[go: up one dir, main page]

WO2002074281A1 - Compositions ophtalmiques et leur utilisation - Google Patents

Compositions ophtalmiques et leur utilisation Download PDF

Info

Publication number
WO2002074281A1
WO2002074281A1 PCT/EP2002/002873 EP0202873W WO02074281A1 WO 2002074281 A1 WO2002074281 A1 WO 2002074281A1 EP 0202873 W EP0202873 W EP 0202873W WO 02074281 A1 WO02074281 A1 WO 02074281A1
Authority
WO
WIPO (PCT)
Prior art keywords
ophthalmic
zwitterionic phospholipid
sub
concentration
nsaid
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
Application number
PCT/EP2002/002873
Other languages
English (en)
Inventor
Anna Ottlecz
George N. Lambrou
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Novartis Pharma GmbH Austria
Novartis AG
Original Assignee
Novartis Pharma GmbH Austria
Novartis Erfindungen Verwaltungs GmbH
Novartis AG
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 Pharma GmbH Austria, Novartis Erfindungen Verwaltungs GmbH, Novartis AG filed Critical Novartis Pharma GmbH Austria
Publication of WO2002074281A1 publication Critical patent/WO2002074281A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

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
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • 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
    • A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears

Definitions

  • the present invention is related to the use of non-steroidal antiinflammatory drugs by noncovalent association with zwitterionic phospholipids, and optionally neutral lipids, such as the triglycerides, in the preparation of a medicament for the treatment of an ocular inflammation.
  • the present invention illustrates the ability of one or more zwitterionic phospholipids to enhance the anti-inflammatory potential of an NSAID.
  • Pharmacological activity of low dose NSA1D to reduce inflammation and pain may also be observed, and in some cases enhanced by chemically associating the NSAID with zwitterionic phospholipid, such as phosphatidyl choline (PC), dipalmitoylphosphatidylcholine (DPPC), and other disaturated phosphatidyl cholines, and the like, preferably the association of NSAID and zwitterionic phospholipid is of an non-covalent nature.
  • the NSAID and zwitterionic phospholipid compositions may be further described as including more or less equimolar amounts of these ingredients.
  • the present invention provides in one aspect a method for enhancing the ocular pharmacological efficacy of a nonsteroidal anti-inflammatory drug (NSAID).
  • This method comprises providing a non-covalently associated combination of a zwitterionic phospholipid with an amount of a nonsteroidal anti-inflammatory drug that provides a reduced pharmacological activity in the absence of said zwitterionic phospholipid.
  • zwitterionic phospholipid embraces a wide range of phospholipids including but not limited to phosphatidylcholine, phosphatidylserine, phosphatidylethanolamine, spingomyelin and other ceramides, as well as various other zwitterionic phospholipids.
  • the amount of nonsteroial anti-inflammatory drug is defined as an amount that provides reduced pharmacological efficacy in the absence of the zwitterionic phospholipid. This efficacy or lack of efficacy is observed in the absence of the zwitterionic phospholipid while the same or about the same amount of the NSAID does demonstrate pharmacological efficacy in the presence of zwitterionic phospholipid. In this regard the phenomenon is observed that the combination of low amounts of nonsteroidal anti-inflammatory drugs with phospholipid have potent pharmacological efficacy while doses of the drug alone (i.e. without zwitterionic phospholipid) do not.
  • NSAID may include any variety of those drugs generally classified as nonsteroidal anti-inflammatory drugs.
  • NSAID include cyclooxygenase-inhibitors
  • a preferred class of compounds is cyclo-oxygenase-2 inhibitors (COX-2).
  • NSAID include ibuprofen, piroxicam, salicylate, aspirin, naproxen, indomethacin, 5-methyl-2-(2'-chloro-6'-fluoroanilino) phenyl acetic acid, diclofenac or any pharmaceutically acceptable salt and/or any mixture thereof.
  • a preferred example is selected from diclofenac sodium and 5-methyl-2-(2'-chloro-6'- fluoroanilino) phenyl acetic acid.
  • VLA-4-inhibitors include for example compounds as being disclosed in WO 99/37605, and in particular compounds of formula Ic:
  • R a is H, CH 3 , Cl or NH 2 ;
  • R 2 is (CH 2 ) 3 OCH 3 or (CH 2 ) 4 OCH 3 ;
  • Another preferred NSAID is selected from a VLA-4 inhibitor and is shown infra, wherein the variables in formula Ic denote: R a is methyl, T is NH, R 2 is (CH 2 ) 3 OCH 3 , and R is 3,4- dimethoxyphenyl:
  • a preferred zwitterionic phospholipid in an addressed composition is dipalmitoyl phosphatidylcholine, phosphatidyl choline or a mixture thereof.
  • compositions are expected to be particularly efficacious in reducing e.g. an inflammation and/or improving the tolerance of an addressed NSAID.
  • a sub-therapeutically effective amount of NSAID is defined as an amount that provides reduced pharmacological efficacy in the absence of a zwitterionic phospholipid.
  • the sub-therapeutically effective amount of an NSAID is typically from 0.005 wt. % - 0.1 wt. %, preferably in the range from 0.01 wt. % - 0.05 wt. %.
  • the amount of zwitterionic phospholipid is typically from 5 - 100 times the concentration of an NSAID, preferably from 10 - 50 times the concentration of a NSAID, and in particular from 15 - 30 times the concentration of an NSAID in wt. % of the total amount of an addressed composition.
  • a particular preferred concentration is 25 times the concentration of an NSAID.
  • the term "sub-therapeutically effective amount" is defined as an amount of the NSAID that provides reduced pharmacological (i.e. anti-inflammatory) efficacy in the absence of non-covalent association with a zwitterionic phospholipid. Accordingly, in one aspect the invention is related to the use of a topical ophthalmic composition for the preparation of an eye medicament for the treatment of an ocular inflammation, which ophthalmic composition comprises
  • Ophthalmic compositions as used in the context of the present invention are either so-called unpreserved single dose compositions, or alternatively so-called preserved multi dose compositions.
  • the multi dose compositions contain a preservative being compatible with the ocular tissue.
  • a preservative is typically a quaternary ammonium salt, and in particular benzalkonium chloride.
  • the amount of preservative needed in a multi dose composition of the present invention can significantly be reduced as compared to a composition not containing a zwitterionic phospholipid.
  • a synergistically increased efficacy and tolerability of a corresponding ophthalmic composition will result.
  • quaternary ammonium salts useful in eye medicaments for preservation are in contrast with the large number of known quaternary ammonium salts ("quats") which are employed for preservation in other fields. This is clearly restricted by the ocular tolerability of an addressed preservative. Accordingly in the present invention quaternary ammonium salts with excellent ocular tolerability are highly preferred.
  • the quaternary ammonium salts useful in accordance with the present invention may be selected from a wide variety of especially ophthalmically acceptable salts and are in particular selected from sepazonium chloride, cetyltrimethylammonium bromide (cetrimide), cetylpyridinium chloride, benzoxonium chloride, benzethonium chloride, domiphen bromide (Bradosol ® ) and benzalkonium chloride
  • a further aspect of the invention is a method of increasing the ocular tolerability in a preserved and/or unpreserved ophthalmic composition, which composition comprises:
  • Still a further aspect relates to a method of treating an ocular inflammation in a subject in need of anti-inflammatory treatment, which method comprises the topical administration of an eye medicament comprising:
  • ophthalmic carriers are for example water, mixtures of water and water- miscible solvents, such as C to C 7 -alkanols, vegetable oils or mineral oils comprising from 0.5 to 5% by weight hydroxyethylcellulose, ethyl oleate, carboxymethyl-cellulose, polyvinyl- pyrrolidone and other non-toxic water-soluble polymers for ophthalmic uses, such as, for example, cellulose derivatives, such as methylcellulose, alkali metal salts of carboxy- methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, methylhydroxypropyl- cellulose and hydroxypropylcellulose, acrylates or methacrylates, such as salts of polyacrylic acid or ethyl acrylate, polyacrylamides, natural products, such as gelatin, alginates, pectins, tragacanth, karaya gum, xanthan gum, carrageenin, agar and acacia, starch derivatives, such
  • Preferred carriers are water, cellulose derivatives, such as methylcellulose, alkali metal salts of carboxymethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, methylhydroxypropylcellulose and hydroxypropylcellulose, neutral Carbopol, or mixtures thereof.
  • concentration of an ophthalmic carrier is, for example, from 1 to 100000 times the concentration of the active ingredient.
  • Buffers, tonicity enhancing agents and preservatives different from quaternary ammonium salts may be used in an ophthalmic composition of the present invention as well.
  • buffer substances are acetate, ascorbate, borate, hydrogen carbonate /carbonate, citrate, gluconate, lactate, phosphate, propionate and TRIS (tromethamine) buffers.
  • Tromethamine and borate buffer are preferred buffers.
  • the amount of buffer substance added is, for example, that necessary to ensure and maintain a physiologically tolerable pH range.
  • the pH range is typically in the range of from 5 to 9, preferably from 6 to 8.5 and more preferably from 6.5 to 8.2.
  • Tonicity enhancing agents are, for example, ionic compounds, such as alkali metal or alkaline earth metal halides, such as, for example, CaCI 2) KBr, KCI, LiCI, Nal, NaBr or NaCI, or boric acid.
  • Non-ionic tonicity enhancing agents are, for example, urea, glycerol, sorbitol, mannitol, propylene glycol, or dextrose.
  • sufficient tonicity enhancing agent is added to impart to the ready-for-use ophthalmic composition an osmolality of approximately from 50 to 1000 mOsmol, preferred from 100 to 400 mOsmol, more preferred from 200 to 400 mOsmol and even more preferred from 250 to 350 mOsmol.
  • compositions of the above-described methods may further include a neutral lipid, such as a triglyceride.
  • a neutral lipid such as a triglyceride.
  • saturated and unsaturated triglycerides may be employed in the present compositions, and include such triglycerides as tripalmitin (saturated) triolein and trilinolein (unsaturated).
  • tripalmitin saturated
  • triolein trilinolein
  • these particular triglycerides are listed here for convenience only, and are merely representative of a variety of useful triglycerides, and is further not intended to be of limiting character.
  • the amount of a neutral lipid is typically from 5 - 100 times the concentration of an NSAID, preferably from 10 - 50 times the concentration of a NSAID, and in particular from 15 - 30 times the concentration of an NSAID in wt. % of the total amount of an addressed composition.
  • a particular preferred concentration is 25 times the concentration of an NSAID.
  • the invention also pertains to the use of a topical ophthalmic composition for the preparation of an eye medicament for the treatment of an ocular inflammation, which ophthalmic composition comprises
  • composition comprises:

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Biophysics (AREA)
  • Molecular Biology (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Ophthalmology & Optometry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

La présente invention concerne l'utilisation de médicaments anti-inflammatoires non stéroïdiens par association non covalente avec des phospholipides zwitterioniques, et facultativement des lipides neutres, tels que les triglycérides, dans la préparation d'un médicament destiné au traitement d'une inflammation oculaire.
PCT/EP2002/002873 2001-03-15 2002-03-14 Compositions ophtalmiques et leur utilisation Ceased WO2002074281A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP01106548 2001-03-15
EP01106548.9 2001-03-15

Publications (1)

Publication Number Publication Date
WO2002074281A1 true WO2002074281A1 (fr) 2002-09-26

Family

ID=8176799

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2002/002873 Ceased WO2002074281A1 (fr) 2001-03-15 2002-03-14 Compositions ophtalmiques et leur utilisation

Country Status (1)

Country Link
WO (1) WO2002074281A1 (fr)

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1990011781A1 (fr) * 1989-04-04 1990-10-18 Alcon Laboratories, Inc. Utilisation de liposomes pour l'apport d'agents therapeutiques a des blessures, des coupures et abrasions
JPH05331050A (ja) * 1992-05-27 1993-12-14 Pola Chem Ind Inc 消炎鎮痛外用剤
JPH05331048A (ja) * 1992-05-28 1993-12-14 Pola Chem Ind Inc 消炎鎮痛外用剤
WO1994005298A1 (fr) * 1992-08-28 1994-03-17 Pharmos Corporation Emulsion sous-micronique comme vehicule pour l'administration oculaire d'un medicament
US5955451A (en) * 1995-05-12 1999-09-21 The University Of Texas System Board Of Regents Methods of enhancing the therapeutic activity of NSAIDS and compositions of zwitterionic phospholipids useful therein

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1990011781A1 (fr) * 1989-04-04 1990-10-18 Alcon Laboratories, Inc. Utilisation de liposomes pour l'apport d'agents therapeutiques a des blessures, des coupures et abrasions
JPH05331050A (ja) * 1992-05-27 1993-12-14 Pola Chem Ind Inc 消炎鎮痛外用剤
JPH05331048A (ja) * 1992-05-28 1993-12-14 Pola Chem Ind Inc 消炎鎮痛外用剤
WO1994005298A1 (fr) * 1992-08-28 1994-03-17 Pharmos Corporation Emulsion sous-micronique comme vehicule pour l'administration oculaire d'un medicament
US5955451A (en) * 1995-05-12 1999-09-21 The University Of Texas System Board Of Regents Methods of enhancing the therapeutic activity of NSAIDS and compositions of zwitterionic phospholipids useful therein

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
DATABASE WPI Section Ch Week 199403, Derwent World Patents Index; Class B05, AN 1994-022817, XP002065029 *
PATENT ABSTRACTS OF JAPAN vol. 018, no. 163 (C - 1181) 18 March 1994 (1994-03-18) *

Similar Documents

Publication Publication Date Title
JP2954356B2 (ja) 高分子４級アンモニウム化合物を含有する保存された眼科用薬剤組成物
US5558876A (en) Topical ophthalmic acidic drug formulations
US6239119B1 (en) Topical administration of amifostine and related compounds
EP1047406A1 (fr) Compositions pharmaceutiques autoclavables, contenant un chelateur
CA2944832A1 (fr) Preparation liquide aqueuse contenant de l'acide 2-amino-3-(4-bromobenzoyl)phenylacetique
AU709580B2 (en) Preservative systems for pharmaceutical compositions containing cyclodextrins
CA2431606A1 (fr) Methode et compositions comprenant des formulations qui contiennent des huiles de lecithine et des ains pour proteger le tractus gastro-intestinal et pour fournir une activite therapeutique amelioree
JP6373867B2 (ja) Ｌｆａ−１阻害剤製剤
JP2010043110A (ja) 高眼圧を低下させるための組成物及び方法
JP2016029094A (ja) 座瘡病変の治療のためのアダパレンと過酸化ベンゾイルとの組合せ
AR055363A1 (es) Formulaciones farmaceuticas que comprenden un beta 2- agonista de accion prolongada para administracion por nebulizacion
EP1108424A1 (fr) Comprimé matriciel permettant la libération prolongée de trimétazidine après administration par voie orale
US6291519B1 (en) Method of preventing damage to eye tissue
CA2660939A1 (fr) Compositions pharmaceutiques destinees au traitement des infections fongiques
CA2730221C (fr) Emulsion d'huile dans l'eau comprenant des ains et des halogenures d'ammonium quaternaire
CN102858352B (zh) 含有鏻抗微生物剂的药物组合物
WO1996022780B1 (fr) Procedes d'amelioration de l'activite therapeutique de medicaments non steroides anti-inflammatoires (nsaids) et compositions de phospholipides zwitterioniques utiles a ces fins
WO2002074281A1 (fr) Compositions ophtalmiques et leur utilisation
CA3010208A1 (fr) Preparation galenique comprenant un medicament topique
ES2460967T3 (es) Método para la prevención de la degradación de una sustancia térmicamente inestable
ES2883956T3 (es) Composición oftálmica que comprende ácido lipoico y ácido hialurónico
JP7378959B2 (ja) 眼科用組成物
WO2025066019A1 (fr) Compositions d'administration topique comprenant des médicaments anti-inflammatoires non stéroïdiens
JP2013510845A (ja) 緑内障および高眼圧症の治療用のプロスタグランジン化合物とｎｓａｉｄを含む医薬組合せ
JP4221073B2 (ja) 乳剤用保存剤および乳剤

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE ES FI GB GD GE GH HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LT LU LV MA MD MK MN MX NO NZ OM PH PL PT RO RU SE SG SI SK TJ TM TN TR TT UA US UZ VN YU ZA ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE TR

121 Ep: the epo has been informed by wipo that ep was designated in this application
REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: JP

WWW Wipo information: withdrawn in national office

Country of ref document: JP