WO2018002018A1 - Zusammensetzung zur bekämpfung von gastroösophagealen refluxerkrankungen - Google Patents
Zusammensetzung zur bekämpfung von gastroösophagealen refluxerkrankungen Download PDFInfo
- Publication number
- WO2018002018A1 WO2018002018A1 PCT/EP2017/065799 EP2017065799W WO2018002018A1 WO 2018002018 A1 WO2018002018 A1 WO 2018002018A1 EP 2017065799 W EP2017065799 W EP 2017065799W WO 2018002018 A1 WO2018002018 A1 WO 2018002018A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- composition
- gastric
- ectoine
- use according
- hydroxyectoine
- Prior art date
Links
- KIIBBJKLKFTNQO-WHFBIAKZSA-N CC(N[C@@H]1C(O)=O)=NC[C@@H]1O Chemical compound CC(N[C@@H]1C(O)=O)=NC[C@@H]1O KIIBBJKLKFTNQO-WHFBIAKZSA-N 0.000 description 1
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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
-
- 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
- A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
- A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
-
- 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
- A61K9/08—Solutions
-
- 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
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Liposomes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/51—Nanocapsules; Nanoparticles
-
- 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
Definitions
- the invention relates to a composition for the treatment and prophylaxis of gastroesophageal reflux diseases, inflammation and damage of the gastric or duodenal mucosa and / or gastric or duodenal ulcers.
- Gastroesophageal reflux diseases are a common phenomenon. In western industrialized countries, the problem occurs among adults in about 10 to 20% of the population at least once a week. In East Asia, the prevalence is 2.5 to 7.8%, in the US, 20% of the adult population weekly, 7% even daily affected by the disease. The disease is primarily due to the fact that gastric acid from the stomach reaches the esophagus. In addition to gastric acid, other gastric contents also enter the esophagus, such as the digestive enzyme pepsin, a peptidase used to digest proteins in food. The damaging effect of stomach acid is enhanced by pepsin.
- the currently common main treatment option is the use of Proton pump inhibitors (PPIs) such as omeprazole and histamine H2 receptor antagonists (H2Ras). Both classes of substances provide suppression of gastric acid production.
- PPIs Proton pump inhibitors
- H2Ras histamine H2 receptor antagonists
- antacids ie gastric acid neutralizing substances.
- Alginates provide for the formation of a tough foam in the stomach, which prevents the reflux of gastric acid into the esophagus.
- gastroesophageal reflux disease is associated with cardiac insufficiency. This is a malfunction of the sphincter (esophageal sphincter), which separates the esophagus and stomach, so that gastric contents return to the esophagus. Other reasons may be excessive gastric acid production or abnormal esophageal peristalsis. Particularly often the problem occurs at night, so in a lying position. Desserts or the enjoyment of tobacco and alcohol can also promote the occurrence of reflux symptoms.
- Gastro-oesophageal reflux disease can manifest as non-erosive reflux disease (NERD), which does not cause esophageal mucosal damage, or erosive reflux disease (erosive esophagitis (ER)) )).
- NERD non-erosive reflux disease
- ER erosive esophagitis
- the mucosa in the esophagus has been shown to change and mucosal damage is detectable. Bleeding and ulcers may occur in the transition between the stomach and the esophagus.
- Another complication of gastro-oesophageal reflux disease can be a narrowing of the esophagus, which in turn leads to dysphagia.
- a Barrett's esophagus endobrachyosophagus
- a metaplastic transformation of the epithelium of the esophagus is observed and multilayer squamous epithelium of the esophagus transforms into a single-layer, prismatic columnar epithelium in the distal region.
- This transformation may be completely circular, especially in the area of the gastro-osseous transition, ie the transition from the stomach to the esophagus.
- Cylindepithelium is indeed more resistant to gastric acid and the gastric enzyme pepsin, but there is a risk of dysplasia.
- a Barrett's esophagus may therefore be a precursor to the development of esophageal carcinoma (Barrett's carcinoma) and must therefore be observed.
- a Barrett's esophagus can lead to the development of ulcers.
- ectoine, hydroxyectoine and salts, esters and amides of ectoine / hydroxyectoine can prevent and treat damage to the gastric or intestinal epithelium.
- this relates to the treatment and prevention of gastritis (gastritis).
- the aggressive gastric acid can attack the gastric mucosa, for example, when the production of the protective mucus layer is disturbed by external factors.
- Ectoin and corresponding derivatives are capable of one Prevent or treat gastritis. Gastritis may develop as a result of reflux oesophagitis.
- Gastritis can lead to gastric ulcers (ulcus ventriculi), which is ultimately also due to the aggressive gastric acid with insufficient protection of the stomach wall and the gastric mucosa against gastric acidity.
- one of the damaging factors is overproduction of stomach acid.
- the formation of gastric ulcers u. a. attributed to damage to the gastric mucosa; insofar as the protection of the gastric mucosa also protects against gastric ulcers.
- duodenum Damage to the epithelium of the duodenum (duodenum) can be prevented by ectoine, hydroxyectin or corresponding salts, esters or amides, which is why the substances are suitable for the prophylaxis and treatment of inflammation of the mucous membrane of the duodenum. Similar to the gastric mucosa, this is a single-layered columnar epithelium.
- the duodenum is the first part of the small intestine that adjoins the stomach. As it is exposed to the highly corrosive gastric contents of digestive enzymes such as pepsin, it can cause inflammation and damage to the duodenum mucosa.
- duodenal ulcer In addition, the food in the duodenum bile from the liver and gallbladder and pancreatic enzymes are supplied. Damage to the duodenal mucosa can result in a duodenal ulcer (ulcus duodeni), which affects about 2 to 10% of people during their lifetime. Also, the development of a duodenal ulcer is based on an imbalance between the mucosa attacking substances such as gastric acid and certain proteases and the mucosal protective factors such as sufficient mucus formation. The protection of the mucous membrane of the duodenum is therefore important for the prevention and treatment of duodenal ulcers.
- ectoine, hydroxyectoine and the abovementioned derivatives of these compounds are suitable for effectively preventing the formation of both gastric and duodenal ulcers and to prevent gastric ulcer formation. / Duodenal ulcer to treat effectively. Even though the damage to the gastric / duodenal mucosa has progressed less far than to the ulcer, damage (erosions) occurring there can be treated and prevented.
- Ectoine and hydroxyectoine are tetrahydropyrimidine derivatives which are synthesized under stress conditions by extremophilic, especially halophilic, microorganisms.
- ectoine and hydroxyectoine various uses have hitherto been described, for example as a moisturizer, for the treatment of vascular leak syndrome (VLS) (DE 10 2006 056 766 A1) or for the treatment of atopic dermatitis (DE 103 30 243 A1).
- VLS vascular leak syndrome
- atopic dermatitis DE 103 30 243 A1
- ectoine 2-methyl-1, 4,5,6-tetrahydropyrimidine-4-carboxylic acid, for hydroxyectoine 5-hydroxy-2-methyl-1, 4,5,6-tetrahydropyrimidine-4-carboxylic acid.
- L-ectoine ((S) -2-methyl-1, 4,5,6-tetrahydropyrimidine-4-carboxylic acid) is shown below:
- composition according to the invention can be used for the treatment and / or prophylaxis of gastroesophageal reflux diseases or pyrosis of varying severity, i. H. both for non-erosive reflux diseases and for reflux esophagitis, in which damage to the mucous membranes of the esophagus can already be detected.
- the treatment options extend to Barrett's esophagus, which is a serious disease with an increased risk of cancer.
- the composition is an aqueous solution, mostly for oral administration.
- ectoine / hydroxyectoins are the alkali or alkaline earth metal salts, especially the salts of potassium, sodium, magnesium and calcium, but also salts with organic bases such. B. with non-toxic aliphatic or aromatic amines in question.
- esters or amides which can likewise be used according to the invention.
- the COOH group of ectoine / hydroxyectoine is replaced by a carboxylic ester function COOR or a carboxylic acid amide function CONHR 'or CONR'R ", where R, R', R" independently of one another are saturated or unsaturated, straight-chain or branched alkyl, Cycloalkyl, aryl, heteroaryl, alkylaryl, arylalkyl, alkoxyalkyl, alkylthioalkyl, aryloxyalkyl or arylthioalkyl groups.
- the hydroxy group can also be reacted with a carboxylic acid of different chain length to give a corresponding ester.
- the respective esters or amides may also be present in ionic or zwitterionic form, ie the invention includes the use of salts of said esters or amides. It is also possible to use the ecto-amide of 2-hydroxy-5-aminobenzoic acid.
- the structural formula is shown below:
- the composition may contain conventional adjuvants, e.g. As carriers, preservatives, bactericides, solubilizers, vitamins, stabilizers, substances for preventing foaming, osmotically active substances, dyes, surface-active substances, emulsifiers, moisturizing substances, viscosity-increasing agents, etc.
- adjuvants e.g. As carriers, preservatives, bactericides, solubilizers, vitamins, stabilizers, substances for preventing foaming, osmotically active substances, dyes, surface-active substances, emulsifiers, moisturizing substances, viscosity-increasing agents, etc.
- As carriers preservatives, bactericides, solubilizers, vitamins, stabilizers, substances for preventing foaming, osmotically active substances, dyes, surface-active substances, emulsifiers, moisturizing substances, viscosity-increasing agents, etc.
- Preservatives are, for example, thiomersal, organic mercury compounds such as phenylmercury, benzalkonium chloride, chlorhexidine, benzyl alcohol, glucose, ethanol and quaternary ammonium salts.
- the formulations of the invention may also include suitable buffering or other pH adjuvant adjuvants to adjust and maintain a desired pH.
- suitable buffering or other pH adjuvant adjuvants to adjust and maintain a desired pH.
- these are pH values between 4 and 8, preferably between 5 and 7.5, more preferably about 7.
- Suitable buffer systems are citrate, phosphate, TRIS, glycine, borate, acetate. These buffer systems can be prepared from substances such as citric acid, monosodium phosphate, disodium phosphate, glycine, boric acid, sodium tetraborate, acetic acid or sodium acetate.
- compositions may contain further active ingredients, but it is readily possible and sufficient for the treatment or prevention of the aging phenomena to use compositions containing only ectoine and / or hydroxyectoine or corresponding salts, esters or amides as active ingredient.
- the concentration of ectoine / hydroxyectoine and / or corresponding salts, esters or amides can be in particular in a range from 10 to 500 mM, preferably 50 to 500 mM, particularly preferably 100 to 500 mM or 100 to 200 mM. These concentrations have been found to be suitable for bringing about the effect of the invention.
- the proportion of ectoine / hydroxyectoine and / or corresponding salts, esters or amides in the composition can be in a range from 0.05 to 20% by weight, preferably 0.1 to 10% by weight. For example, a good effect could be observed in a range between 0.5 and 2% by weight.
- composition may be present as a solution, preferably as an aqueous solution. Also possible is the presence as a suspension, emulsion or microemulsion.
- the composition containing the active ingredient may also be encapsulated in nanostructures or in the form of liposomes. This is particularly advantageous if the composition contains no preservative.
- Corresponding methods for encapsulation and for the production of liposomes are known in principle from the prior art.
- an in vitro cell culture model with the mucus-forming epithelial cells TR146 was used to simulate the situation in the esophagus.
- the cells were with the Digestive enzyme containing pepsin acidic solutions and then treated with ectoine.
- a 96 well microtiter plate was spiked with TR146 cells grown until near surface coverage was almost achieved. Subsequently, the cells were treated with an acid dilute HCl solution together with pepsin in a cell culture medium for a period of 10 minutes. The concentration of pepsin was 2 U / ml. Thereafter, the cells were washed with PBS (phosphate buffered saline) and incubated overnight with either ectoine or as a control of pure solvent. After incubation, a cell number study was performed using a Neutral Red Cytotox Assay. This is a cyanine-based nucleic acid dye. The assay is based on the fact that the plasma membrane of damaged or dead cells becomes permeable to the dye and this binds to the DNA of the cell, which is associated with a corresponding increase in fluorescence.
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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- Biomedical Technology (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicinal Preparation (AREA)
Abstract
Description
Claims
Priority Applications (8)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
KR1020197001217A KR20190022636A (ko) | 2016-06-29 | 2017-06-27 | 위식도 역류 질환을 조절하기 위한 조성물 |
EP17740627.9A EP3478291A1 (de) | 2016-06-29 | 2017-06-27 | Zusammensetzung zur bekämpfung von gastroösophagealen refluxerkrankungen |
US16/312,805 US20190350930A1 (en) | 2016-06-29 | 2017-06-27 | Composition for controlling gastroesophageal reflux diseases |
RU2019102199A RU2019102199A (ru) | 2016-06-29 | 2017-06-27 | Композиция для лечения гастроэзофагеальных рефлюксных болезней |
CN201780039420.2A CN109328063A (zh) | 2016-06-29 | 2017-06-27 | 用于控制胃食管反流病的组合物 |
MX2018016372A MX2018016372A (es) | 2016-06-29 | 2017-06-27 | Composicion para controlar enfermedades de reflujo gastroesofagico. |
AU2017291188A AU2017291188A1 (en) | 2016-06-29 | 2017-06-27 | Composition for controlling gastroesophageal reflux diseases |
BR112018077078-7A BR112018077078A2 (pt) | 2016-06-29 | 2017-06-27 | composição para combater doenças do refluxo gastroesofágico |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE102016111882.6A DE102016111882A1 (de) | 2016-06-29 | 2016-06-29 | Zusammensetzung zur Bekämpfung von gastroösophagealen Refluxerkrankungen |
DE102016111882.6 | 2016-06-29 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2018002018A1 true WO2018002018A1 (de) | 2018-01-04 |
Family
ID=59366370
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP2017/065799 WO2018002018A1 (de) | 2016-06-29 | 2017-06-27 | Zusammensetzung zur bekämpfung von gastroösophagealen refluxerkrankungen |
Country Status (10)
Country | Link |
---|---|
US (1) | US20190350930A1 (de) |
EP (1) | EP3478291A1 (de) |
KR (1) | KR20190022636A (de) |
CN (1) | CN109328063A (de) |
AU (1) | AU2017291188A1 (de) |
BR (1) | BR112018077078A2 (de) |
DE (1) | DE102016111882A1 (de) |
MX (1) | MX2018016372A (de) |
RU (1) | RU2019102199A (de) |
WO (1) | WO2018002018A1 (de) |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE10330243A1 (de) | 2003-07-03 | 2005-01-20 | bitop Aktiengesellschaft für biotechnische Optimierung | Verwendung von aus extremophilen Bakterien gewonnenen Osmolyten zur Herstellung von Arzneimitteln zur äusserlichen Behandlung der Neurodermitis |
DE102006056766A1 (de) | 2006-12-01 | 2008-06-05 | Bitop Ag | Verwendung von kompatiblen Soluten |
CN102210681B (zh) * | 2011-04-29 | 2013-01-30 | 山东弘立医学动物实验研究有限公司 | 四氢嘧啶及其衍生物在制备治疗消化道疾病药物中的应用 |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7048910B2 (en) * | 2000-09-07 | 2006-05-23 | Merck Patent Gmbh | Use of ectoine or ectoine derivatives for oral care |
EP2435018A2 (de) * | 2009-05-28 | 2012-04-04 | Merck Patent GmbH | Antischuppenmittel |
DE102012013482A1 (de) * | 2012-07-09 | 2014-01-09 | Bitop Ag | Zusammensetzung zur Förderung der Wiederherstellung von verletztem Körpergewebe |
-
2016
- 2016-06-29 DE DE102016111882.6A patent/DE102016111882A1/de not_active Withdrawn
-
2017
- 2017-06-27 BR BR112018077078-7A patent/BR112018077078A2/pt not_active Application Discontinuation
- 2017-06-27 US US16/312,805 patent/US20190350930A1/en not_active Abandoned
- 2017-06-27 EP EP17740627.9A patent/EP3478291A1/de not_active Withdrawn
- 2017-06-27 WO PCT/EP2017/065799 patent/WO2018002018A1/de unknown
- 2017-06-27 CN CN201780039420.2A patent/CN109328063A/zh active Pending
- 2017-06-27 AU AU2017291188A patent/AU2017291188A1/en not_active Abandoned
- 2017-06-27 RU RU2019102199A patent/RU2019102199A/ru not_active Application Discontinuation
- 2017-06-27 KR KR1020197001217A patent/KR20190022636A/ko unknown
- 2017-06-27 MX MX2018016372A patent/MX2018016372A/es unknown
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE10330243A1 (de) | 2003-07-03 | 2005-01-20 | bitop Aktiengesellschaft für biotechnische Optimierung | Verwendung von aus extremophilen Bakterien gewonnenen Osmolyten zur Herstellung von Arzneimitteln zur äusserlichen Behandlung der Neurodermitis |
DE102006056766A1 (de) | 2006-12-01 | 2008-06-05 | Bitop Ag | Verwendung von kompatiblen Soluten |
CN102210681B (zh) * | 2011-04-29 | 2013-01-30 | 山东弘立医学动物实验研究有限公司 | 四氢嘧啶及其衍生物在制备治疗消化道疾病药物中的应用 |
Non-Patent Citations (1)
Title |
---|
BADILLO RAUL ET AL: "Diagnosis and treatment of gastroesophageal reflux disease.", WORLD JOURNAL OF GASTROINTESTINAL PHARMACOLOGY AND THERAPEUTICS 06 AUG 2014, vol. 5, no. 3, 6 August 2014 (2014-08-06), pages 105 - 112, XP055400982 * |
Also Published As
Publication number | Publication date |
---|---|
CN109328063A (zh) | 2019-02-12 |
RU2019102199A (ru) | 2020-07-29 |
AU2017291188A1 (en) | 2019-01-24 |
MX2018016372A (es) | 2019-04-22 |
DE102016111882A1 (de) | 2018-01-04 |
KR20190022636A (ko) | 2019-03-06 |
BR112018077078A2 (pt) | 2019-04-02 |
EP3478291A1 (de) | 2019-05-08 |
US20190350930A1 (en) | 2019-11-21 |
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