LV10382B - New medicinal preparation - Google Patents
New medicinal preparation Download PDFInfo
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- LV10382B LV10382B LVP-93-1388A LV931388A LV10382B LV 10382 B LV10382 B LV 10382B LV 931388 A LV931388 A LV 931388A LV 10382 B LV10382 B LV 10382B
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Classifications
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- 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
-
- 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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
Description
LV 10382
Description
The present invention relates to an oral pharmaceutical controlled release multiple units dosage form in which individual units containing an active substance are surrounded by a coating vvhich releases the 5 active substance through diffusion.
Technical Background
The term "controlled release multiple units formulation" (Bechgaard & Hegermann Nielsen, 1978) indicates 10 a pharmaceutical formulation comprising a multiplicity (typically at least 100) of individual coated(or "microencapsulated") units contained in the formulation in such a form that the individual units will be made available from the formulation upon disintegration of the formulation in the stomach of animals, including humāns, who have ingested the formulation. Typically, the multiple units formulation may be a gelatin capsule or a tablet vvhich disintegrates in the stomach to make available a multiplicity of coated units. 15
Controlled release multiple units formulations aim at a controlled release of active substance in a predetermined pattern to reduce and delay the peak plasma concentration vvithout affecting the extent of drug availability. Due to a lovver peak plasma concentration, the frequency of undesirable side-effects may be reduced, and due to the delay in the time it takes to obtain the peak plasma concentration and the 20 prolongation of the time above the therapeutically active plasma concentration, the dosage frequency may be reduced to a dosage taken only tvvice or once a day, in order to improve patient compliance. A further advantage of the controlled release multiple units dosage form is that high local concentration of the active substance in the gastrointestinal system is avoided, due to the units being distributed freely 25 throughout the gastrointestinal tract.
Drug release from a controlled release dosage form is generally controlled by a coating outside an active core. The release can be achieved 30 a) by diffusion: the coating svvells in aqueous environment so that the active substance can diffuse through the stagnant liquid phase contained in the coating polymer, or b) by osmosis: the coating is semipermeable, i.e. only vvater can penetrate the coating polymer and dissolve the active substance, this will lead to a pressure buildup inside the coating, in order to allow the 35 active to be released from the unit a hole or channel with a well defined area must be formed in the coating, this can be achieved either by laser drilling (SE Patent 435 897 - US Patent 4256108 to Aiza) or by incorporation of a substance vvhich will form the channels by erosion after ingestion (US Patent 4687660 and European Patent Application 0171 457 to VVellcome), should the coating have any weak spots or cracks in it these will increase the release area and as a result give varying dissolution rātes 40 for different units, i.e. zero order release will not be achieved for the hole dose, or c) by erosion: the coating vvill disintegrate by a process dependent on, e.g. enzymes or pH and leave the active core exposed to rapid dissolution. The importance of a pH independent diffusion with respect to obtaining a reproducible rāte of availability and to minimizing intra- and intersubject variations 45 is knovvn (GB Patent No. 1468172 and Bechgaard & Baggesen, 1980). It is also knovvn that controlled drug release in vivo can be achieved through an erodable process by enteric coating of a multiple units dosage form (Green, 1966; McDonald et al., 1977; Bogentoft et al., 1978).
The present invention deals with multiple units dosage forms controlled by diffusion membranes. Contrary 50 to previously knovvn diffusion membranes used for multiple unit dosages the membrane according to the invention is non-swellable in vvater and gastrointestinal fluids. Furthermore the polymer used must be insoluble in and impermeable to vvater and pores are formed in the membrane after ingestion by a pH independent erosion process. The pores vvill give the coating a sponge-like appearance and vvill be filled vvith stagnant liquid vvhere the active substance can diffuse out from the core. 55
Disclosure of the Invention A number of coatings employed in connection vvith pharmaceutical controlled release multiple units formulations have been observed to suffer from the disadvantage that they change their release charac-60 teristics in the course of time. This means that it is not possible to maintain a reproducible release rāte of an active substance contained in the multiple units formulation as a variable release rāte has been observed for such coatings. In accordance vvith the present invention, it has unexpectedly been found that by selecting a special type of controlled release system vvhich has not previously been used or disclosed 2 LV 10382 for multiple units formulations many problems connected to multiple units formulations can be avoided.
In macro scale, i.e. for tablets, controlled release systems based on coatings containing pore-creating substances has been disclosed in, e.g. the GB Patent No. 1186990, the US Patent No. 3538214 and in the US Patent No. 4557925. The present release system is based on the principle of coating a core including an active substance with a film essentially consisting of a polymer that is insoluble in and impermeable to vvater and gastrointestinal fluids, and in vvhich a vvater-soluble pore-creating substance is randomly distributed. It is also required that the polymer is non-swellable in water and gastrointestinal fluids. When applying this controlled release system to multiple units formulations it was unexpectedly found that important advantages could be obtained.
It was thus found that it is possible to coat different types of pārticies, including crystals, in ordinary coating equipment, i.e. in different types of Standard equipment normally available in a pharmaceutical industry. From this follows that the manufacturing process is comparatively easy and cheap. Additionally it was found that a uniform essentially zero order controlled release rāte could be obtained also vvhen relatively non-uniform pārticies were used as cores. This is usually not the case in conventional multiple units controlled release formulations, For example diffusion controlled release from multiple units vvhere the polymer swells are dependent on the thickness of the diffusion layer which will differ with time since the polymer will release the active substance while the swelling continues. This will lead to different release rātes at the beginning and end of the release period vvhich will result in a release more similar to first order release than zero order. Osmotic controlled multiple units on the other hand are dependent on both the ability of the substances in the core to draw vvater into it, vvhich may lead to lovvered release rāte at the end of the release period if the osmotic active and drug active substances are not the same, and the coating quality, vvhich, if it has any weak spots or cracks in it, increases the release area. Such defects give varying dissolution rātes for different units, i.e. zero order release vvill not be achieved for the multiplicity of the units contained in a dose.
Another advantage of the present invention is the possibility of adjusting the release rāte by changing the film thickness. In currently commercially used multiple unit systems this possibility seems to exist in a rather unpredictable manner and only up to a certain film thickness. In the present system, on the contrary, an essentially linear correlation exists betvveen the release rāte and the film thickness. This means that for a given type of film the release rāte decreases vvhen the film thickness increases in a proportional manner in accordance with Fick’s first law of diffusion.
It is also possible to change the release rāte by changing the ratio betvveen the pore-creating substance and the coating polymer. This gives the present system a unique possibility to utilizē active substances with very different solubilities, vvhich is a great advantage over the existing multiple units controlled release systems.
Thus, one aspect of the invention relates to an oral pharmaceutical controlled release multiple units formulation characterized by individual units containing an active substance, vvhich units are provided vvith an outer coating consisting essentially of a polymer that is insoluble in, impermeable to and non-swellable in vvater and gastrointestinal fluids, and a vvater-soluble pore-creating substance vvhich is randomly distributed in the polymer. Another aspect of the invention is formulation in vvhich units of the type described above are combined vvith uncoated units vvhich comprise the same or another active substance for instant release thereof, and/or vvith non-diffusion coated units vvhich have been provided vvith a coating selected from hydrophilic coatings, hydrophobic coatings, vvaterbased coatings and organic coatings imparting desired properties to the unit such as acid or alkali resistance, storage stability, taste masking, light stability, coloring, improved process ability, etc. The ratio betvveen diffusion coated or non-diffusion coated units in the composition may be adjusted according to, for instance, the desired release characteristics of the composition, but is preferably in the range of about 10:90 to 90:10 of diffusion coated units to uncoated or non-diffusion coated units.
The oral pharmaceutical controlled release multiple units formulation according to the invention vviil typically be a gelatin capsule containing a multiplicity of the units, typically more than 100, a sachet containing a multiplicity of the units, typically more than 500, or a tablet made from a multiplicity of the units, typically more than 100, in such a manner that the tablet vvill after ingestion disintegrate in the stomach into a multiplicity of individual units. I each of the three above mentioned formulations the units vvill be freely distributed throughout the gastrointestinal tract shortly after ingestion. 3 LV 10382
Detailed Description of the Invention Coating 5 The coating polymer should have good film forming and adhesive properties, and should be readily soluble in organic solvents such as acetone, methylene chlorid, methylethyl ketone or mixtures of acetone and ethanol or methylene chloride. Suitable polymers are non swelling cellulose derivatives, acrylic polymers and vinyl polymers. The coating polymer is a polymer containing 80-95 % vveight by weight viny! chloride, 1-19 % vveight by vveight vinyl acetate and 0-10 % vveight by vveight vinyl alcohol. Preferably containing jo 88-94 % vveight by vveight vinyl chloride, 2-5 % vveight by vveight vinyl acetate and 3-5 % vveight by vveight vinyl alcohol.
Preferably plasticizers also are present in the coating. The amount may vary betvveen 1 to 50 % vveight by vveight of the coating polymer, preferably betvveen 10 and 40 %. Examples of suitable plasticizers are 15 acetyItributyIcitrate, polyethylene glycol, blovvn castor oil and glyceryl triacetate, Furthermore, the coating may include sodium bicarbonate as stabilizing aģent in amount betvveen 1 and 20 % vveight by vveight of the coating polymer, preferably 5 to 15 % vveight by vveight of the coating polymer.
The pore-creating substance used according to the present invention should be highly vvater-soluble, 20 insoluble in the solvent used for coating, pharmacologically acceptable and essentially free from own pharmacological effects in the amounts used. Especially preferred are sugars such as saccharose and lactose, and salts such as sodium chloride.
The particle size of the pore-creating substance may vary betvveen 0.1 and 100, preferably betvveen 0.5 25 and 50 pm. The ratio betvveen the amount of pore-creating substance and coating polymer depends on the desired dissolution rāte. Generally the ratio should be betvveen 0.05 and 5, preferably betvveen 0.1 and 2.
The coating thickness is aiso dependent on the desired dissolution rāte. It may vary betvveen 5 and 300 30 pm, preferably 10 and 150 pm.
Cores
The individual units of the multiple units formulations according to the invention are coated cores consisting 35 of crystals or pellets. The crystal units are substantially monolithic crystals. The pellets are constituted by a combination of active substance and excipients. One major type of pellets consists of an excipient seed-particle vvith active substance applied to its surface. Typical pellets of this type are the so-called “non-pareil" pellets vvhere the seeds are in the form of spherical pārticies of saccharose. In another peliet formulation principle of this type the seeds are in the form of crystalline saccharose. Another major type 40 of pellets consists of cross-sectionally substantially homogenous pārticies prepared e.g. wet-granulation of extrusion.
The diameter of the cores is normally about 0.1-1.5 mm, preferably about 0.4-1.2 mm, preferably vvith a range of about 0.4 mm vvithin a specific formulation. 45
Active substance
The active substance in the formulations according to the invention may be any active substance vvhich is advantageously administered in a controlled release multiple units formulations. Examples of suitable 50 active substances are found among almost ali therapeutic groups, including diuretics, antiepileptics, sedatives, antiarrythmics, antirheumatics, β-blockers, vasidilators, analgesics, bronchodilators, hormones, vitamīns, oral antidiabetics, antibiotics, antihypertensives, antiinflammatory drugs, antimicrobial aģents and antidepresants, polypeptides, enzymes and mucopolysaccharides. 55 As examples of active substances may be mentioned phenylpropanolamine, potassium chloride, quinidine salts, lithium carbonate, acetyl cystein, depyridamol, theophylline, choline theophyllinate, dextropropoxyphene, dextromethorphan, salbutamol, terbutaline, digoxin, furosemide, propranolol, ibuprofen, lidocaine, mepyramine, morphine, nitroglycerine, clonidine, disopyramide, verapamil, captopril, prazocin, nifedipine, diltiazem, paracetamol, indomethacin, ticlopedine, oxybutynin and noscapine.
Among these substances, some are characterized as having a pH-independent solubility, others as having pH-dependent solubility. Active substances having a pH-dependent solubility are preferably incorporated in cores in combination vvith buffering substance such as sodium bicarbonate, citric acid, succinic acid or 4 60 LV 10382 tartaric acid, in order to obtain a dissolution of active substance which is substantially independent of the gastrointestinal pH variations through vvhich the units will pass.
Method
Generally the method of producing the coated multiple unit preparation according to the invention comprises the steps of dissolving the polymer in a solvent, preparing a suspension of the pore-creating substance, mixing the suspension of pore-creating substance and the solvent solution of the polymer to form a coating fluid, prepare multiple unit cores containing an active substance in the form of crystals or pellets, applying the coating fluid to the core units, and drying the units in order to evaporate the solvent and provide polymer-coated multiple units having the vvater-soluble pore-creating substance randomly distributed vvithin the coating.
The solvent for the polymer can be selected from, e.g. acetone, methylene chloride, methylethyl ketone or mixtures of acetone and ethanol or methylene chloride.
The pore-creating pārticies are micronized either by dry milling or by wet-milling to a defined particle size, preferably betvveen 0.5 pm and 50 pm. The pārticies are dispersed in solvents such as those previously mentioned, and mixed with the terpolymer solution.
The coating fluid may, as previously stated, include a plasticizer and sodium bicarbonate.
Coloring matter can also be incorporated in the coating fluid, and insoluble coloring materiāls are preferred.
The coating fluid, in the form of a suspension, is then applied on drug-containing cores. A special advantageous feature is that the coating process can be performed in ordinary coating equipment, i.e. in different types of Standard equipment normally available in a pharmaceutical industry. This is due to the good film forming and adhesive properties of the coating material, and the easiness of solvent evaporation from the system. Examples of such coating equipment are pan coating in sugar-coating pans or perforated film-coating pans, Wurster coating, and other fluid-bed coating procedures. From this follovvs that the manufacturing process is comparatively easy and cheap.
The follovving examples further illustrate the invention but should not be construed as limiting to the invention.
Example 1
Theophylline is a weak acid (pKa = 8.7) vvhich is poorly soluble in vvater. The cores used in this example contain 60 % theophylline on non-parils and have a particle size of 0.8-1.0 mm. These cores (1.0 kg) are coated with a coating suspension of the following composition:
Terpolymer containing 92% vinylchloride, 4% vinylacetate and 4% vinylalcohol vveight by vveight 390 g Micronized sucrose (particle size 1-10 pm) 930 g Acetyl tributyl citrate 89 g Blovvn castor oil 68 g Sodium bicarbonate 34 g Aceton ad 10.000 g
The coating suspension is applied on the cores with an airless spray-coating device in a coating pan. Samples are taken after the application of 1.0, 2.0 and 3.0 kg of the suspension.
Tabie 1 shovvs the dissolution rāte of a dose corresponding to 90 mg theophylline. The dissolution testing is performed according to the USP XXI basket method (100 rpm). There is a linear correlation betvveen the release rāte and the coating thickness, and the release rāte is essentially independent of the pH. A uniform zero order release rāte is observed during the major part of the release time. 5 LV 10382
Table 1
Time (hours) A Released amount of theophylline (%) 0.2 M TRĪS buffer pH 7.4 B C C 0.1 M HCI 1 46 18 10 11 2 84 39 24 28 3 98 58 37 44 4 100 76 49 59 5 90 62 73 6 96 73 86 7 99 83 94 Θ 90 99 9 94 100 10 96 101 11 97 101 12 98 102 A: 2.5 mg coating material per cm2 of the cores B: 5.9 mg coating material per cm2 of the cores C: 9.0 mg coating material per cm2 of the cores 5 10 15 20 25 Example 2
Choline theophyllinate is a salt of theophylline readily soluble in water. The cores used in this example contain 30 % choline theophyllinate on sugar crystals and have a particle size of 0.7 - 1.0 mm. These cores (1.0 kg) are coated with a suspension of the following compositions;
Terpolymer containing 92% vinylchloride, 4% vinylacetate and 4% vinylalcohol vveight by vveight 295 g Micronized sucrose (particle size 1-10 pm) 930 g Acetyl tributyl citrate 30 g Blovvn castor oil 23 g Sodium bicarbonate 34 g Titanium dioxide 59 g Aceton ad 10.000 g
Table 2 shovvs the dissolution rāte of a dose corresponding to 90 mg theophylline. The dissolution rāte testing according to the USP XXI basket method (100 rpm). The dissolution rāte is considerably higher 45 than in Example 1 due to the much higher solubility of the choline salt of theophylline than of pure theophylline. Despite the higher dissolution rāte there is stili a linear correlation betvveen the release rāte and the coating thickness. 40 The coating suspension is applied on the cores with an airless spray-coating device in a coating pan. Samples are taken after the application of 2.0, 2.5, 3.0 kg of the suspension.
Table 2
Time (hours) Released amount of theophylline (%) pH 7.4 0.2 M TRĪS buffer A B C 0.33 96 86 76 0.67 100 99 98 1.00 100 100 A: 3.7 mg coating material per cm2 of the cores B: 4.6 mg coating material per cm2 of the cores C: 5.5 mg coating material per cm2 of the cores 50 55 60 6 LV 10382
Example 3
Diltiazem hydrochloride is an ammonium salt readily soluble in water. The core used in this example contain 44 % diltiazem hydrochloride or non-pareils and have a particle size of 0.7 - 1.1 mm. These cores (0.9 kg) are coated with a coating suspension of the following composition:
Terpolymer containing 92% vinylchloride, 4% vinylacetate and 4% vinylalcohol vveight by vveight 409 g Micronized sucrose (particle size 1-10 pm) 930 g Acetyl tributyl citrate 70 g Blovvn castor oil 52 g Sodium bicarbonate 34 g Aceton ad 10.000 g
Table 3 shows the dissolution rāte of a doze corresponding to 120 mg diltiazem hydrochloride. The dissolution testing is performed according to the USP XXI basket method (100 rpm). The solubility of this ammonium salt is similar to that of the salt in Example 2. The dissolution rāte is therefore also similar. Also here is the linear correlation betvveen the release rāte and the coating thickness obvious.
The coating suspension is applied on the cores with an airless spray-coating device in a coating pan. Samples are taken after the application of 1.6, 2.3 and 3.0 kg of the suspension.
Table 3
Time (hours) Released amount of diltiazem hydrochloride (%) 0.05 M phosphate buffer pH 7.4 A B C 0.25 48 34 27 0.50 79 67 56 0.75 91 85 80 1.00 96 91 85 1.25 98 94 91 1.50 99 97 94 1.75 100 98 96 2.00 101 99 97 A: 6.8 mg coating material per cm2 of the cores B: 9.8 mg coating material per cm2 of the cores C: 12.4 mg coating material per cm2 of the cores 7 LV 10382
Claims 1. Oral pharmaceutical multiple units formulation comprising individual cores containing a pharmaco-logical active substance, said cores being provided with a coating consisting essentially of a 5 polymer, that is insoluble in, impermeable to and non-swellable in water and gastrointestinal fluīds whereby said polymer is a polymer containing 80-95% vveight by weight vinyl chloride, 1 - 19 % weight by weight vinyl acetate and 0 - 10 % vveight by vveight vinyl alcohol, and a vvater-soluble pore-creating substance, vvhich is randomly distributed in said polymer, whereby said coated cores form units providing an essentia!ly zero order diffusion controlled release rāte of said active 10 substance. 2. Formulation according to claim 1, characterized in that the polymer is a terpolymer containing 88 - 94 % vveight by vveight vinyl chloride, 2 - 5 % vveight by vveight vinyl acetate and 3 - 5 % vveight by vveight vinyl alcohol. 15 20 3. Formulation according to any of the claims 1-2, characterized in that the pore-creating substance is selected from the group consisting of sugars and salts. 4. Formulation according to any of the preceding claims, characterized in that it also comprises uncoated cores containing the same or another active substance for the instant release thereof. 25 30 35 40 45 5. Formulation according to any of the claims 1-4, characterized in that it also includes non-diffusion coated cores provided vvith a coating selected from hydrophilic, hydrophobic, vvaterbased or organic coatings. 6. Method of preparing an oral pharmaceutical multiple units formulation comprising individual cores containing a pharmacological active substance, said cores being provided vvith a coating consisting essentially of a polymer, that is insoluble in, impermeable to and non-swellable in vvater and gastrointestinal fluids whereby said polymer is a polymer containing 80 95 % vveight by vveight vinyl chloride, 1 - 19 % vveight by vveight vinyl acetate and 0 - 10 % vveight by vveight vinyl alcohol, and a vvater-soluble pore-creating substance, vvhich is randomly distributed in said polymer, whereby said coated cores form units providing an essentially zero order diffusion controlled release rāte of said active substance, said method comprising the steps of dissolving the polymer in a solvent, preparing a suspension of the pore-creating substance, mixing the suspension of pore-creating substance and the solvent solution of the polymer to form a coating fluid, prepare multiple unit cores containing an active substance in the form of crystals or pellets, applying the coating fluid to the core units, and drying the units in order to evaporate the solvent and provide polymer-coated multiple units having the vvater-soluble pore-creating substance ran-domly distributed vvithin the coating. 7. Method according to claim 6. characterized in that the polymer is a terpolymer containing 88 -94 % vveight by vveight vinyl chloride, 2 - 5 % vveight by vveight vinyl acetate and 3 - 5 % vveight by vveight vinyl alcohol. 8. Method according to any of the claims 6-7, characterized in that the pore-creating substance is selected from the group consisting of sugars and salts. 50 55 60
Claims (8)
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
SE19888803822A SE8803822D0 (en) | 1988-10-26 | 1988-10-26 | NOVEL DOSAGE FORM |
Publications (2)
Publication Number | Publication Date |
---|---|
LV10382A LV10382A (en) | 1995-02-20 |
LV10382B true LV10382B (en) | 1995-12-20 |
Family
ID=20373739
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
LVP-93-1388A LV10382B (en) | 1988-10-26 | 1993-12-28 | New medicinal preparation |
Country Status (14)
Country | Link |
---|---|
KR (1) | KR0120111B1 (en) |
CN (1) | CN1043957C (en) |
AT (1) | ATE90556T1 (en) |
DK (1) | DK175608B1 (en) |
FI (1) | FI102455B1 (en) |
HU (1) | HU201883B (en) |
IE (1) | IE62640B1 (en) |
IL (1) | IL92036A (en) |
LV (1) | LV10382B (en) |
NO (1) | NO179478C (en) |
NZ (1) | NZ231093A (en) |
PH (1) | PH26653A (en) |
PT (1) | PT92103B (en) |
ZA (1) | ZA898127B (en) |
-
1989
- 1989-10-14 AT AT89119102T patent/ATE90556T1/en not_active IP Right Cessation
- 1989-10-17 IE IE334289A patent/IE62640B1/en unknown
- 1989-10-18 IL IL92036A patent/IL92036A/en not_active IP Right Cessation
- 1989-10-20 NZ NZ231093A patent/NZ231093A/en unknown
- 1989-10-25 NO NO894255A patent/NO179478C/en unknown
- 1989-10-25 PH PH39411A patent/PH26653A/en unknown
- 1989-10-25 FI FI895059A patent/FI102455B1/en not_active IP Right Cessation
- 1989-10-25 PT PT92103A patent/PT92103B/en not_active IP Right Cessation
- 1989-10-26 CN CN89108221A patent/CN1043957C/en not_active Expired - Fee Related
- 1989-10-26 HU HU895452A patent/HU201883B/en not_active IP Right Cessation
- 1989-10-26 KR KR89015471A patent/KR0120111B1/en not_active IP Right Cessation
- 1989-10-26 ZA ZA898127A patent/ZA898127B/en unknown
- 1989-10-26 DK DK198905339A patent/DK175608B1/en not_active IP Right Cessation
-
1993
- 1993-12-28 LV LVP-93-1388A patent/LV10382B/en unknown
Also Published As
Publication number | Publication date |
---|---|
IE62640B1 (en) | 1995-02-22 |
LV10382A (en) | 1995-02-20 |
NO894255D0 (en) | 1989-10-25 |
FI102455B (en) | 1998-12-15 |
KR900005965A (en) | 1990-05-07 |
FI102455B1 (en) | 1998-12-15 |
FI895059A0 (en) | 1989-10-25 |
HU895452D0 (en) | 1990-01-28 |
IL92036A0 (en) | 1990-07-12 |
DK533989D0 (en) | 1989-10-26 |
DK533989A (en) | 1990-04-27 |
PT92103A (en) | 1990-04-30 |
KR0120111B1 (en) | 1997-10-17 |
CN1042071A (en) | 1990-05-16 |
NO179478C (en) | 1996-10-16 |
PH26653A (en) | 1992-09-04 |
PT92103B (en) | 1995-08-09 |
HU201883B (en) | 1991-01-28 |
IE893342L (en) | 1990-04-26 |
IL92036A (en) | 1993-07-08 |
CN1043957C (en) | 1999-07-07 |
NO894255L (en) | 1990-04-27 |
HUT52399A (en) | 1990-07-28 |
NO179478B (en) | 1996-07-08 |
DK175608B1 (en) | 2004-12-27 |
NZ231093A (en) | 1992-06-25 |
ATE90556T1 (en) | 1993-07-15 |
ZA898127B (en) | 1990-08-29 |
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