WO2003011305A1 - Composition a base de glycosaminoglycan et d'un peroxyde pour le traitement de la keratoconjonctivite seche - Google Patents

Composition a base de glycosaminoglycan et d'un peroxyde pour le traitement de la keratoconjonctivite seche Download PDF

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Publication number
WO2003011305A1
WO2003011305A1 PCT/EP2002/008488 EP0208488W WO03011305A1 WO 2003011305 A1 WO2003011305 A1 WO 2003011305A1 EP 0208488 W EP0208488 W EP 0208488W WO 03011305 A1 WO03011305 A1 WO 03011305A1
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WO
WIPO (PCT)
Prior art keywords
hydrogen peroxide
composition
amount
glycosaminoglycan
dry eye
Prior art date
Application number
PCT/EP2002/008488
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English (en)
Inventor
Maggy Babiole Saunier
György Lajos KIS
Original Assignee
Novartis Ag
Novartis Pharma Gmbh
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 Novartis Ag, Novartis Pharma Gmbh filed Critical Novartis Ag
Publication of WO2003011305A1 publication Critical patent/WO2003011305A1/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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/40—Peroxides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses

Definitions

  • the present invention relates to ophthalmic pharmaceutical compositions for treatment of dry eye symptoms comprising a hyaluronate and a method of treating dry eye symptoms with said compositions.
  • Dry eye also known as or keratoconjunctivitis sicca (KCS) and dyslacrima
  • KCS keratoconjunctivitis sicca
  • dyslacrima refer to, or are a component of, a variety of disorders that results from any condition or circumstance that decreases tear secretion or increases tear film evaporation.
  • Patients suffering from dry eye may experience symptoms such as e.g. foreign body sensation, burning, ocular itching, ocular inflammation, persistent irritation, feeling of dryness and hyperemia. In severe cases, dry eye can seriously impair a person's vision. Dry eye results in a breakdown of the pre- ocular tear film which commonly results in dehydration of the exposed outer surface and hence the symptoms described above.
  • Dry eye symptoms may be treated by administering, e.g. instilling, artificial tears to the eye in order to supplement the ocular tear film.
  • tear substitutes are disclosed e.g. in US 5,209,927, US 5,294,607 and US 4,409,205 which are incorporated herein by reference.
  • ophthalmic multidose composition that will better alleviate the symptoms of dry eye and is safe.
  • Excellent antimicrobial preservation preferably as defined as European Pharmacopeia (Eur. Ph.) criteria A for ophthalmic preparations, e.g. as described in Eur. Ph. Supplement 2001, Section 5.1.3, page 293 to 295, is required.
  • E.g. in the case of bacteria e.g. after 6 hours, 99.0% of microorganisms and after 24 hours, 99.9% of microorganisms and after 28 days, 100% of microorganisms have to be killed relative to the initial concentration of microorganisms.
  • fungi e.g.
  • the present invention provides for ophthalmic compositions for treatment of dry eye symptoms which compositions meet the criteria A requirements for efficacy of antimicrobial preservation of the Eur. Ph. (Eur. Ph. Supplement 2001, Section 5.1.3) for ophthalmic preparations.
  • EP 354 186 discloses a method of preserving ophthalmic solutions having a hydrogen peroxide content of about 0.001% to about 0.1 % by weight. Applicants have found that compositions comprising
  • the glycosaminoglycan is preferably e.g. hyaluronic acid, hylan, hylaluronan, heparin, heparan sulphate, chondroitin sulfate, keratin sulphate or dermatan sulphate or ophthalmically acceptable salts thereof, or mixtures thereof, preferably hyaluronic acid, hyaluronan derivatives or an ophthalmically acceptable salt thereof.
  • the glycosaminoglycan may be present e.g. in an amount of 0.05 to 5%, preferably 1 to 4% by weight based on the total weight of composition.
  • Hyaluronic acid (Fiedler, H.P.; 1996; Lexikon der Hilfsstoffe fur Pharmazie. Kosmetik und anqrenzende füre; Editio Cantor Verlag Aulendorf (Germany), p. 763) is e.g. known and commercially available from Vitrolife AB, Sweden, or from Pentapharm AG, Switzerland, e.g. under the names hyaluronic acid Pentapharm or hyaluronic acid BT.
  • hyaluronic acid is in form of its alkali salts, preferably sodium hyaluronate.
  • Hyaluronic acid may be obtained e.g. from cocks combs or may be manufactured biotechnically.
  • the preferred molecular weight of the hyaluronate is e.g. above about 750O00 Daltons to e.g. below about 4 million Daltons, more preferred from about 1 million Daltons to about 3.5 million Daltons.
  • the stabilized hydrogen peroxide generated from source of hydrogen peroxide is preferably hydrogen peroxide, sodium perborate e.g. sodium perborate tetrahydrate or sodium perborate decahydrate, sodium peroxide and urea peroxide, more preferably sodium perborate.
  • compositions for treatment of dry eye symptoms comprising i) a glycosaminoglycan, e.g. a hyaluronate, and ii) stabilized hydrogen peroxide generated from a source of hydrogen peroxide for providing an effective trace amount of resultant hydrogen peroxide in an amount of about 0.02 to about 0.035% by weight based on the total weight of composition, e.g. generated from sodium perborate tetrahydrate in an amount of about 0.10 to about 0.15% by weight based on the total weight of composition.
  • a glycosaminoglycan e.g. a hyaluronate
  • stabilized hydrogen peroxide generated from a source of hydrogen peroxide for providing an effective trace amount of resultant hydrogen peroxide in an amount of about 0.02 to about 0.035% by weight based on the total weight of composition, e.g. generated from sodium perborate tetrahydrate in an amount of about 0.10 to about 0.15% by weight based on the total weight of composition.
  • compositions of the present invention may further comprise a stabilizer.
  • Preferred stabilizers include chelating agents having phosphonic acid or phosphonate groups.
  • a preferred group of chelating agents are organophosphonates, particularly amino tri(lower alkylene phosphonic acids).
  • a variety of such chelating agents are known and commercially available from Monsanto Company, St. Louis, under the trade name Dequest®. Examples of such compounds include e.g. diethylene triamine penta(methylene phosphonic acid); hexa- methylene-diaminetetra (methylenephosphonic acid); ethylenediaminetetra(methylenephos- phonic acid); and aminotrimethylene phosphonates.
  • a particularly preferred chelating agent is diethylene triamine penta(methylene phosphonic acid), as known and commercially available under the trade name Dequest® 2060.
  • a stabilizer is present in an amount from about 0.00001 to 0.5%, more preferably from about 0.0001 to 0.1% by weight based on the total weight of composition.
  • compositions of the present invention may further comprise a tonicity enhancing agent.
  • Suitable tonicity enhancing agents are, e.g. i) ionic compounds, such as alkali metal or alkaline earth metal halides, such as sodium chloride, sodium bromide, sodium iodide, lithium chloride, potassium chloride, potassium bromide, potassium iodide, calcium chloride e.g. as its 2-hydrate, magnesium chloride e.g. as its 6-hydrate, or boric acid, and/or ii) non-ionic compounds such as urea, or polyols e.g. glycerol, sorbitol, mannitol, propylene glycol, or dextrose.
  • a mixture of ionic and/or non-ionic tonicity enhancers is present.
  • the compositions of the present invention comprise glycerol.
  • sufficient tonicity enhancing agent is added to impart to the ready-for-use ophthalmic composition a hypotonic osmolality of approximately from 150 to 400 mOsmol, preferred from 200 to 350 mOsmol, more preferred from 220 to 280 mOsmol.
  • the tonicity agent is present in an amount which is sufficient to achieve an ophthalmically compatible composition having a hypotonic osmolality.
  • the tonicity agent is present in an amount from about 0.01 to 10%.
  • a pharmaceutically acceptable buffer system may be added.
  • buffer substances are acetate e.g. sodium acetate 3-hydrate, ascorbate, borate, e.g. sodium borate, hydrogen carbonate/carbonate, citrate e.g. tri-sodium citrate 2-hydrate, gluconate, lactate, phosphate e.g. Na 2 HPO 4 , NaH 2 PO 4 or KH 2 PO 4 , propionate, tromethamine (tris-(hydroxymethyl)-amino- methane, TRIS) buffers and mixtures thereof.
  • Borate buffer is preferred.
  • the buffer substance added is typically of an amount to ensure and maintain a physiologically tolerable pH range.
  • the buffer will be present in an amount from about 0.05 to 2.5%, preferably from about 0.1 to 1.5% by weight based on the total amount of composition.
  • the pH range is generally in the range of from 6.5 to 9, preferably from 7.0 to 8.5 and more preferably from 7.5 to 8.0.
  • the desired pH may be adjusted by addition of acid, e.g. HCI, or base, sodium hydroxide.
  • compositions further comprising an ophthalmic carrier.
  • ophthalmic carriers are typically adapted for topical administration, and are for example, water, mixtures of water and water-miscible solvents, such as d- to C 7 - alkanols, vegetable oils or mineral oils comprising from 0.5 to 5% by weight hydroxyethyl- cellulose, ethyl oleate, carboxymethyl-cellulose, polyvinyl-pyrrolidone, or water-soluble polymers for ophthalmic uses, such as, for example, cellulose derivatives, such as methyl- cellulose, alkali metal salts of carboxy-methylcellulose, hydroxymethylcellulose, hydroxethyl- cellulose, methylhydroxypropyl-cellulose and hydroxypropylcellulose, preferably water.
  • the compositions of the present invention are in form of a solution, e.g. artificial tears, e.g. having a viscosity of about 2 to about 60 mPas as determined using a capillary viscosimeter according to Eur. Ph., or in form of a gel, e.g. having a viscosity of about 200 to about 2000 mPas as determined using a rotary viscosimeter according to Eur. Ph..
  • the compositions of the present invention are in form of a solution and are substantially free of organic polymers other than glycosaminoglycans.
  • any particular excipient may have alternative or multiple functions, e.g. boric acid may act as e.g. tonicity enhancer and/or buffer after addition of base e.g. sodium hydroxide.
  • the ophthalmic composition of the present invention consists of i) a glycosaminoglycan, e.g. a hyaluronate, e.g. in an amount of 0.05 to 4% by weight, ii) stabilized hydrogen peroxide generated from a source of hydrogen peroxide for providing an effective trace amount of resultant hydrogen peroxide in an amount of about 0.02 to about 0.035% by weight, e.g. sodium perborate tetrahydrate in an amount of about 0.10 to about 0.15% by weight, iii) a stabilizer, e.g. in an amount of 0.0001 to 0.1% by weight, iv) one or more tonicity agents, e.g. in an amount of 0.01 to 10.0% by weight, v) a buffering agent, e.g. in an effective amount to maintain a pH of 6 to 8, and vi) water.
  • a glycosaminoglycan e.g. a hyaluronate
  • this invention provides a method of preserving an ophthalmic composition comprising a glycosaminoglycan, e.g. according to Eur. Ph. criteria A, which method comprises adding stabilized hydrogen peroxide generated from a source of hydrogen peroxide, e.g. sodium perborate, for providing an effective trace amount of resultant hydrogen peroxide in an amount of about 0.02 to about 0.035% by weight to the ophthalmic composition, e.g. adding sodium perborate tetrahydrate in an amount of about 0.10 to about 0.15% by weight.
  • a source of hydrogen peroxide e.g. sodium perborate
  • the ophthalmic compositions of the present invention may be prepared in conventional manner e.g. by mixing the excipients.
  • the compositions of the present invention may be packaged in conventional manner.
  • the compositions of the present invention may be stored in single or multiple unit dosage form, e.g. closed bottles, tubes or other containers made from glass, plastic such as e.g. polyethylene, polyethylene terephthalate, or polypropylene, or metal or combinations thereof.
  • bottles may contain about 1 to 5 ml of the compositions of the present invention.
  • the container may be fitted with a dropper to facilitate administration.
  • compositions of the present invention may be formulated in conventional manner e.g. to be particularly adapted for topical ophthalmic use.
  • procedures for formulation are not particularly described herein such formulation procedures may for example be known in the art, or analogous to those known in the art or to procedures described herein. Representative procedures are disclosed in for example, Remington's Pharmaceutical Sciences, 19th Ed., Mack Publ., Co., 1995, H. Sucker et al, Pharmazeutician Technologie, 2nd Edition, Thieme, 1991 , R: H. Mueller et al, Pharmazeutician Technologie: Moderne Arzneistoffformen, 2nd Edition,maschineliche Verlagsgesellschaft, Stuttgart, 1998, L. Lachman et al.
  • excipients used may e.g. be those known in the art e.g. in the Lexikon der Hilfsstoffe f ⁇ r Pharmazie. Kosmetik und anqrenzende füre; Fiedler, H.P.; 1996; Editio Cantor Verlag Aulendorf (Germany), and Handbook of Pharmaceutical Excipients. Kibbe, A.H.; 2000, a joint publication of Pharmaceutical Press, London (UK), and American Pharmaceutical Association, Washington (US), references referred to above, or analogous to those known in the art or new excipients having analogous function to those described in the art or herein.
  • compositions of the present invention are useful for the treatment of dry eye, or, more specifically, its symptoms, as indicated e.g. in standard animal trials and clinical trials. Additionally, these compositions can slow down the progress of the syndrome and reverse its effects including, in moderate to severe cases of dry eye, corneal staining, which is made evident by use of Rose Bengal or Fluorescein.
  • the ocular tolerance of the ophthalmic compositions of the present invention may be assessed with the test described infra:
  • the upper eyelid of the right eye is carefully pulled away from the eyeball and 50 microliter of the test substance is instilled (single dose instillation) on the outer superior part of the bulbar conjunctiva of three albino rabbits using a gauged automatic pipette.
  • the contralateral eye is used as non treated control.
  • the eyelid is gently closed for about one second.
  • visual ocular examinations are carried out e.g. using a pen lamp. Anterior segment aspect is evaluated and scored according to Draize method. In addition discomfort is scored.
  • a clinical trial may be effected to test the efficacy and tolerability of about 30 to 40 microlitre of compositions of the present invention administered once a day by instillation onto the ocular surface, e.g. to the inside lower lid, to groups of, e.g. 10 to 25, healthy volunteers, or patients suffering from allergic conjunctivitis. The trial lasts e.g. 8 days.
  • the subjects are examined to determine the effect against dry eye symptoms, e.g. fast onset of action and long duration of action and good tolerability.
  • composition of the present invention to be administered will naturally depend on a variety of factors, e.g. choice of salt, excipients, formulation properties, and severity of the condition.
  • the dosage regimen is 10-50 microlitres of composition administered to the lower conjunctival sac of the affected eye, e.g. using a dropper.
  • composition of the present invention to be administered is from about 1 to 20 doses of 10-50 microliters of composition, typically three times a day. Frequency of dosing is variably dependent upon the severity of the syndrome. For severe cases dosing may occur 20 times per day. The frequency is reduced when signs of the disease state show improvement. At that time dosing may be as infrequent as one dose daily or once every two or three days.
  • the present invention provides a) an ophthalmic composition as defined above for use in the treatment of dry eye symptoms, e.g. foreign body sensation, burning, and hyperemia, b) a method for treating dry eye symptoms or a condition treatable by glycosaminoglycan therapy comprising administering a composition of the present invention to the eye of a patient in need thereof, or c) the use of a composition of the present invention in the preparation of a medicament for the treatment of dry eye symptoms.
  • dry eye symptoms e.g. foreign body sensation, burning, and hyperemia
  • a method for treating dry eye symptoms or a condition treatable by glycosaminoglycan therapy comprising administering a composition of the present invention to the eye of a patient in need thereof, or c) the use of a composition of the present invention in the preparation of a medicament for the treatment of dry eye symptoms.
  • the present invention provides a method of treating dry eye symptoms comprising administering a composition comprising i) a glycosaminoglycan e.g. a hyaluronate, e.g. in an amount of 0.05 to 4% by weight, and ii) stabilized hydrogen peroxide generated from a source of hydrogen peroxide for providing an effective trace amount of resultant hydrogen peroxide in an amount of about 0.02 to about 0.035% by weight, e.g. sodium perborate tetrahydrate in an amount of about 0.10 to about 0.15% by weight.
  • a glycosaminoglycan e.g. a hyaluronate
  • stabilized hydrogen peroxide generated from a source of hydrogen peroxide for providing an effective trace amount of resultant hydrogen peroxide in an amount of about 0.02 to about 0.035% by weight, e.g. sodium perborate tetrahydrate in an amount of about 0.10 to about 0.15% by weight.
  • the present invention provides a method of treating dry eye symptoms comprising instilling a composition into the eye wherein said composition essentially consists of i) a glycosaminoglycan e.g. a hyaluronate, e.g. in an amount of 0.05 to 4% by weight, ii) stabilized hydrogen peroxide generated from a source of hydrogen peroxide for providing an effective trace amount of resultant hydrogen peroxide in an amount of 0.02 to 0.035% by weight, e.g. sodium perborate tetrahydrate in an amount of about 0.10 to about 0.15% by weight, iii) a stabilizer, e.g.
  • Example 1 to 5 amounts given in gram if not otherwise stated
  • Example 6 to 10 amounts given in gram if not otherwise stated
  • compositions of examples 6 to 10 meet the criteria A requirements for efficacy of antimicrobial preservation of the Eur. Ph. (Eur. Ph. Supplement 2001 , Section 5.1.3) for ophthalmic preparations.
  • compositions of examples 11 to 14 meet the criteria A requirements for efficacy of antimicrobial preservation of the Eur. Ph. (Eur. Ph. Supplement 2001, Section 5.1.3) for ophthalmic preparations.

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  • Health & Medical Sciences (AREA)
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Abstract

La présente invention concerne des compositions pharmaceutiques de type ophtalmique destinées plus particulièrement au traitement de la kératoconjonctivite sèche. Ces compositions comprennent essentiellement un hyaluronate stabilisé et du peroxyde d'hydrogène. L'invention concerne également le traitement de la kératoconjonctivite sèche.
PCT/EP2002/008488 2001-07-31 2002-07-30 Composition a base de glycosaminoglycan et d'un peroxyde pour le traitement de la keratoconjonctivite seche WO2003011305A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP01118406 2001-07-31
EP01118406.6 2001-07-31

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WO2003011305A1 true WO2003011305A1 (fr) 2003-02-13

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008011836A2 (fr) 2006-07-25 2008-01-31 Osmotica Corp. Solutions ophtalmiques
JP2009506064A (ja) * 2005-08-26 2009-02-12 ノバルティス アクチエンゲゼルシャフト 安定および保存化ケトチフェン眼用組成物
WO2009111170A1 (fr) * 2008-02-29 2009-09-11 Bausch & Lomb Incorporated Formulations pharmaceutiques comprenant des matériaux polyanioniques et une source de peroxyde d’hydrogène
EP2250980A1 (fr) 2009-05-15 2010-11-17 Laboratoires THEA Kit pour l'évaluation personnalisée et la sélection de larmes artificielles

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4973580A (en) * 1985-05-17 1990-11-27 Opocrin S.P.A. Laboratorio Farmacobiologico Depolymerized dermatan sulfates endowed with an antithrombotic, fibrinolytic, antiinflammatory activity and pharmaceutical compositions containing such
EP0710483A1 (fr) * 1994-10-06 1996-05-08 ALFA WASSERMANN S.p.A. Utilisation de glycosaminoglycanes pour la fabrication d'un médicament pour le traitement de l'insuffisance rénale chronique
WO2000019981A1 (fr) * 1998-10-08 2000-04-13 Karagoezian Hampar L Preparations synergiques antimicrobiennes, dermatologiques et ophtalmiques renfermant un chlorite et du peroxyde d'hydrogene

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4973580A (en) * 1985-05-17 1990-11-27 Opocrin S.P.A. Laboratorio Farmacobiologico Depolymerized dermatan sulfates endowed with an antithrombotic, fibrinolytic, antiinflammatory activity and pharmaceutical compositions containing such
EP0710483A1 (fr) * 1994-10-06 1996-05-08 ALFA WASSERMANN S.p.A. Utilisation de glycosaminoglycanes pour la fabrication d'un médicament pour le traitement de l'insuffisance rénale chronique
WO2000019981A1 (fr) * 1998-10-08 2000-04-13 Karagoezian Hampar L Preparations synergiques antimicrobiennes, dermatologiques et ophtalmiques renfermant un chlorite et du peroxyde d'hydrogene

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
DEBBASCH C ET AL: "[Cytotoxicity evaluation of three tear substitutes used in the treatment of dry eye syndromes]. Evaluation de la cytotoxicite de trois substituts lacrymaux utilises dans le traitement des syndromes secs.", JOURNAL FRANCAIS D OPHTALMOLOGIE, (2000 NOV) 23 (9) 863-9., XP001028692 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2009506064A (ja) * 2005-08-26 2009-02-12 ノバルティス アクチエンゲゼルシャフト 安定および保存化ケトチフェン眼用組成物
WO2008011836A2 (fr) 2006-07-25 2008-01-31 Osmotica Corp. Solutions ophtalmiques
WO2009111170A1 (fr) * 2008-02-29 2009-09-11 Bausch & Lomb Incorporated Formulations pharmaceutiques comprenant des matériaux polyanioniques et une source de peroxyde d’hydrogène
EP2250980A1 (fr) 2009-05-15 2010-11-17 Laboratoires THEA Kit pour l'évaluation personnalisée et la sélection de larmes artificielles

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