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EP0465588A1 - 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

Info

Publication number
EP0465588A1
EP0465588A1 EP19900906472 EP90906472A EP0465588A1 EP 0465588 A1 EP0465588 A1 EP 0465588A1 EP 19900906472 EP19900906472 EP 19900906472 EP 90906472 A EP90906472 A EP 90906472A EP 0465588 A1 EP0465588 A1 EP 0465588A1
Authority
EP
European Patent Office
Prior art keywords
liposomes
cholesterol
mol
polymer
diameter
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.)
Withdrawn
Application number
EP19900906472
Other languages
German (de)
English (en)
Other versions
EP0465588A4 (en
Inventor
Jack Michael Shaw
Diana Maria Cordova
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.)
Alcon Vision LLC
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
Publication of EP0465588A1 publication Critical patent/EP0465588A1/fr
Publication of EP0465588A4 publication Critical patent/EP0465588A4/en
Withdrawn legal-status Critical Current

Links

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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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Ophthalmology & Optometry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Dispersion Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Physics & Mathematics (AREA)
  • Optics & Photonics (AREA)
  • Medicinal Preparation (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

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'oeil.
EP19900906472 1989-04-04 1990-04-03 The use of liposomes for the delivery of therapeutic agents to wounds, cuts and abrasions Withdrawn EP0465588A4 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US33316489A 1989-04-04 1989-04-04
US333164 1989-04-04

Publications (2)

Publication Number Publication Date
EP0465588A1 true EP0465588A1 (fr) 1992-01-15
EP0465588A4 EP0465588A4 (en) 1992-06-03

Family

ID=23301595

Family Applications (1)

Application Number Title Priority Date Filing Date
EP19900906472 Withdrawn EP0465588A4 (en) 1989-04-04 1990-04-03 The use of liposomes for the delivery of therapeutic agents to wounds, cuts and abrasions

Country Status (8)

Country Link
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)

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AU655919B2 (en) * 1990-02-22 1995-01-19 Macnaught Pty Limited Artificial tears
IT1240683B (it) * 1990-04-26 1993-12-17 Zambon Spa Composizione farmaceutica contenente egf
DE9312509U1 (de) * 1993-08-20 1993-10-28 Euro-Celtique S.A., Luxemburg/Luxembourg Präparate zur äußeren Verabreichung von antiseptischen und/oder die Wundheilung fördernden Wirkstoffen
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
DE69730476T2 (de) * 1996-04-19 2005-11-17 Tsubota, Kazuo, Funabashi Albumin als aktiver Bestandteil zur Behandlung von Bindehaut- und Hornhautverletzungen und von trockenen Augen
EP0982025A1 (fr) * 1998-08-28 2000-03-01 Wilhelm Prof. Dr. Stoffel Larmes artificielles
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
ATE340561T1 (de) 1999-05-27 2006-10-15 Euro Celtique Sa Verwendung von antiseptika zur herstellung von arzneimitteln zur prophylaxe und behandlung von entzündungen im korperinneren des menschen
GB9919131D0 (en) * 1999-08-14 1999-10-13 Depuy Int Ltd Joint lubrication
WO2002074281A1 (fr) * 2001-03-15 2002-09-26 Novartis Ag Compositions ophtalmiques et leur utilisation
BR0210994A (pt) * 2001-06-15 2004-06-08 Cornerstone Pharmaceuticals Compostos farmacêuticos e de diagnósticos contendo nanopartìculas úteis para tratamento de tecidos e células
DE10141018A1 (de) * 2001-08-22 2003-03-13 Eth Zuerich Eidgenoessische Te Verwendung von negativ geladenen Phospholipiden, sowie Zusammensetzungen umfassend Phospholipide zur Behandlung des Auges
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
CU23043A1 (es) 2001-12-20 2005-05-20 Ct Ingenieria Genetica Biotech Composicion farmaceutica que contiene factor de crecimiento epidrmico (egf) para la prevencion de la amputacion de pie diabetico.
CA2368656A1 (fr) * 2002-01-21 2003-07-21 Vasogen Ireland Limited Appariement recepteur-ligand pour produire une reeaction anti-inflammatoire
AU2003201569B2 (en) * 2002-01-21 2008-09-11 Vasogen Ireland Limited Pharmaceutically acceptable phosphate-glycerol carrying bodies
AU2003266884A1 (en) * 2002-09-16 2004-04-30 Vasogen Ireland Limited Accelerating recovery from trauma
AU2003275850A1 (en) * 2002-10-25 2004-05-13 Vasogen Ireland Limited Cyclooxygenase regulation with ps 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)
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
US8808715B1 (en) * 2004-11-23 2014-08-19 Georgia Regents Research Institute, Inc Methods and compositions for modulating keratinocyte function
EP1928420A1 (fr) * 2005-09-26 2008-06-11 Vasogen Ireland Limited Traitement d'inflammations et d'anomalies vasculaires de l'oeil
CU23411B6 (es) * 2005-12-29 2009-09-08 Ct Ingenieria Genetica Biotech Uso tópico del factor de crecimiento epidérmico en liposomas para prevenir la amputación del pie diabético
CU23388B6 (es) 2006-01-31 2009-07-16 Ct Ingenieria Genetica Biotech Composición farmacéutica de microesferas para prevenir la amputación del pie diabético
ES2284398B2 (es) * 2006-04-27 2008-12-16 Universidad Complutense De Madrid Formulacion de vesiculas liposomales en soluciones acuosas con caracteristicas de pelicula lagrimal.
KR100752990B1 (ko) 2006-08-02 2007-08-30 주식회사 대웅 나노리포좀 및 천연 추출물을 포함하는 피부 질환의 예방또는 치료용 조성물
CA2717133C (fr) * 2008-02-29 2016-04-26 Nagoya Industrial Science Research Institute Liposome pour une administration au segment posterieur de l'oeil et composition pharmaceutique pour une maladie du segment posterieur de l'oeil
JP2011518124A (ja) * 2008-03-26 2011-06-23 ユニバーシティ・オブ・オックスフォード 小胞体ターゲッティングリポソーム
EP2123258A1 (fr) * 2008-05-23 2009-11-25 Liplasome Pharma A/S Liposomes pour l'administration de médicaments
CN102427804A (zh) 2009-03-27 2012-04-25 牛津大学之校长及学者 降低胆固醇水平的脂质体
MX393897B (es) * 2016-08-18 2025-03-24 Troy Bremer Suministro de urea a células de la mácula y retina mediante el uso de construcciones de liposoma.

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Also Published As

Publication number Publication date
WO1990011781A1 (fr) 1990-10-18
JPH04505319A (ja) 1992-09-17
KR920700691A (ko) 1992-08-10
AU5429790A (en) 1990-11-05
IL93996A0 (en) 1991-01-31
CA2013770A1 (fr) 1990-10-04
AU633078B2 (en) 1993-01-21
ZA902593B (en) 1991-01-30
EP0465588A4 (en) 1992-06-03

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