IL105870A - Pharmaceutical soft capsules containing lysine clonixinate and their preparation - Google Patents
Pharmaceutical soft capsules containing lysine clonixinate and their preparationInfo
- Publication number
- IL105870A IL105870A IL10587093A IL10587093A IL105870A IL 105870 A IL105870 A IL 105870A IL 10587093 A IL10587093 A IL 10587093A IL 10587093 A IL10587093 A IL 10587093A IL 105870 A IL105870 A IL 105870A
- Authority
- IL
- Israel
- Prior art keywords
- lysine clonixinate
- filling
- capsule
- polyethylene glycol
- capsules
- Prior art date
Links
- CVNFYQCHAWFYQI-ZSCHJXSPSA-N clonixin lysine salt Chemical compound NCCCC[C@H](N)C(O)=O.CC1=C(Cl)C=CC=C1NC1=NC=CC=C1C(O)=O CVNFYQCHAWFYQI-ZSCHJXSPSA-N 0.000 title claims description 33
- 229960003763 lysine clonixinate Drugs 0.000 title claims description 33
- 238000002360 preparation method Methods 0.000 title claims description 7
- 239000007901 soft capsule Substances 0.000 title description 5
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 30
- 239000002775 capsule Substances 0.000 claims description 25
- 239000007903 gelatin capsule Substances 0.000 claims description 17
- 229920001223 polyethylene glycol Polymers 0.000 claims description 17
- 239000002202 Polyethylene glycol Substances 0.000 claims description 15
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 15
- 229920000159 gelatin Polymers 0.000 claims description 14
- 235000019322 gelatine Nutrition 0.000 claims description 14
- 239000000203 mixture Substances 0.000 claims description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 13
- 239000004480 active ingredient Substances 0.000 claims description 9
- 108010010803 Gelatin Proteins 0.000 claims description 7
- 239000001828 Gelatine Substances 0.000 claims description 7
- 239000008273 gelatin Substances 0.000 claims description 7
- 235000011852 gelatine desserts Nutrition 0.000 claims description 7
- 239000011159 matrix material Substances 0.000 claims description 5
- 238000000034 method Methods 0.000 claims description 5
- RUOJZAUFBMNUDX-UHFFFAOYSA-N propylene carbonate Chemical compound CC1COC(=O)O1 RUOJZAUFBMNUDX-UHFFFAOYSA-N 0.000 claims description 5
- 230000000202 analgesic effect Effects 0.000 claims description 3
- 239000002260 anti-inflammatory agent Substances 0.000 claims description 3
- 229940121363 anti-inflammatory agent Drugs 0.000 claims description 3
- 239000000730 antalgic agent Substances 0.000 claims description 2
- 239000000463 material Substances 0.000 description 5
- 238000009472 formulation Methods 0.000 description 4
- 239000004014 plasticizer Substances 0.000 description 4
- 230000001225 therapeutic effect Effects 0.000 description 4
- 239000003814 drug Substances 0.000 description 3
- 210000001035 gastrointestinal tract Anatomy 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 230000003628 erosive effect Effects 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 208000025814 Inflammatory myopathy with abundant macrophages Diseases 0.000 description 1
- 150000008545 L-lysines Chemical class 0.000 description 1
- CLOMYZFHNHFSIQ-UHFFFAOYSA-N clonixin Chemical compound CC1=C(Cl)C=CC=C1NC1=NC=CC=C1C(O)=O CLOMYZFHNHFSIQ-UHFFFAOYSA-N 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 235000015872 dietary supplement Nutrition 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 235000011389 fruit/vegetable juice Nutrition 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 239000007902 hard capsule Substances 0.000 description 1
- 239000007887 hard shell capsule Substances 0.000 description 1
- 239000003906 humectant Substances 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 239000008203 oral pharmaceutical composition Substances 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 229940068918 polyethylene glycol 400 Drugs 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 238000009877 rendering Methods 0.000 description 1
- 239000007905 soft elastic gelatin capsule Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4866—Organic macromolecular compounds
-
- 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
- A61K31/455—Nicotinic acids, e.g. niacin; Derivatives thereof, e.g. esters, amides
-
- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
- A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
-
- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4858—Organic compounds
-
- 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]
Landscapes
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pain & Pain Management (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Engineering & Computer Science (AREA)
- Neurosurgery (AREA)
- Rheumatology (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
imam Pharmaceutical soft capsules containing lysine clonixinate and their preparation ROEMMERS S.A.I.C.F.
C. 90141 Pharmaceutical soft capsules containing lysine clonixinate and a process for their preparation The present invention relates to a pharmaceutical composition for oral administration containing as active ingredient the analgesic and anti-inflammatory agent lysine clonixinate. The invention also concerns a process for the preparation of soft capsules that comprise lysine clonixinate.
The L-lysine salt of 2-[ (3-chloro-2- -methylphenyl) amino] -3-pyridine carboxylic acid, or lysine clonixinate, is described in patent specifications DE 2.253.134 and US 3.973.027. In both of these specifications there is reference to formulations for oral, parenteral and rectal administration.
Oral administration constitutes a preferred route for administering lysine clonixinate, but tablets are the only type of formulation known in the art and existing in the market. However, it has been observed that the administration of lysine clonixinate in the forms of solid tablets -or of powder filled, hard shell capsules- present the problem of inducing some local erosion in the digestive tract. On the other hand, the time of onset of the therapeutic action following oral administration of the drug is. an important consideration: It is highly desirable from the patient's point of view that the drug begin to relieve pain or inflammation as quickly as possible. Therefore, the development of an oral pharmaceutical formulation of lysine clonixinate that provides more rapid therapeutic onset and less discomfort would be interesting .
Soft elastic gelatin capsules are widely used as an alternative to powder-filled hard-shell capsules or tablets for the oral administration of pharmaceuticals, vitamins, dietary supplements and the like. These soft capsules are often preferred by patients since they are easier to swallow than conventional hard capsules or tablets.
With a highly water soluble compound, as lysine clonixinate is, a soft gelatin capsule formulation faces the problem of embrittelement of the shell, with the corresponding leaking of the fill material. The prevention of the oxidation of the lysine clonixinate in a filling in the form of solution or dispersion constitutes an extra problem in this case.
It is an object of the present invention to provide soft gelatin capsules containing an effective unit dosage amount of lysine clonixinate, said capsules being stable during a long time, easy to manufacture with the standard machinery, and providing rapid onset of the therapeutic activity upon oral administration of the capsule, with less harmful side-effects than the lysine clonixinate tablets currently in the market.
An embodiment of the present invention is a pharmaceutical dosage unit form of the type soft gelatin capsule with a filling comprising lysine clonixinate as active ingredient, said filling being based on a hydrophilic matrix comprising polyethylene glycol having an average molecular weight of from about 200 to 1000, or a mixture of the polyethylene glycol with propylene glycol and/or propylene carbonate, glycerol in 3 to 10% by weight, and water in 5 to 15% by weight (all concentration values relate to the filling) .
The recommended contents of lysine clonixinate per dosage unit is from 20 to 300 mg, preferably 125 mg. The preferred polyethylene glycol has an average molecular weight of about Instead of polyethylene glycol, propylene glycol or propylene carbonate may be utilized.
The capsule filling may if desired contain additional ingredients such as preservatives, flavouring and/or sweetening agents. Lysine clonixinate is kept virtually dissolved in the filling and it is quickly released to the digestive tract when the capsule shell dissolves.
A further embodiment of the invention is a filling comprising lysine clonixinate as active ingredient in a hydrophilic matrix of the type described above.
According to the invention a pharmaceutical dosage unit is provided with lysine clonixinate as active ingredient, comprising a soft gelatine capsule as described above, with a content of lysine clonixinate of 20 mg to 300 mg, preferably 125 mg.
Another embodiment according to the invention is a process for the preparation of soft gelatine capsules with a filling comprising lysine clonixinate as active ingredient comprising the simultaneous or successive steps: (a) forming the gelatine capsules, and (b) filling the capsules with lysine clonixinate as active ingredient, a hydrophilic matrix comprising polyethylene glycol having an average molecular weight of from about 200 to 1000 or a mixture of said polyethylene glycol with propylene glycol and/or propylene carbonate, glycerol in 3 to 10% by weight, and water in 5 to 15% by weight (all concentration values relate to the filling) .
A further embodiment according to the invention is the use (method of treatment) of the above mentioned capsules as analgetics or anti-inflammatory agents.
The filling of the present invention may be used with a conventional soft gelatin capsule shell. In one conventional shell formulation, there is included about 30-35 parts by weight of gelatin, about 15-48 parts by weight of a plasticiser, such as glycerol or sorbitol, and about 16-40 parts by weight of water. Additionally, the gelatin shell may contain preservatives, such as mixed parabens in minor proportions. In a conventional manner, the gelatin composition is mixed and melted under vacuum conditions. The capsules may be simultaneously formed and filled using conventional methods and apparatus. The gelatin capsules are formed into the desired shape and size so that they can be readily swallowed, usually with the aid of water. The resulting capsule is soluble in water and in gastrointestinal juices.
The interval of average molecular weight (from about 200 to 1000) for the polyethylene glycol used in the filling of the present invention is crucial, because polyethylene glycols of much lower molecular weight tend to diffuse through the shells of conventional soft gelatin capsules. In turn, the use of polyethylene glycols with higher molecular weight tends to result in a too viscous, unpu pable vehicle, difficult to manufacture by ordinary machinery.
The contents of glycerol (3-10%) and water (5-15%) in the filling corresponding to the dosage units of the present invention are crucial to reduce any undesirable interaction between the polyethylene glycol and the soft gelatin shell. Glycerol and water act as humectants by setting up a sort of equilibrium between the moisture content of the filling and the soft gelatin capsule shell. Similarly, glycerol acts as eguilibrium plasticiser so that the polyethylene glycol does not remove excessive amounts of plasticisers from the soft gelatin capsule shell. Thus, water and glycerol prevent the polyethylene glycol from rendering the soft gelatin capsule hard, brittle, and subject to damage and leaking during handling. Preferred filling compositions according to the present invention are those of Example 1.
The fact that lysine clonixinate is kept in solution in the filling of the capsules, and therefore it is quickly released to the digestive tract when the shell dissolves, gives the capsules of the present invention a higher bioavailability than that of the corresponding tablets known in the art. This feature, which is illustrated by the pharmacokinetic results of Example 2, represents a more rapid therapeutic onset for the patient, and therefore an advantage over the current tablets in the market.
The administration of the dosage unit forms of the present invention has another advantage: When the shell dissolves, lysine clonixinate diffuses very quickly in its environment. Thus, local erosion -and its associated damage or discomfort- is smaller than with the current tablets.
Capsules of the present invention have been easily prepared with standard machinery and have proved stable for more than a year under high humidity conditions, as illustrated in the accompanying Example 3.
EXAMPLE 1 Preparation of soft gelatin capsules of lysine clonixinate Two fill materials having the compositions per capsule shown in Table 1 were prepared. The fill materials were thoroughly mixed under nitrogen atmosphere, and they were encapsulated in conventional soft gelatin shells. The fill materials proved to be nondilatant and compatible with conventional soft gelatin capsule manufacturing processes, such as those disclosed, for example, in US 2.288.327 and US 2.318.718. Besides, the gelled fill materials were temperature stable and did not remove excessive amounts of water or plasticisers from the soft elastic gelatin shell.
TABLE 1 Typical capsule filling compositions (in mg/capsule) Ingredients Filling A Filling B lysine clonixinate 125 125 polyethylene glycol 400 344 293 anhydrous glycerol 35 31 water 56 50 EXAMPLE 2 Pharmacokinetics comparative test between soft gelatin capsules and tablets of lysine clonixinate A conventional pharmacokinetics comparative study was carried out with 28 healthy fasting human volunteers. Fourteen of them received a single 125 mg dose of commercially available lysine clonixinate tablets, whereas the other 14 received the same dose in the form of soft gelatin capsules with the filling composition A of Table 1. The obtained pharmacokinetic results are those shown in Table 2.
TABLE 2 Pharmacokinetic parameters of two pharmaceutical forms Parameter Gelatine Capsules Tablets t¾ (h) 0.17 0.29 AUC (jug/h/ml) 10.36 10.09 cmax (Mg/ml) 4.8 5.6 Notes: t^ = half life; tmax = time at which Cmax is attained; AUC = Area Under Curve; Cmax = maximum Concentration.
EXAMPLE 3 Stability test of soft gelatin capsules of lysine clonixinate The stability of the two typical soft gelatin capsules prepared according to Example 1 were studied over a period of 36 months, in conditions of 20-252C and 50-70% relative humidity. It was observed that the capsules were stable, without signs of embrittelement , and that the active ingredient was not altered, e.g. by oxidation.
Claims (6)
1. A pharmaceutical dosage unit form of the type soft gelatin capsule with a filling comprising lysine clonixinate as active ingredient, said filling being based on a hydrophilic matrix comprising polyethylene glycol having an average molecular weight of from about 200 to 1000, or a mixture of the polyethylene glycol with propylene glycol and/or propylen carbonate, glycerol in 3 to 10% by weight, and water in 5 to 15% by weight.
2. The soft gelatine capsule of claim 1 wherein the polyethylene glycol has an average molecular weight of about 400. *
3. The soft gelatine capsule of claim 1 comprising a contents of lysine clonixinate from 20 to 300 mg.
4. The soft gelatine- capsule of claim 3 comprising a contents of lysine clonixinate of 125 mg.
5. A process for the preparation of a soft gelatin ; capsule with a filling comprising lysine clonixinate, comprising the simultaneous or successive steps of (a) forming the gelatine capsules, and (b) filling the capsules with lysine clonixinate as active ingredient, a hydrophylic matrix comprising polyethylene glycol having an average molecular weight of from about 200 to 1000, or a mixture of said polyethylene glycol with propylene glycol and/or propylene carbonate, glycerol, in 3 to 10% by weight, and water in 5 to 15% by weight.
6. A soft gelatin capsule as claimed in claim 1 or 2 for use as an analgesic and/or anti-inflammatory agent. For the Applicants, REINHQPD"COHN AND PARTNERS
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE4219702A DE4219702A1 (en) | 1992-06-16 | 1992-06-16 | Pharmaceutical soft capsules containing lysine clonixinate and a process for the production thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IL105870A0 IL105870A0 (en) | 1993-10-20 |
| IL105870A true IL105870A (en) | 1996-12-05 |
Family
ID=6461132
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IL10587093A IL105870A (en) | 1992-06-16 | 1993-06-01 | Pharmaceutical soft capsules containing lysine clonixinate and their preparation |
Country Status (13)
| Country | Link |
|---|---|
| EP (1) | EP0574822A1 (en) |
| JP (1) | JPH0665078A (en) |
| KR (1) | KR940000108A (en) |
| CN (1) | CN1037934C (en) |
| AU (1) | AU656078B2 (en) |
| CA (1) | CA2098410A1 (en) |
| DE (1) | DE4219702A1 (en) |
| FI (1) | FI932768A (en) |
| IE (1) | IE930446A1 (en) |
| IL (1) | IL105870A (en) |
| MX (1) | MX9303582A (en) |
| NO (1) | NO932097L (en) |
| ZA (1) | ZA934222B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE19849848A1 (en) * | 1998-10-29 | 2000-05-04 | Lohmann Therapie Syst Lts | Oral application, spontaneous disintegration with liquid and dosage form and process for its preparation |
| KR20030042935A (en) * | 2001-11-26 | 2003-06-02 | 알앤피코리아 주식회사 | Clonixin lysinate formulation |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3337570A (en) * | 1965-10-23 | 1967-08-22 | Schering Corp | Substituted nicotinic acids and method for the manufacture thereof |
| US4144332A (en) * | 1976-01-05 | 1979-03-13 | The Regents Of The University Of Michigan | Process for alleviating proliferative skin diseases |
| DE4037554A1 (en) * | 1990-11-26 | 1992-05-27 | Roemmers Sa | MEDICAMENT FOR TOPICAL APPLICATION |
-
1992
- 1992-06-16 DE DE4219702A patent/DE4219702A1/en not_active Withdrawn
-
1993
- 1993-06-01 IL IL10587093A patent/IL105870A/en not_active IP Right Cessation
- 1993-06-03 AU AU40009/93A patent/AU656078B2/en not_active Ceased
- 1993-06-09 EP EP93109279A patent/EP0574822A1/en not_active Ceased
- 1993-06-09 NO NO932097A patent/NO932097L/en unknown
- 1993-06-10 KR KR1019930010541A patent/KR940000108A/en not_active Application Discontinuation
- 1993-06-11 JP JP5166129A patent/JPH0665078A/en active Pending
- 1993-06-15 IE IE044693A patent/IE930446A1/en not_active IP Right Cessation
- 1993-06-15 ZA ZA934222A patent/ZA934222B/en unknown
- 1993-06-15 MX MX9303582A patent/MX9303582A/en not_active Application Discontinuation
- 1993-06-15 CA CA002098410A patent/CA2098410A1/en not_active Abandoned
- 1993-06-16 CN CN93107267A patent/CN1037934C/en not_active Expired - Fee Related
- 1993-06-16 FI FI932768A patent/FI932768A/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| NO932097D0 (en) | 1993-06-09 |
| KR940000108A (en) | 1994-01-03 |
| CN1037934C (en) | 1998-04-08 |
| CA2098410A1 (en) | 1993-12-17 |
| ZA934222B (en) | 1994-01-17 |
| MX9303582A (en) | 1994-04-29 |
| EP0574822A1 (en) | 1993-12-22 |
| DE4219702A1 (en) | 1993-12-23 |
| NO932097L (en) | 1993-12-17 |
| AU656078B2 (en) | 1995-01-19 |
| IL105870A0 (en) | 1993-10-20 |
| JPH0665078A (en) | 1994-03-08 |
| FI932768A (en) | 1993-12-17 |
| FI932768A0 (en) | 1993-06-16 |
| IE930446A1 (en) | 1993-12-29 |
| AU4000993A (en) | 1993-12-23 |
| CN1083702A (en) | 1994-03-16 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FF | Patent granted | ||
| KB | Patent renewed | ||
| RH | Patent void |