AU8930791A - Solid dosage forms of almokalant and processes for manufacture thereof - Google Patents
Solid dosage forms of almokalant and processes for manufacture thereofInfo
- Publication number
- AU8930791A AU8930791A AU89307/91A AU8930791A AU8930791A AU 8930791 A AU8930791 A AU 8930791A AU 89307/91 A AU89307/91 A AU 89307/91A AU 8930791 A AU8930791 A AU 8930791A AU 8930791 A AU8930791 A AU 8930791A
- Authority
- AU
- Australia
- Prior art keywords
- almokalant
- tablets
- solid dosage
- tablet
- dosage form
- 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.)
- Abandoned
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
- A61K31/74—Synthetic polymeric materials
- A61K31/795—Polymers containing sulfur
-
- 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
- A61K31/275—Nitriles; Isonitriles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
- A61K47/58—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. poly[meth]acrylate, polyacrylamide, polystyrene, polyvinylpyrrolidone, polyvinylalcohol or polystyrene sulfonic acid resin
- A61K47/585—Ion exchange resins, e.g. polystyrene sulfonic acid resin
-
- 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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/06—Antiarrhythmics
Landscapes
- Health & Medical Sciences (AREA)
- Public Health (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Chemical Treatment Of Metals (AREA)
Description
SOLID DOSAGE FORMS OF ALMOKALANT AND PROCESSES FOR MANUFACTURE THEREOF
Field of the invention
This invention relates to solid dosage forms of the antiarrhythmic drug almokalant (p-INN) formulated as immediate release (IR) tablets and extended release (ER) tablets as well as processes for manufacture thereof.
Specifically the invention relates to the use of the polystyrene sulphonate complex of almokalant in solid dosage forms.
Background of the invention
No solid dosage forms containing the polystyrene sulphonate complex of almokalant have been reported. The polystyrene sulphonate complex of almokalant is described in the European patent application EP 90850242.0 (our ref. H 1020-1), which is not publically available at the time of filing the basic application in Sweden, but will be so shortly thereafter.
Almokalant (p-INN), 4-[3-[ethyl[3-(propylsulfinyl)- propyl]amino]-2-hydroxypropoxy]-benzonitrile free base is a viscous, sticky substance, problematic to handle in the manufacture of solid dosage forms. It has a pronounced tendency to give a repellent odorous degradation product with a smell resembling old onions.
Several different ways were tested in order to prepare a solid dosage form of almokalant. Commonly used methods had the following disadvantages.
Due to the instability of the base and its tendency to
worsen tablet binding properties, solid dosage forms of the free base are difficult to produce. See further reference example III.-
Tablets prepared by conventional technique, with almokalant dissolved in an acidic granulating solution, have inferior stability properties and develop a repelling onion-like odour. See further reference examples I and III.
The use of complexes of drug substances with ion exchange resins in pharmaceutical formulation is described previously. A way to obtain a controlled release suspension containing codeine is described by Amsel L.P. et al "Unique Oral Controlled Release Systems": In-Vivo Drug Release Pattern pp 83-93 where a complex between codeine and an ion exchange resin is coated with a diffusion membrane and then formulated into a suspension. In addition, Pennwalt Corporation has published a series of patents describing the use of ion exchange resins having pharmacologically active substances absorbed thereon for use in controlled release preparations either as such or further coated with diffusion membranes (US Pat 4,221,778, EP 0171 528, EP 0 254 811). Other uses of ion exchange resin complexes with drugs in pharmaceutical formulation is for example summarized by Raghunathan et al. J Pharm Sci 1981, 70, (No 4), 379-384.
Description of the invention
The aim of the present invention is to provide solid dosage forms of the antiarrhythmic drug almokalant, formulated as IR-tablets and ER-tablets with improved stability and minimal odour. ER-tablets can be formulated by a variety of formulation principles, such as for instance hydrophilic gel-matrix tablets, matrix tablets, membrane diffusion controlled formulations, osmotic pressure controlled dosage forms etc.
As the use of solid substances in tablet manufacture in general is advantageous and facilitates the production different ways to prepare solid dosage forms were investigated.
As it had been noticed that the compound almokalant as such in acidic solutions has a good stability, which make it possible to autoclave it without noteworthy degradation, the addition of acid compounds were tested.
Although complex-binding to ion-exchange resins of viscous, unstable, pharmacologically active agents, to form a stabile solid complex suitable for pharmaceutical processing has not been previously described, this was tested with almokalant.
Thus, it was tested to use the polystyrene sulfonate complex of almokalant in the formulation of pharmaceutica dosage forms. It was then unexpectedly found that almokalant polystyrene sulphonate complex (A-PSS) , had a much better stability, less repelling odour and was much easier to handle in tablet manufacture.
To form ER tablets it is necessary to mix the formed complex with e.g. a hydrophilic matrix. It is especially preferable to use hydroxypropyl methylcellulose as the ge forming substance. It is further preferred to use a mixture of HPMC containing both low and high molecular weight HPMC.
The use of different mixtures of HPMC gives according to known technics (Journal of Controlled release, 5 (1987) 159-172), different release rates of the active ingredien almokalant.
EXAMPLES
Example 1
Immediate release tablets of almokalant were prepared by mixing A-PSS 90 parts, lactose 85 parts, microcrystalline cellulose 91 parts and polyvinyl pyrrolidone 27 parts and then granulating the mixture with purified water.
After drying the granulate was milled and then mixed with sodium stearyl fumarate and compressed to tablets.
A reference preparation was produced by dissolving the free base in a 2M hydrochloric acid solution and using this solution to granulate the excipients.
A-PSS tablet Ref. Ex 1 Ex I
1. A-PSS corresp. to almokalant 50.0
Almokalant - 50.0
2. Lactose pwd 84.5 Lactose anhydrous Avicel® PH 101 Povidone® K-25
Polyvinyl pyrrolidone, cross-linked Aerosil
3. Water, purified Hydrochloric acid 2M (corresp. to HC1)
4. Sodium stearyl fumarate Magnesium stearate Talcum Polyvinyl pyrrolidone, cross-linked
The A-PSS tablet was prepared by first mixing ingredients 1 and 2. The mixture was granulated with 3. After drying and milling 4 was admixed, whereupon compression to
tablets was performed on a Korsch Pharmapress 100.
The reference tablet (Ref. ex. I) was prepared by making a granulating solution of the ingredients 1 and 3. The powders in 2 were mixed and then granulated with the prepared solution. After drying and milling the lubricant, glidant and disintegrant in 4 were admixed and tablets compressed on the same machine.
Punches: Tablet weight: Hardness: Disintegration:
Stability data of storage in glass bottles. Degradation measured as area sum of byproducts in a HPLC-system
0.81 2.11 0.88 2.83
1.82 3.41
3.5 months in 25°C 0.88 2.87
Example 2
Immediate release tablets of almokalant were prepared by mixing A-PSS 90 parts, lactose 85 parts, microcrystalline cellulose 91 parts and polyvinyl pyrrolidone 27 parts and then granulating the mixture with purified water. After drying the granulate was milled and then mixed with the lubricant sodium stearyl fumarate whereupon compression to tablets was done.
A reference preparation (Ref. ex. II) was produced by dissolving the free base in an aqueous tartaric acid solution and using this solution to granulate the excipients.
A-PSS tablet Ref. tablet Ex 2 Ex II
1. A-PSS corresp. to almokalant 50.0 Almokalant 50.0
2. Lactose pwd 84.5 Lactose anhydrous Avicel® PH 101 Polyvidone K-25 3. Water, purified Tartaric acid 4. Sodium stearyl fumarate Talcum Polyvinyl pyrrolidone, cross-linked
Punches: Tablet weight: Hardness: Disintegration:
The A-PSS tablets were prepared by first mixing ingredients 1 and 2. The mixture was granulated with 3. After drying and milling 4 was admixed, whereupon compression to tablets were performed on a Korsch Pharmapress 100.
The reference tablet (Ref. ex. II) was prepared by making a granulating solution of 1 and 3. The powders 2 were mixed and granulated with the solution. After drying and milling the lubricant, glidant and disintegrant in 4 were admixed and tablets were compressed on the same machine.
The odour intensity of the two formulations were compared
immediately after manufacturing and after 1 month of storage in glass bottles .
Odour intensity
A-PSS tablets Ref. Ex. 2 Ex. II
Freshly prepared + ++
(some smell, but (pronounced smell not of onions. ) of onions. )
1 month +++
(some smell, but (strong smell of not of onions. ) of onions)
Example 3
Immediate release tablets of almokalant can be prepared in suitable strengths.
In Ex. 1 and 2 a 50 rag preparation was described. Below are examples of 70 mg and 1.8 mg preparations shown.
The A-PSS tablets were prepared by first mixing the ingredients 1. The mixture was granulated with a solution made of ingredients 2. After drying and milling ingredients 3 were admixed, whereupon compression to tablets were performed on a Korsch Pharmapress 100.
Punches: 10 mm 5.5x10.5 mm
Tablet weight: 322 mg 150 mg Hardness: 9-10 kP 9-10 kP
Disintegration (without discs): 0.6-1.0 min. 0.2-0.4 min.
Example 4
Extended release tablets of almokalant were prepared by mixing A-PSS 95 parts, hydroxypropyl methylcellulose (HPMC) 50 cps 40 parts, HPMC 10000 cps 160 parts and hydroxypropyl cellulose (HPC) 50 parts and then granulating the mixture with ethanol 99.5%. After drying the granulate was milled and then mixed with sodium stearyl fumarate whereupon compression to tablets was done.
A reference preparation (Ref. ex. Ill) was made by dissolving the free base in ethanol (99.5%) and using this solution to granulate the dry excipients, and otherwise following the same way of production.
Example 4 Ref.ex. Ill
Ingredient mg/tablet mg/tablet
1. A-PSS corresp. to almokalant 50.0 Almokalant 50.0
2. HPMC 50 cps (Metolose® 60SH50) 40.0 40.0
3 . HPMC 10000 cps (Methocel ®^ E10MCR) 4. H HPPCC LLFF ((KKlluuccee:l® LF) 5. Ethanol 99. 5% 6. Sodium stearyl fumarate (Pruv ®*)
Ingredients 1 to 4 were mixed. The mixture was granulated with ethanol. After drying and milling the granulate was mixed with 6.
Compression to tablets was performed on a Korsch
Pharmapress 100 with 11 mm circular punches. The tablet machine was equipped with compression force registration.
Tablets made using the free base have inferior binding properties.
Odour intensit
Freshly prepared
The release rate was determined from 6 individual tablets using USP dissolution apparatus 2 with the paddle rotating at 100 r/min and the tablet placed in a stationary basket above the paddle, 500 ml buffer solution pH 6.8 kept at 37°C was used as dissolution medium.
Example 5
Extended release tablets of almokalant can be prepared in suitable strengths and with different release rates.
In Ex. 4 a preparation with 50 mg strength is described. Below follows examples of 10 mg and 100 mg.
10 mg 100 mg Ex. 5a Ex. 5b
Ingredient mg/tablet
1. A-PSS corresp. to almokalant
2. Lactose pwd HPMC 50 cps (Metolose® 60SH50)
HPMC lOOOOcps (Methocel® E10MCR) HPC LF (Klucel® LF)
3. Polyethylene glycol 20M (Carbowax® 20M) 30.0 Polyethylene glycol 6000 (Carbowax® 6000) 42.0
4. Water, purified 70.0 98.1
5. Sodium stearyl fumarate (Pruv ) 1.6 2.3
1 and 2 were mixed. The mixture was granulated with a solution made of 3 and 4. After drying and milling the granulate was mixed with 5.
Compression to tablets was performed on a Korsch Pharmapress 100. The tablet machine was equipped with compression force registration.
The release rate was determined from 6 individual tablets using USP dissolution apparatus 2 with the paddle rotating at 100 r/min and the tablet placed in a stationary basket above the paddle. 500 ml buffer solution pH 6.8 kept at 37°C was used as dissolution medium.
10 mg ER tablet 100 mg ER tablet
Ex. 5a Ex. 5b cumulative cumulative hours % released % released average (min-max) average (min-max)
2 27 (27-28) 17 (17-18)
4 44 (43-45) 28 (26-29)
6 37 (35-39)
8 72 (70-75)
10 55 (52-60)
12 105 (96-109)
20 91 (84-95)
24 100(99-101)
Examples 6-7
Controlled release tablets were prepared by granulating 54.3 parts active substance, 30.0 parts mannitol, 154 parts HPMC 50 cps, 221 parts HPMC 10,000 cps, 37.5 parts HPC, 0.3 parts propyl gallate with a solution of 45 parts PEG 20,000 (Ex. 6) or PVP K-25 (Ex. 7) dissolved in 105 parts of water. The dried granulate was lubricated with 2.7 parts of sodium stearyl fumarate.
Example 6 Example 7
Ingredient mg/tablet
1. A-PSS corresp. to almokalant
2. Mannitol pwd
3. HPMC (Metolose® 60SH50) 4. HPMC (Methocel® E10MCR)
5. HPC (Klucel® LF)
6. Propyl gallate
7. PEG (Carbowax® 20M) PVP (Povidone® K-25) 8. Water
9. Sodium stearyl fumarate (Pruv )
Ingredients 1 to 6 were mixed. The mixture was granulated with a solution made of 7 and 8. After drying the granulate was mixed with 9.
Compression to tablets were performed on a Korsch Pharmapress 100 with 11 mm circular punches. The tablet machine was equipped with compression force registration .
Example 6 Example 7
Tablet weight: 545 mg 545 mg
compression force (kN) : tablet hardness (kP):
The release rate was determined in USP dissolution apparatus 2 with the paddle rotating at 100 r/min and the tablet placed in a stationary basket above the paddle. 500 ml buffer solution pH 6.8 kept at 37°C was used as dissolution medium.
Cumulative % released Average (min-max)
Example 6 Example 7
2h 17(17-18) 18(17-18)
4h 28(28-29) 28(28-29)
6h 38(38-39) 38(37-39) lOh 55(54-56) 54(53-56)
16h 74(73-76) 73(71-74)
The examples show that PEG 20000 and PVP K-25 both function in the process.
Discussion
From the examples it is quite obvious that the use of almokalant free base in pharmaceutical formulation - apart from the inconvenience of handling a sticky, viscous substance - results in dosage forms with inferior stability and palatability as well as in inferior technical properties. The use of almokalant polystyrene sulphonate complex in pharmaceutical formulation eases the handling and results in more stabile and more palatable dosage forms.
The best mode of carrying out the invention known at present is to prepare the formulation according to Examples 6-7.
Claims (7)
1. A pharmaceutical dosage form of almokalant wherein said almokalant in the form of a complex with polystyrene sulphonate optionally mixed with pharmaceutical excipients forms an oral solid dosage form.
2. A dosage form according to claim 1 wherein the pharmaceutical excipients contain a hydrophilic matrix.
3. A dosage form according to claim 2 wherein the hydrophilic matrix is hydroxypropyl methylcellulose.
4. A dosage form according to claim 3 wherein the hydroxypropyl methylcellulose contains both low and high molecular weight hydroxypropyl methylcellulose.
5. A process for the manufacture of a solid dosage form according to claim 1 wherein a) almokalant is reacted with polystyrene sulphonic acid to form a complex b) the complex is mixed with pharmaceutical excipients and an oral solid dosage form is prepared according to any known method.
6. A process according to claim 5, wherein the pharmaceutical excipients contain a hydrophilic matrix.
7. A process according to claim 6, wherein the hydrophilic matrix is hydroxypropyl methylcellulose.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SE9003902A SE9003902D0 (en) | 1990-12-07 | 1990-12-07 | SOLID DOSAGE FORMS OF A DRUG |
| SE9003902 | 1990-12-07 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| AU8930791A true AU8930791A (en) | 1992-07-08 |
Family
ID=20381121
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU89307/91A Abandoned AU8930791A (en) | 1990-12-07 | 1991-12-03 | Solid dosage forms of almokalant and processes for manufacture thereof |
Country Status (26)
| Country | Link |
|---|---|
| EP (1) | EP0560821A1 (en) |
| JP (1) | JPH06503312A (en) |
| CN (1) | CN1063039A (en) |
| AP (1) | AP258A (en) |
| AU (1) | AU8930791A (en) |
| BG (1) | BG97851A (en) |
| CA (1) | CA2097178A1 (en) |
| CZ (1) | CZ103793A3 (en) |
| FI (1) | FI932554A (en) |
| HU (1) | HUT64217A (en) |
| IE (1) | IE914137A1 (en) |
| IL (1) | IL100150A0 (en) |
| IS (1) | IS3788A7 (en) |
| LT (1) | LTIP1717A (en) |
| MA (1) | MA22355A1 (en) |
| MX (1) | MX9102325A (en) |
| MY (1) | MY106776A (en) |
| NZ (1) | NZ240731A (en) |
| PT (1) | PT99719A (en) |
| SE (1) | SE9003902D0 (en) |
| SK (1) | SK55693A3 (en) |
| TN (1) | TNSN91117A1 (en) |
| TW (1) | TW215057B (en) |
| WO (1) | WO1992010172A1 (en) |
| YU (1) | YU186891A (en) |
| ZA (1) | ZA919264B (en) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE19602757A1 (en) * | 1996-01-26 | 1997-07-31 | Boehringer Mannheim Gmbh | Solid instant release dosage forms and processes for their manufacture |
| GB9611328D0 (en) * | 1996-05-31 | 1996-08-07 | Zeneca Ltd | Pharmaceutical compositions |
| US6024981A (en) * | 1997-04-16 | 2000-02-15 | Cima Labs Inc. | Rapidly dissolving robust dosage form |
| JP4504467B2 (en) * | 1998-07-30 | 2010-07-14 | 佐藤製薬株式会社 | Orally disintegrating tablets |
| JP7426685B2 (en) * | 2018-06-14 | 2024-02-02 | 株式会社東洋新薬 | tablet |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SE8705150D0 (en) * | 1987-12-23 | 1987-12-23 | Haessle Ab | NOVEL ANTIARRHYTHMIC AGENTS |
| IL90245A (en) * | 1988-05-11 | 1994-04-12 | Glaxo Group Ltd | Resin adsorbate comprising ranitidine together with a synthetic cation exchange resin, its preparation and pharmaceutical compositions containing it |
| SE8902236D0 (en) * | 1989-06-20 | 1989-06-20 | Haessle Ab | NOVEL POLYSTYRENESULPHONATE |
-
1990
- 1990-12-07 SE SE9003902A patent/SE9003902D0/en unknown
-
1991
- 1991-11-22 ZA ZA919264A patent/ZA919264B/en unknown
- 1991-11-25 IL IL100150A patent/IL100150A0/en unknown
- 1991-11-25 TW TW080109239A patent/TW215057B/zh active
- 1991-11-26 NZ NZ240731A patent/NZ240731A/en unknown
- 1991-11-27 YU YU186891A patent/YU186891A/en unknown
- 1991-11-28 IE IE413791A patent/IE914137A1/en unknown
- 1991-12-02 MX MX9102325A patent/MX9102325A/en unknown
- 1991-12-02 AP APAP/P/1991/000338A patent/AP258A/en active
- 1991-12-03 CZ CS931037A patent/CZ103793A3/en unknown
- 1991-12-03 MA MA22639A patent/MA22355A1/en unknown
- 1991-12-03 EP EP91920708A patent/EP0560821A1/en not_active Withdrawn
- 1991-12-03 CA CA002097178A patent/CA2097178A1/en not_active Abandoned
- 1991-12-03 WO PCT/SE1991/000815 patent/WO1992010172A1/en not_active Application Discontinuation
- 1991-12-03 HU HU9301670A patent/HUT64217A/en unknown
- 1991-12-03 AU AU89307/91A patent/AU8930791A/en not_active Abandoned
- 1991-12-03 JP JP4500117A patent/JPH06503312A/en active Pending
- 1991-12-03 SK SK55693A patent/SK55693A3/en unknown
- 1991-12-06 PT PT99719A patent/PT99719A/en not_active Application Discontinuation
- 1991-12-06 IS IS3788A patent/IS3788A7/en unknown
- 1991-12-06 MY MYPI91002267A patent/MY106776A/en unknown
- 1991-12-06 TN TNTNSN91117A patent/TNSN91117A1/en unknown
- 1991-12-07 CN CN91112789A patent/CN1063039A/en active Pending
-
1993
- 1993-06-04 FI FI932554A patent/FI932554A/en not_active Application Discontinuation
- 1993-06-04 BG BG97851A patent/BG97851A/en unknown
- 1993-12-30 LT LTIP1717A patent/LTIP1717A/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| CZ103793A3 (en) | 1994-02-16 |
| ZA919264B (en) | 1992-08-26 |
| IE914137A1 (en) | 1992-06-17 |
| LTIP1717A (en) | 1995-07-25 |
| CN1063039A (en) | 1992-07-29 |
| NZ240731A (en) | 1993-10-26 |
| IL100150A0 (en) | 1992-08-18 |
| BG97851A (en) | 1994-04-29 |
| MX9102325A (en) | 1992-06-01 |
| CA2097178A1 (en) | 1992-06-08 |
| WO1992010172A1 (en) | 1992-06-25 |
| MA22355A1 (en) | 1992-07-01 |
| AP9100338A0 (en) | 1992-01-31 |
| TNSN91117A1 (en) | 1992-10-25 |
| MY106776A (en) | 1995-07-31 |
| SE9003902D0 (en) | 1990-12-07 |
| SK55693A3 (en) | 1993-10-06 |
| YU186891A (en) | 1994-04-05 |
| FI932554A0 (en) | 1993-06-04 |
| EP0560821A1 (en) | 1993-09-22 |
| JPH06503312A (en) | 1994-04-14 |
| AP258A (en) | 1993-06-03 |
| HUT64217A (en) | 1993-12-28 |
| FI932554A (en) | 1993-06-08 |
| HU9301670D0 (en) | 1993-09-28 |
| PT99719A (en) | 1992-10-30 |
| TW215057B (en) | 1993-10-21 |
| IS3788A7 (en) | 1992-06-08 |
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