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WO1990011781A1 - Utilisation de liposomes pour l'apport d'agents therapeutiques a des blessures, des coupures et abrasions - Google Patents

Utilisation de liposomes pour l'apport d'agents therapeutiques a des blessures, des coupures et abrasions Download PDF

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Publication number
WO1990011781A1
WO1990011781A1 PCT/US1990/001664 US9001664W WO9011781A1 WO 1990011781 A1 WO1990011781 A1 WO 1990011781A1 US 9001664 W US9001664 W US 9001664W WO 9011781 A1 WO9011781 A1 WO 9011781A1
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WO
WIPO (PCT)
Prior art keywords
liposomes
cholesterol
mol
polymer
diameter
Prior art date
Application number
PCT/US1990/001664
Other languages
English (en)
Inventor
Jack Michael Shaw
Diana Maria Cordova
Original Assignee
Alcon Laboratories, Inc.
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 Alcon Laboratories, Inc. filed Critical Alcon Laboratories, Inc.
Priority to KR1019910701279A priority Critical patent/KR920700691A/ko
Publication of WO1990011781A1 publication Critical patent/WO1990011781A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • 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
    • 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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant
    • 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
    • A61P27/02—Ophthalmic agents

Definitions

  • This Invention is directed to methods for treating wounds, cuts, and abrasions caused by Injury, trauma, surgery or disease through the delivery of therapeutic healing agents to such sites. More particularly, the Invention is directed to the delivery of therapeutic agents to wounds, cuts and abrasions on the cornea or ocular surface of the eye via l lposome and
  • Uposome-polymer compositions which specifically adsorb or adhere to the wound, cut or abrasion.
  • Liposomes are sac or vesicle-Hke bllayer structures made of phospholipids.
  • Iiposomes as delivery vehicles for drugs or other therapeutic agents.
  • Liposomes as delivery vehicles of therapeutic agents to the eye is also known; see for example, U.S. Patent No. 4,649,047 Issued to R. Kaswan, March 10, 1987 disclosing the treatment of traumatic or surgical
  • 4,588,578 issued to Fountain et al., May 13, 1986 discloses the preparation of bloactlve agent carrying lipid vesicles which can be applied topically for the treatment of ocular disease such as glaucoma.
  • Skuta et al. in American Journal of Ophthalmology, Vol.103, No.5, May, 1987 disclose the delivery of 5-fluorouracil In a Hposome via subconjunctlval Injection as a method for inhibiting flbroblast proliferation following posterior sclerectomles.
  • Skuta et al. characterize their delivery system as an advantageous, sustained release delivery system; prior methods of treatment with the free drug required frequent subconjunctlval Injections.
  • liposomes for certain types of targeted drug delivery in the,eye has been described previously.
  • Norley et al., in J. Immunol., Vol.136, No.2 disclose the targeting of drug-loaded liposomes to Herpes Simplex virus (HSV) Infected comeal cells, in vitro.
  • HSV Herpes Simplex virus
  • the targeting moiety Incorporated in the liposomes is an antiviral monoclonal antibody to glycoprotem D of HSV containing a covalently-bound fatty acyl chain. This "Immunoliposome" was shown to bind specifically to HSV Infected rabbit comeal cells.
  • the sole figure illustrates adsorption of liposomes of the present Invention to corneal wounds versus their relative nonadsorption to unwounded corneas.
  • This Invention is directed to methods for treating wounds by the delivery of therapeutic agents in liposomes to the wound site.
  • the liposomes preferentially adsorb to wound sites and not to healthy tissue surrounding the sites.
  • the Invention is directed to the delivery of therapeutic agents in liposomes to wounds on the surface of the eye, such as the cornea, conjunctiva and sclera. Because the Hposome carriers bioadsorb almost exclusively to the wound site on the ocular surface, the amount of therapeutic agent normally administered as a free agent can be significantly reduced. Consequently, the therapeutic Index or margin of safety of a drug delivered according to the method of this invention will be improved.
  • liposomes will preferentially bioadsorb, with a high degree of specificity, to corneal wounds, such as cuts and abrasions.
  • the present Invention is based on the surprising discovery that liposomes adhere to wound sites but not to the surrounding healthy tissue.
  • wound Includes cuts, scrapes, abrasions or tissue damage caused by Injury, trauma, surgery or disease.
  • therapeutic agents which are known to be effective in the treatment of wounds can, according to this Invention, be delivered specifically to wound sites with any nontoxic phosphollpid/cholesterol Hposome.
  • the liposomes containing therapeutic agents are useful for treating wounds of the eye, particularly the cornea.
  • Liposomes which can be used according to this Invention include any liposoae which bioadsorbs to a wound site,
  • liposomes will comprise a llpld and will typically comprise 50-90 mol% of one or more synthetic or naturally occurring phospholiplds and 10-50 molar percent (mol%) cholesterol.
  • Phospholiplds which can be used in formulating liposomes for use according to the present invention include: phosphatidylcholine, phosphatldylglycerol, phos ⁇ hatidylethanolamine or phosphatldylserlne with diacyl chains of typically 14 to 18 carbons of either the saturated or monoene variety.
  • lipids Including phospholiplds, which can be used in the formllation of the liposomes include, but are not limited to: phosphatidylinositol, sphlngoi ⁇ yeHn, phosphatidic add, cerebrosldes, cardlolipin and Iysophospholipids.
  • the liposomes can be prepared by a number of methods, including but not limited to, procedures for preparing
  • MLV multilamellar
  • SUV small unllamellar
  • LUV large unilamellar
  • SPLV piurilamellar
  • REV reverse-phase evaporation
  • liposomes which are relatively small, that is, 10 to 500 nanometers (nm) in diameter, preferably less than 100 nm in diameter exhibit maximal wound site coverage in comparison to the larger MLV-type liposomes of 500 to 10,000 nm in diameter.
  • the preferred Uposome composition of the present invention comprises: phosphatldylchollne (50 mol%); the
  • the preferred liposomes are 20 to 200 nm in diameter, preferably less than 100 nm.
  • the production of liposomes of less than 100 nm is accomplished by passing MLV liposomes through a Microfluldizer R (Microfluidics, Corp., Newton, Mass.) and their size will typically vary less than about 30%.
  • the liposomes of the present Invention When composed of phosphatldylchollne with saturated acyl chains, the liposomes of the present Invention have an aqueous liquid-crystalline phase transition of between about 35 and 42 degrees centigrade, preferably close to the human physiological temperature of 37 degrees centigrade.
  • the liposomes of the present invention which are composed of phosphatldylchollne with monoene containing acyl chains, exhibit phase transitions well below zero degrees centigrade, and also show good bioadsorptlve properties to wound sites.
  • This invention is not limited to only phosphollpld or phospholipid/cholesterol containing liposomes, but also comprises phospholipid/cholesterol liposomes containing polymers.
  • These liposome-polymer combinations provide for formulations with increased viscosity. Any polymer which will provide for increased viscosity around the liposomes, and is compatible with the tissues of the eye can be used.
  • the polymer(s) are added to provide for a composition with a viscosity of between about 5 cps. and 1000 cps., preferably between about 15 cps. and 200 cps.
  • Examples of polymers which can be used according to the methods of this invention Include natural polymers such as
  • polysaccharldes e.g. alglnate, starch, modified celluloses such as hydroxypropylmethylcellulose and hydroxyethylcellulose
  • gelatins e.g. albumin, casein, chitosan and collagen
  • synthetic polymers which can be used include polylactideglycolide copolymer, polylactlde, polyhydroxyethylmethacrylate,
  • polyesteramides polyorthoesters, polymethacrylate
  • the liposomes in their viscous matrix provide for longer retention of the formulation in the eye and therefore bloadsorptlon of the liposomes to the wound site over longer time periods.
  • the percentage of polymer in the Uposome formulation will depend on the polymer Itself, but in general the concentration of polymer can range from about 0.25 - 3.0 wt.%.
  • Therapeutic agents which can be delivered to wound sites in uposome or Hposome/polymer formulations which bioadsorb to such sites comprise all therapeutic agents useful for the treatment of wounds, cuts and abrasions caused by Injury, trauma, surgery and/or disease.
  • Such therapeutic agents will typically comprise, but are not limited to: growth factors, steroids, antloxldants, nonsteroldal ant1Inflammatory agents, antibiotics, Immunomodulators, antiallerglcs and compounds which make up basement membranes, such as fibronectln and lamlnln.
  • Further agents include "biological response modifiers" (I.e. agents whose mechanisms of action Involve the individual's own biological response); see, Oldham, Biological Response Modifiers, Chapter 1, Torrence (Ed.) Academic Press, 1985, Incorporated herein by reference.
  • the liposomes containing the therapeutic agent or drug for the treatment of wounds are applied topically to the eye.
  • the administration, sequence of administration when more than one therapeutic agent is used, and the concentrations of the therapeutic agents in the liposomes of the present invention depends on numerous factors. These factors can include: the specific therapeutic agent or agents to be used, the nature of the wound, and various clinical factors, Including the extent and type of wound being treated, the medical history of the patient and symptoms associated with the wound, such as Inflammation or edema, etc. Selection of the specific
  • the amount and frequency of therapeutic agent normally administered as the free agent can be reduced.
  • the amount of therapeutic agent administered in liposomes according to the present invention can be reduced by up to about 2/3 of the dose administered by other methods such as in aqueous drops, ointments or suspensions.
  • the following examples are directed to the binding of liposomes and liposomes comprising therapeutic agents to corneal wounds.
  • the examples are illustrative of the preferential binding of the liposomes to wound sites, but they are in no way limiting.
  • fluorescent dye film was then rehydrated with Dulbecco's phosphate buffered saline containing 0.9 mM calcium and 0.49 mM magnesium (10 ml). The pH was adjusted to 7.4 with dilute sodium hydroxide. This rehydratlon resulted in the spontaneous formation of multilamellar liposomes.
  • Freshly dissected rabbit corneas were washed in BSS Plus R (Alcon Laboratories, Inc.). The corneas were placed in plastic culture dishes and either cut or scraped medially through the epithelial surface with a scalpel blade. Immediately following the cutting or scraping, 1 ⁇ 1 of the fluorescentlabeled Uposome formulation was applied to the corneal surface. After 0.5 min the corneas were washed 3 times with 5 ml BSS Plus R at 37°C in a CO 2 Incubator using a rotary shaker.
  • Each cornea was examined using fluorescence microscopy by viewing the corneas in a chamber created by two glass
  • the flow cell consists of a plastic block (11.5 X 11.5 cm X 1.2 cm) in which four 1 cm holes were bored for viewing under phase.
  • a recessed area -2.5 X 2.5 cm and -2.5 mm deep was machined over and around each hole and an 18 X 18 mm coverslip adhered with silicon grease to the block within the recessed area.
  • a thin shallow Inset ledge -0.3 mm deep was machined within the 2.5 X 2.5 cm recessed area for accommodating a top coverslip of 25 X 25 mm adhered to the ledge using silicon grease.
  • Each wounded cornea was in turn placed on an 18 X 18 mm coverslip in one chamber of the flow cell and covered with a 25 X 25 mm top coverslip.
  • the corneas were constantly perfused with BSS Plus R and the temperature was maintained at 37°C
  • Video images of the fluorescent-labeled liposomes present on the corneal surface were recorded at a magnification of 1134X.
  • the Images appeared black and white with the white regions representing those areas In which the labeled liposomes were located. The black areas in the Images
  • liposomes used according to the methods of the present Invention can be used to deliver wound treating agents to wounds because they preferentially adhere to wound sites and not to unwounded sites.
  • composition can be applied topically to the eye to promote reepitheliatlon of a wounded cornea.
  • EGF Epidermal Growth Factor
  • the phospholiplds and cholesterol are weighed as dry lyophilized powders in a glass container (230 mg phosphatldylchollne, 140 mg phosphatldylglycerol, 50 mg cholesterol) followed by the addition of 1 ml t-butanol.
  • the mixture is then solubilized by gentle mixing in a 40°C water bath, sterile filtered and then freeze dried to remove the t-butanol.
  • the lyophilized llpld powder is then rehydrated with 100 ⁇ g of sterile EGF dissolved in
  • Example 3 Dulbecco's phosphate buffered saline containing 0.9 mM calcium and 0.49 mM magnesium (10 ml). This rehydratlon will result in the spontaneous formation of multilamellar liposomes containing EGF. To maximize entrapment of EGF in the liposomes, the formulation is freeze dried a second time then rehydrated with 10ml sterile delonized water before use.
  • the phospholiplds and cholesterol are weighed as dry lyophilized powders in a glass container followed by the addition of tertiary-butanol (about 4 ml/4 mg of total lipld).
  • Llpophilic drugs and therapeutic agents which are soluble in tertiarybutanol can be added at this point at concentrations effective for the treatment of wounds.
  • the mixture is then completely solubllized by gentle mixing in a 40°C water bath and then freeze dried to remove the tertiary-butanol.
  • the lyophilized powder is rehydrated with Dulbecco's phosphate buffered saline containing 0.9 mM calcium and 0.49 mH magnesium. The pH is adjusted to 7.4 with dilute sodium hydroxide. Water soluble drugs and
  • Multilamellar liposomes containing drugs or therapeutic agents are formed by Incubation and mixing in a rotary water bath at 40°C. For maximum entrapment of water soluble drugs and therapeutic agents, the solution can be freeze dried again and dried again and rehydrated with water followed by further
  • the multilamellar liposomes can be passed through a Microfluidizer R (Microfluldlcs, Corp.) repeatedly until the desired proportion of smaller liposomes 1s obtained.
  • Microfluidizer R Microfluldlcs, Corp.
  • some Uposome formulations for example, some of those containing proteins, should not be passed through the microfluidizer because of denaturation of the protein.
  • powdered gelatin (Swine, skin type 1, Sigma Chemical Co., St. Louis, MO.) is added at a concentration of 25 mg/ml formulation. The mixture is then gently heated and mixed at 40°C until the gelatin is solubllized.

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Abstract

Procédés d'apport d'agents thérapeutiques à des blessures par l'intermédiaire de liposomes qui se fixent de préférence sur les blessures. Sont également décrits des procédés d'apport d'agents thérapeutiques contenus dans des liposomes à des blessures sur la surface oculaire de l'÷il.
PCT/US1990/001664 1989-04-04 1990-04-03 Utilisation de liposomes pour l'apport d'agents therapeutiques a des blessures, des coupures et abrasions WO1990011781A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
KR1019910701279A KR920700691A (ko) 1989-04-04 1990-04-03 상처부위, 절개부위, 찰과상 부위에 치료제의 투여에 대한 리포좀(liposomes)의 용도

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US33316489A 1989-04-04 1989-04-04
US333,164 1989-04-04

Publications (1)

Publication Number Publication Date
WO1990011781A1 true WO1990011781A1 (fr) 1990-10-18

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EP (1) EP0465588A4 (fr)
JP (1) JPH04505319A (fr)
KR (1) KR920700691A (fr)
AU (1) AU633078B2 (fr)
CA (1) CA2013770A1 (fr)
IL (1) IL93996A0 (fr)
WO (1) WO1990011781A1 (fr)
ZA (1) ZA902593B (fr)

Cited By (32)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991012808A1 (fr) * 1990-02-22 1991-09-05 Macnaught Pty Limited Larmes artificielles
EP0454026A1 (fr) * 1990-04-26 1991-10-30 ZAMBON GROUP S.p.A. Composition pharmaceutique contenant le facteur de croissance épidermique pour le traitement des désordres neurodégénérescents
EP0639373A1 (fr) * 1993-08-20 1995-02-22 Euroceltique S.A. Préparations pour l'application externe d'agents antiseptiques et/ou d'agents favorisant la cicatrisation
US5589189A (en) * 1994-09-14 1996-12-31 Nexstar Pharmaceuticals, Inc. Liposome dispersion
WO1997039769A1 (fr) * 1996-04-19 1997-10-30 R-Tech Ueno, Ltd. Composition de medicament comprenant de l'albumine en tant que principe actif
US5863556A (en) * 1993-08-20 1999-01-26 Euro-Celtique, S.A. Preparations for the external application of antiseptic agents and/or agents promoting the healing of wounds
EP0982025A1 (fr) * 1998-08-28 2000-03-01 Wilhelm Prof. Dr. Stoffel Larmes artificielles
WO2001012245A1 (fr) * 1999-08-14 2001-02-22 Depuy International Limited Lubrifiant pour articulations
WO2002074281A1 (fr) * 2001-03-15 2002-09-26 Novartis Ag Compositions ophtalmiques et leur utilisation
WO2003018028A1 (fr) * 2001-08-22 2003-03-06 Eidgenoessische Technische Hochschule Zuerich Compositions renfermant des phospholipides charges negativement et servant a traiter et/ou a prevenir la degenerescence maculaire et methode de fabrication associee
WO2003024422A1 (fr) * 2001-09-18 2003-03-27 Vasogen Ireland Limited Procede permettant d'accelerer la guerison d'un traumatisme au moyen d'entites synthetiques ou naturelles simulant l'apoptose
WO2003061667A1 (fr) * 2002-01-21 2003-07-31 Vasogen Ireland Limited Corps portant du phosphate-glycerol pharmaceutiquement acceptable
WO2004024123A1 (fr) * 2002-09-16 2004-03-25 Vasogen Ireland Limited Acceleration du retablissement suite a des traumas
WO2004037271A1 (fr) * 2002-10-25 2004-05-06 Vasogen Ireland Limited Regulation de la cyclooxygenase au moyen de phosphatidylcholine liposomes
WO2004037270A1 (fr) * 2002-10-25 2004-05-06 Vasogen Ireland Limited Regulation de cyclooxygenase avec des liposomes pg
WO2004082688A1 (fr) * 2003-03-20 2004-09-30 Vasogen Ireland Limited Agonistes et antagonistes de recepteur de phosphatidylglycerol (pg)
WO2007038549A1 (fr) * 2005-09-26 2007-04-05 Vasogen Ireland Limited Traitement d'inflammations et d'anomalies vasculaires de l'oeil
WO2007073704A1 (fr) * 2005-12-29 2007-07-05 Centro De Ingeniería Genética Y Biotecnología Utilisation topique du facteur de croissance epidermique dans des liposomes afin de prevenir l'amputation du pied diabetique
ES2284398A1 (es) * 2006-04-27 2007-11-01 Universidad Complutense De Madrid Formulacion de vesiculas liposomales en soluciones acuosas con caracteristicas de pelicula lagrimal.
US7297344B1 (en) 1999-05-27 2007-11-20 Euro-Celtique, S.A. Preparations for the promotion of wound healing in the upper respiratory tract and/or ear
US7300667B1 (en) 1999-05-27 2007-11-27 Euro-Celtique, S.A. Preparations for the application of anti-inflammatory, especially antiseptic agents and/or agents promoting the healing of wounds, to the lower respiratory tract
WO2008016258A1 (fr) * 2006-08-02 2008-02-07 Daewoong Co., Ltd. Nanoliposome utilisant de la léthicine estérifiée et son procédé de preparation, et composition de prevention et de traitement de maladies de la peau en comportant
AU2003201569B2 (en) * 2002-01-21 2008-09-11 Vasogen Ireland Limited Pharmaceutically acceptable phosphate-glycerol carrying bodies
US7468194B1 (en) 1999-05-27 2008-12-23 Euro-Celtique, S.A. Preparations for the application of anti-inflammatory agents
EP1401396A4 (fr) * 2001-06-15 2009-08-05 Cornerstone Pharmaceuticals Compositions pharmaceutique et de diagnostic contenant des nanoparticules utiles pour le traitement de tissus et de cellules cibles
EP2123258A1 (fr) * 2008-05-23 2009-11-25 Liplasome Pharma A/S Liposomes pour l'administration de médicaments
WO2009118658A3 (fr) * 2008-03-26 2010-03-11 University Of Oxford Liposomes ciblant le réticulum endoplasmique
US7799760B2 (en) 2001-12-20 2010-09-21 Centro De Ingenieria Genetica Y Biotecnologia Use of pharmaceutical composition containing epidermal growth factor (EGF) for diabetic foot amputation prevention
EP2255788A4 (fr) * 2008-02-29 2013-07-10 Nagoya Ind Science Res Inst Liposome pour une administration au segment postérieur de l' il et composition pharmaceutique pour une maladie du segment postérieur de l' il
US8703744B2 (en) 2009-03-27 2014-04-22 The Chancellor, Masters And Scholars Of The University Of Oxford Cholesterol level lowering liposomes
US8741848B2 (en) 2006-01-31 2014-06-03 Centro De Ingenieria Genetica Y Biotecnologia Pharmaceutical composition of microspheres for preventing diabetic foot amputation
US8808715B1 (en) * 2004-11-23 2014-08-19 Georgia Regents Research Institute, Inc Methods and compositions for modulating keratinocyte function

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JP4669665B2 (ja) * 2004-04-12 2011-04-13 正彦 阿部 細胞毒性のないポリカチオン修飾リポソームおよびその製造方法
EP3500312B1 (fr) * 2016-08-18 2024-04-10 Troy Bremer Administration d'urée à des cellules de la macula et de la rétine à l'aide de constructions de liposomes.

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Cited By (46)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991012808A1 (fr) * 1990-02-22 1991-09-05 Macnaught Pty Limited Larmes artificielles
EP0454026A1 (fr) * 1990-04-26 1991-10-30 ZAMBON GROUP S.p.A. Composition pharmaceutique contenant le facteur de croissance épidermique pour le traitement des désordres neurodégénérescents
US5200396A (en) * 1990-04-26 1993-04-06 Zambon Group S.P.A. Method of treating neurodegenerative disorders using epidermal growth factor
EP0639373A1 (fr) * 1993-08-20 1995-02-22 Euroceltique S.A. Préparations pour l'application externe d'agents antiseptiques et/ou d'agents favorisant la cicatrisation
US5863556A (en) * 1993-08-20 1999-01-26 Euro-Celtique, S.A. Preparations for the external application of antiseptic agents and/or agents promoting the healing of wounds
US5589189A (en) * 1994-09-14 1996-12-31 Nexstar Pharmaceuticals, Inc. Liposome dispersion
WO1997039769A1 (fr) * 1996-04-19 1997-10-30 R-Tech Ueno, Ltd. Composition de medicament comprenant de l'albumine en tant que principe actif
WO2000012061A1 (fr) * 1998-08-28 2000-03-09 Wilhelm Stoffel Liquide lacrymal de synthèse
EP0982025A1 (fr) * 1998-08-28 2000-03-01 Wilhelm Prof. Dr. Stoffel Larmes artificielles
US7468194B1 (en) 1999-05-27 2008-12-23 Euro-Celtique, S.A. Preparations for the application of anti-inflammatory agents
US7300667B1 (en) 1999-05-27 2007-11-27 Euro-Celtique, S.A. Preparations for the application of anti-inflammatory, especially antiseptic agents and/or agents promoting the healing of wounds, to the lower respiratory tract
US7297344B1 (en) 1999-05-27 2007-11-20 Euro-Celtique, S.A. Preparations for the promotion of wound healing in the upper respiratory tract and/or ear
WO2001012245A1 (fr) * 1999-08-14 2001-02-22 Depuy International Limited Lubrifiant pour articulations
WO2002074281A1 (fr) * 2001-03-15 2002-09-26 Novartis Ag Compositions ophtalmiques et leur utilisation
EP1401396A4 (fr) * 2001-06-15 2009-08-05 Cornerstone Pharmaceuticals Compositions pharmaceutique et de diagnostic contenant des nanoparticules utiles pour le traitement de tissus et de cellules cibles
WO2003018028A1 (fr) * 2001-08-22 2003-03-06 Eidgenoessische Technische Hochschule Zuerich Compositions renfermant des phospholipides charges negativement et servant a traiter et/ou a prevenir la degenerescence maculaire et methode de fabrication associee
WO2003024422A1 (fr) * 2001-09-18 2003-03-27 Vasogen Ireland Limited Procede permettant d'accelerer la guerison d'un traumatisme au moyen d'entites synthetiques ou naturelles simulant l'apoptose
US7799760B2 (en) 2001-12-20 2010-09-21 Centro De Ingenieria Genetica Y Biotecnologia Use of pharmaceutical composition containing epidermal growth factor (EGF) for diabetic foot amputation prevention
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JPH04505319A (ja) 1992-09-17
CA2013770A1 (fr) 1990-10-04
EP0465588A4 (en) 1992-06-03
EP0465588A1 (fr) 1992-01-15
KR920700691A (ko) 1992-08-10
ZA902593B (en) 1991-01-30
IL93996A0 (en) 1991-01-31
AU5429790A (en) 1990-11-05
AU633078B2 (en) 1993-01-21

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