DE4033524A1 - 1-(Tert.-butylamino)-3-((6-chloro-m-tolyl)-oxy)-2-propanol - for transdermal use to reduce total cholesterol content and for treatment of atherosclerosis - Google Patents
1-(Tert.-butylamino)-3-((6-chloro-m-tolyl)-oxy)-2-propanol - for transdermal use to reduce total cholesterol content and for treatment of atherosclerosisInfo
- Publication number
- DE4033524A1 DE4033524A1 DE4033524A DE4033524A DE4033524A1 DE 4033524 A1 DE4033524 A1 DE 4033524A1 DE 4033524 A DE4033524 A DE 4033524A DE 4033524 A DE4033524 A DE 4033524A DE 4033524 A1 DE4033524 A1 DE 4033524A1
- Authority
- DE
- Germany
- Prior art keywords
- butylamino
- tolyl
- oxy
- propanol
- chloro
- 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.)
- Granted
Links
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 title claims abstract description 18
- 235000012000 cholesterol Nutrition 0.000 title claims abstract description 8
- 201000001320 Atherosclerosis Diseases 0.000 title claims description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N 2-propanol Substances CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 title abstract 2
- 241000124008 Mammalia Species 0.000 claims abstract description 7
- 150000003626 triacylglycerols Chemical class 0.000 claims abstract description 4
- 102000015779 HDL Lipoproteins Human genes 0.000 claims abstract 2
- 108010010234 HDL Lipoproteins Proteins 0.000 claims abstract 2
- 102000007330 LDL Lipoproteins Human genes 0.000 claims abstract 2
- 108010007622 LDL Lipoproteins Proteins 0.000 claims abstract 2
- HQIRNZOQPUAHHV-UHFFFAOYSA-N bupranolol Chemical compound CC1=CC=C(Cl)C(OCC(O)CNC(C)(C)C)=C1 HQIRNZOQPUAHHV-UHFFFAOYSA-N 0.000 claims description 17
- 150000002632 lipids Chemical class 0.000 abstract description 11
- 239000002876 beta blocker Substances 0.000 abstract description 6
- 210000004369 blood Anatomy 0.000 abstract description 4
- 239000008280 blood Substances 0.000 abstract description 4
- 239000011505 plaster Substances 0.000 abstract description 4
- 229920002367 Polyisobutene Polymers 0.000 abstract description 3
- 239000012458 free base Substances 0.000 abstract description 2
- 239000011159 matrix material Substances 0.000 abstract description 2
- 239000011140 metalized polyester Substances 0.000 abstract description 2
- 239000011888 foil Substances 0.000 abstract 2
- 125000006309 butyl amino group Chemical group 0.000 abstract 1
- 230000009249 intrinsic sympathomimetic activity Effects 0.000 abstract 1
- 229920000728 polyester Polymers 0.000 abstract 1
- 229960000330 bupranolol Drugs 0.000 description 10
- 102000004895 Lipoproteins Human genes 0.000 description 8
- 108090001030 Lipoproteins Proteins 0.000 description 8
- AQHHHDLHHXJYJD-UHFFFAOYSA-N propranolol Chemical compound C1=CC=C2C(OCC(O)CNC(C)C)=CC=CC2=C1 AQHHHDLHHXJYJD-UHFFFAOYSA-N 0.000 description 6
- 102000004506 Blood Proteins Human genes 0.000 description 3
- 108010017384 Blood Proteins Proteins 0.000 description 3
- WJUUZHQWGKSLIJ-UHFFFAOYSA-N Bupranolol hydrochloride Chemical compound Cl.CC1=CC=C(Cl)C(OCC(O)CNC(C)(C)C)=C1 WJUUZHQWGKSLIJ-UHFFFAOYSA-N 0.000 description 3
- 230000000923 atherogenic effect Effects 0.000 description 3
- 229940097320 beta blocking agent Drugs 0.000 description 3
- 229960003712 propranolol Drugs 0.000 description 3
- 230000001681 protective effect Effects 0.000 description 3
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 229920006267 polyester film Polymers 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 238000008214 LDL Cholesterol Methods 0.000 description 1
- 241000220317 Rosa Species 0.000 description 1
- 230000000778 atheroprotective effect Effects 0.000 description 1
- 102000012740 beta Adrenergic Receptors Human genes 0.000 description 1
- 108010079452 beta Adrenergic Receptors Proteins 0.000 description 1
- 229960003620 bupranolol hcl Drugs 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000003292 diminished effect Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000003925 fat Substances 0.000 description 1
- 125000005456 glyceride group Chemical group 0.000 description 1
- 230000001322 lipid blood level Effects 0.000 description 1
- 230000037356 lipid metabolism Effects 0.000 description 1
- 230000008604 lipoprotein metabolism Effects 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 229930193551 sterin Natural products 0.000 description 1
- 230000001975 sympathomimetic effect Effects 0.000 description 1
- 229940100640 transdermal system Drugs 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
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
- A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
- A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
- A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
- A61K9/7046—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds
- A61K9/7053—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained by reactions only involving carbon to carbon unsaturated bonds, e.g. polyvinyl, polyisobutylene, polystyrene
-
- 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
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
Landscapes
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Dermatology (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Description
Die Erfindung betrifft die Verwendung von 1-(tert-butylamino) 3-((6-chloro-m-tolyl)oxy)-2-propanol zur Senkung des Lipid blutspiegels bei Säugern in einer transdermalen Applikations form.The invention relates to the use of 1- (tert-butylamino) 3 - ((6-chloro-m-tolyl) oxy) -2-propanol to lower the lipid blood levels in mammals in a transdermal application shape.
Atherosklerose ist eine der bedeutsamsten und häufigsten Er krankungen. Als ein Risikofaktor für ihre Entstehung gilt ein erhöhter Blutlipidspiegel, insbesondere ein erhöhter Choleste rolspiegel. Ein Ansatzpunkt für Prophylaxe und Therapie wird darin gesehen, den Lipidgehalt des Blutes zu senken.Atherosclerosis is one of the most significant and common Er diseases. A is considered a risk factor for their emergence increased blood lipid levels, especially increased cholesterol roll mirror. A starting point for prophylaxis and therapy is seen in lowering the lipid content of the blood.
Der Lipidgehalt, insbesondere das Verhalten der Plasmalipide und Plasmalipoproteine wird durch β-Rezeptorenblocker beein flußt.The lipid content, especially the behavior of the plasma lipids and plasma lipoproteins are affected by β-receptor blockers flows.
Von einigen Betablockern ist bekannt, daß sie die Plasmalipid spiegel dahingehend beeinflussen, daß sie die Konzentrationen von Plasmaproteinen hoher Dichte (HDL) erniedrigen und von Plasmaproteinen niedriger Dichte (LDL) erhöhen. Den HDL wird in der Pathogenese der Atherosklerose ein protektiver, den LDL ein negativer Effekt zugeschrieben.Some beta blockers are known to be plasma lipid mirror that they affect the concentrations of high density plasma proteins (HDL) and of Increase low-density plasma proteins (LDL). The HDL will in the pathogenesis of atherosclerosis a protective, the LDL attributed a negative effect.
β-Rezeptorenblocker, die die Plasmalipoproteine in der be schriebenen Art beeinflussen, sollten daher das Atheroskle rose-Risiko erhöhen. Während durch β-Blocker mit intrinsischer sympathomimetischer Aktivität (ISA) die Beeinflussung der Plasmalipide und Plasmalipoproteine vermindert erscheint, wird bei β-Blockern ohne ISA das Verhalten der Plasmalipide und -lipoproteine als kritisch angesehen. β-receptor blockers that the plasma lipoproteins in the be influence the written type, should therefore the atheroskle increase rose risk. While through intrinsic β-blockers sympathomimetic activity (ISA) influencing the Plasma lipids and plasma lipoproteins appear diminished in β-blockers without ISA the behavior of the plasma lipids and -lipoproteins considered critical.
1-(tert-butylamino)-3-((6-chloro-m-tolyl)oxy)-2-propanol, auch als Bupranolol bezeichnet, ist ein nichtselektiver ß-Rezepto renblocker ohne ISA.1- (tert-butylamino) -3 - ((6-chloro-m-tolyl) oxy) -2-propanol, too called bupranolol, is a non-selective ß-receptor Renblocker without ISA.
Bupranolol sollte daher den Blutlipidspiegel in der Weise be einflussen, daß die Plasmaproteine niedriger Dichte erhöht und diejenigen hoher Dichte erniedrigt werden.Bupranolol should therefore be in the way of blood lipid levels influence that the low density plasma proteins increase and those high density are lowered.
Malig et al. in Zeitschrift für Allgemeinmedizin, S. 2047 ff. (2051), Heft 30, 1980 beschreiben den Verlauf der Laborparame ter des Serumcholesterins unter Betadrenol 100-Medikation; Betadrenol® 100 entspricht 100 mg Bupranolol HCl. Sie stellten fest, daß bei oraler Applikation von Bupranolol das Serumcho lesterin von 223 mg/100 ml auf 195 mg/100 ml am Ende einer 14-tägigen Therapie gesenkt war. Eine differenzierende Unter suchung nach HDL-Cholesterinwerten oder LDL-Cholesterinwerten fand nicht statt. Da alle Klassen von Lipoproteinen Choleste rin enthalten, kann diesem Ergebnis kein Hinweis entnommen werden, daß spezielle Lipoproteine wie HDL und/oder LDL zu diesem Ergebnis einen besonderen Beitrag leisten. Die Autoren stellten weiterhin für Triglyceride erhöhte Werte fest. Tri glyceriden oder Neutralfetten wird jedoch ein hohes atheroge nes Potential zugerechnet.Malig et al. in Journal of General Medicine, p. 2047 ff. (2051), Issue 30, 1980 describe the course of the laboratory parameters serum cholesterol under Betadrenol 100 medication; Betadrenol® 100 corresponds to 100 mg bupranolol HCl. They posed found that with oral administration of bupranolol the serum cho lesterine from 223 mg / 100 ml to 195 mg / 100 ml at the end of one 14-day therapy was lowered. A differentiating sub search for HDL cholesterol or LDL cholesterol did not take place. Because all classes of lipoproteins cholesterol rin, no information can be derived from this result that special lipoproteins such as HDL and / or LDL too make a special contribution to this result. the authors continued to see elevated levels of triglycerides. Tri However, glycerides or neutral fats become high atherogenic potential.
Überraschenderweise wurde nun gefunden, daß die Verwendung von Bupranolol in einer transdermalen Applikationsform die Parame ter des Lipid- und Lipoproteinstoffwechsels günstig beein flußt.Surprisingly, it has now been found that the use of Bupranolol in a transdermal application form the parame ter of lipid and lipoprotein metabolism favorably affected flows.
Die erfindungsgemäße Verwendung des Bupranolols führt zu einer Abnahme der Konzentration des Gesamtcholesterins, zu einer Ab nahme der Konzentration der Triglyceride und des LDL-Chole sterins.The use of bupranolol according to the invention leads to a Decrease in total cholesterol concentration, to an ab took the concentration of the triglycerides and the LDL chole sterins.
Die Konzentration des HDL-Cholesterins nimmt zu. Den High- Density-Lopoproteinen kommt insbesondere eine Schutzwirkung von Atherosklerose zu. The concentration of HDL cholesterol increases. The high Density lopoproteins in particular have a protective effect from atherosclerosis to.
Völlig überraschend war, daß durch Verwendung von Bupranolol in einer transdermalen Applikationsform gezielt die Konzentra tion der Lipoproteine, denen gegenüber der Atherosklerose eine protektive Wirkung zukommt, gesteigert werden kann und die Konzentrationen der atherogen wirkenden Lipoproteine gesenkt werden können.It was completely surprising that by using bupranolol in a transdermal application form the concentra tion of lipoproteins, which are at least opposite to atherosclerosis protective effect, can be increased and the Concentrations of the atherogenically active lipoproteins reduced can be.
In einer Studie wurden 40 Patienten (22 Männer und 18 Frauen) randomisiert zwei gleichgroßen Gruppen zugeteilt. Sie erhiel ten 8 Wochen lang entweder Bupranolol-TTS, täglich 1 Pflaster à 30 mg oder Propranolol, täglich 160 mg als Retard-Kapsel.One study included 40 patients (22 men and 18 women) randomly assigned to two groups of equal size. You would get For 8 weeks either bupranolol TTS, 1 patch daily 30 mg each or propranolol, 160 mg daily as a prolonged-release capsule.
Tabelle 1 zeigt, daß Bupranolol in einer transdermalen galeni schen Zubereitung im Vergleich zu Propranolol die Werte der Plasmalipide und -lipoproteine günstig im Sinne einer athero protektiven Wirkung beeinflußt.Table 1 shows that bupranolol in a transdermal galeni preparation compared to propranolol the values of Plasma lipids and lipoproteins cheap in terms of athero protective effect.
Der atherogene IndexThe atherogenic index
nahm im Mittel um 17,6% ab. Im Propranolol nahm der atherogene Index im Mittel um 4% zu.decreased on average by 17.6%. In propranolol, the atherogenic index increased on average by 4%.
Das Pflaster wird, wie im Ausführungsbeispiel 4 der EP 01 86 019 ausführlich beschrieben, hergestellt.The patch is, as in embodiment 4 of EP 01 86 019 described in detail, manufactured.
Das Bupranolol-Pflaster besitzt folgenden Aufbau: Es ist ein Matrixsystem, bestehend aus einem mehrschichtig aufgebauten, insgesamt ca. 0,1 mm dicken arzneistoffbeladenen Kontaktfilm, aus hochmolekularem Polyisobutylen (PIB), der nach außen durch eine Polyesterfolie abgedeckt wird. Ein Pfla ster von 25 cm2 enthält 30 mg Bupranolol in Form der freien Base; die Freisetzungsfläche des transdermalen Systems wird durch eine silikonisierte und metallisierte Polyesterfolie ge schützt, die vor Applikation entfernt wird.The Bupranolol patch has the following structure: It is a matrix system consisting of a multi-layered, approx. 0.1 mm thick drug-laden contact film made of high-molecular polyisobutylene (PIB), which is covered on the outside by a polyester film. A plaster of 25 cm 2 contains 30 mg of bupranolol in the form of the free base; The release surface of the transdermal system is protected by a siliconized and metallized polyester film, which is removed before application.
Claims (5)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE4033524A DE4033524A1 (en) | 1990-10-22 | 1990-10-22 | 1-(Tert.-butylamino)-3-((6-chloro-m-tolyl)-oxy)-2-propanol - for transdermal use to reduce total cholesterol content and for treatment of atherosclerosis |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE4033524A DE4033524A1 (en) | 1990-10-22 | 1990-10-22 | 1-(Tert.-butylamino)-3-((6-chloro-m-tolyl)-oxy)-2-propanol - for transdermal use to reduce total cholesterol content and for treatment of atherosclerosis |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| DE4033524A1 true DE4033524A1 (en) | 1992-04-23 |
| DE4033524C2 DE4033524C2 (en) | 1992-08-20 |
Family
ID=6416790
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE4033524A Granted DE4033524A1 (en) | 1990-10-22 | 1990-10-22 | 1-(Tert.-butylamino)-3-((6-chloro-m-tolyl)-oxy)-2-propanol - for transdermal use to reduce total cholesterol content and for treatment of atherosclerosis |
Country Status (1)
| Country | Link |
|---|---|
| DE (1) | DE4033524A1 (en) |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4482533A (en) * | 1982-01-11 | 1984-11-13 | Key Pharmaceuticals, Inc. | Polymeric diffusion matrix containing propranolol |
| DE3333240A1 (en) * | 1983-09-12 | 1985-03-28 | Schering AG, 1000 Berlin und 4709 Bergkamen | MEDIUM FOR TRANSDERMAL APPLICATION OF MEDICINAL PRODUCTS |
| EP0272045A2 (en) * | 1986-12-11 | 1988-06-22 | Beecham Group Plc | Topical drug release system |
| EP0306926A2 (en) * | 1987-09-08 | 1989-03-15 | Teikoku Seiyaku Kabushiki Kaisha | Salbutamol-containing plaster and method of producing |
| DE3843557A1 (en) * | 1988-12-23 | 1990-06-28 | Beiersdorf Ag | Transdermal therapeutic system for administering clenbuterol |
-
1990
- 1990-10-22 DE DE4033524A patent/DE4033524A1/en active Granted
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4482533A (en) * | 1982-01-11 | 1984-11-13 | Key Pharmaceuticals, Inc. | Polymeric diffusion matrix containing propranolol |
| DE3333240A1 (en) * | 1983-09-12 | 1985-03-28 | Schering AG, 1000 Berlin und 4709 Bergkamen | MEDIUM FOR TRANSDERMAL APPLICATION OF MEDICINAL PRODUCTS |
| EP0272045A2 (en) * | 1986-12-11 | 1988-06-22 | Beecham Group Plc | Topical drug release system |
| EP0306926A2 (en) * | 1987-09-08 | 1989-03-15 | Teikoku Seiyaku Kabushiki Kaisha | Salbutamol-containing plaster and method of producing |
| DE3843557A1 (en) * | 1988-12-23 | 1990-06-28 | Beiersdorf Ag | Transdermal therapeutic system for administering clenbuterol |
Non-Patent Citations (7)
| Title |
|---|
| - C.Lippold. Pharm.Ind. 49, 1987, S.1295-1300 * |
| 106 1987: 107802x * |
| 85 1979: 104302w * |
| 90 1979: 21154b * |
| Chemical Abstracts: 111 1989: 219218w * |
| SCHETTLER, G. * |
| u.a.: Betablocker und Lipidstoff- wechsel. Springer-Verlag Berlin, Heidelberg, New York, Tokyo, 1984, S.52 u.53 * |
Also Published As
| Publication number | Publication date |
|---|---|
| DE4033524C2 (en) | 1992-08-20 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| OP8 | Request for examination as to paragraph 44 patent law | ||
| D2 | Grant after examination | ||
| 8364 | No opposition during term of opposition | ||
| 8330 | Complete disclaimer |