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 PDF

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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
Application number
PCT/IT2007/000261
Other languages
English (en)
French (fr)
Other versions
WO2007116428A3 (en
WO2007116428A8 (en
Inventor
Francesco Santangelo
Francesco Paolo Pilato
Original Assignee
Bio3 Research Srl
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Bio3 Research Srl filed Critical Bio3 Research Srl
Priority to MX2008012974A priority Critical patent/MX2008012974A/es
Publication of WO2007116428A2 publication Critical patent/WO2007116428A2/en
Publication of WO2007116428A8 publication Critical patent/WO2007116428A8/en
Publication of WO2007116428A3 publication Critical patent/WO2007116428A3/en

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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.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Immunology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Urology & Nephrology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
PCT/IT2007/000261 2006-04-10 2007-04-06 Oral pharmaceutical composition containing cystine or cysteine with glutathione against oxidative stress resulting from haemodialysis WO2007116428A2 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
MX2008012974A MX2008012974A (es) 2006-04-10 2007-04-06 Composicion farmaceutica oral que contiene cistina o cisteina con glutationa, para la prevencion y el tratamiento de tension oxidante originada por hemodialisis, y dispositivo medico para su administracion.

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IT000206A ITRM20060206A1 (it) 2006-04-10 2006-04-10 Composizione farmaceutica orale contenente cistina o cisteina con glutatione per la prevenzione ed il trattamento dello stress ossidativo da emodialisi e dispositivo medico di somministrazione
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 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 (it)
IT (1) ITRM20060206A1 (it)
MX (1) MX2008012974A (it)
WO (1) WO2007116428A2 (it)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2527802A (en) * 2014-07-02 2016-01-06 Olimed Ltd Tablet with differentiated absorption
FR3092491A1 (fr) * 2019-02-11 2020-08-14 Bretagne Chimie Fine Utilisation non-thérapeutique par voie orale d’une composition pour blanchir et/ou éclaircir la peau comprenant de la cystine et du glutathion dans un rapport cystine/glutathion allant de 1,5 à 4

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0146265A2 (en) * 1983-11-15 1985-06-26 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
WO2000028977A1 (en) * 1998-09-29 2000-05-25 Thione International, Inc. Antioxidant gel for gingival conditions
WO2001002004A1 (en) * 1999-07-02 2001-01-11 Lee Hibahl Peritoneal dialysis solution containing antioxidant for treating renal failure
WO2005058305A1 (en) * 2003-12-19 2005-06-30 Bio 3 Research S.R.L. The use of cystine or cysteine for the prevention and treatment of oxidative stress caused by haemodialysis and of acute or chronic kidney diseases

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0146265A2 (en) * 1983-11-15 1985-06-26 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
WO2000028977A1 (en) * 1998-09-29 2000-05-25 Thione International, Inc. Antioxidant gel for gingival conditions
WO2001002004A1 (en) * 1999-07-02 2001-01-11 Lee Hibahl Peritoneal dialysis solution containing antioxidant for treating renal failure
WO2005058305A1 (en) * 2003-12-19 2005-06-30 Bio 3 Research S.R.L. The use of cystine or cysteine for the prevention and treatment of oxidative stress caused by haemodialysis and of acute or chronic kidney diseases

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
MOBERLY J B ET AL: "ELEVATION OF WHOLE-BLOOD GLUTATHIONE IN PERITONEAL DIALYSIS PATIENTS BY L-2-OXOTHIAZOLIDINE-4-CARBOXYLATE, A CYSTEINE PRODRUG (PROCYSTEINE)" JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY, WILLIAMS AND WILKINS, BALTIMORE, MD, US, vol. 9, no. 6, June 1998 (1998-06), pages 1093-1099, XP008046078 ISSN: 1046-6673 *
SULIMAN M E ET AL: "Effects of high-dose folic acid and pyridoxine on plasma and erythrocyte sulfur amino acids in hemodialysis patients" JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY 1999 UNITED STATES, vol. 10, no. 6, 1999, pages 1287-1296, XP008085534 ISSN: 1046-6673 *

Cited By (7)

* Cited by examiner, † Cited by third party
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 (fr) * 2019-02-11 2020-08-14 Bretagne Chimie Fine Utilisation non-thérapeutique par voie orale d’une composition pour blanchir et/ou éclaircir la peau comprenant de la cystine et du glutathion dans un rapport cystine/glutathion allant de 1,5 à 4
WO2020165084A1 (fr) * 2019-02-11 2020-08-20 Bretagne Chimie Fine Utilisation non-thérapeutique par voie orale d'une composition pour blanchir et/ou éclaircir la peau comprenant de la cystine et du glutathion dans un rapport cystine/glutathion allant de 1,5 à 4
JP2022510729A (ja) * 2019-02-11 2022-01-27 ブルターニュ シミ フィヌ シスチンとグルタチオンを含有し、シスチン／グルタチオン比が１．５～４である皮膚を白くする及び／又は明るくするための組成物の非治療的経口使用
JP7108796B2 (ja) 2019-02-11 2022-07-28 ブルターニュ シミ フィヌ シスチンとグルタチオンを含有し、シスチン／グルタチオン比が１．５～４である皮膚を白くする及び／又は明るくするための組成物の非治療的経口使用
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

Also Published As

Publication number Publication date
ITRM20060206A1 (it) 2007-10-11
WO2007116428A3 (en) 2008-03-13
KR20090024673A (ko) 2009-03-09
MX2008012974A (es) 2008-12-18
WO2007116428A8 (en) 2007-12-13

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