WO1995010294A1 - Compositions pharmaceutiques contenant de la n-acetylcarnosine destinees au traitement de la cataracte - Google Patents

Compositions pharmaceutiques contenant de la n-acetylcarnosine destinees au traitement de la cataracte Download PDF

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Publication number
WO1995010294A1
WO1995010294A1 PCT/EP1994/003340 EP9403340W WO9510294A1 WO 1995010294 A1 WO1995010294 A1 WO 1995010294A1 EP 9403340 W EP9403340 W EP 9403340W WO 9510294 A1 WO9510294 A1 WO 9510294A1
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WO
WIPO (PCT)
Prior art keywords
acetylcarnosine
carnosine
cataract
administration
treatment
Prior art date
Application number
PCT/EP1994/003340
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English (en)
Inventor
Mark A. Babizhayev
Edoardo Bozzo Costa
Original Assignee
Bruschettini S.R.L.
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 Bruschettini S.R.L. filed Critical Bruschettini S.R.L.
Priority to AU78127/94A priority Critical patent/AU7812794A/en
Publication of WO1995010294A1 publication Critical patent/WO1995010294A1/fr

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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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles

Definitions

  • the present invention relates to the use of N- acetylcarnosine for the preparation of a medicament useful in the prevention and therapy of cataract, and to pharmaceutical compositions containing N- acetylcarnosine as the active ingredient.
  • Cataract is a pathology of the eye, consisting in the progressive clouding of crystalline lens.
  • lens clouding is due to the diffusion of toxic products deriving from peroxidation of the lipids from retina through the vitreous body to the lens (Babizhayev and Deyev, Biochimica et Biophysica Acta, 1004 (1989), 124-133 and references cited therein).
  • Carnosine N- ⁇ -alanyl-L-histidine
  • a natural dipeptide present in the muscle tissue of various species of vertebrates has been used in the preventive and therapeutical treatments of cataract (Babizhayev, Biochimica et Biophysica Acta, 1004 (1989), 363-371; Boldyrev et al..; Biochem. Intern. 15, 1105-1113) due to its antioxidant properties.
  • N-acetylcarnosine has a therapeutical and preventive activity stronger and longer lasting than carnosine .
  • N-acetylcarnos ine or a pharmaceutically acceptable salt thereof for the preparation of a medicament useful in the treatment of eye diseases , particularly of the different forms of cataract .
  • N-Acetylcarnosine was isolated from rabbit muscle and kidney tissues (Sobue, K. ; Kanishi, H; Nakajima, T.; J. Neuroche.; 2 (6), 81975) 126-2).
  • Patents in the name of Nippon Chemiphar disclose the preparation and the use of N-acetylcarnosine
  • JP8784063 also claims solid pharmaceutical compositions containing a
  • N-acetylcarnosine aluminium salt for the treatment of ulcer.
  • N-acetylcarnosine can be prepared by acetylation of carnosine with conventional procedures known to those skilled in the art.
  • the purification of the final product is carried out by chromatography on silica gel column, which procedure requires a remarkable amount of solvents.
  • N-acetylcarnosine can be prepared synthetical ly by acetyl ating ⁇ -alanine by any known method , for example with acetic anhydride in alkal i medium. Subsequently, the resulting N-acetyl- ⁇ -alanine is derivatized with pentafluorophenol, according to the method described by M. Bodansky in "The Practise of Peptide Synthesis", 1984, to give N-acetyl- ⁇ -alanine pentafluorophenyl ester. In the subsequent step, the ester is reacted with histidine methyl ester, to give the dipeptide, thereafter the final product is obtained by hydrolysis of the ester.
  • N-acetylcarnosine pharmacologically acceptable salts can be prepared by procedures known to those skilled in the art. As already mentioned, N- acetylcarnosine has higher pharmacological properties than carnosine.
  • N-acetylcarnosine pharmacokinetics in the eye district was studied according to the following method. Pharmacological treatment
  • the control eyes were subjected to the aspiration of the aqueous humour at the times of the two pharmacological treatments, i.e. 15 and 30 minutes.
  • the solutions of the tested compounds were administered to the right eyes as a single subconjunctival injection in an amount of 0.2 ml or using the procedure of ultrasound administration 5 (phonophoresis) 30 min prior to the surgical incision.
  • the application of ultrasounds was carried out under topical anaesthesia (1-2 drops of a 0.5% Trimecaine solution).
  • the corresponding left eyes were treated similarly with the carrier.
  • the rabbit eyes were subjected to topical anaesthesia by instillation of 5% Trimecaine, then 0.1 ml of 0.5% Novocaine were injected subconjunctively and in the extraocular tissues to 5 induce anaesthesia of the lid and of the two vertical straight muscles.
  • a stab incision was performed 1-2 mm from the limbus in the temporal superior quadrant and, using a 25-gauge needle connected to an insulin syringe, 0.1-0.2 ml of aqueous humour were aspirated 0 from the eye anterior chamber and immediately introduced into an Eppendorf test tube with addition of 0.8 ml of ethanol.
  • the test tubes were kept in an ice- bath until extraction.
  • the plates were developed with 3:3:1 chloroform/methanol/25% aqueous ammonia; developer ninhydrine (solution in acetone). Ion exchange chromatography. After deproteinization of the aqueous humour samples, solubilization in ethanol and drying, approximately 100-200 ⁇ l of the extractive portion of the aqueous humour samples were used for the analysis on an amino acid analyzer Chromaspec (Renk Hilger, UK) equipped with a column filled with "DOWEX" resin and a two-channel ninhydrin detector. The analysis was performed against an amino acids standard mixture and ⁇ -thienylalanine as the internal standard. The elution was carried out under standard conditions from pH 2.2 to pH 11.5; at 40°C. Results a) HPLC.
  • N-acetylcar- 30 Carnosine 3.6010.00 35.712.7 nosine (OD) 2) derivative Carrier (OS) 2)
  • N-acetylcar- 30 1. Carnosine 3.6010.01 41.511.8 nosine (OD) 3) derivative
  • Each value is the average 1 S.D. of at least 5 measurements; *P ⁇ 0.05, **P ⁇ 0.001, ***P ⁇ 0.02 compared with the carrier administrations:
  • Each value is the average 1 S.D. of at least 5 measurements tv
  • A Carnosine 1% (80 ⁇ l) , instillation
  • B Carrier (80 ⁇ l), instillation
  • C Carnosine 1% (0.2 ml), subconjunctival injection
  • D Carrier (0.2 ml), subconjunctival injection
  • N.S. not significant.
  • Carnosine concentration in aqueous humour extracts after the amino acid analysis is aqueous humour extracts after the amino acid analysis.
  • Carnosine (OD) 2) 30 12.6+2.0 >0.1 25.513.0 >0.1 Carrier (0S) 2) 30 18.114.3 26.115.7
  • Each value is the average 1 S.D. of at least 3 measurements; 1) instillation; 2) subconjunctival injection, 3) phonophoresis.
  • N-acetylcarnosine is a pro-drug of L-carnosine.
  • L-Carnosine tends to accumulate in aqueous humour within 15-30 min after the topical administration of 1% N-acetylcarnosine to the eye.
  • Carnosine administration is ineffective as this is quickly metabolized by carnosinase present in the eye.
  • the administration routes have different effectiveness and they are, starting from the most effective: phonophoresis, subconjunctival injection, instillation.
  • N-acetylcarnosine After topical administration to the eye of 1% N- acetylcarnosine, its biotransformation leads to formation of carnosine in aqueous humour, where it acts as an antioxidant towards lipids. N-acetylcarnosine antioxidizing activity. Numerous studies postulate that reactive oxygen species produced in the crystalline lens can start the process of cataractogenesis (Varma, S.D. et al.; Curr. Eye Res. 3 (1984), 35-58; Bhuyan , K.C., et al. Curr. Eye Res. 3 (1984) 67-81) .
  • Superoxide anion radical, hydroxyl radical, hydrogen peroxide and singlet oxygen can be generated by photochemical reactions in the lens' surroundings triggering the development of different forms of cataract (Zigler, J.S. et al.; Photobiol., 33 (1981), 869-875; Spector, A. et al., Exp. Eye Res. 33 (1981), 673-681; Yegorov, S. ; et al. Biophysics 32, (1987), 184-186).
  • the model used in this test is the system of the metal-catalyzed liposomes oxidation.
  • Phospholipids for the liposome preparation were obtained according to the modified Bligh-Dyer procedure (Can. J. Biochem. Physiol. 37 (1959) 911-917). Briefly, one part by volume of hen egg yolk was gradually mixed with 3.75 parts by vol. of a 1:2 chloroform-methanol mixture (v/v) . During 5 minutes, 1.25 parts by vol. of chloroform and the same portion of water were added to the mixture with strong stirring. Within 25-30 minutes in the cold, a mixture stratified in two layers. The lower layer was collected and evaporated. The residue was taken up in pentane.
  • the resulting phospholipids were used to prepare liposomes, according to the modified reverse-phase evaporation technique (Arnhold, J. et al., Pharmazia 40 (1985), 808). 100 mg of phospholipids were dissolved in 15 ml chloroform in a round-bottom flask and 5 ml of 0.1 M Tris buffer (pH 7.4) were added. The flask was immersed in a water-bath at 30°C. After thorough mixing, nitrogen was bubbled through a glass capillary, removing chloroform at a rate of 0.5-1.0 ml/min until obtaining a turbid, non viscous liposome suspension. The average hydrodynamic diameter of the vesicles was 350 nm.
  • Liposome peroxidation was started adding 2.5 ⁇ M FeSO. and 200 ⁇ M ascorbate in 0.1 M Tris HCl buffer (pH 7.4). The incubation was performed at 37°C. The LPO concentration was measured by TBA reaction. The peroxidation reaction was stopped by addition of 2.0 ml of 0.25 M HCl containing 15% TCA, cooled with ice. TBA (0.125%) was then added to the mixture and followed by boiling for 15 min. After cooling, the mixture was centrifuged at 3,000 rpm for 15 min and the absorbance of the supernatant was read as subtraction at 535 and 600 nm.
  • the antioxidant activity of 20 and 10 mM N- Acetylcarnosine and carnosine was proved.
  • the antioxidant activity of the compounds is expressed as nmoles TBA-reactive substance/mg of lipids, as well as inhibition percentage (100%-MDA residue(%)) for each concentration and incubation time.
  • the control incubations were carried out in the absence of histidine-containing compounds which contained the essential ingredients of the liposome peroxidation system. The results are shown in the following Table 4, wherein each value is the average of three measurements.
  • N-acetylcarnosine The iri vitro antioxidant activity of N- acetylcarnosine is lower than that of carnosine, however, as evidenced above, the topical administration of N-acetylcarnosine provides n vivo the optimum conditions for the antioxidant activity of carnosine to take place, thanks to the biotransformation of N- acetylcarnosine into carnosine.
  • the known biological antioxidants mainly act according to specific mechanisms (Halliwell, B, et al., Free Radicals in Biology and Medicine, Clarendon, Oxford, 1985).
  • Various antioxidant enzymes such as superoxide dismutase, or catalase, can only react in an aqueous environment.
  • N-acetylcarnosine has been found to exert its antioxidant activity both in the lipid phase (biological membranes) and in the aqueous one (aqueous humour). This involves a clear advantage in the treatment of eye diseases, whose genesis has an oxidative component, such as cataract, open-angle primary glaucoma, inflammatory and retina diseases.
  • OS P nuclear, cortic. 20/40 20/40 20/40 20/40 20/40 20/50
  • OS E post cortical 20/100 20/100 20/80 20/70 20/70
  • the present invention also relates to the ophthalmic pharmaceutical forms containing N- acetylcarnosine or a pharmaceutically acceptable salt thereof as the active ingredient.
  • Ophthalmic pharmaceutical forms can be prepared according the conventional procedures known to those skilled in the art, for example as described in "Remington's Pharmaceutical Sciences Handbook" XVII ed. , Mack. Pub. Ed.; USA. Examples of pharmaceutical compositions are solutions or injectable emulsions, collyriums, ointments.
  • the compositions of the invention can also contain, if desired, pharmaceutically acceptable excipients. Dosages and posology will be chosen by the clinician, depending on the severity of the diseases and the patient's conditions (age, sex, weight).
  • compositions of the invention will contain from 0.5 to 2%, preferably 1%, by weight of N- acetylcarnosine.
  • Example 1 Composition for the topical eye administration, two to four times/day, of collyriums containing N-acetyl carnosine.

Abstract

L'invention se rapporte à l'utilisation de la N-acétylcarnosine dans la préparation d'un médicament utile dans la prévention et la thérapie de la cataracte, ainsi qu'aux compositions pharmaceutiques contenant la N-acétylcarnosine en tant que principe actif.
PCT/EP1994/003340 1993-10-15 1994-10-10 Compositions pharmaceutiques contenant de la n-acetylcarnosine destinees au traitement de la cataracte WO1995010294A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU78127/94A AU7812794A (en) 1993-10-15 1994-10-10 Pharmaceutical compositions containing n-acetylcarnosine for the treatment of cataract

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
ITMI932189A IT1270905B (it) 1993-10-15 1993-10-15 Composizioni farmaceutiche contenenti n-acetilcarnosina per il trattamento della cataratta
ITMI93A002189 1993-10-15

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WO1995010294A1 true WO1995010294A1 (fr) 1995-04-20

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AU (1) AU7812794A (fr)
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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999001103A2 (fr) * 1997-07-04 1999-01-14 Vladimir Evgenievich Nebolsin Derives de peptides, sels de ces derives acceptables sur le plan pharmaceutique, procede de production de ces derives, utilisation de ces derniers et composition pharmaceutique
WO2001006868A1 (fr) * 1999-07-28 2001-02-01 Biomar Group Aliment pour salmonides
WO2002026940A1 (fr) * 2000-09-26 2002-04-04 The Beta Peptide Foundation Pty Ltd Compositions et procedes permettant de retarder, de prevenir et de rajeunir ou d'inverser la senescence des cellules
WO2004028536A1 (fr) * 2002-09-30 2004-04-08 Babizhayev Mark A Methode de traitement topique de maladies de l'oeil, composition et dispositif conçus pour ce traitement
EP1586332A4 (fr) * 2003-01-20 2009-11-11 Innovative Vision Products Inc Utilisation combinee d'un inhibiteur de carnosinase presentant des l-carnosines et composition associee
US7776364B2 (en) 2006-03-24 2010-08-17 Advanced Scientific, Llc Non-surgical method for treating cataracts in mammals including man
US7960350B2 (en) 2003-10-24 2011-06-14 Ader Enterprises, Inc. Composition and method for the treatment of eye disease
WO2016016847A1 (fr) 2014-07-31 2016-02-04 Consiglio Nazionale Delle Ricerche Dérivés obtenus à partir d'acide hyaluronique et de carnosine
EP2993172A1 (fr) 2014-09-04 2016-03-09 Nicox Science Ireland Composés de la carnosine donneurs d'oxyde nitrique
IT202000014017A1 (it) 2020-06-11 2021-12-11 Fidia Farm Spa Nuovi derivati ottenuti da acido ialuronico e carnosina

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5640613A (en) * 1979-09-13 1981-04-16 Nippon Chemiphar Co Ltd Novel type remedy for peptic ulcer
WO1990006102A1 (fr) * 1988-09-28 1990-06-14 Peptide Technology Limited Compose et procede ralentissant la reticulation de collagene
WO1993004690A1 (fr) * 1991-09-09 1993-03-18 Peptide Technology Limited Procede de traitement de complications liees au diabete et de la pathologie du diabete

Patent Citations (3)

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Publication number Priority date Publication date Assignee Title
JPS5640613A (en) * 1979-09-13 1981-04-16 Nippon Chemiphar Co Ltd Novel type remedy for peptic ulcer
WO1990006102A1 (fr) * 1988-09-28 1990-06-14 Peptide Technology Limited Compose et procede ralentissant la reticulation de collagene
WO1993004690A1 (fr) * 1991-09-09 1993-03-18 Peptide Technology Limited Procede de traitement de complications liees au diabete et de la pathologie du diabete

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A. BOLDYREV ET AL., BIOKHIMIYA, vol. 57, no. 9, 1992, MOSCOW, pages 1360 - 1365 *
A.A. BOLDYREV ET AL.: "THE ANTIOXIDATIVE PROPERTIES OF CARNOSINE, A NATURAL HISTIDINE CONTAINING DIPEPTIDE", BIOCHEMISTRY INTERNATIONAL, vol. 15, no. 6, 1987, pages 1105 - 1113 *
CHEMICAL ABSTRACTS, vol. 108, no. 25, 20 June 1988, Columbus, Ohio, US; abstract no. 216324, "EFFECT OF L-CARNOSINE ON INTRAOCULAR PRESSURE" *
CHEMICAL ABSTRACTS, vol. 118, no. 5, 1 February 1993, Columbus, Ohio, US; abstract no. 34689, "DIRECT MEASUREMENTS OF INTERACTIONS OF CARNOSINE AND ITS DERIVATIVES WITH FREE RADICALS" *
DATABASE WPI Week 8123, Derwent World Patents Index; AN 81-40901D, "DIGESTIVE ULCER TREATMENT AGENT-CONTAINS N-ACETYL-CARNOSINE AS ACTIVE COMPONENT" *
M.A. BABIZHAYEV: "ANTIOXIDANT ACTIVITY OF L-CARNOSINE, A NATURAL HISTIDINE-CONTAINING DIPEPTIDE IN CRYSTALLINE LENS", BIOCHIMICA ET BIOPHYSICA ACTA, vol. 1004, no. 3, 1989, pages 363 - 371 *
V.N. ERMAKOVA ET AL., BYULL. EKSP. BIOL. MED., vol. 105, no. 4, 1988, pages 451 - 453 *

Cited By (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999001103A2 (fr) * 1997-07-04 1999-01-14 Vladimir Evgenievich Nebolsin Derives de peptides, sels de ces derives acceptables sur le plan pharmaceutique, procede de production de ces derives, utilisation de ces derniers et composition pharmaceutique
WO1999001103A3 (fr) * 1997-07-04 1999-03-25 Vladimir Evgenievich Nebolsin Derives de peptides, sels de ces derives acceptables sur le plan pharmaceutique, procede de production de ces derives, utilisation de ces derniers et composition pharmaceutique
WO2001006868A1 (fr) * 1999-07-28 2001-02-01 Biomar Group Aliment pour salmonides
WO2002026940A1 (fr) * 2000-09-26 2002-04-04 The Beta Peptide Foundation Pty Ltd Compositions et procedes permettant de retarder, de prevenir et de rajeunir ou d'inverser la senescence des cellules
JP2011037892A (ja) * 2002-09-30 2011-02-24 Mark A Babizhayev 治療手段
JP2006504701A (ja) * 2002-09-30 2006-02-09 マーク・エー・バビザイェフ 眼疾患の局所的治療方法、並びに、その治療用組成物及び治療用手段
US9044425B2 (en) 2002-09-30 2015-06-02 Mark A. Babizhayev Method for topical treatment of eye disease and composition and device for said treatment
US7795203B2 (en) 2002-09-30 2010-09-14 Babizhayev Mark A Method for topical treatment of eye disease and composition and device for said treatment
JP2011037891A (ja) * 2002-09-30 2011-02-24 Mark A Babizhayev 薬剤組成物の製造のための水性眼科用組成物の使用、及び水性眼科用組成物
WO2004028536A1 (fr) * 2002-09-30 2004-04-08 Babizhayev Mark A Methode de traitement topique de maladies de l'oeil, composition et dispositif conçus pour ce traitement
EP1586332A4 (fr) * 2003-01-20 2009-11-11 Innovative Vision Products Inc Utilisation combinee d'un inhibiteur de carnosinase presentant des l-carnosines et composition associee
US7960350B2 (en) 2003-10-24 2011-06-14 Ader Enterprises, Inc. Composition and method for the treatment of eye disease
US8338381B2 (en) 2003-10-24 2012-12-25 ADER Enterprise, Inc. Composition and method for the treatment of eye disease
US7776364B2 (en) 2006-03-24 2010-08-17 Advanced Scientific, Llc Non-surgical method for treating cataracts in mammals including man
WO2016016847A1 (fr) 2014-07-31 2016-02-04 Consiglio Nazionale Delle Ricerche Dérivés obtenus à partir d'acide hyaluronique et de carnosine
EP2993172A1 (fr) 2014-09-04 2016-03-09 Nicox Science Ireland Composés de la carnosine donneurs d'oxyde nitrique
WO2016034619A1 (fr) 2014-09-04 2016-03-10 Nicox Science Ireland Composés de carnosine donneurs d'oxyde nitrique
US10093696B2 (en) 2014-09-04 2018-10-09 Nicox Science Ireland Nitric oxide donating carnosine compounds
IT202000014017A1 (it) 2020-06-11 2021-12-11 Fidia Farm Spa Nuovi derivati ottenuti da acido ialuronico e carnosina
EP3922268A1 (fr) 2020-06-11 2021-12-15 Fidia Farmaceutici S.p.A. Nouveaux dérivés obtenus à partir d'acide hyaluronique et de carnosine

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IT1270905B (it) 1997-05-13
AU7812794A (en) 1995-05-04
ITMI932189A0 (it) 1993-10-15
ITMI932189A1 (it) 1995-04-15

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