WO1990011079A1 - Emploi de phosphoglycerides de monoacyle pour ameliorer la penetration de medicaments ophtalmiques dans la cornee - Google Patents

Emploi de phosphoglycerides de monoacyle pour ameliorer la penetration de medicaments ophtalmiques dans la cornee Download PDF

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Publication number
WO1990011079A1
WO1990011079A1 PCT/US1990/001584 US9001584W WO9011079A1 WO 1990011079 A1 WO1990011079 A1 WO 1990011079A1 US 9001584 W US9001584 W US 9001584W WO 9011079 A1 WO9011079 A1 WO 9011079A1
Authority
WO
WIPO (PCT)
Prior art keywords
composition
monoacyl
lysolecithin
phosphoglyceride
drug
Prior art date
Application number
PCT/US1990/001584
Other languages
English (en)
Inventor
Tai-Lee Ke
Eugene R. Cooper
Douglas F. Hager
Jamieson Charles Keister
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 KR1019910701215A priority Critical patent/KR920700651A/ko
Publication of WO1990011079A1 publication Critical patent/WO1990011079A1/fr

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Classifications

    • 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
    • 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

Definitions

  • the present invention relates to the field of ophthalmic drug delivery. More particularly, this Invention relates to enhancement of the penetration of ophthalmic drugs and other therapeutic agents through the cornea of the eye.
  • the epithelium In order for a drug to pass through the cornea, it must penetrate three layers of tissue, namely, the epithelium, stroma and the endothelium. Except for highly Upophilic drugs, the epithelium is the main barrier to drug penetration of the cornea. Penetration of the stroma basically involves diffusion of the drug through a barrier which Is approximately 360 microns thick. There are currently no known methods of enhancing drug
  • BAC benzalkonium chloride
  • DMSO dimethyl sulfoxide
  • EDTA ethylenedlamine tetraacetate
  • AZONE R 1- dodecylazayl-cycloheptan-2-one
  • a principal objective of the present invention is to provide for a method of enhancing the ability of drugs and therapeutic agents to penetrate the cornea.
  • a further objective of the present Invention is to provide topical ophthalmic compositions containing one or more agents for enhancing the corneal penetration of the active ingredlent(s) contained therein.
  • Figure I compares the amount of a drug, para-aminoclonidine, found in the aqueous humor of rabbits which were administered the drug with and without lysophosphatidylchollne C18:0 (Lysopc).
  • Figure II compares the amount of a drug, para-aminoclonidine, found in the aqueous humor of rabbits which were administered the drug with polyvlnyl alcohol (PVA), with lysopc and PVA and without either lysopc or PVA.
  • PVA polyvlnyl alcohol
  • the present Invention is based on the discovery that amphlpathlc monoacyl phosphoglycerldes effectively and safely enhance the corneal penetration of ophthalmic drugs.
  • These penetration enhancers can be used in compositions comprising any ophthalmic drug which, to be effective, must be substantially taken up by the aqueous humor, ciliary processes and other tissues in the eye upon topical administration. Examples of classes of ophthalmic drugs with which the monoacyl
  • phosphoglycerldes of the present Invention can be used, include: steroids, growth factors, cycloplegics, miotics, mydriatics, therapeutic proteins and peptides, antioxidants, aldose reductase inhibitors, nonsteroidal antiinflammatories, immunomodulators, antiallergies, antimicrobials and anti-glaucoma agents.
  • the penetration enhancing monoacyl phosphoglycerldes used in the present invention have the following structure:
  • R 1 and R 2 is hydrogen, thiol, hydroxyl, amino, lower alkyl, lower alkoxy (eg. methyl, ethyl, methoxy or ethoxy) or alkyl sulflde and the other is an esterlfied, etherifled or amidifled hydrophoblc group, and R 3 is a hydrophllic group.
  • the preferred hydrophoblc groups include saturated and unsaturated aliphatic hydrocarbon groups which range from 14 to 24 carbons in length with zero to 5 double bonds.
  • the aliphatic hydrocarbon groups can be straight or branched chain and may be substituted by one or more aromatic, cycloaliphatic or hydrophilic (e.g.
  • Suitable hydrophllic groups (R 3 ) include 0-inositol, choline, 0-choline, 0-carnltlne, 0-(CH 2 ) 3 -choline, 0-glycerol and 0-lysophosphatidylglycerol.
  • the preferred monoacyl phosphoglycerides are
  • lysophospholipids such as Iysophosphatidyicholine, lysophosphatidylinositol, (lysolecithin), Iysocardiolipin,
  • lysodesoxyliplds lysophosphorylipids and ⁇ -lyso-r-0-alkyl or 0- alkenyl phospholipids such as DL- ⁇ -Lysolecithin-r-0-hexadecyl and DL- ⁇ -Lysolecithin-r-0-alkyl.
  • the most preferred monoacyl phosphoglycerlde is 1-acyl lysophosphatidylcholine (C18:0, C18:1, C16:0 or C16:1).
  • the monoacyl phosphoglycerides which are useful in the present invention may be described as being "amphlpathic", since they include both hydrophilic and hydrophobic groups. While not wishing to be bound by any theory, it is believed that
  • amphipathic monoacyl phosphoglycerldes enhance the corneal penetration of drugs by partition and interaction with protein, glycoprotein and lipld components present in the membrane of the corneal epithelium. Such interaction is believed to alter the degree of order of the proteins and lipids in the membrane, thereby modifying the function of the epithelium as a barrier to drug penetration. Whatever the mechanism, the net result is that drug penetration of the epithelium is enhanced.
  • monoacyl phosphoglycerides in accordance with the present invention to enhance corneal penetration of drugs significantly Increases the amount of drug which is able to penetrate the cornea.
  • the degree of enhancement will vary with different drugs, but in some cases may be as much as 3-fold or more. Because drugs can more effectively penetrate the cornea, less drug is lost due to flow down the punctum and therefore less drug need be administered to effectively treat a particular Indication. This is particularly beneficial when It is necessary to administer drugs which cause severe systemic side effects.
  • the amount of monoacyl phosphoglycerlde required in order to enhance corneal penetration will depend on various factors, such as the solubility, partition coefficient and molecular weight of the ophthalmic drug or therapeutic agent; the exdplents (surfactants, preservatives, polymers) present in the formulation; and the particular monoacyl phosphoglyceride being used. In general, the more lipophilic the drug to be delivered, the less monoacyl phosphoglyceride Is required to enhance penetration, and the higher the concentration of monoacyl phosphoglycerlde, the better the corneal penetration. Typically, one or more monoacyl phosphoglycerides will be used in an amount of from about 0.001% to about 0.5% (weight/volume) preferably from about 0.01 to 0.1%.
  • the monoacyl phosphoglycerldes can be used in any topical drug delivery system wherein an excipient or vehicle will not substantially impair or prevent the monoacyl
  • the monoacyl phosphoglycerldes can be formulated in compositions which are solutions, suspensions, ointments, gels or films.
  • the type of composition will depend on, among other things, the chemical and physical properties of the drug or therapeutic agent to be delivered. These properties are well known to a person of ordinary skill In the art of drug formulation and delivery,
  • the present invention further comprises the use of polymers in conjunction with the monoacyl phosphoglycerides to enhance ocular bioavailability.
  • the compositions of the present invention are retained on the cornea longer. As a result, the penetration enhancing components of the compositions can more effectively interact with the corneal epithelium to enhance penetration of the desired drugs or therapeutic agents Into the eye. It has been found that the use of polymers In conjunction with monoacyl
  • phosphoglycerides can provide for up to about a 9 to 10 fold increase in the amount of drug or therapeutic agent made available to the eye.
  • the effectiveness of the monoacyl phosphoglycerides is improved when the viscosity of the
  • compositions containing the monoacyl phosphoglycerides is increased up to about 1000 centipoise (cps), preferably between about 50 cps. to 300 cps. Polymers are added to provide for this desired viscosity increase.
  • cps centipoise
  • any synthetic or natural polymer which will increase viscosity and is compatible with tissues of the eye and the ingredients of the monoacyl phosphoglycerlde compositions can be used.
  • Such polymers are referred to herein as "viscosity enhancing, ophthalmically acceptable polymers.” Examples include, but are not limited to: natural polysaccharldes and gums, such as: alginates, carrageenan, guar, karaya, locust bean, tragacanth and xanthan; and synthetic polymers, such as:
  • proteins and synthetic polypeptides which enhance viscosity and are ophthalmically acceptable can be used to increase the viscosity of the compositions to provide for better bioavallability.
  • proteins which can be used include: gelatin, collagen, albumin and casein.
  • the preferred viscosity enhancing agents are one or more polymers selected from: PVA, HPMC and HEC.
  • the most preferred agent is HPMC.
  • the viscosity enhancing agents are added to provide for compositions with a viscosity of between about 50 and 300 cps.
  • the preferred method for enhancing the penetration of a drug or therapeutic agent comprises the use of lysophosphatidylcholine (C18:0) at a concentration of about 0.01% to 0.05% in combination with the polymer HPMC in an amount sufficient to provide a composition with a viscosity of about 50 to about 300 cps.
  • compositions which, according to the present invention, comprise monoacyl phosphoglycerldes, the corneal penetration enhancing properties of the monoacyl phosphoglycerides and their use to enhance corneal penetration.
  • composition which can be used to treat glaucoma.
  • the formulation is prepared in two parts.
  • the hydroxypropylmethylcellulose is first dissolved in purified water to make an approximately 10% solution. This solution is then clarified by filtration and sterilized by autoclaving.
  • the mixture is warmed to 40 + 5°C for approximately 30 minutes to complete dissolution of the lysophosphatldylcholine.
  • the pH of the solution is adjusted to 6.5 and the solution is sterilized by sterile filtration.
  • the two solutions are mixed aseptically, stirred, and the remaining purified water is used to bring the solution to final volume.
  • Approximately 85% (8.5 ml) of the batch volume of purified water was added to a container.
  • AH of the ingredients were then added to the container: 0.002g potassium chloride; 0.080g sodium chloride; 0.0021g monobasic potassium phosphate; 0.0216g dibasic sodium phosphate; 0.25g para-aminoclonidine.
  • the ingredients were mixed well.
  • 0.003g lysopc was added to the container and sonnicated with heat (30°C) for 30 minutes.
  • the pH was adjusted to pH 6.0 with IN HCl (0.20 ml).
  • the solution was then filtered through a sterilizing filter Into a sterile receiving vessel.
  • Purified water q.s.

Abstract

L'invention concerne l'emploi de phosphoglycérides de monoacyle, améliorant la pénétration de médicaments ophtalmiques appliqués localement, dans l'épithélium cornéen.
PCT/US1990/001584 1988-03-29 1990-03-28 Emploi de phosphoglycerides de monoacyle pour ameliorer la penetration de medicaments ophtalmiques dans la cornee WO1990011079A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
KR1019910701215A KR920700651A (ko) 1988-03-29 1990-03-28 안과용 약제의 각막 투과를 향상시키기 위한 모노아실 포스포글리세라이드(monoacyl phosphoglycerides)의 용도

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US32992489A 1989-03-29 1989-03-29
US329,924 1989-03-29

Publications (1)

Publication Number Publication Date
WO1990011079A1 true WO1990011079A1 (fr) 1990-10-04

Family

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1990/001584 WO1990011079A1 (fr) 1988-03-29 1990-03-28 Emploi de phosphoglycerides de monoacyle pour ameliorer la penetration de medicaments ophtalmiques dans la cornee

Country Status (7)

Country Link
EP (1) EP0465580A4 (fr)
JP (1) JPH04504258A (fr)
AU (1) AU631204B2 (fr)
CA (1) CA2013225A1 (fr)
IL (1) IL93925A0 (fr)
WO (1) WO1990011079A1 (fr)
ZA (1) ZA902442B (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0502766A1 (fr) * 1991-03-05 1992-09-09 Institut De Recherche Biologique S.A. Compositions diététiques à base de lipides phosphorylés et leur utilisation dans l'amélioration des troubles de la vision
US7595411B2 (en) 1997-08-18 2009-09-29 Max-Planck-Gesellschaft Zur Foerderung Der Wissenschaften E.V. Phospholipid-analogous compounds
EP2574341A1 (fr) 2004-03-29 2013-04-03 University Of South Florida Traitement efficace des tumeurs et du cancer avec de la triciribine et composés apparentés

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5109118A (en) * 1989-07-06 1992-04-28 Yutaka Mizushima Modified biologically active proteins
WO2010064636A1 (fr) * 2008-12-02 2010-06-10 ロート製薬株式会社 Composition ophtalmique
US20210038612A1 (en) * 2018-04-03 2021-02-11 Hyderabad Eye Research Foundation Mucoadhesive drug delivery system for ocular administration of fluoroquinolone antibiotics

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1988009163A1 (fr) * 1987-05-22 1988-12-01 Danbiosyst U.K. Limited Systeme d'administration d'un medicament facilitant sa fixattion

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS62270521A (ja) * 1986-05-16 1987-11-24 Green Cross Corp:The フルルビプロフエン眼投与製剤

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1988009163A1 (fr) * 1987-05-22 1988-12-01 Danbiosyst U.K. Limited Systeme d'administration d'un medicament facilitant sa fixattion

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACT, Volume 106, No. 16, issued 20 April 1987. SCHULTE, "Ophthamic Compositions containing Bihenamine and their use in the Treatment or Prevention of Inflammation". See Page 402, Column 1, Abstract No. 125931T, Lines 11 & 12. *
See also references of EP0465580A4 *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0502766A1 (fr) * 1991-03-05 1992-09-09 Institut De Recherche Biologique S.A. Compositions diététiques à base de lipides phosphorylés et leur utilisation dans l'amélioration des troubles de la vision
FR2673513A1 (fr) * 1991-03-05 1992-09-11 Inst Rech Biolog Sa Nouvelles compositions dietetiques a base de lipides phosphoryles et leur utilisation dans l'amelioration des troubles de la vision.
US7595411B2 (en) 1997-08-18 2009-09-29 Max-Planck-Gesellschaft Zur Foerderung Der Wissenschaften E.V. Phospholipid-analogous compounds
US7939683B2 (en) 1997-08-18 2011-05-10 Max-Planck-Gesellschaft Zur Forderung Der Wissenschaften E.V. Phospholipid-analogous compounds
US8497388B2 (en) 1997-08-18 2013-07-30 Max-Planck-Gesellschaft Zur Foerderung Der Wissenschaften. E.V. Phospholipid-analogous compounds
EP2574341A1 (fr) 2004-03-29 2013-04-03 University Of South Florida Traitement efficace des tumeurs et du cancer avec de la triciribine et composés apparentés

Also Published As

Publication number Publication date
IL93925A0 (en) 1990-12-23
ZA902442B (en) 1991-01-30
EP0465580A4 (en) 1992-03-18
CA2013225A1 (fr) 1990-09-29
JPH04504258A (ja) 1992-07-30
AU5403090A (en) 1990-10-22
AU631204B2 (en) 1992-11-19
EP0465580A1 (fr) 1992-01-15

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