WO2007116428A2 - Oral pharmaceutical composition containing cystine or cysteine with glutathione against oxidative stress resulting from haemodialysis - Google Patents
Oral pharmaceutical composition containing cystine or cysteine with glutathione against oxidative stress resulting from haemodialysis Download PDFInfo
- Publication number
- WO2007116428A2 WO2007116428A2 PCT/IT2007/000261 IT2007000261W WO2007116428A2 WO 2007116428 A2 WO2007116428 A2 WO 2007116428A2 IT 2007000261 W IT2007000261 W IT 2007000261W WO 2007116428 A2 WO2007116428 A2 WO 2007116428A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- cysteine
- cystine
- treatment
- glutathione
- haemodialysis
- 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.)
- Ceased
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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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
-
- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
- A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/06—Tripeptides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
Definitions
- the subject of the present invention is an oral composition of cysteine or of its oxidized disulphide form (cystine) in mixture with an effective amount of glutathione for the prevention and treatment of oxidative stress deriving from haemodialysis treatment in patients affected by chronic renal insufficiency.
- cysteine or of its oxidized disulphide form (cystine) in mixture with an effective amount of glutathione for the prevention and treatment of oxidative stress deriving from haemodialysis treatment in patients affected by chronic renal insufficiency.
- the invention also relates to a medical device in the form of a kit comprising single- dose quantities of the composition referred to above and of a second composition of pure cystine or cysteine, said compositions being designed to be administered separately to a patient under haemodialysis so as to increase, in the initial step of extracorporeal circulation, the level of glutathione in the shortest time possible in order to contrast rapidly the oxidative stress resulting from haemodialysis treatment.
- Oxidative stress is defined as an imbalance between the antioxidizing physiological systems of protection and the increased production of oxygen or nitrogen radicals by the cells of the immune system. The consequence may be damage to the molecular structure of the proteins, sugars, and lipids parallel to the damage to the cellular functionality that jeopardizes also the functionality of the vital organs themselves of the organism. Oxidative stress has been seen to be particularly manifest in patients affected by renal insufficiency and subjected to haemodialysis .
- ROSs reactive oxygen species
- oxidative stress causes a greater facility in regard to infections due to the defective immune response, amyloidosis, and accelerated atherosclerosis, on account of continuous activation of the immunocompetent cells.
- This situation triggers an inflammatory response, with consequent continuous release of cytokines and lysosomal proteolytic enzymes, and stimulation of the production of free radicals: in practice, oxidative stress becomes a self-generating process, and induces a condition of chronic inflammation.
- cardiovascular complications which constitute the main cause of death in patients affected by chronic renal insufficiency. At a local level, these complications present with alteration of the endothelium, accumulation of lipids, formation of thrombi and occlusion of the lumen.
- N-acetylcysteine (see, for example, Kidney Int.,. Vol. 64 (2003), pp. 82-91; Current Med. Chem. , 2003, 10, pp. 1241-53).
- the document No. WO 01/02004 describes the use of N- acetylcysteine by means of intravenous injection prior to and/or during haemodialysis treatment.
- the inventor has been able to clarify that surprisingly the addition of a significant amount of glutathione to an oral composition of cystine or cysteine, used for the prevention and treatment of oxidative stress resulting from haemodialysis treatment in patients affected by chronic renal insufficiency, introduces an unexpected synergistic effect with respect to the composition containing just cystine or cysteine alone and has an immediate influence, if taken in the initial step of extracorporeal circulation, on the immune functions thanks to its role of anti-oxidant and of scavenger of radicals, without awaiting hepatic synthesis .
- glutathione a tripeptide constituted by glutamic acid, cysteine and glycine, performs many physiological functions, including the anti-oxidizing capacity, the storage and transportation of cystine, the synthesis of the desoxyribonucleotide and the regulation of the metabolism of leukotrienes and prostaglandins.
- GSH is the substrate of GSH peroxidase, which deactivates the peroxides, the substrate of GSH dehydrogenase, which regenerates the anti- oxidizing molecules, such as ascorbate, and finally the substrate of GSH-S-transferase, which detoxifies the xenobiotics .
- GSH glycosylcholine
- cysteine with an effective amount of glutathione is preferred, but other substances known to have antioxidizing properties can possibly be added, such as, purely by way of example, taurine, lipoic acid, luteine, and vitamins A, C and E. Consequently, forming the subject of the present invention are compositions containing cystine or cysteine with an effective amount of glutathione, which can be administered by oral route, for the prevention and treatment of oxidative stress deriving from haemodialysis treatment in patients affected by chronic renal insufficiency. Said compositions will be prepared according to conventional methods well known in the pharmaceutical field, such as the ones described in ⁇ Remington' s Pharmaceutical Handbook", Mack Publishing ,Co. , N. Y., USA.
- compositions of the invention will be normally administered before haemodialysis in order to contrast ⁇ 4 the fastest way possible the oxidative stress that is triggered when extracorporeal circulation starts, which will subsequently be kept under control with the mere administration of cystine or cysteine. It is preferable for said compositions to be administered in the form of composition with unit oral dose.
- cystine or cysteine with glutathione can possibly be associated to non-toxic antioxidants that can be administered by oral route, in particular vitamins A, C and E, lycopene, lipoic acid, luteine, ascorbic acid and taurine. Vitamin E and taurine are preferred.
- compositions may be in the form of tablets, capsules, oral preparations, powders, granules, lozenges, or re- constitutable powders, but preferably in the liquid form, as syrups, solutions or suspensions.
- the solid compositions may contain: conventional excipients, for example binders, such as cellulose, mannitol, lactose; diluents, such as calcium carbonate, calcium phosphate and lactose; agents of compression; lubricants, such as magnesium stearate; disintegrating agents, such as starch, polyvinylpyrrolidone and starch derivatives; colouring agents; aromatizing agents and the like.
- binders such as cellulose, mannitol, lactose
- diluents such as calcium carbonate, calcium phosphate and lactose
- agents of compression such as lubricants, such as magnesium stearate
- disintegrating agents such as starch, polyvinylpyrrolidone and starch derivatives
- colouring agents such as aromatizing agents and the like.
- the liquid compositions may contain conventional excipients, for example suspending agents, such as sorbitol, methylcellulose, hydroxyethylcellulose, carboxyl-methylcellulose; preservatives, for example, methyl or propyl p- hydroxybenzoate or sorbic acid, and, if desired, conventional aromatizing or colouring agents.
- suspending agents such as sorbitol, methylcellulose, hydroxyethylcellulose, carboxyl-methylcellulose
- preservatives for example, methyl or propyl p- hydroxybenzoate or sorbic acid
- aromatizing or colouring agents for example, aromatizing or colouring agents.
- Example 1 Non-gastroresistant tablet containing:
- Vitamin C 25.00 mg
- a medical device in the form of a kit for separate administration, as syrup, of the composition with a base of cystine or cysteine and glutathione and of the composition with the just cystine or cysteine, at the start and end of haemodialysis .
- the kit is constituted by a certain number of packs formed by pairs of contiguous single- dose containers to be separated from one another by tearing along pre-defined lines.
- the containers are made of plastic material that are closed at the top by an aluminium foil or a removable polyethylene film.
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Immunology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Gastroenterology & Hepatology (AREA)
- Urology & Nephrology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
Described herein is an oral pharmaceutical composition containing cystine or cysteine with glutathione, for the prevention and treatment of oxidative stress resulting from haemodialysis treatment in patients affected by chronic renal insufficiency.
Description
ORAL PHARMACEUTICAL COMPOSITION CONTAINING CYSTINE OR CYSTEINE WITH GLUTATHIONE FOR THE PREVENTION AND TREATMENT OF OXIDATIVE STRESS RESULTING FROM HAEMODIALYSIS, AND MEDICAL DEVICE
FOR ADMINISTRATION THEREOF
***
The subject of the present invention is an oral composition of cysteine or of its oxidized disulphide form (cystine) in mixture with an effective amount of glutathione for the prevention and treatment of oxidative stress deriving from haemodialysis treatment in patients affected by chronic renal insufficiency.
The invention also relates to a medical device in the form of a kit comprising single- dose quantities of the composition referred to above and of a second composition of pure cystine or cysteine, said compositions being designed to be administered separately to a patient under haemodialysis so as to increase, in the initial step of extracorporeal circulation, the level of glutathione in the shortest time possible in order to contrast rapidly the oxidative stress resulting from haemodialysis treatment.
STATE OF THE ART Oxidative stress is defined as an imbalance between the antioxidizing physiological systems of protection and the increased production of oxygen or nitrogen radicals by the cells of the immune system. The consequence may be damage to
the molecular structure of the proteins, sugars, and lipids parallel to the damage to the cellular functionality that jeopardizes also the functionality of the vital organs themselves of the organism. Oxidative stress has been seen to be particularly manifest in patients affected by renal insufficiency and subjected to haemodialysis .
The interpretation of this phenomenon is attributed to the bio-incompatibility between the circulating blood cells of the patient and the dialysis membranes, in addition to other phenomena, such as the chronic uremic state. This bio-incompatibility induces an excessive production of reactive oxygen species (ROSs) by the immune system, and at the same time the reduction in the antioxidizing capacity of the organism due to the loss of antioxidizing molecules, such as reduced glutathione (GSH) , vitamin A, vitamin C, and vitamin E through the filters of the dialytic membranes.
One of the consequences of this abnormal immune response is a condition of oxidative stress, which causes a greater facility in regard to infections due to the defective immune response, amyloidosis, and accelerated atherosclerosis, on account of continuous activation of the immunocompetent cells. This situation triggers an inflammatory response, with consequent continuous release of cytokines and
lysosomal proteolytic enzymes, and stimulation of the production of free radicals: in practice, oxidative stress becomes a self-generating process, and induces a condition of chronic inflammation.
The main consequence of oxidative stress is constituted by cardiovascular complications, which constitute the main cause of death in patients affected by chronic renal insufficiency. At a local level, these complications present with alteration of the endothelium, accumulation of lipids, formation of thrombi and occlusion of the lumen.
At a systemic level, chronic oxidative stress stimulates the synthesis of proteins of the acute phase by the liver, at the expense of the synthesis of other proteins, such as albumin and transferrin: the consequence is malnutrition, further aggravated by the catabolic degradation of the muscular proteins and by the reduction in appetite.
Examples of treatment of oxidative stress with administration of products having anti- oxidizing activity have been reported. The product currently most widely used for the prevention and treatment of oxidative stress is N-acetylcysteine (see, for example, Kidney Int.,. Vol. 64 (2003), pp. 82-91; Current Med. Chem. , 2003, 10, pp. 1241-53). In particular, the document No. WO 01/02004 describes the use of N-
acetylcysteine by means of intravenous injection prior to and/or during haemodialysis treatment.
According to Nakanishi et al.r Kidney Int.
March 2003; 63(3): 1137-40, the plasmatic concentration of cysteine and also of homocysteine increases in patients with chronic renal insufficiency subjected to dialysis.
Consequently, it would not seem logical to increase further the concentration of cysteine in these patients.
DESCRIPTION OF THE INVENTION
In a prior patent application, there has instead been proposed, for the prevention and treatment of oxidative stress, the direct therapeutic use of cystine or cysteine instead of their derivatives, for the preparation of a medicament to be administered by oral route.
Following upon further tests, the inventor has been able to clarify that surprisingly the addition of a significant amount of glutathione to an oral composition of cystine or cysteine, used for the prevention and treatment of oxidative stress resulting from haemodialysis treatment in patients affected by chronic renal insufficiency, introduces an unexpected synergistic effect with respect to the composition containing just cystine or cysteine alone and has an immediate influence, if taken in the initial step of extracorporeal circulation, on the immune functions thanks to its role of
anti-oxidant and of scavenger of radicals, without awaiting hepatic synthesis .
It is known, that glutathione, a tripeptide constituted by glutamic acid, cysteine and glycine, performs many physiological functions, including the anti-oxidizing capacity, the storage and transportation of cystine, the synthesis of the desoxyribonucleotide and the regulation of the metabolism of leukotrienes and prostaglandins.
GSH is the substrate of GSH peroxidase, which deactivates the peroxides, the substrate of GSH dehydrogenase, which regenerates the anti- oxidizing molecules, such as ascorbate, and finally the substrate of GSH-S-transferase, which detoxifies the xenobiotics .
The effect of GSH on the immune function is directly linked to its role as anti-oxidant and scavenger of radicals. This is because GSH is the best system for maintaining the state, of cellular oxido-reduction and on the other hand the integrity and function of the protein. Furthermore, the physiological importance of ROSs is also significant in regulating the functions of intracellular signalling and activation of the transcription factors encoded during the synthesis of pro-inflammatory molecules, for example cytokines and leukotrienes.
The use of cysteine with an effective amount of glutathione is preferred, but other substances
known to have antioxidizing properties can possibly be added, such as, purely by way of example, taurine, lipoic acid, luteine, and vitamins A, C and E. Consequently, forming the subject of the present invention are compositions containing cystine or cysteine with an effective amount of glutathione, which can be administered by oral route, for the prevention and treatment of oxidative stress deriving from haemodialysis treatment in patients affected by chronic renal insufficiency. Said compositions will be prepared according to conventional methods well known in the pharmaceutical field, such as the ones described in λλRemington' s Pharmaceutical Handbook", Mack Publishing ,Co. , N. Y., USA.
The amount of cystine and of glutathione will depend upon various factors, such as the seriousness of the condition^ and the weight of the patient. However, a unit dosage will generally contain from 200 to 500 mg of cystine or cysteine in mixture with approximately from 10 to 100 mg of glutathione. The compositions of the invention will be normally administered before haemodialysis in order to contrast ±4 the fastest way possible the oxidative stress that is triggered when extracorporeal circulation starts, which will subsequently be kept under control with the mere administration of cystine or cysteine.
It is preferable for said compositions to be administered in the form of composition with unit oral dose.
According to a further aspect of the invention, cystine or cysteine with glutathione can possibly be associated to non-toxic antioxidants that can be administered by oral route, in particular vitamins A, C and E, lycopene, lipoic acid, luteine, ascorbic acid and taurine. Vitamin E and taurine are preferred.
According to the invention, the compositions may be in the form of tablets, capsules, oral preparations, powders, granules, lozenges, or re- constitutable powders, but preferably in the liquid form, as syrups, solutions or suspensions.
The solid compositions may contain: conventional excipients, for example binders, such as cellulose, mannitol, lactose; diluents, such as calcium carbonate, calcium phosphate and lactose; agents of compression; lubricants, such as magnesium stearate; disintegrating agents, such as starch, polyvinylpyrrolidone and starch derivatives; colouring agents; aromatizing agents and the like. The liquid compositions may contain conventional excipients, for example suspending agents, such as sorbitol, methylcellulose, hydroxyethylcellulose, carboxyl-methylcellulose; preservatives, for example, methyl or propyl p- hydroxybenzoate or sorbic acid, and, if desired,
conventional aromatizing or colouring agents.
Given below, purely by way of example, is a preferred formulation for solid composition.
Example 1 - Non-gastroresistant tablet containing:
Cysteine: 500.00 mg
Glutathione: 50.00 mg
Vitamin C: 25.00 mg
Lecithin of soya: 21.-50 mg Lactose: 25.00 mg
Avicel PH: 102 30.00
Maize starch: 30.00 mg
Magnesium stearate: 10.00 mg
Talcum: 15.00 mg Titanium dioxide: 2.50 mg
As mentioned previously, there has also been developed a medical device in the form of a kit for separate administration, as syrup, of the composition with a base of cystine or cysteine and glutathione and of the composition with the just cystine or cysteine, at the start and end of haemodialysis .
The kit is constituted by a certain number of packs formed by pairs of contiguous single- dose containers to be separated from one another by tearing along pre-defined lines. Preferably, the containers are made of plastic material that are closed at the top by an aluminium foil or a removable polyethylene film.
Claims
1. An oral pharmaceutical composition containing cystine or cysteine with glutathione for the prevention and treatment of oxidative stress resulting from haemodialysis treatment in patients affected by chronic renal insufficiency.
2. The composition according to Claim 1, in which cystine or cysteine are administered in unit doses ranging from 500 to 1000 mg in mixture with an amount of approximately 10 to 100 mg of glutathione .
3. The composition according to Claim 1 or Claim 2, in which cystine or cysteine with glutathione are used in association with other substances, such as taurine, lipoic acid, luteine, and vitamins A, C and E.
4. A medical device in the form of a kit for the prevention and treatment of oxidative stress resulting from haemodialysis treatment in patients affected by chronic renal insufficiency, characterized in that it comprises two oral pharmaceutical compositions to be administered separately to a patient undergoing haemodialysis treatment of which the first comprises cystine or cysteine with the addition of a significant amount of glutathione and the second only cystine or cysteine.
5. Use of a medical device according to Claim 4, in which the composition of cystine or cysteine with glutathione is administered before haemodialysis treatment and the one with cystine or cysteine is administered after said treatment.
6. A method for the prevention and treatment of oxidative stress resulting from haemodialysis in patients affected by chronic renal insufficiency, comprising the oral administration to said patients of an amount ranging from 500 to
1000 mg of cystine or cysteine in mixture with an amount ranging from 10 to 100 mg of glutathione before haemodialysis treatment and an amount ranging from 500 to 1000 mg of pure cysteine and/or cysteine after the same treatment.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| MX2008012974A MX2008012974A (en) | 2006-04-10 | 2007-04-06 | Oral pharmaceutical composition containing cystine or cysteine with glutathione against oxidative stress resulting from haemodialysis. |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT000206A ITRM20060206A1 (en) | 2006-04-10 | 2006-04-10 | ORAL PHARMACEUTICAL COMPOSITION CONTAINING CYSTINE OR CISTEIN WITH GLUTATHYATE FOR THE PREVENTION AND TREATMENT OF OXIDATIVE STRESS FROM HEMODIALYSIS AND MEDICAL ADMINISTRATION DEVICE |
| ITRM2006A000206 | 2006-04-10 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| WO2007116428A2 true WO2007116428A2 (en) | 2007-10-18 |
| WO2007116428A8 WO2007116428A8 (en) | 2007-12-13 |
| WO2007116428A3 WO2007116428A3 (en) | 2008-03-13 |
Family
ID=38480485
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/IT2007/000261 Ceased WO2007116428A2 (en) | 2006-04-10 | 2007-04-06 | Oral pharmaceutical composition containing cystine or cysteine with glutathione against oxidative stress resulting from haemodialysis |
Country Status (4)
| Country | Link |
|---|---|
| KR (1) | KR20090024673A (en) |
| IT (1) | ITRM20060206A1 (en) |
| MX (1) | MX2008012974A (en) |
| WO (1) | WO2007116428A2 (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2527802A (en) * | 2014-07-02 | 2016-01-06 | Olimed Ltd | Tablet with differentiated absorption |
| FR3092491A1 (en) * | 2019-02-11 | 2020-08-14 | Bretagne Chimie Fine | Non-therapeutic oral use of a composition for whitening and / or lightening the skin comprising cystine and glutathione in a cystine / glutathione ratio ranging from 1.5 to 4 |
| EP4216939A4 (en) * | 2020-09-28 | 2024-10-23 | Georgia Tech Research Corporation | USE OF CYSTIN AND ITS DERIVATIVES AS ANTITHROMBOTIC AND THROMBOLYTIC AGENTS |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0146265B1 (en) * | 1983-11-15 | 1991-04-03 | Kyowa Hakko Kogyo Co., Ltd. | Process for producing a compound from its precursor using an enzymatic activity of bacterium |
| US5576287A (en) * | 1994-04-29 | 1996-11-19 | Wake Forest University | Method for treating acute renal disease and failure |
| US6228347B1 (en) * | 1997-12-01 | 2001-05-08 | Thione International, Inc. | Antioxidant gel for gingival conditions |
| KR100390630B1 (en) * | 1999-07-02 | 2003-07-07 | 이희발 | Peritoneal dialysis solutions containing antioxidants |
| ITMI20032528A1 (en) * | 2003-12-19 | 2005-06-20 | Francesco Santangelo | USE OF CYSTINE OR CISTEIN FOR PREVENTION AND THE |
-
2006
- 2006-04-10 IT IT000206A patent/ITRM20060206A1/en unknown
-
2007
- 2007-04-06 WO PCT/IT2007/000261 patent/WO2007116428A2/en not_active Ceased
- 2007-04-06 KR KR1020087027326A patent/KR20090024673A/en not_active Withdrawn
- 2007-04-06 MX MX2008012974A patent/MX2008012974A/en not_active Application Discontinuation
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2527802A (en) * | 2014-07-02 | 2016-01-06 | Olimed Ltd | Tablet with differentiated absorption |
| GB2527802B (en) * | 2014-07-02 | 2019-10-16 | Olimed Ltd | An orally disintegrating tablet with differentiated absorption |
| FR3092491A1 (en) * | 2019-02-11 | 2020-08-14 | Bretagne Chimie Fine | Non-therapeutic oral use of a composition for whitening and / or lightening the skin comprising cystine and glutathione in a cystine / glutathione ratio ranging from 1.5 to 4 |
| WO2020165084A1 (en) * | 2019-02-11 | 2020-08-20 | Bretagne Chimie Fine | Non-therapeutic oral use of a composition for whitening and/or lightening the skin comprising cystine and glutathione in a cystine-glutathione ratio ranging from 1.5 to 4 |
| KR20210125502A (en) * | 2019-02-11 | 2021-10-18 | 브르타뉴 쉬미 핀 | Non-therapeutic oral use of a composition for skin whitening and/or lightening comprising cystine and glutathione in a cystine-glutathione ratio of 1.5 to 4 |
| JP2022510729A (en) * | 2019-02-11 | 2022-01-27 | ブルターニュ シミ フィヌ | Non-therapeutic oral use of a composition containing cystine and glutathione to whiten and / or lighten the skin with a cystine / glutathione ratio of 1.5-4. |
| JP7108796B2 (en) | 2019-02-11 | 2022-07-28 | ブルターニュ シミ フィヌ | Non-therapeutic oral use of a composition for whitening and/or brightening the skin containing cystine and glutathione and having a cystine/glutathione ratio of 1.5-4 |
| US11969494B2 (en) | 2019-02-11 | 2024-04-30 | Bretagne Chimie Fine | Non-therapeutic oral use of a composition for whitening and/or lightening the skin comprising cystine and glutathione in a cystine-glutathione ratio ranging from 1.5 to 4 |
| KR102842003B1 (en) | 2019-02-11 | 2025-08-05 | 브르타뉴 쉬미 핀 | Non-therapeutic oral use of a composition for skin whitening and/or lightening comprising cystine and glutathione in a cystine-glutathione ratio of 1.5 to 4 |
| EP4216939A4 (en) * | 2020-09-28 | 2024-10-23 | Georgia Tech Research Corporation | USE OF CYSTIN AND ITS DERIVATIVES AS ANTITHROMBOTIC AND THROMBOLYTIC AGENTS |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2007116428A8 (en) | 2007-12-13 |
| MX2008012974A (en) | 2008-12-18 |
| WO2007116428A3 (en) | 2008-03-13 |
| KR20090024673A (en) | 2009-03-09 |
| ITRM20060206A1 (en) | 2007-10-11 |
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