DK167735B1 - FIXED PREPARATION CONTAINING AN ALUMINUM SALT OF A SUCCHAROSE SULFATESTER AND POLYETHYLENE LYCOL, AND PROCEDURE FOR PREPARING THE PREPARATION - Google Patents
FIXED PREPARATION CONTAINING AN ALUMINUM SALT OF A SUCCHAROSE SULFATESTER AND POLYETHYLENE LYCOL, AND PROCEDURE FOR PREPARING THE PREPARATION Download PDFInfo
- Publication number
- DK167735B1 DK167735B1 DK218587A DK218587A DK167735B1 DK 167735 B1 DK167735 B1 DK 167735B1 DK 218587 A DK218587 A DK 218587A DK 218587 A DK218587 A DK 218587A DK 167735 B1 DK167735 B1 DK 167735B1
- Authority
- DK
- Denmark
- Prior art keywords
- tablets
- preparation
- acc
- aluminum salt
- sucralfate
- Prior art date
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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
-
- 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
- A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
Description
i DK 167735 B1in DK 167735 B1
Opfindelsen angår et fast præparat indeholdende et aluminiumsalt af en saccharosesulfatester (almindelig kendt som sucralfat) og polyethylenglycol, .samt .en.-fremgangsmåde til fremstilling af et sådant sucralfatpræpa-5 rat. Ved fremgangsmåden ifølge opfindelsen blandes sucralfat med polyethylenglycol til opnåelse af forøget desintegrerbarhed og dispergerbarhed, hvilket gør sucralfat mere egnet som medicin.The invention relates to a solid composition containing an aluminum salt of a sucrose sulfate ester (commonly known as sucralfate) and polyethylene glycol, as well as to a process for preparing such sucralfate preparation. In the process of the invention, sucralfate is mixed with polyethylene glycol to give increased disintegrability and dispersibility, making sucralfate more suitable as a medicine.
Sucralfat anvendes i stor udstrækning til be-10 handling af mavesår, da det kan beskytte substratproteinet (evne til at beskytte maveslimhinden) og undertrykke aktiviteten af pepsin i mavesaft samt neutralisere syre indholdet i mavesaften. Det er almindeligt kendt, at sucralfat bindes kraftigt til protein-15 bestanddelen af vævet under et mavesår til dannelse af et lag, som kemisk beskytter det angrebne område mod mavevæskes kraftige fordøjelsesevne og derved fremmer helingsprocessen (Nakazawa, S. et al., Dig. Dis. Sci., 26, 297 (1981); og A. Ishimori et al., Igaku to 20 Yakugaku, 9,25 (1983).Sucralfate is widely used to treat gastric ulcers as it can protect the substrate protein (ability to protect the gastric mucosa) and suppress the activity of pepsin in gastric juice as well as neutralize the acid content of the gastric juice. It is well known that sucralfate binds strongly to the protein component of the tissue during a gastric ulcer to form a layer that chemically protects the affected area from the strong digestive power of the stomach and thereby promotes the healing process (Nakazawa, S. et al., Dig. Dis. Sci., 26, 297 (1981); and A. Ishimori et al., Igaku to Yakugaku, 9.25 (1983).
På den anden side er sucralfat uopløseligt i vand, og præparater af det skal nemt kunne désintegreres og dispergeres, for at de effektivt kan bindes til et område, der er angrebet af mavesår.On the other hand, sucralfate is insoluble in water, and preparations of it must be easily disintegrated and dispersed in order to effectively bind to an area affected by gastric ulcer.
25 Der er blevet udført forskellige undersøgelser for at udvikle et sucralfatpræparat med forbedret evne til at kunne desintegreres og dispergeres. Det har nu vist sig, at dette kan opnåes ved blanding af sucralfat ned polyethylenglycol. Opfindelsen bygger på denne op-30 dagelse.Various studies have been performed to develop a sucralfate preparation with improved ability to disintegrate and disperse. It has now been found that this can be achieved by mixing sucralfate with polyethylene glycol. The invention is based on this up-30 day.
Fra WO-A-8601406 (side 3, linie 8-14) kendes et præparat indeholdende sucralfat og polyethylenglycol.WO-A-8601406 (page 3, lines 8-14) discloses a composition containing sucralfate and polyethylene glycol.
Der er imidlertid tale om et vandigt suspensionspræparat indeholdende flydende polyethylenglycol.However, it is an aqueous suspension preparation containing liquid polyethylene glycol.
35 Fra H.P. Fielder: Lexikon der Hilfstoffe fur35 From H.P. Fielder: Lexikon der Hilfstoffe fur
Pharmazie, Kosmetik und angrenzenden Gebietes, vol. 2, 2. ed., side 726-731 (spec, side 729, 2. kolonne) er det kendt, at polyethylenglycol kan anvendes som hjælpemiddel iPharmazie, Kosmetik und angrenzenden Gebietes, vol. 2, 2nd ed., Pages 726-731 (spec, pages 729, second column), it is known that polyethylene glycol can be used as an aid in
urv ΙΌ/ /OO D Iurv ΙΌ // OO D I
2 tabletter indeholdende antacider, og vedrørende fremstillingen anføres det, at de antacide stoffer indføres i en smelte af polyethylenglycol (molvægt 3000-10000).2 tablets containing antacids, and regarding the preparation it is stated that the antacids are introduced into a melt of polyethylene glycol (molecular weight 3000-10000).
Der er her tale om egentlige antacider, hvortil sucral-5 fat ikke hører, idet det hører til de såkaldte mucosa-protektive midler med en anden virkningsmekanisme end antacider, jf. ovenfor.These are actual antacids which do not belong to sucralcate, as they belong to the so-called mucosa-protective agents with a different mechanism of action than antacids, cf. above.
Fig. 1 og 2 viser desintegrerings-og disperge-ringsprofilerne af sucralfatpræparater ifølge op-10 findelsen og af sammenligningspræparater.FIG. 1 and 2 show the disintegration and dispersion profiles of sucralfate compositions according to the invention and of comparative compositions.
Ved fremgangsmåden ifølge opfindelsen kan et su-cralfat blandes med 0,1 vægt% eller mere polyethylenglycol. Skønt den øvre grænse for mængden af polyethylenglycol ikke er kritisk, anvendes det sædvanligvis i en 15 mængde på mindre end 50 vægt%. Molekylvægten af den polyethylenglycol, som skal blandes med sulcralfatet, er ikke begrænset til nogen speciel værdi. Ved peroral administrering-tillader sucralfatpræparatet ifølge opfindelsen sucralfatet at 20 blive effektivt bundet til det af mavesår angrebne område. Sucralfatpræparatet ifølge opfindelsen kan formuleres i forskellige doseringsformer, såsom pulvere, fint granulat, granulat, tabletter og kapsler. Til dette formål kan anvendes forskellige tilsætningsstoffer, 25 såsom bindemidler, desintegreringsmidler, smøremidler, fortyndingsmidler og farvestoffer.In the process of the invention, a sucralfate can be mixed with 0.1% by weight or more of polyethylene glycol. Although the upper limit of the amount of polyethylene glycol is not critical, it is usually used in an amount of less than 50% by weight. The molecular weight of the polyethylene glycol to be mixed with the sulcral phosphate is not limited to any particular value. By oral administration, the sucralfate composition of the invention allows the sucralfate to be effectively bonded to the area affected by gastric ulcer. The sucralfate composition of the invention may be formulated in various dosage forms such as powders, fine granules, granules, tablets and capsules. For this purpose, various additives such as binders, disintegrants, lubricants, diluents and dyes can be used.
Opfindelsen belyses nærmere ved hjælp af de følgende eksempler.The invention is further illustrated by the following examples.
30 EKSEMPEL 1EXAMPLE 1
Et aluminiumsalt af saccharosesulfatester (sucralfat: 3920 g) blev omhyggeligt blandet med 2000 g af en vandig opløsning af 4% polyethylenglycol 35 (molvægt 1500) i et blandeapparat. Blandingen blev granuleret i en cylindrisk granulator forsynet med et net med maskestørrelse på 0,7 mm55. Granulatet blev tørret ved 3 DK 167735 B1 60°C i 3 timer i et tørreskab med bakker. Det tørrede granulat blev sigtet gennem en 16-mesh sigte til opnåelse af små korn. Små korn til sammenligning blev fremstillet ved samme fremgangsmåde som ovenfor, 5 bortset fra at den vandige opløsning af 4% polyethylen-glycol blev erstattet med vand.An aluminum salt of sucrose sulfate ester (sucralfate: 3920 g) was carefully mixed with 2000 g of an aqueous solution of 4% polyethylene glycol 35 (molecular weight 1500) in a mixer. The mixture was granulated in a cylindrical granulator fitted with a mesh of 0.7 mm55 mesh. The granulate was dried at 60 ° C for 3 hours in a tray drying cabinet. The dried granules were sieved through a 16-mesh sieve to obtain small grains. Comparable small grains were prepared by the same procedure as above except that the aqueous solution of 4% polyethylene glycol was replaced with water.
Evnen til at kunne desintegreres og dispergeres for de 2 prøver af små korn er vist i fig. 1 udtrvkt som den ændring i uklarhed som optrådte, når værdien af en 10 kontrolsuspension blev sat til 1. Kontrol suspensionen blev fremstillet ved grundig dispergering af 1 g sucralfat i 1000 ml vand med ultralyd, og uklarheden af denne kontrolsuspension blev målt ved 540 nm med en lagtykkelse i detektorcellen på 1 cm. Måling af uklar-15 hed er beskrevet nærmere nedenfor: suspensioner hver indeholdende 200 mg sucralfat blev anbragt i 5 rør i et apparat til afprøvning af_ desintegration (testvæske: 1000 ml vand ved 37 - 2°C) og uklarhederne af væskeprøver udtaget ca. 5 cm under 20 overfladen af testvæskerne blev målt. På grundlag af de opnåede resultater blev de specifikke uklarheder af de enkelte prøver derefter beregnet.The ability to disintegrate and disperse for the 2 samples of small grains is shown in FIG. 1 expressed as the change in cloudiness that occurred when the value of a 10 control suspension was added to 1. The control suspension was prepared by thoroughly dispersing 1 g of sucralfate in 1000 ml of ultrasonic water and the turbidity of this control suspension was measured at 540 nm with a layer thickness in the detector cell of 1 cm. Measurement of cloudiness is described in more detail below: suspensions each containing 200 mg of sucralfate were placed in 5 tubes in a disintegration test apparatus (test liquid: 1000 ml of water at 37 - 2 ° C) and the cloud samples of liquid samples taken approx. 5 cm below the surface of the test fluids was measured. Based on the results obtained, the specific ambiguities of the individual samples were then calculated.
De to prøver af små korn blev underkastet en accelereret prøvning ved 40°C og 75% relativ fugtighed 25 16 måneder, og deres dispersionsgrad blev bedømt ved hjælp af specifik uklarhed, som blev beregnet som beskrevet ovenfor. Resultaterne er vist i tabel 1.The two samples of small grains were subjected to an accelerated test at 40 ° C and 75% relative humidity for 25 months, and their degree of dispersion was assessed by specific turbidity calculated as described above. The results are shown in Table 1.
Tabel 1 20 Ændring i specifik uklarhed p.g.a. accelerering ved 40°C og 75% relativ fugtighed i 6 månederTable 1 20 Change in specific obscurity due to acceleration at 40 ° C and 75% relative humidity for 6 months
Prøve tid: 2 min. 5 min. 20 min.Sample time: 2 min. 5 min. 20 min.
Små korn ifølge før acc._0,93 0,95 0,96 35 eksempel 1_efter acc._0,85 0,92 0,95Small grains according to before acc. 0.93 0.95 0.96 Example 1 after acc. 0.85 0.92 0.95
Små korn til før acc._0,28_0,33_0,41 sammenligning efter acc. 0,16 0,18 0,19 DK 167735 Bl 4Small grains for before acc._0,28_0,33_0.41 comparison after acc. 0.16 0.18 0.19 DK 167735 Bl 4
Tallene viser den betydelig bedre desintegrerbar-hed og dispergerbarhed, som udvises af kornene . i det faste præparat ifølge opfindelsen.The figures show the significantly better disintegrability and dispersibility exhibited by the grains. in the solid composition of the invention.
5 EKSEMPEL 2 4.000 g sucralfat blev omhyggeligt blandet med 2.000 g af en vandig opløsning af 10% polyethylengly-col (mol vægt 6.000) i et blandéapparat. Blandingen 10 blev sigtet gennem en 16-mesh sigte til fremstilling af et granulat, som blev tørret ved 60°C i 3 timer i tørreskab med bakker og klasificeret ved passage gennem en 10-mesh sigte.EXAMPLE 2 4,000 g of sucralfate was carefully mixed with 2,000 g of an aqueous solution of 10% polyethylene glycol (mole weight 6,000) in a blender. Mixture 10 was sieved through a 16 mesh screen to produce a granulate which was dried at 60 ° C for 3 hours in a tray drying cabinet and classified by passage through a 10 mesh screen.
De resulterende små korn (4.000 g) blev blandet 15 med 1.376 g krystallinsk cellulose og 24 g magnesium-stearat, og der blev blandet i 5 minutter i et blande-apparat af V-type.The resulting small grains (4,000 g) were mixed with 1,376 g of crystalline cellulose and 24 g of magnesium stearate and mixed for 5 minutes in a V-type mixer.
Det resulterende pulver blev anbragt i en roterende tabletmaskine forsynet med forme og stempler 20 (12 mm^) og presset under et totalt tryk på ca. 2,5 ton til opnåelse af tabletter hver af en vægt på 700 mg.The resulting powder was placed in a rotary tablet machine provided with molds and pistons 20 (12 mm 2) and pressed under a total pressure of approx. 2.5 tons to obtain tablets each weighing 700 mg.
Tabletter til sammenligning blev fremstillet på samme måde som beskrevet ovenfor, bortset- fra at den vandige opløsning af 10% polyethylenglycol blev 25 erstattet med en vandig opløsning af 10% hydroxypro-pyl cellulose (Nisso HPC-L fra Nippon Soda Co., Ltd.)Comparative tablets were prepared in the same manner as described above except that the aqueous solution of 10% polyethylene glycol was replaced with an aqueous solution of 10% hydroxypropyl cellulose (Nisso HPC-L from Nippon Soda Co., Ltd. )
Evnen til at kunne desintegreres og dispergeres af de to tabletprøver er vist i fig. 2 som den ændring 1 uklarhed som optrådte, når værdien af en kontrol-30 suspension blev sat til 1. Kontrolsuspensionen blev fremstillet ved grundig dispergering af 1.000 mg sucralfat, 344 mg krystallinsk cellulose og 6 mg mågnesiumstearat i 1.000 ml vand med ultralyd, og uklarheden af denne kontrolsuspension blev målt ved 540 nm 35 i en derektorcelle med en lagtykkelse på 1 cm. Målinger af uklarheder er beskrevet mere specielt nedenfor: 2 tabletter fra hver prøve blev anbragt i et apparat til afprøvning af desintegration (testvæske: 1.000 mlThe ability to disintegrate and disperse by the two tablet samples is shown in FIG. 2 as the change 1 blur that occurred when the value of a control suspension was set to 1. The control suspension was prepared by thoroughly dispersing 1,000 mg sucralfate, 344 mg crystalline cellulose and 6 mg magnesium stearate in 1,000 ml water with ultrasound, and the blur of this control suspension was measured at 540 nm 35 in a detector cell with a layer thickness of 1 cm. Measurements of cloudiness are described more specifically below: 2 tablets from each sample were placed in a disintegration test apparatus (test liquid: 1,000 ml
Claims (2)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP9990186 | 1986-04-30 | ||
| JP9990186 | 1986-04-30 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DK218587D0 DK218587D0 (en) | 1987-04-29 |
| DK218587A DK218587A (en) | 1987-10-31 |
| DK167735B1 true DK167735B1 (en) | 1993-12-13 |
Family
ID=14259677
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK218587A DK167735B1 (en) | 1986-04-30 | 1987-04-29 | FIXED PREPARATION CONTAINING AN ALUMINUM SALT OF A SUCCHAROSE SULFATESTER AND POLYETHYLENE LYCOL, AND PROCEDURE FOR PREPARING THE PREPARATION |
Country Status (9)
| Country | Link |
|---|---|
| JP (1) | JP2542210B2 (en) |
| DE (1) | DE3714159C2 (en) |
| DK (1) | DK167735B1 (en) |
| ES (1) | ES2017805A6 (en) |
| FI (1) | FI89457C (en) |
| FR (1) | FR2598084B1 (en) |
| IT (1) | IT1208416B (en) |
| NO (1) | NO174085C (en) |
| SE (1) | SE503233C2 (en) |
Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2735559B2 (en) * | 1988-03-02 | 1998-04-02 | 中外製薬株式会社 | Suspension |
| BR9507533A (en) * | 1994-04-26 | 1997-09-02 | Chugai Pharmaceutical Co Ltd | Fused granulated sucralfate preparations and a process for their production |
| KR19980701891A (en) * | 1995-02-02 | 1998-06-25 | 나가야마 나오루 | Sucralate formulations |
| ES2112765B1 (en) * | 1995-08-02 | 1999-03-01 | Cantabria Ind Farmaceutica Sa | PROCEDURE FOR OBTAINING RADIOLOGICAL CONTRAST FORMULATIONS, FOR GASTROINTESTINAL EXPLORATIONS FOR EXTEMPORARY AND DIRECT USE. |
| TW201132646A (en) * | 2010-02-22 | 2011-10-01 | Daiichi Sankyo Co Ltd | Oral solid extended release dosage form |
| TW201141544A (en) | 2010-02-22 | 2011-12-01 | Daiichi Sankyo Co Ltd | Oral solid extended release dosage form |
| KR102127625B1 (en) | 2012-09-03 | 2020-06-29 | 다이이찌 산쿄 가부시키가이샤 | Hydromorphone hydrochloride-containing oral sustained-release pharmaceutical composition |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3430809A1 (en) * | 1984-08-22 | 1986-03-06 | Merck Patent Gmbh, 6100 Darmstadt | SUCRALFAT SUSPENSION |
-
1987
- 1987-04-28 NO NO871759A patent/NO174085C/en unknown
- 1987-04-28 DE DE3714159A patent/DE3714159C2/en not_active Expired - Lifetime
- 1987-04-28 FI FI871852A patent/FI89457C/en not_active IP Right Cessation
- 1987-04-29 IT IT8767365A patent/IT1208416B/en active
- 1987-04-29 ES ES8701280A patent/ES2017805A6/en not_active Expired - Lifetime
- 1987-04-29 SE SE8701787A patent/SE503233C2/en not_active IP Right Cessation
- 1987-04-29 DK DK218587A patent/DK167735B1/en not_active IP Right Cessation
- 1987-04-30 JP JP62104612A patent/JP2542210B2/en not_active Expired - Lifetime
- 1987-04-30 FR FR878706196A patent/FR2598084B1/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| NO174085B (en) | 1993-12-06 |
| DK218587D0 (en) | 1987-04-29 |
| FI871852A (en) | 1987-10-31 |
| FR2598084B1 (en) | 1991-04-26 |
| ES2017805A6 (en) | 1991-03-01 |
| FR2598084A1 (en) | 1987-11-06 |
| FI89457C (en) | 1993-10-11 |
| NO174085C (en) | 1994-03-16 |
| IT1208416B (en) | 1989-06-12 |
| SE8701787D0 (en) | 1987-04-29 |
| DK218587A (en) | 1987-10-31 |
| NO871759L (en) | 1987-11-02 |
| JPS63107933A (en) | 1988-05-12 |
| DE3714159A1 (en) | 1987-11-05 |
| SE8701787L (en) | 1987-10-31 |
| NO871759D0 (en) | 1987-04-28 |
| DE3714159C2 (en) | 1996-09-19 |
| FI89457B (en) | 1993-06-30 |
| JP2542210B2 (en) | 1996-10-09 |
| SE503233C2 (en) | 1996-04-22 |
| IT8767365A0 (en) | 1987-04-29 |
| FI871852A0 (en) | 1987-04-28 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| AU602582B2 (en) | Cimetidine compositions | |
| US4950484A (en) | Pharmaceutical tablet, pharmaceutical granulate and process for their preparation | |
| DE60210828T2 (en) | PHARMACEUTICAL PELLETS CONTAINING TAMSULOSINE AND ITS PRODUCTION PROCESS | |
| DE3123453C2 (en) | Refined starch, process for its production and its use in pharmaceuticals | |
| CN101836978A (en) | The solid preparation that contains single crystal form | |
| KR20100012867A (en) | Solid dosage forms comprising tadalafil | |
| US6291462B1 (en) | Oral medicinal preparations with reproducible release of the active ingredient gatifloxacin or its pharmaceutically suitable salts or hydrates | |
| EP0844881B1 (en) | Laxative comprising lactitol and psyllium | |
| DK167735B1 (en) | FIXED PREPARATION CONTAINING AN ALUMINUM SALT OF A SUCCHAROSE SULFATESTER AND POLYETHYLENE LYCOL, AND PROCEDURE FOR PREPARING THE PREPARATION | |
| EP0809995B1 (en) | New diacerhein formulations obtained by active principle inclusion in polysaccharide hydrogels | |
| JPS5927820A (en) | Slow release product containing suloctidil | |
| US4012498A (en) | Sustained release tablet formulations | |
| US5547943A (en) | Sucralfate preparation | |
| CN104146977A (en) | Pantoprazole sodium enteric coated tablet and preparation method thereof | |
| EP0549794A1 (en) | Stock solution of sucralfate suspended in water and production thereof | |
| US2871157A (en) | Laxative powders containing di-n-octyl sulfosuccinates | |
| US20220273577A1 (en) | Powdered plant preparation, the manner in which it is obtained, microgranules and tablets obtained from that preparation and the ways of producing them | |
| RU2149001C1 (en) | Nootropic drug and method of its preparing | |
| CN104382936B (en) | A kind of oral solid formulation of sulfonation dehydrogenation rosin acid bismuth and preparation method thereof | |
| Kumar et al. | Optimisation of aceclofenac fast dissolving tablets employing starch xanthate using 23 factorial design | |
| DE2621906A1 (en) | NEW THERAPEUTIC MIXTURE AND METHOD FOR PRODUCING IT | |
| JPS61151116A (en) | Production of pharmaceutical composition containing 5-(3-n-butyloxalylaminophenyl)tetrazole | |
| JPH0332495Y2 (en) | ||
| TW202118515A (en) | Cellulose composition, tablet and orally disintegrating tablet including cellulose, glucose and sorbitol | |
| Kristoffersson et al. | In Vitro Availability of Nitrofurantoin from Different Tablet Batches |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| B1 | Patent granted (law 1993) | ||
| PUP | Patent expired |