropivacaine hydrochloride.
Background of the invention Post operative pain relief is still a problem within modern surgery. According to a newly published study about 70% of all patients treated surgically felt moderate to severe pain after the surgical treatment.
The need for qualified pain relief is greatest during the first 24 hours after the surgical treatment. The traditional method to treat the patients is to give narcotics intramuscularly or intravenously. Such treatment is often insufficient as narcotic analgetics have many negative effects. One disadvantage is depression of the breathing, which may occur even after treatment. This means that the patient must be intensively looked after by specialists.
A patient, who has been treated with morfine is tired, apathetic and is often feeling sick. The patient thus has no interest in things around him. It is thus difficult to take care of the patient and make him participate in respitatory exercises and prophylaxis for thromboses.
One method is administration epidurally, by infusion or ~'~~46 2~
intermittent injections of local anaesthetics. Such treatments can only be carried out on patients with epidural catheters being taken care of at an intensive care or post surgical unit by specially trained persons.
There has been a long felt need at ward leval to be able to give a greater group of patients qualified pain relief by epidural infusion of e.g. local anaesthetics instead of opiates. -Normally, with local anaesthetics a good blockade of the pain is obtained. The draw back is the motor blockade in the legs, which is disturbing to the patients, who wants to give up the pain relief treatment in advance. Among other effects the motor blockade means that the patient cannot leave his bed without assistance as the legs will not bear.
Outline of the invention According to the present invention it has surprisingly been found that the local anaesthetic agent ropivacaine, described e.g. in WO/85/00599, in form of its hydrochloride can be given to the patient in a dosage which gives pain relief with minimal effect on motor function. This is at a dosage of lower than 0.5% by weight, especially from 0.01% to 0.45% by weight. Such low dosages are normally considered to be ineffective.
The normal dosage is from 0.5-2% by weight.
The local anaesthetic compound used according to the invention is in the form of its pharmaceutically acceptable salts. It is especially preferred to use ropivacaine hydrochloride.
The local anaesthetic is incorporated into a solution.
The local anaesthetic composition contains less than 0.5% by weight of the local anaesthetic compound, preferably from 0.01 up to 0.45% by weight, especially preferred 0.1-0.3% by weight.
In a use aspect, the invention provides use of a pharmaceutically acceptable salt of ropivacaine for the manufacture of a medicament with sensoric block and with minimal motor blockade, for pain relief post operatively and in labour wherein the concentration of ropivacaine is lower than 0.5% by weight.
In a further use aspect, the invention provides use of a pharmaceutically acceptable salt of ropivacaine in a concentration lower than 0.5% by weight for pain relief post operatively and in labour with minimal motor blockade.
The invention also provides a pharmaceutical preparation for use in pain relief post operatively and in labour with minimal motor blockade, wherein the active ingredient is a pharmaceutically acceptable salt of ropivacaine in a concentration lower than 0.5% by weight.
The invention also provides a commercial package, comprising a pharmaceutical preparation according to the invention and associated therewith instructions for use thereof for pain relief post operatively and in labour.
3a Pharmaceutical preparations Examples 1-3 Solution 5 mg/ml, 3 mg/ml, 2 mg/ml Examples Ropivacaine hydrochloride monohydrate 0.53 kg 0.32 kg 0.21 kg sodium hydroxide 2M to pH 5.0-6.0 _ Purified water qs ad 100 kg 100 kg 100 kg Ropivacaine is dissolved in the water. Sodium hydroxide is added to pH 5.0-6Ø The resulting solution is autoclaved.
The best mode of carrying out the invention known at present is to use the preparations according to Example 3.
Biological test A~double blind study_of sensory and motor blockade with 0.1%, 0.2%; 0.3% ropivacaine and 0.25% bupivacaine during continous epidural infusion in healthy male volunteers.
'/
Background The aim of the study was to find a low concentration of ropivacaine giving a sufficient sensory block but as little or no motor block at all during continous epidural infusion. This study is a first step towards finding a low concentration of ropivacaine which later will be used for treatment of post operative pain in patients. 37 volunteers participated in the study. They were divided into 5 treatment groups, receiving either 0.1%, 0.2% or 0.3% ropivacaine or 0.25% bupivacaine. There was also a control group receiving 0.9% saline. All solutions were first given as a bolus dose of 10 ml, followed by a continous epidural infusion at a rate of 10 ml/hour for 21 hours. During the infusion both motor and sensory blockade was tested using different methods. The postural stability of the volunteers was also evaluated.
Preliminary results Group 1. No motor and sensory block was acheived in the volunteers receiving saline.
Group 2. Bupivacaine 0.25% gave a good segmental spread (from the lower part of the abdomen to the lower part of the extremities) of sensoric block during the infusion.
All of the volunteers had a high degree of motor block and 75% (6/8) could not stand up at any occasion during the infusion.
Group 3. Ropivacaine 0.3% gave an equal duration of sensory blockade compared to bupivaciane 0.25%. The upper segmental spread of sensoric block was somewhat higher than for bupivacaine. The lower segmental spread of sensoric block was, after 10 hours of continous infusion, WO 95/00148 a ~ ~ J ~~~ PCT/SE94100496 shifted up to just below the knees compared to bupivacaine and at the end of infusion was found above = the knees. The motorblock was somewhat less profound compared to bupivacaine. 5 out of 7 volunteers could not 5 stand at any occasion during the infusion to perform the postural stability tests.
Group 4. Ropivacaine 0.2% gave an equal sensory block compared to bupivacaine 0.25% in the lower part of the abdomen, but showed a less sensory block around the ancles. After 10 hours of continous infusion the sensory block was less than for both ropivacaine 0.3% and bupivacaine. The motor block was less profound compared to the 0.3% ropivacaine as well as to the 0.25%
bupivacaine solution. 25% (2/8) of the volunteers could not at any occasion stand up whereas the rest of the volunteers (6/8) could at some point during the infusion make some of the postural tests.
Group 5. Ropivacaine 0.1% gave, during the first 5 hours of the infusion, a more narrow spread of the sensory block compared to the 0.2% ropivacaine solution. Normal sensation returned after 8 hours of the epidural infusion.
No serious or unexpected adverse events could be noted in any of the test groups.
It was found that bupivacaine gives 75% higher motor blockade than ropivacaine, which only gives 25% at comparable dosage levels.
At the dosages 0.3% and 0.2% ropivacaine gives about the same motor blockade. At the dosage 0.1% it is less.
conclusion From the unique effect of ropivacaine the conclusion can be drawn that said compound is especially useful for administering at low dosage to patients in the need of post surgical and labour pain treatment, with good balance between sufficient sensoric block and a desirable minimal degree of motor block.
The local anaesthetic composition contains less than 0.5% by weight of the local anaesthetic compound, preferably from 0.01 up to 0.45% by weight, especially preferred 0.1-0.3% by weight.
In a use aspect, the invention provides use of a pharmaceutically acceptable salt of ropivacaine for the manufacture of a medicament with sensoric block and with minimal motor blockade, for pain relief post operatively and in labour wherein the concentration of ropivacaine is lower than 0.5% by weight.
In a further use aspect, the invention provides use of a pharmaceutically acceptable salt of ropivacaine in a concentration lower than 0.5% by weight for pain relief post operatively and in labour with minimal motor blockade.
The invention also provides a pharmaceutical preparation for use in pain relief post operatively and in labour with minimal motor blockade, wherein the active ingredient is a pharmaceutically acceptable salt of ropivacaine in a concentration lower than 0.5% by weight.
The invention also provides a commercial package, comprising a pharmaceutical preparation according to the invention and associated therewith instructions for use thereof for pain relief post operatively and in labour.
3a Pharmaceutical preparations Examples 1-3 Solution 5 mg/ml, 3 mg/ml, 2 mg/ml Examples Ropivacaine hydrochloride monohydrate 0.53 kg 0.32 kg 0.21 kg sodium hydroxide 2M to pH 5.0-6.0 _ Purified water qs ad 100 kg 100 kg 100 kg Ropivacaine is dissolved in the water. Sodium hydroxide is added to pH 5.0-6Ø The resulting solution is autoclaved.
The best mode of carrying out the invention known at present is to use the preparations according to Example 3.
Biological test A~double blind study_of sensory and motor blockade with 0.1%, 0.2%; 0.3% ropivacaine and 0.25% bupivacaine during continous epidural infusion in healthy male volunteers.
'/
Background The aim of the study was to find a low concentration of ropivacaine giving a sufficient sensory block but as little or no motor block at all during continous epidural infusion. This study is a first step towards finding a low concentration of ropivacaine which later will be used for treatment of post operative pain in patients. 37 volunteers participated in the study. They were divided into 5 treatment groups, receiving either 0.1%, 0.2% or 0.3% ropivacaine or 0.25% bupivacaine. There was also a control group receiving 0.9% saline. All solutions were first given as a bolus dose of 10 ml, followed by a continous epidural infusion at a rate of 10 ml/hour for 21 hours. During the infusion both motor and sensory blockade was tested using different methods. The postural stability of the volunteers was also evaluated.
Preliminary results Group 1. No motor and sensory block was acheived in the volunteers receiving saline.
Group 2. Bupivacaine 0.25% gave a good segmental spread (from the lower part of the abdomen to the lower part of the extremities) of sensoric block during the infusion.
All of the volunteers had a high degree of motor block and 75% (6/8) could not stand up at any occasion during the infusion.
Group 3. Ropivacaine 0.3% gave an equal duration of sensory blockade compared to bupivaciane 0.25%. The upper segmental spread of sensoric block was somewhat higher than for bupivacaine. The lower segmental spread of sensoric block was, after 10 hours of continous infusion, WO 95/00148 a ~ ~ J ~~~ PCT/SE94100496 shifted up to just below the knees compared to bupivacaine and at the end of infusion was found above = the knees. The motorblock was somewhat less profound compared to bupivacaine. 5 out of 7 volunteers could not 5 stand at any occasion during the infusion to perform the postural stability tests.
Group 4. Ropivacaine 0.2% gave an equal sensory block compared to bupivacaine 0.25% in the lower part of the abdomen, but showed a less sensory block around the ancles. After 10 hours of continous infusion the sensory block was less than for both ropivacaine 0.3% and bupivacaine. The motor block was less profound compared to the 0.3% ropivacaine as well as to the 0.25%
bupivacaine solution. 25% (2/8) of the volunteers could not at any occasion stand up whereas the rest of the volunteers (6/8) could at some point during the infusion make some of the postural tests.
Group 5. Ropivacaine 0.1% gave, during the first 5 hours of the infusion, a more narrow spread of the sensory block compared to the 0.2% ropivacaine solution. Normal sensation returned after 8 hours of the epidural infusion.
No serious or unexpected adverse events could be noted in any of the test groups.
It was found that bupivacaine gives 75% higher motor blockade than ropivacaine, which only gives 25% at comparable dosage levels.
At the dosages 0.3% and 0.2% ropivacaine gives about the same motor blockade. At the dosage 0.1% it is less.
conclusion From the unique effect of ropivacaine the conclusion can be drawn that said compound is especially useful for administering at low dosage to patients in the need of post surgical and labour pain treatment, with good balance between sufficient sensoric block and a desirable minimal degree of motor block.
Claims (13)
1. ~Use of a pharmaceutically acceptable salt of ropivacaine for the manufacture of a medicament with sensoric block and with minimal motor blockade, for pain relief post operatively and in labour wherein the concentration of ropivacaine is lower than 0.5% by weight.
2. ~Use according to claim 1, wherein ropivacaine is in the form of its hydrochloride.
3. ~Use according to claim 1 or 2, wherein the concentration of ropivacaine is from 0.01 up to 0.45% by weight.
4. ~Use according to claim 3, wherein the concentration of ropivacaine is 0.2% by weight.
5. ~Use of a pharmaceutically acceptable salt of ropivacaine in a concentration of lower than 0.5% by weight for pain relief post operatively and in labour with minimal motor blockade.
6. ~Use according to claim 5, wherein ropivacaine is in the form of its hydrochloride.
7. ~Use according to claim 5 or 6, wherein the concentration of ropivacaine is from 0.01 up to 0.45% by weight.
8. ~Use according to claim 7, wherein the concentration of ropivacaine is 0.2% by weight.
9. ~A pharmaceutical preparation for use in pain relief post operatively and in labour with minimal motor blockade, wherein the active ingredient is a pharmaceutically acceptable salt of ropivacaine in a concentration lower than 0.5% by weight.
10. ~A pharmaceutical preparation according to claim 9, wherein ropivacaine is in the form of its hydrochloride.
11. ~A pharmaceutical preparation according to claim 9 or 10, wherein the concentration of ropivacaine is from 0.01 up to 0.45% by weight.
12. ~A pharmaceutical preparation according to claim 11, wherein the concentration of ropivacaine is 0.2%
by weight.
by weight.
13. A commercial package, comprising a pharmaceutical preparation according to any one of claims 9 to 12 and associated therewith instructions for use thereof for pain relief post operatively and in labour.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SE19939302218A SE9302218D0 (en) | 1993-06-28 | 1993-06-28 | NEW USE |
| SE9302218-4 | 1993-06-28 | ||
| PCT/SE1994/000496 WO1995000148A1 (en) | 1993-06-28 | 1994-05-26 | Use of ropivacaine in the manufacture of a pharmaceutical with analgetic effect with minimal motor blockade |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2165446A1 CA2165446A1 (en) | 1995-01-05 |
| CA2165446C true CA2165446C (en) | 2005-07-05 |
Family
ID=20390432
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002165446A Expired - Fee Related CA2165446C (en) | 1993-06-28 | 1994-05-26 | Use of ropivacaine in the manufacture of a pharmaceutical with analgetic effect with minimal motor blockade |
Country Status (32)
| Country | Link |
|---|---|
| US (2) | US5670524A (en) |
| EP (1) | EP0706395B1 (en) |
| JP (1) | JP3725541B2 (en) |
| CN (1) | CN1074918C (en) |
| AT (1) | ATE216237T1 (en) |
| BR (1) | BR9406865A (en) |
| CA (1) | CA2165446C (en) |
| CZ (1) | CZ283300B6 (en) |
| DE (2) | DE69430427T2 (en) |
| DK (1) | DK0706395T3 (en) |
| EE (1) | EE03205B1 (en) |
| ES (1) | ES2099048T3 (en) |
| FI (1) | FI956269L (en) |
| GR (1) | GR970300013T1 (en) |
| HU (1) | HU218949B (en) |
| IL (1) | IL110006A (en) |
| IS (1) | IS4174A (en) |
| LT (1) | LT3449B (en) |
| LV (1) | LV12918B (en) |
| MY (1) | MY119360A (en) |
| NO (1) | NO955313L (en) |
| NZ (1) | NZ268110A (en) |
| PH (1) | PH31258A (en) |
| PL (1) | PL175518B1 (en) |
| PT (1) | PT706395E (en) |
| RU (1) | RU2152215C1 (en) |
| SA (1) | SA94150010B1 (en) |
| SE (1) | SE9302218D0 (en) |
| SG (1) | SG49078A1 (en) |
| SK (1) | SK280111B6 (en) |
| TW (1) | TW285640B (en) |
| WO (1) | WO1995000148A1 (en) |
Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SE9302218D0 (en) * | 1993-06-28 | 1993-06-28 | Ab Astra | NEW USE |
| BR9802536A (en) * | 1997-07-21 | 1999-07-20 | Darwin Discovery Ltd | Method for anesthetizing a human patient before surgery |
| US20060270708A1 (en) * | 2005-05-25 | 2006-11-30 | Navinta Llc | Novel process for preparation of isotonic aqueous injection of ropivacaine |
| USRE46397E1 (en) | 2007-11-07 | 2017-05-09 | Svip5 Llc | Slow release of organic salts of local anesthetics for pain relief |
| CA2873138A1 (en) * | 2012-05-10 | 2013-11-14 | Cellixbio Private Limited | Compositions and methods for the treatment of local pain |
| WO2013168167A1 (en) * | 2012-05-10 | 2013-11-14 | Painreform Ltd. | Depot formulations of a hydrophobic active ingredient and methods for preparation thereof |
| US8558008B2 (en) | 2013-02-28 | 2013-10-15 | Dermira, Inc. | Crystalline glycopyrrolate tosylate |
| EP3842419B1 (en) | 2013-02-28 | 2024-04-03 | Journey Medical Corporation | Method of making threo glycopyrrolate tosylate |
| US9006462B2 (en) | 2013-02-28 | 2015-04-14 | Dermira, Inc. | Glycopyrrolate salts |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ATE40994T1 (en) * | 1983-08-01 | 1989-03-15 | Astra Laekemedel Ab | L-N-N-PROPYLPIPECOLIC-2,6-XYLIDIDE AND ITS PRODUCTION. |
| SE9302218D0 (en) * | 1993-06-28 | 1993-06-28 | Ab Astra | NEW USE |
-
1993
- 1993-06-28 SE SE19939302218A patent/SE9302218D0/en unknown
-
1994
- 1994-05-26 CN CN94192664A patent/CN1074918C/en not_active Expired - Fee Related
- 1994-05-26 AT AT94919912T patent/ATE216237T1/en not_active IP Right Cessation
- 1994-05-26 EP EP94919912A patent/EP0706395B1/en not_active Expired - Lifetime
- 1994-05-26 CA CA002165446A patent/CA2165446C/en not_active Expired - Fee Related
- 1994-05-26 PT PT94919912T patent/PT706395E/en unknown
- 1994-05-26 WO PCT/SE1994/000496 patent/WO1995000148A1/en not_active Ceased
- 1994-05-26 BR BR9406865A patent/BR9406865A/en not_active Application Discontinuation
- 1994-05-26 SG SG1996005829A patent/SG49078A1/en unknown
- 1994-05-26 DE DE69430427T patent/DE69430427T2/en not_active Expired - Lifetime
- 1994-05-26 JP JP50268795A patent/JP3725541B2/en not_active Expired - Fee Related
- 1994-05-26 FI FI956269A patent/FI956269L/en not_active Application Discontinuation
- 1994-05-26 HU HU9503692A patent/HU218949B/en not_active IP Right Cessation
- 1994-05-26 DE DE0706395T patent/DE706395T1/en active Pending
- 1994-05-26 SK SK1646-95A patent/SK280111B6/en not_active IP Right Cessation
- 1994-05-26 RU RU96101169/14A patent/RU2152215C1/en not_active IP Right Cessation
- 1994-05-26 CZ CZ953364A patent/CZ283300B6/en not_active IP Right Cessation
- 1994-05-26 US US08/256,319 patent/US5670524A/en not_active Expired - Lifetime
- 1994-05-26 PL PL94312198A patent/PL175518B1/en not_active IP Right Cessation
- 1994-05-26 NZ NZ268110A patent/NZ268110A/en not_active IP Right Cessation
- 1994-05-26 DK DK94919912T patent/DK0706395T3/en active
- 1994-05-26 ES ES94919912T patent/ES2099048T3/en not_active Expired - Lifetime
- 1994-06-01 TW TW083105008A patent/TW285640B/zh not_active IP Right Cessation
- 1994-06-08 IS IS4174A patent/IS4174A/en unknown
- 1994-06-09 PH PH48413A patent/PH31258A/en unknown
- 1994-06-13 IL IL11000694A patent/IL110006A/en not_active IP Right Cessation
- 1994-06-14 SA SA94150010A patent/SA94150010B1/en unknown
- 1994-06-17 LT LTIP1958A patent/LT3449B/en not_active IP Right Cessation
- 1994-06-27 MY MYPI94001663A patent/MY119360A/en unknown
- 1994-11-03 EE EE9400347A patent/EE03205B1/en not_active IP Right Cessation
-
1995
- 1995-12-27 NO NO955313A patent/NO955313L/en not_active Application Discontinuation
-
1997
- 1997-05-05 US US08/851,062 patent/US5834489A/en not_active Expired - Lifetime
- 1997-05-30 GR GR970300013T patent/GR970300013T1/en unknown
-
2002
- 2002-07-15 LV LVP-02-131A patent/LV12918B/en unknown
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