WO1995014488A1 - Compositions et procedes de traitement des yeux secs et d'autres troubles occulaires - Google Patents

Compositions et procedes de traitement des yeux secs et d'autres troubles occulaires Download PDF

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Publication number
WO1995014488A1
WO1995014488A1 PCT/US1994/013582 US9413582W WO9514488A1 WO 1995014488 A1 WO1995014488 A1 WO 1995014488A1 US 9413582 W US9413582 W US 9413582W WO 9514488 A1 WO9514488 A1 WO 9514488A1
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surfactant
epithelial
composition
secretion
conjunctival
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PCT/US1994/013582
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English (en)
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Gregory S. Hageman
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Ocutech, Inc.
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Priority to AU12941/95A priority Critical patent/AU1294195A/en
Publication of WO1995014488A1 publication Critical patent/WO1995014488A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • A61K38/1709—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/44—Vessels; Vascular smooth muscle cells; Endothelial cells; Endothelial progenitor cells

Definitions

  • This invention relates to ophthalmic compositions and methods for the treatment of dry eyes (keratoconjunctivitis sicca) and other ocular disorders. More particularly, this invention relates to a ophthalmic compositions and methods comprising a non-conjunctival, epithelial-derived secretion particularly suitable for the alleviation of ocular disorders.
  • Dry eyes is a general term referring to a broad category of diseases involving abnormalities of the tear film. Approximately 400,000 people in the United States alone currently suffer from this affliction. In general, dry eye syndrome is a condition that is characterized by a decrease in the production of aqueous tears and/or tear film dysfunction, ultimately leading to ocular surface disease. Untreated, this disease can cause permanent structural damage to the cornea and, in some cases, visual loss, and constitutes one of the major reasons for patients to seek ocular medical care. The symptoms associated with dry eyes are often exacerbated in subjects using contact lenses. In some cases, contact lens intolerance is caused in part or in total by the condition of dry eyes and the symptoms thereof.
  • the morbidity associated with dry eyes is related to changes of the ocular surface that give rise to a spectrum of clinical abnormalities, including punctate erosions, corneal filaments, mucous plaques, epithelial defects, and in some cases, corneal ulcers.
  • the symptoms of this disease often include redness, irritation, tearing, burning, stinging, foreign body sensation, blurred vision, and mucous discharge, all of which may be exasperated by exposure to environmental irritants.
  • compositions for treating dry eye have been used.
  • methods for the treatment of dry eyes include preservation of existing tears, stimulation of tear production (see, e. g. , Shoenwald et al., US Patent 4,820,737 (1989)), anti-inflammatory therapy, diminution of tear viscosity, hormone treatment, and surgical intervention
  • topical tear substitutes artificial tears
  • Currently available artificial tears, used in the treatment of dry eyes and other pathologies related to the inefficient secretion or synthesis of tear constituents consist primarily of various aqueous-based solutions, with or without preservatives. These artificial tear solutions provide relatively poor coverage and lubricating properties compared to normal, natural tear film. As such, frequent reapplication is necessary.
  • aqueous solutions of inert, substituted, cellulose ethers such as methyl cellulose has also been utilized.
  • Other substituted cellulose ethers such as hydroxyethyl cellulose, hydroxypropyl methyl cellulose, and hydroxypropyl cellulose have been subsequently utilized as polymeric components in artificial tear formulations.
  • Each of these polymerics imparts high viscosities to the tear formulations, even when employed in relatively low concentrations. It has been this impartation of high viscosity to the formulations which has been believed to prolong retention time of the tear substitute in the fornices and over the preocular surface.
  • the ocular retention time is not a direct function of the vehicle viscosity.
  • the use of highly viscous polymeric solutions also results in unpleasant side effects to the user. For example, insufficient lubrication of the lids and the tendency for encrustations to form at the lid margins produces irritation and discomfort.
  • Hydrophilic polymerics such as polyvinyl alcohol and polyvinyl pyrrolidone, combining good film-generating properties with relatively low viscosities in aqueous solutions, have been utilized. Such formulations, however, remain less than satisfactory inasmuch as they do not provide good wetting properties.
  • Compositions consisting essentially of phospholipids and/or hyaluronic acids have also been proposed as potential therapeutic agents for treating ocular disorders. Glonek et al., US Patent No. 4,914,088; Hills et al., WO 91/12808. However, the existence and extent of clinical efficacy of these compositions remains doubtful.
  • the subject invention provides improved compositions and methods for the treatment of ocular disorders, including dry eyes.
  • the invention comprises correcting deficiencies in the tear film by topical application of an ophthalmic composition to the ocular surface of the eye.
  • This ophthalmic composition comprises a non-conjunctival, epithelial-derived secretion.
  • the composition will further comprise an ophthalmically-acceptable carrier.
  • epithelial-derived secretions include pulmonary surfactants, either natural or synthetic analogs thereof.
  • Natural pulmonary surfactants include surfactant-associated protein, for example, SP-A, SP-B, SP-C, and SP-D.
  • One embodiment of this invention utilizes Survanta®, Exosurf Neonatal , or Infasurf® as the epithelial-derived secretion.
  • compositions of the present invention provide relief for aqueous-deficient, lipid-deficient, and/or mucus-deficient eyes and are effective also therapeutically in situations where protein, carbohydrate, and/or lipid abnormalities exist.
  • the compositions can be used intraocularly in anterior or posterior procedures, for example, as lubricants during cataract surgery or vitrectomy procedures.
  • Some ophthalmic compositions of the present invention are similar to the physiological composition of the normal tear film.
  • the compositions usually exhibit an increased tear break up time, enhanced film stability, and improved wettability and viscosity.
  • many of the ophthalmic compositions provided herein are believed to be compatible with the use of contact lenses.
  • FIG. 1 compares tear break-up time (TBUT) for SurvantaTM, Hypotears PFTM and no treatment.
  • Fig. 2 compares TBUT for Exosurf NeonatalTM,
  • Fig. 3 compares TBUT for SurvantaTM and Hypotears PFTM at different times after treatment.
  • Fig. 4 shows values of TBUT at different dosages of SurvantaTM.
  • Epithelial refers to tissue that forms the surface of an organ or organism and serves to enclose and protect the other tissues of the organ or organism.
  • Consjunctival refers to the ocular conjunctiva; the mucous membrane covering the anterior surface of the eye and lining the lids.
  • Non-conjunctival refers to epithelial other than the conjunctiva.
  • Secretio (s) refers to those molecular substance(s) that result from, leave, or separate from, a cell or bodily fluid.
  • a secretion is produced by a cell or gland and has chemical and/or physical properties different from the body from which is produced.
  • secretion also includes derivative compositions obtained from a naturally occurring secretion.
  • Derivative compositions may contain only a single component from the naturally occurring secretion, for example, a surfactant protein.
  • derivative compositions do not include compositions in which lipids and/or glycosaminoglycans, such as hyaluronic acid are the only active component(s) .
  • secretion also includes analogs of naturally occurring secretions or derivative compositions, as described above.
  • analog refers to molecular substance(s) that have structural or biologically functional properties similar to the naturally occurring secretion or derivative composition for use in an ophthalmic composition.
  • the analog is synthetically constructed.
  • a surfactant protein such as SP-A
  • SP-A that is synthesized by recombinant DNA techniques is an analog of the naturally occurring SP-A protein.
  • the recombinant protein likely shares the primary amino acid sequence and most of the biological properties of the naturally occurring protein, but may differ in certain respect, such as in post-translational modifications.
  • “Pulmonary surfactant” refers to those molecular substances forming a layer over alveolar surfaces and tending to stabilize alveolar volume by reducing surface tension and altering the relationship between surface tension and surface area.
  • “surfactant” refers to a compound having the ability to reduce surface tension on a surface and/or reduce surface tension at an air/liquid interface. Procedures for determining the surfactant activity of substances described herein can be found in Sarin et al., European patent publication No. 0,413,956, published 1991.
  • the term “pulmonary surfactant” is used generically to encompass derivative compositions and analogs.
  • Natural pulmonary surfactants are prepared from lavage of mammalian lungs (e. g. , porcine or bovine) or washes of tissue extracts therefrom, or from amniotic fluid. The components can be isolated from the wash by centrifugation or lyophilization and resuspended in an aqueous solution at a concentration effective for opthalmic use.
  • Components of a natural pulmonary surfactant include phospholipids (e. g.
  • neutral lipids e. g. , triglycerides, cholesterol, cholesterol esters, steroids, terpenes
  • proteins, glycoproteins, glycosaminoglycans e. g. , heparin sulfate, heparin, chondroitin s
  • the proportions (w/v) of the major components are about 80-95% phospholipid, 2-10% neutral lipid, and 5-10% protein. Trace components or components not contributing to ophthalmic activity are sometimes removed from the natural pulmonary surfactant. Artificial surfactants are prepared by mixing components (particularly lipids) from commercially available purified sources. Artificial surfactants sometimes omit, or contain reduced proportions of, protein components.
  • “Surfactant-associated protein” refers to a specific class of proteins found in pulmonary surfactant. Pulmonary surfactant contains at least four families of surfactant- associated proteins, SP-A, SP-B, SP-C, and SP-D. These substances appear to be important for the adsorption of phospholipids to an air-liquid interface. They also serve as regulators of surfactant phospholipid metabolism, for example, by promoting uptake of phospholipids by certain cells.
  • glycoproteins refer to proteins with covalently linked oligosaccharides.
  • the covalent protein-carbohydrate linkage may be N-glycosidic (N-glycans) or O-glycosidic (0- glycans) .
  • the polypeptide chains generally carry a number of short heterosaccharide chains, and these, in turn, almost always include N-acetylhexosamines and hexoses. The last member of the chain is very often sialic acid or L-fucose.
  • the oligosaccharide chains are often branched, and rarely contain more than 15 monomers, although the number of saccharide chains on a polypeptide varies widely.
  • glycoprotein- containing solutions generally have high viscosities.
  • glycosaminoglycans or “mucopolysaccharides” refer to long, unbranched polysaccharide chains composed of repeating disaccharide units wherein one of the two sugar residues in the repeating disaccharide is always an amino sugar (e. g. , N- acetylglucosamine or N-acetylgalactosamine) .
  • glycosaminoglycans have been distinguished by their sugar residues, the type of linkage between these residues, and the number and location of sulfate groups: (1) hyaluronic acid; (2) chondroitin sulfate and dermatan sulfate; (3) heparin sulfate and heparin; and (4) keratin sulfate.
  • sulfate groups (1) hyaluronic acid; (2) chondroitin sulfate and dermatan sulfate; (3) heparin sulfate and heparin; and (4) keratin sulfate.
  • Proteoglycans refer to glycosaminoglycans (mucopolysaccharides) covalently bound to core proteins.
  • lipid encompasses a heterogeneous group of fats and fat-like substances that are usually water-insoluble. Lipids usually contain aliphatic hydrocarbons as a major constituent. Lipids may be positively charged, negatively charged, or neutral. Charged lipids include phospholipids such as phosphoglycerides, phosphoglycolipids, phosphodiol lipids, phosphosphingolipids, phosphatidyl-glycerols, phosphatidylinositols, diphosphatidylglycerols phosphatidylsugars, and plas alogen analogs. See generally, Lehninger, Biochemistry (2d ed. Worth, N.Y.), at pp. 279-306). Neutral lipids include triglycerides, cholesterol esters, waxes, isoprenoids, and cholesterol.
  • compositions of the instant invention refers to the amount of composition sufficient to induce a desired biological result. That result can be alleviation of the signs, symptoms, or causes of an ocular disorder, such as dry eyes, or any other desired alteration of an ophthalmic biological system.
  • Optically- or therapeutically-acceptable carrier refers to a carrier medium which does not interfere with the effectiveness of the ophthalmic biological activity of the active ingredients and which is not toxic to the host or patient.
  • water-soluble means that a composition exhibits a solubility of at least about 50 ⁇ g/ml and usually at least about 100 ⁇ g/ml in aqueous solvents.
  • the compositions of the invention may or may not be water soluble, depending on their components. For example, a composition with a high percentage of lipids is likely to be insoluble.
  • the preocular tear film is a complex layer that covers the anterior surface of the eye, where it increases the optical resolution of the eye, inhibits microbiological contamination, prevents dehydration of the cornea, and provides a source of oxygen to the cornea.
  • the tear film comprises three distinct layers - the lipid, aqueous, and mucous layers - from its anterior to posterior, respectively.
  • the lipid layer is approximately 0.1 ⁇ m thick and is secreted primarily by the Meibomian glands. This layer is comprised of esters, triacyl glycerols, free sterols, sterol esters, and fatty acids, and behaves as a film that is essentially independent of the aqueous layer underneath. The lipid layer appears to participate in preventing evaporation from the aqueous phase. In addition, it has been suggested that the non-polar nature of the lipid layer prevents surface contamination of the tear film with highly polar skin lipids, which could lead to rapid dissolution of the tear film.
  • the bulk of the tear film consists of the aqueous layer which is approximately 7 ⁇ m thick and is secreted by the lacrimal glands. As many as 60 proteins are present in this layer, in addition to glycoproteins, glucose, urea, and electrolytes.
  • the mucous layer secreted by the goblet cells of the conjunctiva and often described as a component of the tear film, is intimately associated with the corneal and conjunctival epithelium and is approximately 0.05 ⁇ m thick. The primary function of this layer is to coat the surface of the corneal epithelium and render it wettable by the aqueous tears.
  • Drv Eves refers to conditions in which the eye may be deficient in either the aqueous or mucous layers of the tear film, including, for example, as in keratoconjunctivitis sicca, hypovitaminosis A, Stevens-Johnson syndrome, ocular pemphigoid, extensive trachoma, Sjogren's syndrome (i.e., dry eyes related to rheumatoid arthritis or other connective tissue disease) , and after chemical burns.
  • disturbances of the lipid composition can cause "dry eyes".
  • This disturbance can result from an inadequacy of the quantity of secretion from the Meibomian glands or from an inadequacy in the quality of the secretion.
  • the compromised lipid layer fails to act as an adequate barrier against evaporation of the aqueous portion of the tear film, thus resulting in one form of the condition known as dry eyes.
  • This form of dry eyes is often associated with forms of conjunctivitis, traumatized bulbar and palpebral conjunctiva, and related lid disease, as well as external ocular surface disease. It also may be due to decreased tear production resulting from diseases or inflammation of the lacrimal gland. Dysfunction of the lacrimal gland is frequently associated with aging.
  • Dry eyes can also occur as a result of treatment with drugs.
  • Many drugs have been described as having an effect on lacrimation. (See Crandall and Leopold (1979) Ophthalmology 86:115.) For example, the following drugs have been reported to decrease tear flow: atropine and scopolamine ( see Erickson (1960) Stanford Med. Bull . 18:34); antihistamines (see Chang (1977) J. Am. Optom. Assoc. 48:319); practolol (see Garner and Rahi (1976) Br. J. Ophthalmol. 65:414); and nitrous oxide, halothane, and enflurane (see Krupin et al. (1977) Arch. Ophthalmol . 95:107).
  • an ophthalmic composition comprising a non- conjunctival, epithelial-derived secretion.
  • These compositions are capable of altering the surface tension of the tear layer, prolonging tear break-up time, and enhancing lubricating properties.
  • these compositions will be compatible with topical ocular application.
  • substantially pure conjunctival, epithelial-derived secretion(s) are provided; in particular, cultured cells from isolated lacrimal or goblet cells can be used.
  • epidermal-derived secretions refer to naturally-occurring secretions, including those secretions of nasal, oral, respiratory, gastrointestinal, mammary, and female reproductive tract origin. See, e. g. , Baraniuk et al. (1990) J. All . Clin . Immunol . 86:620-627;
  • secretions typically originate as a combination of transudates from the vascular system and glycoconjugates derived from secretory cells and glandular elements (e. g. , goblet cells and/or serous or seromucous glands) .
  • the present invention also contemplates the use of epithelial-derived secretion(s) that are either synthetically or genetically produced, for example, using recombinant DNA and molecular biology techniques, or cultured, for example, from isolated lacrimal, goblet, or other epithelial cells, including cultured epithelial cell supernatant, as well as whole cell extracts, homogenates, and other cellular fractions of cultured epithelial cells.
  • combinations of epithelial-derived secretions derived from more than one source can be employed in the compositions and methods described herein.
  • Epithelial-derived secretions typically occur as complex mixtures and may include inorganic ions, lipids, secreted proteins, chemical mediators, and other products from plasma cells, mast cells, basophils, epithelial cells, and other cells within the epithelial mucosa. Epithelial-derived secretions need not necessarily be purified prior to utilization in the ophthalmic compositions of the present invention.
  • pulmonary surfactant is utilized as the epithelial-derived secretion.
  • Pulmonary surfactants usually contain one or more of four proteins, commonly referred to as SP-A, SP-B, SP-C, and SP-D that are thought to be important for normal surfactant function in vivo. (See Weaver and Whitsett (1988) Semin . Perinatol . 12:213.).
  • pulmonary surfactant consists of phospholipids, in particular, of dipalmitoyl phosphatidylcholine and smaller amounts of unsaturated phosphatidylcholine and phosphatidylglycerol.
  • pulmonary surfactant proteins and peptides found in pulmonary surfactant include mucus glycoproteins, surface muco-substance, surfactant hypophase (produced by Clara or type II alveolar cells) , lysozyme, lactoferrin, secretory piece, regulatory neuropeptides, fibronectin, and the like. See, e. g. , Jeffrey (1987) Eur. J". Respir. Dis . 71 Supp. 153:34-42.
  • compositions of the invention consist essentially of the specific protein component(s) of pulmonary surfactant, i.e., the surfactant-associated proteins, as the epithelial-derived secretion.
  • these surfactant-associated proteins include the hydrophobic, low molecular weight, surfactant-associated proteins commonly known as SP-B, SP-C, and SP-D, as well as the larger molecular weight, hydrophilic surfactant-associated protein known as SP-A. (See Weaver and Whitsett (1991) Biochem. J. 273:249-264.) SP-A, a glycoprotein of 228 amino acids, is synthesized in type II alveolar cells and is associated with intracellular and extracellular lamellar bodies.
  • SP-A The charge and size heterogeneity of SP-A varies among species.
  • This protein facilitated the adsorption to and spreading of dipalmitoyl phosphatidylcholine at the air-liquid interface
  • studies have now suggested that its major contribution towards surface activity is to enhance the effects of SP-B and/or SP-C.
  • SP-B has a molecular weight of 18,000 under nonreducing conditions and a molecular weight of 5000-8000 under reducing conditions.
  • the reduced form of SP-B consists of 79 amino acids and has a high cysteine content (7 cysteines in a total of 79 residues) .
  • Two regions of 23 and 24 amino acids with a high content of both hydrophobic and cationic residues are possible sites for interaction with the lipid and aqueous layers of the tear film.
  • SP-C has a molecular weight of 4500-8000 under both reducing and nonreducing conditions.
  • the monomeric form of SP-C consists of 35 amino acids and has 2 palmitoyl groups covalently liked to the polypeptide chain.
  • a continuous hydrophobic domain of 23 residues with a high valine content probably plays an important role in the interaction with the lipid layer by forming a membrane-spanning domain.
  • SP-B and SP-C can be obtained following the procedures of Oosterlaken-Dijksterhuis et al. (1991) Biochemistry 30:10965.
  • SP-D A fourth surfactant-associated protein, SP-D, has recently been identified in rat bronchoalveolar lavage fluid.
  • SP-D consists of a charge train of proteins (M r 43,000 pi 6-8) that forms disulfide-bonded trimers.
  • SP-D is similar to SP-A in that it contains a bacterial collagenase-sensitive domain, hydroxyproline, asparagine-linked oligosaccharide and lectin- like activity, but differs in the presence of hydroxylysine and hydroxylysine glycosides.
  • surfactant-associated proteins can be employed individually or in any combination. Preferred combinations includes SP-B and/or SP-C.
  • Survanta® a natural bovine lung extract containing phospholipids, neutral lipids, fatty acids, and surfactant- associated proteins (beractant, available from Ross Laboratories, Columbus, OH) to which colfosceril palmitate, palmitic acid and tripalmitin are added, is utilized as the surfactant-associated protein.
  • the resulting composition provides 25 mg/ml phospholipids, 0.5-1.75 mg/ml triglycerides, 1.4-3.5 mg/ml free fatty acids, and less that 1.0 mg/ml proteins.
  • Survanta® contains both SP-B and SP-C as protein components, but lacks SP-A.
  • Other embodiments will employ other commercially or non- commercially available substances having the physical and physiological properties of Survanta®, including but not limited to, the protein-free synthetic lung surfactant Exosurf NeonatalTM (comprising colfosceril palmitate, cetyl alcohol, and tyloxapol, available from Burroughs Wellcome Co., Research Triangle Park, NC) .
  • fragments of surfactant-associated proteins and analogs thereof can be utilized to produce the compositions described herein. See, e. g. , Sarin et al., EPA 413,956 (1991). These fragments and analogs can be naturally isolated, chemically synthesized and/or recombinantly produced. The fragments or analogs will usually share a biologically activity of the naturally occurring protein from which they derive. For example, fragments are usually capable of lowering surface tension on the surface of a liquid in which they are dispersed. In some embodiments, these surfactant-associated protein fragments and analogs thereof will be combined with lipid(s) .
  • Artificial or synthetic pulmonary surfactant synthesized from mixtures of synthetic compounds that may or may not be constituents of natural surfactant comprises another type of epithelial-derived secretion according to the present invention.
  • These synthetic or artificial pulmonary surfactant can be reconstructed in vitro from surfactant-associated proteins or fragments or analogs thereof, synthesized using recombinant DNA and molecular biology techniques or isolated from natural or cultured sources, and from mixtures of phospholipids and neutral lipids. See, e. g. , Benson et al. PCT Publication No. WO89/04326 and Schilling et al. British Patent No. 2,181,138.
  • synthetic polypeptide-phospholipid complexes can be utilized in the compositions and methods described herein.
  • Phospholipids useful in forming synthetic pulmonary surfactants by admixture with polypeptides are well known in the art. See, e. g. , Notter et al. (1987) Clin . Perinatology 14:433-79.
  • Suitable natural isolated, chemically synthesized and/or recombinant proteins and peptides for use according to the present invention (and isolative and recombinant techniques for obtaining them) are disclosed in the following publications: Weber European patent publication No. 0,335,133, published 1988; Tanaka U.S. patent No. 4,338,301; Tanaka U.S. Patent No.
  • WO86/03408 Whitsett (1991) U.S. Patent No. 5,013,720; Clement U.S. Patent No. 4,826,821; Jackson (1989) U.S. Patent No. 4,861,756; and Whitsett PCT Publication No. WO86/06943.
  • Other synthetic pulmonary surfactants include the compositions comprising the SP18 monomer-related polypeptide described in Cochrane et al. (1992) U.S. Patent No. 5,164,369 admixed with a phospholipid.
  • Modified natural surfactants also may find use in the compositions described herein. Modified natural surfactants generally are prepared by e. g.
  • separating lipids from proteins in natural surfactant obtained form lung minces or alveolar lavage followed in some cases by selective addition (or removal) of certain compounds, and suspension procedures designed to restore the desired surface properties.
  • protein-depleted lipid extracts of natural pulmonary surfactant have the ability to reduce the surface tension of a pulsating bubble to near 0 mN/m at minimum bubble size and to promote lung expansion and survival of surfactant-deficient prematurely delivered animals. See, e. g. , Yu et al. PCT Publication No. WO 92/04906.
  • a further example of an epithelial-derived secretion which can be utilized to prepare the ophthalmic compositions of the present invention is mucus.
  • Mucus is the clear, viscid secretion of mucous membranes and consists of mucin and various inorganic salts suspended in water.
  • Mucin is a secretion, comprising proteoglycans and glycoproteins, from the goblet cells of the intestine, the submaxillary glands, and other mucous glandular cells.
  • epithelial-derived secretions typically include various proteins, glycoproteins, mucoproteins, proteoglycans, glycosaminoglycans, and the like, immunoglobulins (e. g. , IgG, IgM, IgA, secretory component), albumin, lactoferrin, transferrin, glucose, glycogen, "intrinsic factor”, inflammatory mediators (e. g. , histamine, prostaglandins, bradykinin, and leukotriene) and various organ- specific enzymes (e. g.
  • the various components can be either synthesized or isolated from natural sources.
  • Preferred components include proteoglycans and glycosaminoglycans.
  • the epithelial-derived secretions or components thereof of the present invention can be combined with an ophthalmically-acceptable carrier.
  • Such carriers can be aqueous or non-aqueous ophthalmically-acceptable sterile liquids.
  • Suitable non-aqueous liquid media include the physiologically acceptable oils such as silicone oil, USP mineral oil, white oil, and vegetable oil, for example, corn oil, peanut oil, and the like.
  • Some embodiments of this invention will utilize an organic solvent such as propylene glycol, either alone or in combination with an aqueous solution, as the carrier.
  • the surfactant-associated proteins can be suspended in an ointment such as lanolin, petrolatum, and other known ointments.
  • the ophthalmically-acceptable carrier is typically an aqueous solution.
  • the carrier will comprise a substantially isotonic solutions which is defined for present purposes as containing 270-310 milliosmoles/ kilogram of solute.
  • Other embodiments will employ a hyperosmolar solution, for example, 5% sodium chloride solutions. See PDR for Ophthalmology (1993), p. 15.
  • the tonicity adjusting agent is employed to bring the final solution tonicity within the stated ranges if not already there due to contributions of the other ingredients.
  • the tonicity adjusting agent is an ionic salt, such as sodium chloride.
  • the ophthalmic composition also will contain a variety of other materials to adjust pH (typically to a pH between about 5.5 to 8.5, preferably between about 6.5 to 7.5), preserve the treatment system, and the like.
  • Suitable buffering agents include alkali metal phosphates, such as sodium and potassium phosphate, or mixtures thereof. These buffering agents are generally present in amounts of from about 0.1 to about 1.0 percent weight/volume. Some embodiments will employ two or more buffering agents.
  • Preservative agents which can be used include benzalkonium chloride in a concentration range of from 1:15,000 to 1:30,000; chlorobutanol in a concentration range of from 0.3% to 0.8%; thimerosal in a concentration range of 0.001% to 0.003%; and phenyl mercuric nitrate in a concentration range of from 1:60,000 to 1:80,000 (volume/volume) .
  • Additional suitable preservatives include sorbic acid, ethylenediaminetetraacetic acid (EDTA) , and other ophthalmically-acceptable preservatives.
  • agents may be added to increase viscosity, promote suspension and/or improve ocular compatibility, such as methyl cellulose in an amount of from 0.1% to 0.7%, or poly(vinyl alcohol) in an amount of from about 0.4% to 2.0% (volume/volume) or non-ionic surfactants, such as polyoxyalkylene oleic esters of sorbitol anhydrides, and the like.
  • methyl cellulose in an amount of from 0.1% to 0.7%
  • poly(vinyl alcohol) in an amount of from about 0.4% to 2.0% (volume/volume)
  • non-ionic surfactants such as polyoxyalkylene oleic esters of sorbitol anhydrides, and the like.
  • additive materials such as medicants (pharmaceutically active agents, such as compounds for the treatment of glaucoma, conjunctivitis, inflammatory ocular conditions, or red eye) , stabilizers, lubricants, vasoconstricting (i.e., decongesting) agents are
  • the ophthalmic composition will further comprise glycosaminoglycan, hyaluronic acid, or other conventional agents for anterior segment surgery, such as Occucoat® (2% hydroxylpropyl methyl cellulose, available from Storz Ophthalmics, Inc., St.
  • Viscoat® sodium chondroitin sulfate-sodium hyaluronate solution, available from Alcon Surgical, Inc., Fort Worth, TX
  • Healon® and Healon® GV sodium hyaluronate, available from Kabi Pharmacia Ophthalmics, Inc., Monrovia, CA
  • Amvisc® and Amvisc® Plus sodium hyaluronate, available from Alcon Surgical, Inc.
  • AMO® Vitrax® solution sodium hyaluronate, Allergan Medical Optics, Irvine, CA
  • Formulation of the ophthalmic compositions of the present invention may be effected in any convenient manner known to the art, such as by simply admixing the desired amount of the specified ingredients, and providing the necessary amount of liquid carrier to provide the necessary dilution.
  • the epithelial-derived secretion in the ophthalmic composition will generally comprise between about 2 and 100%, more preferably, between about 10 and 50%, of the composition.
  • the amounts of the active compound within these ranges, dissolved in a suitable ophthalmically-acceptable carrier, have been demonstrated to effectively increase tear break-up time and alleviate the symptoms of dry eyes, as described further below.
  • the method of application of the ophthalmic compositions of the instant invention to the subject is by topical application of a therapeutically- or pharmaceutically- effective amount of the treatment composition to the ocular surface.
  • Conventional means for dispensing the treatment composition are suitable.
  • application of the treatment composition may be by spray dispenser, eye drop, and the like.
  • slow or extended-release systems including, collagen shields, for example, Bio-Cor® Collagen Corneal Shields (a clear, pliable, thin film fabricated from porcine scleral tissue, available from Bausch and Lomb) , other biological-based systems, systems employing liposomes, and polymeric delivery systems, can be utilized with the compositions described herein to provide a continuous source of the ophthalmic composition to the eye. Examples of these delivery systems are described in "Ophthalmic Drug Delivery Systems", Mitra (ed.), Marcel Dekker, Inc.: New York, NY (1993).
  • treatment composition is in the form of an aqueous solution or emulsion
  • a single drop from a conventional eyedropper is satisfactory.
  • Preferred dosage comprises application of one or more drops several times daily.
  • the preferred dosage is believed to be capable of providing relief for periods of time at least several fold greater than that of commercial formulations, dependent upon the subject.
  • compositions of the present invention instilled drop-wise in the eye, swell the tear meniscus and, with normal blinking, the tear meniscus becomes thoroughly admixed with the tear film.
  • the flooded tear meniscus returns to its steady- state size and the superficial lipid layer is reestablished over the aqueous layer.
  • the ophthalmic compositions of the present invention interact favorably with both the superficial lipid layer and the underlying mucous layer, enhancing film stability.
  • compositions are frequently packaged with labelling indicating their suitability for formulating medicaments for ophthalmic use.
  • label provides information as to the formulation of the compositions and/or the recommended ophthalmic treatment regime.
  • compositions of the present invention can lower the surface tension of the tear film by increasing the film pressure of the lipid without interfering with the integrity thereof, the film pressure of an insoluble film such as lipid over water being defined as the difference between the surface tension of the pure water surface and that of the lipid-covered water surface.
  • compositions of the present invention do not affect adversely the clarity of the aqueous tear layer. Moreover, the compositions of this invention are compatible with the use of contact lenses. Finally, the compositions do not contribute to hydrophobic contamination of the mucus layer, but on the contrary, are capable of forming a hydrophilic layer in the absence of a functional mucus layer, having all of the functional properties of a normal mucus layer.
  • the compositions of the present invention topically applied, provide relief for both aqueous-deficient, lipid- deficient, and mucus-deficient eyes, provide highly effective lipid-masking and scavenging layers, and are effective also therapeutically in situations where protein, carbohydrate, and/or lipid abnormalities exist.
  • the compositions can be used as lubricants for intra-ocular lenses and for post-cataract surgery.
  • the epithelial-derived secretion or component(s) thereof can be applied directly to the ocular surface or can be diluted with a suitable ophthalmically-acceptable carrier.
  • a suitable ophthalmically-acceptable carrier are generally known in the art.
  • an aqueous-base system wherein the carrier includes a buffer system to provide a suitable pH, a viscolyzer to provide suitable viscosity for eye comfort, an antibacterial agent, and a chemical preservative is used.
  • Dacriose which is a sterile ophthalmic irrigating solution from Iolab (Claremont, CA) , containing water, sodium phosphate, potassium chloride, sodium hydroxide, disodium ethylenediamine tetraacetic acid, sodium chloride, and benzoalkonium chloride.
  • the normal tear film maintains an uninterrupted surface for a finite but adequate period of time to both protect the eye and to permit clear vision without blinking. Blinking restores and maintains the tear film. Certain conditions, such as forcibly restraining blinking, can cause the tear film to become discontinuous.
  • the measurement of the time (in seconds) required for the tear film to evidence areas of discontinuity when blinking is suspended, is known as tear break-up time (BUT) .
  • Measurement of TBUT is a standard screening test for assessing the efficacy of therapeutics for treating tear film disorders (see Lemp, Diagnosis and Treatment of Tear Deficiencies in Clinical Ophthalmology (eds., Duane, T.D. & Jagger E. , Harper & Rowe, 1988)).
  • BUT has been measured by adding fluorescein, a fluorescent dye, and observing the stained tear film with light passed through a cobalt blue filter.
  • Other workers have employed optical imaging (for example, as described in Norn "Tear Film Break Up Time. A Review” in Holly (1986) riie Preocular Tear Film, pp. 52-54 and Glonek et al. (1990) U.S. Patent No. 4,914,088).
  • This test is performed with an ophthalmometer without the use of fluorescein dye.
  • a baseline BUT value is established. Larger BUTs represent a more stable tear film.
  • the effectiveness of ophthalmic compositions is investigated by comparison of BUT for various test solutions and controls versus a baseline BUT value for each eye tested.
  • test solution is added to the eye by depressing the lower eyelid and placing one standard drop of the test solution into the inferior fornix (the space between the lower eyelid and the eye) .
  • the eyelid is then released, the subject is asked to blink at five second intervals, and one minute is allowed for the tear film to stabilize.
  • the BUT measurement is then made with the ophthalmometer.
  • the BUT test is performed prior to the addition of a test solution and then following the use of a test solution.
  • a recovery (waiting) time is required between trials.
  • the recovery procedure involves irrigation (flushing) of the front surface of the eye with sterile saline. Following irrigation, a recovery time of 20 minutes is provided to allow for stabilization of the tear film. If BUT is not consistent with initial baseline findings, further recovery time is provided until BUT times have returned to normal.
  • the ophthalmic compositions of the present invention can be tested as described below.
  • a first group consisting of 10 patients with dry eye (untreated tear break up time (TBUT) ⁇ 10 sec) and a second group consisting of 10 patients without dry eye (TBUT ⁇ 10 sec) each received SurvantaTM in the right eye.
  • Third and fourth groups consisting of 10 patients with and without dry eye, each received Exosurf NeonatalTM in the right eye. At least 5 patients in each group were treated with SurvantaTM or Exosurf NeonatalTM at a dilution of 1:10; the remaining patients received SurvantaTM or Exosurf NeonatalTM at dilution of 1:25, 1:50, or 1:100 to determine the efficacious dose range.
  • Hypotears PFTM is a mixture of polyvinyl alcohol and LipidenTM polymeric vehicle (polyethylene glycol 400 dextrose, EDTA, and water) manufactured by CibaVision.
  • TBUT was measured using a slit lamp after staining the eye with fluorescein (using the procedure described in the specification, at p. 19, second paragraph) .
  • Fig. 1 compares TBUT (sec) from 14 patients receiving SurvantaTM at a 1:10 dilution, Hypotears PFTM or no treatment. Similar data comparing 10 patients receiving Exosurf NeonatalTM at a dilution of 1:10, Hypotears PFTM or no treatment are shown in Fig. 2. These data support a number of conclusions.
  • Treatment with SurvantaTM at a 1:10 dilution results in a significant increase in TBUT values, 2.4 to 3.5 fold greater than Hypotears PFTM or no treatment (p ⁇ 0.01).
  • Treatment with Exosurf NeonatalTM at a 1:10 dilution significantly increases TBUT values by a factor of 1.6 to 2.0 compared with Hypotears PFTM or no treatment (p ⁇ 0.01).
  • the increased TBUT values from treatment with SurvantaTM are significantly greater than those from Exosurf NeonatalTM (p ⁇ 0.05).
  • retention of increased TBUT was noted up to 25 min after treatment with SurvantaTM (see Fig. 3) , in contrast to treatment with Hypotears PFTM, after which TBUT returned to baseline within minutes.
  • VBT visual blur time
  • test solution is added to the eye by depressing the lower eyelid and placing one standard drop into the inferior fornix.
  • the eyelid is released, the subject's attention is directed to a standard vision testing chart, and the subject is asked to blink at five second intervals until the blur resolves.
  • the time required for the blur to resolve, in seconds, is recorded as the VBT. This time may vary from several seconds to minutes. Times of less than 30 seconds are desirable.
  • Rose bengal is a vital dye that stains injured epithelial cells. It stains dry, desiccated epithelium, while those cells are still in situ. This test involves the application of 1% Rose Bengal to the eye. The amount of staining is then rated according to the list of ratings of Kaufman et al. (1963) Archives of Ophthalmology 69:926.
  • compositions of the present invention can also be evaluated using other testing procedures well known in the art. Examples of these protocols include the Snellen visual acuity test, the Schirmer test (see Lamberts (1987) "Physiology of the Tear Film” in T ⁇ e Cornea, S olin and Thoft, Eds., Little Brown and Company: Boston, pp. 38-52) , conjunctival cytology, contrast sensitivity, and evaluations of patient comfort and blink rate.
  • the invention includes a number of general concepts which can be expressed as follows.
  • One general aspect of the invention is the use of a natural pulmonary surfactant for manufacture of a medicament for treating ophthalmic diseases, such as dry eye.
  • a second feature of the invention is the use of active component(s) of a pulmonary surfactant for the same purpose.
  • Preferred components include surfactant-specific proteins B and C.
  • active components are formulated in a medicament with phospholipids and/or neutral lipids in proportions and amounts simulating the concentrations of the same in a natural pulmonary surfactant.
  • active components of a natural pulmonary surfactant are used to supplement conventional ophthalmic compositions.
  • Yet another aspect of the invention is the use of a natural pulmonary surfactant as a source for purifying active components suitable for manufacture of a medicament for treating ophthalmic disease.

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Abstract

L'invention concerne une composition ophtalmique comprenant une ou des sécretions non conjonctivales d'origine épithéliale, un ou des composants, ou un ou des analogues de celles-ci. Les sécrétions non-conjonctivales d'origine épithéliale comprennent typiquement un tensio-actif pulmonaire ou bien un ou des composants de celui-ci, tels qu'une protéine associée à un tensio-actif. La composition comprend également, habituellement, un excipient ophtalmique acceptable, de plus elle peut contenir divers additifs, tampons, substances médicinales et analogues.
PCT/US1994/013582 1993-11-24 1994-11-23 Compositions et procedes de traitement des yeux secs et d'autres troubles occulaires WO1995014488A1 (fr)

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AU12941/95A AU1294195A (en) 1993-11-24 1994-11-23 Compositions and methods for the treatment of dry eyes and other ocular disorders

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998030233A1 (fr) * 1997-01-14 1998-07-16 Ramot University Authority For Applied Research & Industrial Development Ltd. Composition pharmaceutique pour le traitement des yeux

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0413957A2 (fr) * 1989-08-22 1991-02-27 Abbott Laboratories Fragments de la protéine de tensio-actif pulmonaire
US5013720A (en) * 1986-05-06 1991-05-07 Abbott Laboratories SAP-6-Val proteins and methods
WO1991012808A1 (fr) * 1990-02-22 1991-09-05 Macnaught Pty Limited Larmes artificielles
WO1992004907A1 (fr) * 1990-09-26 1992-04-02 Fred Possmayer Agents tensioactifs pulmonaires naturels et extraits lipidiques de ces agents
US5306483A (en) * 1989-07-27 1994-04-26 Scientific Development & Research, Inc. Phospholipid delivery system

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5013720A (en) * 1986-05-06 1991-05-07 Abbott Laboratories SAP-6-Val proteins and methods
US5306483A (en) * 1989-07-27 1994-04-26 Scientific Development & Research, Inc. Phospholipid delivery system
EP0413957A2 (fr) * 1989-08-22 1991-02-27 Abbott Laboratories Fragments de la protéine de tensio-actif pulmonaire
WO1991012808A1 (fr) * 1990-02-22 1991-09-05 Macnaught Pty Limited Larmes artificielles
WO1992004907A1 (fr) * 1990-09-26 1992-04-02 Fred Possmayer Agents tensioactifs pulmonaires naturels et extraits lipidiques de ces agents

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
OPHTHALMOLOGICA, Volume 201, issued 1990, G. RIEGER, "Lipid-Containing Eye Drops: A Step Closer to Natural Tears", pages 206-212. *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998030233A1 (fr) * 1997-01-14 1998-07-16 Ramot University Authority For Applied Research & Industrial Development Ltd. Composition pharmaceutique pour le traitement des yeux
US7723287B1 (en) 1997-01-14 2010-05-25 Ramot At Tel-Aviv University Ltd. Treatment of the eye with a pharmaceutical composition

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