US20100305046A1 - Stable cyclosporine containing ophthalmic emulsion for treating dry eyes - Google Patents

Stable cyclosporine containing ophthalmic emulsion for treating dry eyes Download PDF

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US20100305046A1
US20100305046A1 US12476600 US47660009A US2010305046A1 US 20100305046 A1 US20100305046 A1 US 20100305046A1 US 12476600 US12476600 US 12476600 US 47660009 A US47660009 A US 47660009A US 2010305046 A1 US2010305046 A1 US 2010305046A1
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Prior art keywords
oil
surfactant
hlb
water
eye
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US12476600
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Zhi-Jian Yu
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Abbott Medical Optics Inc
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Abbott Medical Optics Inc
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/0012Galenical forms characterised by the site of application
    • A61K9/0048Eye, e.g. artificial tears
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K38/00Medicinal preparations containing peptides
    • A61K38/04Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/12Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
    • A61K38/13Cyclosporins
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/10Dispersions; Emulsions
    • A61K9/107Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers

Abstract

Disclosed herein are stable oil-in-water emulsion ophthalmic topical liquid compositions having an average particle size less than 1 μm including at least one plant-derived oil other than castor oil wherein the oil comprises only aliphatic side chains free of polar pendent groups. The oil-in-water emulsion ophthalmic topical liquid compositions also include a hydrophilic surfactant having an HLB value between approximately 10 and 14, a vegetable oil-derived hydrophobic non-co-block surfactant having unsaturated side chains that contain less than four oxygen atoms having an HLB value between approximately 4 and 6 and is a liquid at room temperature. The oil-in-water emulsion ophthalmic topical liquid compositions disclosed herein can further include an amount of cyclosporine A effective to relieve dry eye symptoms.

Description

    FIELD OF THE INVENTION
  • [0001]
    Disclosed herein are stable oil-in-water emulsions suitable for ophthalmic use. More specifically, the stable oil-in-water emulsions disclosed herein are useful for treating ophthalmic conditions such as dry eyes and the like. Moreover, these stable oil-in-water emulsions are also suitable as carriers for hydrophobic drugs such as cyclosporine.
  • BACKGROUND OF THE INVENTION
  • [0002]
    Oil-in-water emulsions generally comprise an aqueous phase having suspended therein discrete oil droplets (particles) surrounded by a layer of at least one water soluble surfactant. Emulsion stability is largely determined by particle size; oil-in-water-emulsions having particle sizes that exceed 1 μm in diameter tend to be less stable and undergo creaming, coagulation and phase separation upon storage. Therefore, for most applications it is desirable to reduce particle size which generally results in significant increases in aqueous phase surfactant concentration. The smaller the particle size, the greater the combined particle surface area resulting in a need for more surfactant in the aqueous phase, thus more free surfactant in solution.
  • [0003]
    Oil-in-water emulsions are useful for treating ophthalmic conditions such as dry eye. Dry eye results from evaporation of naturally occurring water from the eye surface. Oil-in-water emulsions restore the eye's natural aqueous layer and provide an oil layer over the newly added aqueous layer to prevent further evaporation. For maximum efficacy the oil must be spread evenly and freely over the eye surface and the solution must be stable on storing to permit frequent application to the eye. However, stable oil-in-water emulsions can contain excessive amounts of free surfactant. The free surfactant can wash away the tear film's natural lipid component and damage the mucin layer covering the cornea or conjunctiva thus exacerbating dry eye. Therefore, stable oil-in-water emulsions having an average particle size less than 1 μm in diameter that contain non-irritating amounts of eye-damaging free surfactant in the aqueous phase are desirable.
  • SUMMARY OF THE INVENTION
  • [0004]
    Provided herein are stable, non-irritating oil-in-water ophthalmic emulsions containing a therapeutically effective amount of cyclosporine A wherein the oil particles average less than 1 μm in diameter. The oil-in-water ophthalmic emulsions presently disclosed comprise oils having non-polar alkyl chains such as, but not limed to the family of unsaturated fatty acids known as omega-3, -6 or -9 oils and a surfactant system to achieve a stable, non-irritating oil-in-water composition.
  • [0005]
    The surfactant system comprises at least two surfactants; the first surfactant has a hydrophile to lipophile balance (HLB) of greater than 8 and a second surfactant having a HLB value of less than 8 wherein the ratio of hydrophilic surfactant to hydrophobic surfactant is approximately 10 to 0.5, alternatively 10 to 1, alternatively 9 to 1, alternatively 8 to 1, alternatively 7 to 1, alternatively 6 to 1, alternatively 5 to 1, alternatively 4 to 1, alternatively 3 to 1, alternatively 2 to 1, alternatively 1 to 1, and all fractions and intermediate ratios included in the broader range of from approximately 10 to approximately 0.5.
  • [0006]
    In one embodiment the surfactant system's HLB ratio of high HLB to low HLB component comprises at least one surfactant having an HLB between 8.0 and 25.0 and at least one other surfactant having an HLB between 7.9 and 1.0.
  • [0007]
    In another embodiment the surfactant system's HLB ratio of high HLB component to low HLB component is 10.0 to 4.9.
  • [0008]
    In another embodiment the surfactant system's HLB ratio of high HLB component to low HLB component is 14.5 to 4.9.
  • [0009]
    In another embodiment the surfactant system's HLB ratio of high HLB component to low HLB component is 10.0 to 2.0.
  • [0010]
    In another embodiment the surfactant system's HLB ratio of high HLB component to low HLB component is 14.5 to 2.0.
  • [0011]
    In yet another embodiment the high HLB surfactant is Lumulse® GRH 40 and the low HLB surfactant is Brij 72 or Brij 93.
  • [0012]
    In one embodiment the non-polar oil comprises an omega-6/9 fatty acid.
  • [0013]
    In another embodiment the omega-6/9 fatty acid is sesame oil or.
  • [0014]
    The stable oil-in-water, non-irritating ophthalmic compositions disclosed herein can also include excipients including, but not limited to buffers, microbicides, demulcents, viscosity modifying agents, metal salts and therapeutic agents.
  • [0015]
    A further embodiment includes an oil-in-water emulsion ophthalmic topical liquid composition having an average particle size less than 1 μm comprising at least one plant-derived oil other than castor oil wherein the oil comprises only aliphatic side chains free of polar pendent groups; a hydrophilic surfactant having an HLB value between approximately 10 and 14; a vegetable oil-derived hydrophobic non-co-block surfactant having unsaturated side chains that contain less than four oxygen atoms, an HLB value between approximately 4 and 6 and is a liquid at room temperature; and wherein in the ophthalmic composition further comprises an amount of cyclosporine A effective to relieve dry eye symptoms.
  • [0016]
    In still another embodiment an oil-in-water emulsion ophthalmic topical liquid composition is provided having an average particle size less than 0.6 μm consisting essentially of at least one plant-derived oil other than castor oil wherein the oil comprises aliphatic side chains free of polar pendent groups; a hydrophilic surfactant having an HLB value between approximately 10 and 11; a vegetable oil-derived hydrophobic non-co-block surfactant having unsaturated side chains that contain less than four oxygen atoms, an HLB value between approximately 4 and 6 and is a liquid at room temperature; and wherein in the ophthalmic composition further comprises an amount of cyclosporine A effective to relieve dry eye symptoms.
  • [0017]
    A further stable oil-in-water emulsion ophthalmic topical liquid composition is provided having an average particle size less than 0.6 μm consisting essentially of sesame oil, a hydrophilic surfactant consisting of Lumulse® GRH-25, a hydrophobic non-co-block surfactant consisting of Brij 93 and wherein in said ophthalmic composition further comprises an amount of cyclosporine A effective to relieve dry eye symptoms.
  • BRIEF DESCRIPTION OF THE DRAWINGS
  • [0018]
    FIG. 1 depicts the cyclosporine distribution in an oil particle made in accordance with the present teaching versus the prior art.
  • [0019]
    FIG. 2 depicts relative particle size based on surfactant types and the affect on surface area.
  • [0020]
    FIG. 3 depicts the molecular structures of the omega fatty acid side chains associated with the non-polar oils described herein and contrasted to the expressly excluded polar oil side chain of castor oil.
  • [0021]
    FIG. 4 depicts the fatty acids of FIG. 3 as naturally occurring triglycerides.
  • DEFINITION OF SELECTED TERMS
  • [0022]
    For the avoidance of doubt, the following terms as used herein are defined as follows. Words or terms not specifically defined shall have the ordinary meaning as known to those skilled in the art of pharmaceutical formulations, emulsion chemistry or opthalmology.
  • [0023]
    The term “clear viscous gel” as used herein refers to a semisolid preparation that is clear and does not flow.
  • [0024]
    The term “demulcent” is used in the usual sense and refers to an agent that relieves irritation of inflamed or abraded lens and/or eye surfaces.
  • [0025]
    The term “emulsion” is used in its customary sense to mean a kinetically stable but thermodynamically unstable homogenous mixture of two liquids which do not normally mix such as oil and water.
  • [0026]
    The term “non-irritating” as used herein is defined as a composition that does not result in subjective discomfort in the majority of users when applied directly or indirectly to the eye surface. It is understood that the condition of the user's eye and idiopathic sensitivity to one or more of the compositions' ingredients may result in irritation or discomfort in some users. However, as used herein “non-irritating” refers to the overall reaction the majority of normal users will experience immediately after, and for a reasonable period of time thereafter, application to the eye surface.
  • [0027]
    The term “non-polar oil” as used herein refers to a pharmaceutically acceptable plant or fish oil that do not have hydroxyl groups pendant to the side chains such as, but not limited to castor oil, which is expressly excluded from the present invention. Moreover, mineral oils, although technically are non-polar oils, are not plant or fish derived and therefore are not included with the definition of “non-polar oil” as used herein and are expressly excluded from the present invention.
  • [0028]
    The term “particle” as used herein refers to a spherical oil droplet suspended in the aqueous phase of an oil-in-water emulsion.
  • [0029]
    The term “paste” as used herein refers to a semisolid preparation which does not flow.
  • [0030]
    The term “stable” is used in its customary sense and means the absence of creaming, flocculation, and phase separation.
  • [0031]
    The term “surface active agent” generally refers to a surfactant, detergent or emulsifier as defined below. However, as used herein “surface active agent” refers specifically to the active lens cleaning component of a multi-purpose solution. However, the term “surface active agent’ used in that context is not intended to limit the contribution the surface active agent may make to other aspects of the composition such as emulsification, stability and enhancing active agent solubility.
  • [0032]
    The term “surfactant” refers to a substance which aids the formation of an emulsion such and includes emulsifiers, detergents and other surface active agents. The terms “emulsifier,” “surface active agent,” “detergent” and “surfactant” are used interchangeably herein. In the context described herein, surfactant system means at least two surfactants, one having and HLB greater than 8 and the other having an HLB less than 8.
  • DETAILED DESCRIPTION OF THE INVENTION
  • [0033]
    Disclosed herein are stable oil-in-water emulsion ophthalmic topical liquid compositions having an average particle size less than 1 μm including at least one plant-derived oil other than castor oil wherein the oil comprises only aliphatic side chains free of polar pendent groups. The oil-in-water emulsion ophthalmic topical liquid compositions also include a hydrophilic surfactant having an HLB value between approximately 10 and 14, a vegetable oil-derived hydrophobic non-co-block surfactant having unsaturated side chains that contain less than four oxygen atoms having an HLB value between approximately 4 and 6 and is a liquid at room temperature. The oil-in-water emulsion ophthalmic topical liquid compositions disclosed herein can further include an amount of cyclosporine A effective to relieve dry eye symptoms.
  • [0034]
    These therapeutic ophthalmic compositions comprise stable oil-in-water emulsions that are non-irritating when applied to the eye. The therapeutic ophthalmic compositions provided herein are useful for lubricating the eye surface (artificial tears) and for treating or relieving the symptoms associated with dry eye. Dry eye syndrome is a prevalent condition for which there is no cure, although symptoms may be relieved with proper diagnosis and treatment. The condition affects more than 3.2 million American women middle-aged and older alone (Schaumberg D A, Sullivan D A, Buring J E, Dana M R. Prevalence of dry eye syndrome among US women. Am J Opthalmol 2003 August; 136(2):318-26). Contact lens wearers, computer users, patients who live and/or work in dry environments, and patients with autoimmune disease are all particularly susceptible to developing dry eye.
  • [0035]
    Oil-in-water emulsions have proven to be useful as ophthalmic conditions for a variety of applications. Successful ophthalmic emulsion solution compositions need to possess two important properties. Ophthalmic emulsion solutions need to stable, that is once formed the emulsion needs to retain its initial properties without separating, coagulating or creaming. Ophthalmic emulsions that solidity (cream) or coagulate are not solutions and therefore, while potentially useful as ointments, are not acceptable as ophthalmic multi-use solutions. Ophthalmic emulsion solutions that separate need to be shaken regularly prior to use with; this step may be inadvertently forgotten resulting in the user applying an ineffective or irritating solution to the eye or lens.
  • [0036]
    Secondly, ophthalmic solution compositions must be non-irritating when applies to the eye. Irritation is generally causes by excessive lipophilic surfactant being present in the aqueous phase. When the ophthalmic composition having excessive aqueous phase lipohilic surfactant is applied to the eye, the surfactant washes away the tear film's natural lipid component and damages the mucin layer covering the cornea or conjunctiva thus irritating the eye and/or exacerbating dry eye syndrome.
  • [0037]
    However, making a stable, non-irritating stable ophthalmic composition solution remains a challenge and has resulted in a number of less than completely satisfactory compromises. This is especially true for multi-use solutions are concerned where the need to balance lens cleaning efficacy with user comfort can be especially challenging. Without wishing to be bound to or limited by this theory, the present inventor has observed that oil-in-water emulsion stability and flow characteristics are at least in part determined by particle size. Thus the smaller the particle size, the inherently more stable the emulsion becomes and the more flowable (spreading evenly over the eye surface). In one embodiment the emulsions disclosed herein have a particle size average less than 1 μm in diameter, in another embodiment the particle size average is less than 0.8 μm in diameter; in another embodiment the particle size average is less than 0.6 μm in diameter; in another embodiment the particle size average is less than 0.4 μm; in another embodiment the particle size average is less than 0.2 μm in diameter; in another embodiment the particle size average is less than 0.1 μm in diameter in diameter.
  • [0038]
    Prior art oil-in-water emulsions achieved increased stability and smaller particle size by increasing the water soluble (higher HLB) surfactants concentration in the emulsion. However, while this practice did decrease particle size and thus increase stability; it also increased the amount of free hydrophilic surfactant present in the ophthalmic composition's aqueous phase thus irritating the eye.
  • [0039]
    Surprisingly, the present inventor has discovered that by closely matching the surfactant system with the oil component, the adverse effects resulting from excessive amounts of free surfactant can be avoided while simultaneously achieving the desired particle size and thus improving the therapeutic emulsion's overall performance. FIG. 1 depicts one embodiment described herein compared with a prior art embodiment. FIG. 1 is not necessarily drawn to scale but serves to depict one aspect of how the present emulsions may achieve their desirable properties over the prior art. Note that prior art embodiment combines the single detergent Lumulse® and a polar oil, castor oil, to achieve a desired emulsion composition. However, the presence of hydroxyl groups on the oil droplet surface reduces the number of sites where the aqueous phase surfactant Lumulse® can interact with the droplet compared with a representative embodiment made according to the present teachings comprised of a non-polar oil and the detergent system described herein. It can be seen in FIG. 1 that proportionally more aqueous phase detergent (in this example Lumulse®) is sequestered on the oil droplet's outer surface with emulsion compositions made in accordance with these teaching resulting in a significantly less free surfactant in the aqueous phase and therefore a less irritating ophthalmic solution.
  • [0040]
    As mentioned briefly above, equally surprising was the effect of choosing the optimal surfactant system to pair with the oil component of the present therapeutic ophthalmic emulsion. The present inventor surprisingly discovered that combining an oil soluble/water insoluble surfactant (hydrophobic surfactant) with a hydrophilic surfactant the total amount of free hydrophilic surfactant in the aqueous phase was remarkably reduced; but only in combination with a non-polar oil. In fact, the present inventor discovered that merely adding a hydrophobic surfactant to the prior art combination of castor oil and a hydrophilic surfactant actually increased the amount to free hydrophilic surfactant in the aqueous phase and thus exacerbated eye irritation. As will be demonstrated in the experimental section included herein, this increase in free hydrophilic surfactant in the aqueous phase results form a significant increase in particle size when a polar oil is used in combination with the surfactant systems disclosed here, which would be completely unexpected given the significant reduction in particle size when the surfactant systems taught herein are used with non-polar oils (See FIG. 2).
  • [0041]
    Moreover, the therapeutic oil-in-water emulsions described herein also include a hydrophobic therapeutic component, specifically cyclosporine A (also spelled cyclosporin or cyclosporin). Cyclosporine A is an immunosuppressant drug widely used in post-allogeneic organ transplant to reduce the activity of the patient's immune system and so the risk of organ rejection. It has been studied in transplants of skin, heart, kidney, liver, lung, pancreas, bone marrow and small intestine. Initially isolated from a Norwegian soil sample, Cyclosporin A, the main form of the drug, is a cyclic nonribosomal peptide of 11 amino acids (an undecapeptide) produced by the fungus Tolypocladium inflatum Gams, and contains D-amino acids, which are rarely encountered in nature. Recently, cyclosporine has been shown to be highly efficacious in treating dry eye and is the primary active ingredient in Restasis®. (See Perry H D et al. Evaluation of topical cyclosporine for the treatment of dry eye disease. Arch Opthalmol. 2008 August; 126(8): 1046-50.).
  • [0042]
    Provided herein are stable, non-irritating oil-in-water multi-use ophthalmic emulsions comprising oil particles suspended in an aqueous phase wherein the oil particle size averages is less than 1 μm in diameter. The oil-in-water ophthalmic emulsions presently disclosed comprise oils having non-polar alkyl chains such as, but not limed to the family of unsaturated fatty acids known as omega-3, -6 or -9 oils (See FIG. 3 and FIG. 4). The stable oil-in-water emulsions include a surfactant system comprising at least one hydrophilic and at least one hydrophobic surfactant. Additionally the stable oil-in-water emulsions may include other excipients such as, but not limited to, demulcents, lubricants, viscosity modifiers, tonicty enhancers, metallic salts, buffers and therapeutic compositions such as cyclosporine A.
  • [0043]
    The non-polar pharmaceutically acceptable oils useful for making the stable oil-in-water therapeutic emulsions described herein include plant-derived unsaturated fatty acids having at least one carbon-carbon double bond in their non-polar alkyl side chains. Particularly desirable examples include the omega fatty acids. Omega-3 fatty acids have the carbon-carbon double bond at the n-3 position from the methyl end of the fatty acid; omega-6 fatty acids have a carbon-carbon double bond in the n-6 position; that is, the sixth bond from the end of the fatty acid and omega-9 fatty acids which have in common a carbon-carbon double bond in the n-9 position; that is, the ninth bond from the end of the fatty acid.
  • [0044]
    As depicted in FIG. 4 oils are often a blend of more than one fatty acid type, for example in one embodiment described herein the oil used for the oil-in-water emulsion is sesame seed oil. Sesame oil has about 43% each of linoleic acid (an omega 6 fatty acid) and oleic acid (an omega 9 fatty acid) (see for example Dina S C et al. Enhancement of skin permeation of ibuprofen from ointments and gels by sesame oil, sunflower oil and oleic acid. Indian J Pharm Sci. 2006; 68:313-316. The entire contents of which are incorporated herein by reference). However neither linoleic acid nor oleic acid have a hydroxyl group on the side chain such as castor oil does and therefore, for the purposes described herein, sesame seed oil is a non-polar oil as that term is used herein. Other suitable non-limiting examples of plant-derived omega fatty acid-containing oils include cherry kernel oil, pumpkin seed oil, hemp seed oil, flax seed oil, perilla seed oil, and blackcurrant seed oil. However, neither castor oil (oils having a polar alkyl chains generally) nor mineral oil (completely non-polar oils) is suitable for use in preparing the oil-in-water compositions described herein and both castor oil and mineral oil expressly excluded from the appended claims.
  • [0045]
    The surfactant system used in accordance with the teaching herein comprises at least two surfactants; the first surfactant has a HLB of greater than 8 (hydrophilic surfactant) and a second surfactant having a HLB of less than 8 (hydrophobic surfactant) wherein the ratio of hydrophilic surfactant to hydrophobic surfactant is approximately 10 to 0.5, alternatively 10 to 1, alternatively 9 to 1, alternatively 8 to 1, alternatively 7 to 1, alternatively 6 to 1, alternatively 5 to 1, alternatively 4 to 1, alternatively 3 to 1, alternatively 2 to 1, alternatively 1 to 1, and all fractions and intermediate ratios included in the broader range of from approximately 10 to 0.5.
  • [0046]
    As is well known in the art, the terms “hydrophilic (hydrophile)” and “hydrophobic (lipophile or lipohilic)” are relative terms. To function as a surfactant, a compound must necessarily include polar or charged hydrophilic moieties as well as non-polar hydrophobic (lipophilic) moieties; i.e., a surfactant compound must be amphiphilic. An empirical parameter commonly used to characterize the relative hydrophilicity and hydrophobicity of non-ionic amphiphilic compounds is the “HLB” value. Surfactants with lower HLB values are more hydrophobic, and have greater solubility in oils, whereas surfactants with higher HLB values are more hydrophilic, and have greater solubility in aqueous solutions.
  • [0047]
    Table 1 provides a general guide to selecting surfactants based on HLB values.
  • [0000]
    HLB
    range Application
    3-6 W/O emulsions
    7-9 Wetting
     8-18 O/W emulsions
     3-15 Detergency
    15-18 Solubilization
  • [0048]
    Using HLB values as a rough guide, hydrophilic surfactants are generally considered to be those compounds having an HLB value greater than about 10, as well as anionic, cationic, or zwitterionic compounds for which the HLB scale is not generally applicable. Similarly, hydrophobic surfactants are compounds having an HLB value less than about 10. It should be appreciated that the HLB value of a surfactant is merely a rough guide generally used to enable formulation of industrial, pharmaceutical and cosmetic emulsions. For many important surfactants, including several polyethoxylated surfactants, it has been reported that HLB values can differ by as much as about 8 HLB units, depending upon the empirical method chosen to determine the HLB value (Schott, J. Pharm. Sciences, 79(1), 87-88 (1990)). Likewise, for certain polypropylene oxide containing block copolymers (poloxamers, available commercially as Pluronic®. surfactants, BASF Corp.), the HLB values may not accurately reflect the true physical chemical nature of the compounds. Finally, commercial surfactant products are generally not pure compounds, but are often complex mixtures of compounds, and the HLB value reported for a particular compound may more accurately be characteristic of the commercial product of which the compound is a major component. Different commercial products having the same primary surfactant component can, and typically do, have different HLB values. In addition, a certain amount of lot-to-lot variability is expected even for a single commercial surfactant product. Keeping these inherent difficulties in mind, and using HLB values as a guide, one skilled in the art can readily identify surfactants having suitable hydrophilicity or hydrophobicity for use in the present invention, as described herein. See Table 2 below for non-limiting examples.
  • [0049]
    The carrier described herein includes at least one hydrophilic surfactant. The hydrophilic surfactant can be any surfactant suitable for use in pharmaceutical compositions. Suitable hydrophilic surfactants can be anionic, cationic, zwitterionic or non-ionic, although non-ionic hydrophilic surfactants are presently preferred. Preferably, the carrier includes a mixture of two or more hydrophilic surfactants, more preferably two or more non-ionic hydrophilic surfactants. Also preferred are mixtures of at least one hydrophilic surfactant, preferably non-ionic, and at least one hydrophobic surfactant.
  • [0050]
    The choice of specific surfactants should be made keeping in mind the particular triglycerides and optional therapeutic agents to be used in the composition, and the range of polarity appropriate for the chosen therapeutic agent. With these general principles in mind, a very broad range of surfactants is suitable for use in the present invention. Providing the surfactant system used in accordance with the teaching herein comprises at least two surfactants; the first surfactant has a HLB value of greater than 8 and a second surfactant having a HLB of less than 8. In one embodiment the surfactant system's HLB ratio of high HLB to low HLB component comprises at least one surfactant having an HLB between 8.0 and 25.0 and at least one other surfactant having an HLB between 7.9 and 1.0. In another embodiment the surfactant system's HLB ratio of high HLB component to low HLB component is 10.0 to 4.9. In another embodiment the surfactant system's HLB ratio of high HLB component to low HLB component is 14.5 to 4.9. In another embodiment the surfactant system's HLB ratio of high HLB component to low HLB component is 10.0 to 2.0. In another embodiment the surfactant system's HLB ratio of high HLB component to low HLB component is 14.5 to 2.0.
  • [0051]
    Such surfactants can be grouped into the following general chemical classes detailed in the Tables herein. The HLB values given in Table 2 below generally represent the HLB value as reported by the manufacturer of the corresponding commercial product. In cases where more than one commercial product is listed, the HLB value in the Tables is the value as reported for one of the commercial products, a rough average of the reported values, or a value that, in the judgment of the present inventors, is more reliable. It should be emphasized that the invention is not limited to the surfactants in the Tables, which show representative, but not exclusive, lists of available surfactants.
  • [0000]
    TABLE 2
    HLB Values for Representative Surfactants
    Surfactant Synonym HLB
    2,4,7,9-Tetramethyl-5- 4.0
    decyne-4,7-diol
    PEG-block-PPG-block- 4.0
    PEG, MN 1100
    PEG-block-PPG-block- 4.0
    PEG, MN 2000
    PEG-block-PPG-block- 4.0
    PEG, MN 2800
    PEG-block-PPG-block- 4.0
    PEG, MN 4400
    Ethylenediamine 4.0
    tetrakis(PO-b-EO) tetrol,
    MN 3600
    Ethylenediamine 4.0
    tetrakis(EO-b-PO) tetrol,
    MN 7200
    Ethylenediamine 4.0
    tetrakis(EO-b-PO) tetrol,
    MN 8000
    Igepal ® CA-210 Polyoxyethylene(2) 4.3
    isooctylphenyl ether
    Sorbitan monooleate Span ® 80 4.3
    PPG-block-PEG-block- 4.5
    PPG, MN 3300
    Igepal CO-210 Polyoxyethylene(2) 4.6
    nonylphenyl ether
    Sorbitan monostearate Span ® 60 4.7
    Brij ® 92/93 Polyoxyethylene(2) oleyl 4.9
    ether
    Brij ® 72 Polyoxyethylene(2) 4.9
    stearyl ether
    Brij ® 52 Polyoxyethylene(2) cetyl 5.3
    ether
    Sorbitan monopalmitate Span ® 40 6.7
    Merpol ® A surfactant 6.7
    2,4,7,9-Tetramethyl-5- 8.0
    decyne-4,7-diol
    ethoxylate
    Triton ® SP-135 8.0
    Sorbitan monolaurate Span ® 20 8.6
    PEG-block-PPG-block- 9.5
    PEG, MN 5800
    PPG-block-PEG-block- 9.5
    PPG, MN 2700
    Brij ® 30 Polyoxyethylene(4) lauryl 9.7
    ether
    Igepal ® CA-520 Polyoxyethylene(5) 10.0
    isooctylphenyl ether
    Igepal ® CO-520 Polyoxyethylene(5) 10.0
    nonylphenyl ether
    Lumulse ® GRH-25 Polyethylene Glycol Ester 10.0
    of Hydrogenated Castor
    Oil
    Polyoxyethylene sorbitol 10.2
    hexaoleate
    Merpol ® SE surfactant 10.5
    Tween ® 85 Polyoxyethylene(20) 11.0
    sorbitan trioleate
    8-Methyl-1-nonanol 11.0
    propoxylate-block-
    ethoxylate
    Polyoxyethylene sorbitan 11.4
    tetraoleate
    Triton ® X-114 Polyoxyethylene(8) 12.4
    isooctylphenyl ether
    Brij ® 76 Polyoxyethylene(10) 12.4
    stearyl ether
    Brij ® 97 Polyoxyethylene(10) oleyl 12.4
    ether
    Merpol ® OJ surfactant 12.5
    Brij ® 56 Polyoxyethylene(10) cetyl 12.9
    ether
    Merpol ® SH surfactant 12.9
    Tergitol ® NP-9 Nonylphenol 12.9
    polyethylene glycol ether
    2,4,7,9-Tetramethyl-5- 13.0
    decyne-4,7-diol
    ethoxylate (5 EO/OH)
    Triton ® SP-190 13.0
    Igepal ® CO-630 Polyoxyethylene(9) 13.0
    nonylphenyl ether
    Triton ® X-100 Polyoxyethylene(10) 13.5
    isooctylphenyl ether
    Lumulse ® GRH-40 Polyethylene Glycol Ester 13.5
    of Hydrogenated Castor
    Oil
    Igepal ® CO-720 Polyoxyethylene(12) 14.2
    nonylphenyl ether
    Polyoxyethylene(12) 14.5
    tridecyl ether
    Polyoxyethylene(18) 14.5
    tridecyl ether
    Igepal ® CA-720 Polyoxyethylene(12) 14.6
    isooctylphenyl ether
    Tween ® 80 Polyoxyethylene(20) 14.9
    sorbitan monooleate
    Tween ® 60 Polyoxyethylene(20) 15.0
    sorbitan monostearate
    PEG-block-PPG-block- 15.0
    PEG, MN 2900
    PPG-block-PEG-block- 15.0
    PPG, MN 2000
    Brij ® 78 Polyoxyethylene(20) 15.3
    stearyl ether
    Brij ® 98 Polyoxyethylene(20) oleyl 15.3
    ether
    Merpol ® HCS surfactant 15.5
    Tween ® 40 Polyoxyethylene(20) 15.6
    sorbitan monopalmitate
    Brij ® 58 Polyoxyethylene(20) cetyl 15.7
    ether
    Polyethylene-block- 16.0
    poly(ethylene glycol)Mn
    2250
    Tween ® 20 Polyoxyethylene(20) 16.7
    sorbitan monolaurate
    Brij ® 35 Polyoxyethylene(23) 16.9
    lauryl ether
    2,4,7,9-Tetramethyl-5- 17.0
    decyne-4,7-diol
    ethoxylate (15 EO/OH)
    Igepal ® CO-890 Polyoxyethylene(40) 17.8
    nonylphenyl ether
    Triton ® X-405 Polyoxyethylene(40) 17.9
    isooctylphenyl ether
    Brij ® 700 Polyoxyethylene(100) 18.8
    stearyl ether
    Igepal ® CO-990 Polyoxyethylene(100) 19.0
    nonylphenyl ether
    Igepal ® DM-970 Polyoxyethylene(150) 19.0
    dinonylphenyl ether
    PEG-block-PPG-block- 20.5
    PEG, MN 1900
    PEG-block-PPG-block- 24.0
    PEG, MN 8400
    Ethylenediamine 24.0
    tetrakis(PO-b-EO) tetrol,
    MN 15000
    PEG-block-PPG-block- 27.0
    PEG, average Mn ca.
    14,600
  • [0052]
    The following are registered trademarks:
  • [0053]
    Igepal® Rhodia Operations Societe Par Actions Simplifiee France 40 Rue De La Haie Coq Aubervilliers France 93306.
  • [0054]
    Brij® ICI Americas Inc. Corporation By Merger With And Change Of Name From Delaware New Murphy Road And Concord Pike Wilmington Del. 19897.
  • [0055]
    Merpol® Stepan Company Corporation By Assignment Delaware 22 West Frontage Road Northfield Ill. 60093.
  • [0056]
    Lumulse® Lambent Technologies Inc. Corporation Georgia 2416 Lynndale Road Fernandina Beach Fla. 32024.
  • [0057]
    Triton® X-100 is a registered trademark of Union Carbide and was purchased from Rohm & Haas Co.
  • [0058]
    Tween® ICI Americas Inc. Corporation By Merger With And Change Of Name From Delaware New Murphy Road And Concord Pike Wilmington Del. 19897.
  • [0059]
    The stable oil-in-water, non-irritating ophthalmic compositions disclosed herein can also include excipients including, but not limited to buffers, microbicides, demulcents, viscosity modifying agents, metal salts and therapeutic agents.
  • [0060]
    In one embodiment the viscosity modifying agent is selected from the group consisting of hyaluronic acid and salts thereof, polyvinylpyrrolidone (PVP), cellulose polymers, including hydroxypropyl methyl cellulose (HPMC), hydroxyethyl cellulose (H EC), ethyl hydroxyethyl cellulose, hydroxypropyl cellulose, methyl cellulose and carboxymethyl cellulose (CMC), dextran 70, gelatin, glycerine, polyethylene glycols, polysorbate 80, propylene glycol, povidone, carbomers (e.g. Carbopol®), polyvinyl alcohol, alginates, carrageenans, and guar, karaya, agarose, locust bean, tragacanth and xanthan gums.
  • [0061]
    In another embodiment the microbicide is a polymeric quaternary amine preservative selected from the group consisting of poly[dimethylimino-w-butene-1,4-diyl]chloride, alpha-[4-tris(2-hydroxyethyl)ammonium]dichloride (Polyquaternium 1®), poly(oxyethyl(dimethyliminio)ethylene dimethyliminio)ethylene dichloride (WSCP®), polyhexamethylene biguanide (PHMB), polyaminopropyl biguanide (PAPB).
  • EXAMPLES Example 1
  • [0062]
    Comparison of Particle Size with Different Surfactant Systems
  • [0000]
    TABLE 3
    Particle size as a function of surfactant system
    % w/w % w/w % w/w % w/w
    Sesame oil 2.5 2.5 2.5 2.5
    Lumulse GRH-40 1.5 1.0 1.0 0.5
    Brij 72 0.5 0.5
    Boric acid 0.60 0.60 0.60 0.60
    Sodium borate 0.15 0.15 0.15 0.15
    10H2O
    NaCl 0.40 0.40 0.40 0.40
    water 94.85 95.35 94.85 95.35
    particle size (um) 4.71 126.95 0.31 0.59
  • [0063]
    It can be seen from the data present in Table 3 that the particle size of a sesame oil in an oil-in-water emulsion decreases significantly when a low HLB value (hydrophobic) surfactant (HLB for Brij 72 is approximately 4.9) is added to the composition in combination with the higher HLB (HLB value for Lumulse® GRH-40 is approximately 13.5). Note that nearly twice as much hydrophilic surfactant is necessary to achieve a particle size less than 1 μm when used alone than when used in combination with a hydrophobic surfactant. The reduced particle size and lower concentration of hydrophilic surfactant in the composition results in less irritating and thus more efficacious ophthalmic compositions.
  • Example 2 Therapeutic Agent Delivery
  • [0064]
    Dry eye syndrome is a prevalent condition for which there is no cure, although symptoms may be relieved with proper diagnosis and treatment. The condition affects more than 3.2 million American women middle-aged and older alone (Schaumberg D A, Sullivan D A, Buring J E, Dana M R. Prevalence of dry eye syndrome among US women. Am J Opthalmol 2003 August; 136(2):318-26). Contact lens wearers, computer users, patients who live and/or work in dry environments, and patients with autoimmune disease are all particularly susceptible to developing dry eye.
  • [0065]
    In order to relieve dry eye symptoms the ophthalmic composition must achieve three basic treatment goals. First it must be easily and conveniently applied directly to the eye surface such that the aqueous component of the emulsion restores the evaporating aqueous layer naturally present on the eye surface and the emulsion's oil phase should form a layer over the aqueous layer reducing or preventing further evaporation. Secondly, the oil-in-water emulsion should be stable such that it does not separate into phases on storage necessitating shaking prior to use (which can be inadvertently forgotten by the user). Third, the stable oil-in-water emulsion must remain sufficiently liquid that it flows easily from a dropper or other applications and does not congeal or for a paste on storage. Therefore, the ideal ophthalmic oil-in-water emulsion used to treat dye eyes and other ophthalmic conditions need to be stable, have acceptable flow characteristics, and be non-irritating to the eye.
  • [0066]
    Cyclosporine is a hydrophobic therapeutic agent that is insoluble in water and therefore must be solubilized prior to being administered to the eye. The prior art formulation uses castor oil to dissolve cyclosporine due to its high solubility in this polar oil. However, castor oil's polarity forms an emulsion having the cyclosporine sequestered near the oil particles' core and away from the particle surface as depicted in FIG. 2B. Consequently cyclosporine transfer to the conjunctiva and cornea tissue is inefficient.
  • [0067]
    Cyclosporine has low solubility in non-polar oils such as sesame oil, soybean oil and flax seed oil. The present inventors discovered that adding a low HLB surfactant to the oil-cyclosporine mixture significantly increased the therapeutic agent's solubility and surprisingly increased cyclosporine delivery to conjunctiva and cornea tissue compared with castor oil containing emulsions (Table 4). FIG. 2A depicts a theoretical oil particle made in accordance with the teachings described herein. Note that the presence of the low HLB surfactant (“Brij”) causes the cyclosporine (depicted in FIG. 2 as solid black dots) to be localized at the perimeter of the oil particle and thus more easily transferred to the eye surface as compared with FIG. 2B were the cyclosporine is sequestered near the oil particle central core.
  • [0000]
    TABLE 4
    Cyclosporine/ Brij 93/oil
    oil weight Cyclosporine
    Oils weight ratio ratio Solubility
    Castor oil  20% 0 soluble
    Sesame oil 5.6% 0 Insoluble
    Sesame oil 6.6% 6.6% soluble
    Soybean 5.6% 0.0% Insoluble
    oil
    Soybean 6.6% 6.6% soluble
    oil
    Flax oil 5.6% 0 Insoluble
    Flax oil 6.6% 6.6% soluble
  • [0068]
    It is important to understand that merely adding Brij, or another low HLB surfactant to a castor oil-cyclosporine mixture will not result in the high efficacy therapeutic agent delivery system as taught herein. In fact adding a low HLB surfactant (Brij) to a castor oil emulsion will result in increasing particle size (see Table 5) causing dramatic increases in free hydrophilic detergent (Lumulse® for example) in the aqueous phase and thus increase eye irritation and reduced drug delivery efficacy.
  • [0000]
    TABLE 5
    Ingredient % w/w % w/w % w/w % w/w
    Castor Oil 2.5 2.5 2.5 2.5
    Lumulse ® 1.0 1.5 1.0 1.5
    GRH-40
    BRIJ 72 0.5 0.5
    Base 96.5 96.0 96.0 95.5
    Solution
    Particle size 1.08 0.16 1.14 4.23
  • [0069]
    To test cyclosporine delivery efficacy of compositions made in accordance with the teachings herein using methods known to those skilled in the art. Five test emulsions were prepared and administered to the eyes of New Zealand white rabbits in accordance with standard methods (see for example Abraham M H, et al., Draize rabbit eye test compatibility with eye irritation thresholds in humans: a quantitative structure-activity relationship analysis. Toxicol Sci. 2003 December; 76(2):384-91. Epub 2003 Sep. 26; see also Gettings S D et al., A comparison of low volume, Draize and in vitro eye irritation test data. III. Surfactant-based formulations. Food Chem. Toxicol. 1998 March; 36(3):209-31. Both of articles are incorporated herein in their entirety by reference).
  • [0070]
    Table 6 demonstrates the superior delivery of test solutions 1, 2 and 3 as compared with the cyclosporine containing and the commercial embodiment, column 5. Table 6a similarly presents data for test emulsions 4 and 5. Emulsion 4 contains 50% more sesame oil, Lumulse® GRH-25, Brij 93 than emulsion 5, other ingredients are identical. All concentrations in tables 6 and 6a are expressed in weight/weight percent Note that the lower concentration of Brij 93 in emulsion 5 results in an increase in cyclosporine delivery to the cornea (even though the ration of Brij 93 to sesame oil remained constant at 0.12) Tissue levels increased significantly using sesame oil/Brij 93 as the basis for the emulsions. The experimentally measured cyclosporine concentrations in the rabbit conjunctiva and cornea tissue are listed in table 6 were normalized for tissue weight.
  • [0000]
    TABLE 6
    Test Test Test Commercial
    Control Solution Solution Solution Castor Oil
    Ingredients Solution #1 #2 #3 Product1
    Cyclosporine A 0.05 0.05 0.05 0.05 0.05
    (CsA)
    Castor Oil 1.25 1.25
    Sesame Oil 1.25 1.25 1.25
    Lumulse ® GRH- 1
    40
    Lumulse ® GRH- 0.5 0.5 0.5
    25
    BRIJ 93 0.05 0.1 0.25
    Boric Acid 0.6 0.6 0.6 0.6
    Sodium borate 0.035 0.07 0.07 0.07
    NaCl 0.14
    PHMB 0.001 0.001 0.001
    Water Q.S. Q.S. Q.S. Q.S.
    Brij 93/oil (g/g) 0 0.04 0.08 0.2 0
    CsA/Conjunctiva 0.52 0.90 0.91 0.78 0.46
    (μg/g)
    CsA/Cornea 0.98 3.97 2.27 1.50 0.99
    (μg/g)
    Increased2 13%  96%  98% 70% 0%
    delivery to
    Conjunctive
    Increased −1% 291% 129% 52% 0%
    delivery to
    Cornea
    1The Commercial Castor Oil used in the comparisons expressed here was Restasis ® a product and trademark of Allergan, Inc., Irvine, California.
    2Increase delivery of CsA relative to Restasis ®
  • [0000]
    TABLE 6a
    Test Test Commercial
    Control Solution Solution Castor Oil
    Ingredients Solution #4 #5 Product3
    Cyclosporine A 0.05 0.05 0.05 0.05
    (CsA)
    Castor Oil 1.25 1.25
    Sesame Oil 1.25 0.83
    Lumulse ® GRH- 1
    40
    Lumulse ® GRH- 0.5 0.33
    25
    BRIJ 93 0.15 0.1
    Boric Acid 0.6 0.6 0.6
    Sodium borate 0.035 0.08 0.08
    NaCl 0.14 0.37 0.37
    PHMB
    Water Q.S. Q.S. Q.S.
    Brij 93/oil (g/g) 0 0.04 0.08 0
    CsA/Conjunctiva 0.52 0.93 0.93 0.46
    (μg/g)
    CsA/Cornea 0.98 1.45 2.26 0.99
    (μg/g)
    Increased4 13% 102% 102%
    delivery to
    Conjunctive
    Increased −1% 46% 128%
    delivery to
    Cornea
    3The Commercial Castor Oil used in the comparisons expressed here was Restasis ® a product and trademark of Allergan, Inc., Irvine, California.
    4Increase delivery of CsA relative to Restasis ®
  • [0071]
    It should be noted here that the present inventor surprisingly observed that therapeutic-containing ophthalmic emulsion solutions made in accordance with the teachings herein are significantly more effective at delivering a hydrophobic therapeutic composition to the eye's surface than current commercial embodiments. Without wishing to be bound by the theory the present inventors proposes that the observed superiority in cyclosporine delivery to the eye can be explained by reference to FIG. 1. Note that in FIG. 1 the hydrophobic drug is localized near the perimeter of the oil particle and is thus more immediately and easily transferred to the eye's surface than in the prior art composition where, as depicted in FIG. 1 the hydrophobic therapeutic is sequestered near the particle's inner core.
  • [0072]
    Table 7 depicts concentration ranges for selected emulsions ingredients made in accordance with the teachings herein. All values are given in weight/weight percents of the total emulsion weight. In one embodiment of the oil-in-water emulsions made in accordance with the teaching herein the concentration of low HLB to non-polar oil can be expressed as a ratio. Expressed in this manner the ratio of low HLB surfactant/non-polar oil is from approximately 0.002 to 4.0, preferably 0.02 to 0.4.
  • [0073]
    Table 8 represents a specific formulation that is useful in treating dye eye in accordance with the teachings herein.
  • [0000]
    TABLE 7
    Concentration range
    Ingredient % w/w Preferred Range % w/w
    Non-polar Oil 0.5 to 3.0   1 to 1.5
    5Cyclosorine A 0.01 to 0.15 0.02 to 0.06
    High HLB Surfactant 0.1-5.0 0.5 to 1.5
    Low HLB Surfactant 0.1-3.0 0.1 to 0.5
    Water Q.S. Q.S.
    5The amount of cyclosporine A used in the opthalmic compositions described here in is an amount that is effective to treat or relieve symptoms associated with dry eye.
  • [0000]
    TABLE 8
    Ingredient % W/W
    Cyclosporine A 0.05
    Sesame oil 1.25
    Lumulse ® GRH-25 0.5
    Brij 93 0.2
    Boric Acid 0.6
    Sodium borate deahydrate 0.46
    PHMB 0.001
    Water for Injection Q.S.
  • Formulations
  • [0074]
    The preparation of the oil-in-water emulsions for the present dry eye-treating compositions is generally as follows. Non-emulsifying agents which are water soluble components, including any water-soluble polymer demulcent(s), are dissolved in the aqueous (water) phase and oil-soluble components including the emulsifying agents are dissolved in the oil phase. The two phases (oil and water) are separately heated to an appropriate temperature. This temperature is the same in both cases, generally a few degrees to 5 to 10 degrees above the melting point of the highest melting ingredients in the case of a solid or semi-solid oil or emulsifying agent in the oil phase. Where the oil phase is liquid at room temperature, a suitable temperature is determined by routine experimentation with the melting point of the highest melting ingredients in the aqueous phase. In cases where all components of either the oil or water phase are soluble in their respective phase at room temperature, no heating may be necessary. The temperature must be high enough that all components are in the liquid state but not so high as to jeopardize the stability of the components. A working temperature range is generally from about 20° C. to about 70° C. To create an oil-in-water emulsion, the final oil phase is gently mixed into either an intermediate, preferably de-ionized water (DI water) phase, or the final aqueous phase to create a suitable dispersion and the product is allowed to cool with or without stirring. In the case wherein the final oil phase is first gently mixed into an intermediate water phase, this emulsion concentrate is thereafter mixed in the appropriate ratio with the final aqueous phase. The final aqueous phase includes the water soluble polymer as well as other aqueous-soluble components. In such cases, the emulsion concentrate and the final aqueous phase need not be at the same temperature or heated above room temperature, as the emulsion has already been formed at this point.
  • [0075]
    Semisolids may form in the process of self-emulsification if the amount of ethylene oxide units in one emulsifier is too large. Generally, if the surfactant or surfactants have more than 10 ethylene oxide units in their structures, the surfactant and oil phase is mixed with a small amount of the total composition water, e.g., about 0.1-10%, to first form a semi-solid substance in the form of a paste, which is thereafter combined with the remaining water. Gentle mixing may then be required until the hydrated emulsifiers are fully dissolved to form the emulsion.
  • [0076]
    In one embodiment, the surfactant and oil are initially combined and heated. A small amount of the aqueous phase is then added to the oil phase to form a semi-solid substance in the form of a paste. Paste is defined here as a semisolid preparation which does not flow. The amount of the aqueous phase added may be from 0.1-10 fold, preferably from 0.5 to 5 fold and most preferably 1-2 fold. After the paste is formed, additional water is added to the paste at the same temperature as above. In some embodiments, the amount of water added is 5-20 fold. The emulsion is then gently mixed. In some embodiments, mixing may occur for 30 minutes to 10 hours.
  • [0077]
    In a preferred embodiment, the particles are then sized. A Horiba LA-920 particle size analyzer may be used according to the manufacturer's instructions for this purpose. In a preferred embodiment, the particles are between 0.08 and 0.18 microns in size before passing to the next step.
  • [0078]
    In the next step, the particles may be mixed with other aqueous components such as water, one or more demulcents and buffer (preferably boric acid based). Optionally, electrolytes, such as calcium chloride dihydrate, magnesium chloride hexahydrate, potassium chloride and sodium chloride, and Kollidon 17 NF may be added. While the electrolytes are not necessary to form the emulsions, they are very helpful to preserve ocular tissue integrity by maintaining the electrolyte balance in the eye. Likewise, the buffer is not critical, but a boric acid/sodium borate system is preferred in one embodiment of the invention because a phosphate-based buffer system will precipitate with the preferred electrolytes.
  • [0079]
    The pH is adjusted to 6.8-8.0, preferably from about 7.3 to 7.7. This pH range is optimal for tissue maintenance and to avoid ocular irritation. A preservative may then be added. In a preferred embodiment, stabilized chlorine dioxide (SCD) (Purogene®) material is added as preservative. (Purogene® is a trademark of BioCide International, Inc. Norman, Okla., U.S.A., and is also available as Purite® which is a trademark of Allergan, Inc.).
  • [0080]
    The oil-in-water emulsions described herein can be sterilized after preparation using autoclave steam sterilization or can be sterile filtered by any means known in the art. Sterilization employing a sterilization filter can be used when the emulsion droplet (or globule or particle) size and characteristics allows. The droplet size distribution of the emulsion need not be entirely below the particle size cutoff of the sterile filtration membrane to be sterile-filtratable. In cases where the droplet size distribution of the emulsion is above the particle size cutoff of the sterile filtration membrane, the emulsion needs to be able to deform or acceptably change while passing through the filtrating membrane and then reform after passing through. This property is easily determined by routine testing of emulsion droplet size distributions and percent of total oil in the compositions before and after filtration. Alternatively, a loss of a small amount of larger droplet-sized material may be acceptable.
  • [0081]
    The emulsions described herein are generally non-aseptically filtered through a clarification filter before sterile filtration or aseptically clarify-filtered after autoclave steam sterilization. In a preferred embodiment, the emulsion is filter sterilized using a 0.22 micron filter. Preferably, 98-99% of the emulsion should pass through the 0.22 micron filter. Note that particles larger than 0.22 micron may pass through by altering their shape temporarily. In a preferred embodiment, the material is then tested to verify the effectiveness of the sterilization step. Storage is preferably below 25° C. in order to maintain stability. Thereafter, the emulsions are aseptically filled into appropriate containers.
  • [0082]
    Compositions according to the teachings herein may be used in methods which comprise administering the composition to an eye of a subject, that is a human or animal, in an amount effective in providing a desired therapeutic effect to the subject. Such therapeutic effect may be an ophthalmic therapeutic effect and/or a therapeutic effect directed to one or more other parts of the subject's body or systemically to the subject's body. In preferred embodiments, the therapeutic effect is treatment and/or relief from symptoms of dry eye.
  • [0083]
    The aqueous phase or component and the oil phase and component used in accordance with the present invention are selected to be effective in the present compositions and to have no substantial or significant deleterious effect, for example, on the compositions, on the use of the compositions, on the contact lens being treated, on the wearer of the treated lens, or on the human or animal in whose eye the present composition is placed.
  • [0084]
    The liquid aqueous medium or component of the present compositions preferably includes a buffer component which is present in an amount effective to maintain the pH of the medium or aqueous component in the desired range. The present compositions preferably include an effective amount of a tonicity adjusting component to provide the compositions with the desired tonicity.
  • [0085]
    The aqueous phase or component in the present compositions may have a pH which is compatible with the intended use, and is often in the range of about 4 to about 10. A variety of conventional buffers may be employed, such as phosphate, borate, citrate, acetate, histidine, tris, bis-tris and the like and mixtures thereof. Borate buffers include boric acid and its salts, such as sodium or potassium borate. Potassium tetraborate or potassium metaborate, which produce boric acid or a salt of boric acid in solution, may also be employed. Hydrated salts such as sodium borate decahydrate can also be used. Phosphate buffers include phosphoric acid and its salts; for example, M2HPO4 and MH2PO4, wherein M is an alkali metal such as sodium and potassium. Hydrated salts can also be used. In one embodiment described herein, Na2HPO4.7H2O and NaH2PO4.H2O are used as buffers. The term phosphate also includes compounds that produce phosphoric acid or a salt of phosphoric acid in solution. Additionally, organic counter-ions for the above buffers may also be employed. The concentration of buffer generally varies from about 0.01 to 2.5 w/v % and more preferably varies from about 0.05 to about 0.5 w/v %.
  • [0086]
    The type and amount of buffer are selected so that the formulation meets the functional performance criteria of the composition, such as surfactant and shelf life stability, antimicrobial efficacy, buffer capacity and the like factors. The buffer is also selected to provide a pH, which is compatible with the eye and any contact lenses with which the composition is intended for use. Generally, a pH close to that of human tears, such as a pH of about 7.45, is very useful, although a wider pH range from about 6 to about 9, more preferably about 6.5 to about 8.5 and still more preferably about 6.8 to about 8.0 is also acceptable. In one embodiment, the present composition has a pH of about 7.0.
  • [0087]
    The osmolality of the present compositions may be adjusted with tonicity agents to a value which is compatible with the intended use of the compositions. For example, the osmolality of the composition may be adjusted to approximate the osmotic pressure of normal tear fluid, which is equivalent to about 0.9 w/v % of sodium chloride in water. Examples of suitable tonicity adjusting agents include, without limitation, sodium, potassium, calcium and magnesium chloride; dextrose; glycerin; propylene glycol; mannitol; sorbitol and the like and mixtures thereof. In one embodiment, a combination of sodium chloride and potassium chloride are used to adjust the tonicity of the composition.
  • [0088]
    Tonicity agents are typically used in amounts ranging from about 0.001 to 2.5 w/v %. These amounts have been found to be useful in providing sufficient tonicity for maintaining ocular tissue integrity. Preferably, the tonicity agent(s) will be employed in an amount to provide a final osmotic value (expressed in osmolality) of 150 to 450 mOsm/kg, more preferably between about 250 to about 330 mOsm/kg and most preferably between about 270 to about 310 mOsm/kg. The aqueous component of the present compositions more preferably is substantially isotonic or hypotonic (for example, slightly hypotonic, e.g., about 240 mOsm/kg) and/or is ophthalmically acceptable. In one embodiment, the compositions contain about 0.14 w/v % potassium chloride and 0.006 w/v % each of calcium and/or magnesium chloride.
  • [0089]
    In addition to tonicity and buffer components, the present compositions may include one or more other materials, for example, as described elsewhere herein, in amounts effective for the desired purpose, for example, to treat contact lenses and/or ocular tissues, for example, to provide a beneficial property or properties to contact lenses and/or ocular tissues, contacted with such compositions. In one embodiment anti-oxidants are added to preserve the solutions' stability as well as to reduce ocular surface free radial damage. Suitable non-limiting examples include vitamin C, vitamin E, vitamin A and butylhydroxytoluene (BHT).
  • [0090]
    Packaging can be in multi-use vials with a preservative, or single use vials without (although not intended as a limitation as to packaging form or function). Additionally, packaging may be conducted using a nitrogen gas flush to prevent or reduce product exposure to atmospheric oxygen and thus preserve product shelf life.
  • [0091]
    In one embodiment, the compositions include a second therapeutic agent in addition to the water-soluble polymer for treatment of dry eye. The compositions described herein are useful, for example, as a carrier or vehicle, for the delivery of at least one additional therapeutic agent to or through the eye. Any suitable therapeutic component may be included in the present compositions provided that such therapeutic component is compatible with the remainder of the composition, does not unduly interfere with the functioning and properties of the remainder of the composition, is effective, for example, to provide a desired therapeutic effect, when delivered in the present composition and is effective when administered to or through the eye. For example, in a very useful embodiment, the delivery of hydrophobic therapeutic components or drugs to or through the eye may be accomplished.
  • [0092]
    Unless otherwise indicated, all numbers expressing quantities of ingredients, properties such as molecular weight, reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term “about.” Accordingly, unless indicated to the contrary, the numerical parameters set forth in the specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained by the present invention. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques.
  • [0093]
    Notwithstanding that the numerical ranges and parameters setting forth the broad scope of the invention are approximations, the numerical values set forth in the specific examples are reported as precisely as possible. Any numerical value, however, inherently contains certain errors necessarily resulting from the standard deviation found in their respective testing measurements.
  • [0094]
    The terms “a,” “an,” “the” and similar referents used in the context of describing the invention (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. Recitation of ranges of values herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range. Unless otherwise indicated herein, each individual value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., “such as”) provided herein is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention otherwise claimed. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the invention.
  • [0095]
    Groupings of alternative elements or embodiments disclosed herein are not to be construed as limitations. Each group member may be referred to and claimed individually or in any combination with other members of the group or other elements found herein. It is anticipated that one or more members of a group may be included in, or deleted from, a group for reasons of convenience and/or patentability. When any such inclusion or deletion occurs, the specification is deemed to contain the group as modified thus fulfilling the written description of all Markush groups used in the appended claims.
  • [0096]
    Certain embodiments are described herein, including the best mode known to the inventors for carrying out the invention. Of course, variations on these described embodiments will become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventor expects skilled artisans to employ such variations as appropriate, and the inventors intend for the invention to be practiced otherwise than specifically described herein. Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context.
  • [0097]
    Specific embodiments disclosed herein may be further limited in the claims using consisting of or and consisting essentially of language. When used in the claims, whether as filed or added per amendment, the transition term “consisting of” excludes any element, step, or ingredient not specified in the claims. The transition term “consisting essentially of” limits the scope of a claim to the specified materials or steps and those that do not materially affect the basic and novel characteristic(s). Embodiments of the invention so claimed are inherently or expressly described and enabled herein.
  • [0098]
    Furthermore, numerous references have been made to patents and printed publications throughout this specification. Each of the above-cited references and printed publications are individually incorporated herein by reference in their entirety.
  • [0099]
    In closing, it is to be understood that the embodiments of the invention disclosed herein are illustrative of the principles of the present invention. Other modifications that may be employed are within the scope of the invention. Thus, by way of example, but not of limitation, alternative configurations of the present invention may be utilized in accordance with the teachings herein. Accordingly, the present invention is not limited to that precisely as shown and described.

Claims (7)

  1. 1. A stable oil-in-water emulsion ophthalmic topical liquid composition having an average particle size less than 1 μm comprising:
    at least one plant-derived oil other than castor oil wherein said oil comprises only aliphatic side chains free of polar pendent groups;
    a hydrophilic surfactant having an HLB value between approximately 10 and 14;
    a vegetable oil-derived hydrophobic non-co-block surfactant having unsaturated side chains that contain less than four oxygen atoms, an HLB value between approximately 4 and 6 and is a liquid at room temperature; and
    wherein in said ophthalmic composition further comprises an amount of cyclosporine A effective to relieve dry eye symptoms.
  2. 2. The ophthalmic composition according to claim 1 wherein the hydrophilic surfactant is Lumulse® GRH-25 and the hydrophobic surfactant is Brij 93.
  3. 3. The ophthalmic composition according to claim 1 wherein the plant-derived non-polar oil is sesame oil.
  4. 4. A stable oil-in-water emulsion ophthalmic topical liquid composition having an average particle size less than 0.6 μm consisting essentially of:
    at least one plant-derived oil other than castor oil wherein said oil comprises aliphatic side chains free of polar pendent groups;
    a hydrophilic surfactant having an HLB value between approximately 10 and 11;
    a vegetable oil-derived hydrophobic non-co-block surfactant having unsaturated side chains that contain less than four oxygen atoms, an HLB value between approximately 4 and 6 and is a liquid at room temperature; and
    wherein in said ophthalmic composition further comprises an amount of cyclosporine A effective to relieve dry eye symptoms.
  5. 5. The ophthalmic composition according to claim 4 wherein the hydrophilic surfactant is Lumulse® GRH-25 and the hydrophobic surfactant is Brij 93.
  6. 6. The ophthalmic composition according to claim 4 wherein the plant-derived non-polar oil is sesame oil.
  7. 7. A stable oil-in-water emulsion ophthalmic topical liquid composition having an average particle size less than 0.6 μm consisting essentially of sesame oil, a hydrophilic surfactant consisting of Lumulse® GRH-25, a hydrophobic non-co-block surfactant consisting of Brij 93 and wherein in said ophthalmic composition further comprises an amount of cyclosporine A effective to relieve dry eye symptoms.
US12476600 2009-06-02 2009-06-02 Stable cyclosporine containing ophthalmic emulsion for treating dry eyes Abandoned US20100305046A1 (en)

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US12476600 US20100305046A1 (en) 2009-06-02 2009-06-02 Stable cyclosporine containing ophthalmic emulsion for treating dry eyes
US13375847 US8828412B2 (en) 2009-06-02 2010-06-02 Stable polyphenol containing ophthalmic emulsion for treating dry eyes
EP20100722891 EP2437722A1 (en) 2009-06-02 2010-06-02 Ophthalmic oil-in-water emulsions containing cyclosporine or a polyphenol
CA 2764327 CA2764327A1 (en) 2009-06-02 2010-06-02 Ophthalmic oil-in-water emulsions containing cyclosporine or a polyphenol
PCT/US2010/037072 WO2010141588A1 (en) 2009-06-02 2010-06-02 Ophthalmic oil-in-water emulsions containing cyclosporine or a polyphenol

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US13375847 Continuation-In-Part US8828412B2 (en) 2009-06-02 2010-06-02 Stable polyphenol containing ophthalmic emulsion for treating dry eyes

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012125400A1 (en) * 2011-03-14 2012-09-20 Acorn Biomedical, Inc. Compositions and methods using adenosine a3 receptor antagonists for the treatment of inflammatory eye diseases
WO2013017571A1 (en) 2011-07-29 2013-02-07 Universität Regensburg Aqueous solutions of lipophilic substances, in particular medicinal solutions
JP2014028789A (en) * 2012-06-27 2014-02-13 Rohto Pharmaceut Co Ltd Aqueous ophthalmic composition
EP2730292A1 (en) * 2011-07-08 2014-05-14 Rohto Pharmaceutical Co., Ltd. Aqueous ophthalmic composition

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP6030565B2 (en) * 2010-12-10 2016-11-24 エヌエス テクノロジーズ プロプライエタリー リミテッドNs Technologies Pty Ltd Miniemulsion, use of the mini-emulsion in the manufacture of a method and medicament for forming a same miniemulsion
KR101492447B1 (en) * 2013-05-20 2015-02-23 주식회사태준제약 Eye composition containing a cyclosporine and a method of preparing the same

Citations (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6235781B1 (en) * 1998-07-14 2001-05-22 Alcon Laboratories, Inc. Prostaglandin product
US20020009507A1 (en) * 2000-01-19 2002-01-24 Alcon Universal Ltd. Use of polyethoxylated castor oil for the treatment of dry eye
US20020032171A1 (en) * 1999-06-30 2002-03-14 Feng-Jing Chen Clear oil-containing pharmaceutical compositions containing a therapeutic agent
US6506412B2 (en) * 2000-11-29 2003-01-14 Sciencebased Health Treatment of dry eye syndrome
US6653327B2 (en) * 1999-04-09 2003-11-25 Sabinsa Corporation Cross-regulin composition of tumeric-derived tetrahydrocurcuminoids for skin lightening and protection against UVB rays
US20040067244A1 (en) * 1999-03-22 2004-04-08 Friedman Doron I. Nano oil in glycerin emulsion
US20050202097A1 (en) * 2004-03-12 2005-09-15 Melbj Holdings, Llc, Florida Lubricant for the ocular surface
US20060015710A1 (en) * 2000-12-26 2006-01-19 Natu Mahesh S Method for sharing host processor for non-operating system uses
US20060088600A1 (en) * 2002-07-17 2006-04-27 Thornion Spencer P Treatment for dry eye syndrome
US20060182771A1 (en) * 2005-02-09 2006-08-17 Dor Philippe J Formulations for ocular treatment
US20060251685A1 (en) * 2003-03-18 2006-11-09 Zhi-Jian Yu Stable ophthalmic oil-in-water emulsions with Omega-3 fatty acids for alleviating dry eye
US20070015710A1 (en) * 2005-07-13 2007-01-18 Allergan, Inc. Cyclosporin compositions
US20070015692A1 (en) * 2005-07-13 2007-01-18 Chang James N Cyclosporin compositions
US20070015694A1 (en) * 2005-07-13 2007-01-18 Allergan, Inc. Cyclosporin compositions
US20080299206A1 (en) * 2006-03-07 2008-12-04 Novavax, Inc. Ophthalmic preparations

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6720001B2 (en) 1999-10-18 2004-04-13 Lipocine, Inc. Emulsion compositions for polyfunctional active ingredients
DE10036871A1 (en) 2000-07-28 2002-02-14 Pharmasol Gmbh Dispersions for the formulation little or poorly soluble drugs
US20030165545A1 (en) * 2002-01-30 2003-09-04 Allergan, Inc. Ophthalmic compositions including oil-in-water emulsions, and methods for making and using same
WO2006050838A3 (en) 2004-11-09 2006-11-16 Novagali Pharma Sa Ophthalmic oil-in-water type emulsion with stable positive zeta potential
US7501393B2 (en) * 2005-07-27 2009-03-10 Allergan, Inc. Pharmaceutical compositions comprising cyclosporins
EP1985298A1 (en) 2007-04-24 2008-10-29 Azad Pharma AG Ophtalmic oil-in-water emulsions containing prostaglandins
EP2346520B1 (en) 2008-11-17 2014-11-26 Laila Pharmaceuticals Pvt. Ltd. Curcuminoids and its metabolites for the application in ocular diseases

Patent Citations (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6235781B1 (en) * 1998-07-14 2001-05-22 Alcon Laboratories, Inc. Prostaglandin product
US20040067244A1 (en) * 1999-03-22 2004-04-08 Friedman Doron I. Nano oil in glycerin emulsion
US6653327B2 (en) * 1999-04-09 2003-11-25 Sabinsa Corporation Cross-regulin composition of tumeric-derived tetrahydrocurcuminoids for skin lightening and protection against UVB rays
US20020032171A1 (en) * 1999-06-30 2002-03-14 Feng-Jing Chen Clear oil-containing pharmaceutical compositions containing a therapeutic agent
US20020009507A1 (en) * 2000-01-19 2002-01-24 Alcon Universal Ltd. Use of polyethoxylated castor oil for the treatment of dry eye
US6506412B2 (en) * 2000-11-29 2003-01-14 Sciencebased Health Treatment of dry eye syndrome
US20060015710A1 (en) * 2000-12-26 2006-01-19 Natu Mahesh S Method for sharing host processor for non-operating system uses
US20060088600A1 (en) * 2002-07-17 2006-04-27 Thornion Spencer P Treatment for dry eye syndrome
US20060251685A1 (en) * 2003-03-18 2006-11-09 Zhi-Jian Yu Stable ophthalmic oil-in-water emulsions with Omega-3 fatty acids for alleviating dry eye
US20050202097A1 (en) * 2004-03-12 2005-09-15 Melbj Holdings, Llc, Florida Lubricant for the ocular surface
US20060182771A1 (en) * 2005-02-09 2006-08-17 Dor Philippe J Formulations for ocular treatment
US20070015710A1 (en) * 2005-07-13 2007-01-18 Allergan, Inc. Cyclosporin compositions
US20070015692A1 (en) * 2005-07-13 2007-01-18 Chang James N Cyclosporin compositions
US20070015694A1 (en) * 2005-07-13 2007-01-18 Allergan, Inc. Cyclosporin compositions
US20080299206A1 (en) * 2006-03-07 2008-12-04 Novavax, Inc. Ophthalmic preparations

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012125400A1 (en) * 2011-03-14 2012-09-20 Acorn Biomedical, Inc. Compositions and methods using adenosine a3 receptor antagonists for the treatment of inflammatory eye diseases
EP2730292A1 (en) * 2011-07-08 2014-05-14 Rohto Pharmaceutical Co., Ltd. Aqueous ophthalmic composition
EP2730292A4 (en) * 2011-07-08 2015-01-14 Rohto Pharma Aqueous ophthalmic composition
WO2013017571A1 (en) 2011-07-29 2013-02-07 Universität Regensburg Aqueous solutions of lipophilic substances, in particular medicinal solutions
JP2014028789A (en) * 2012-06-27 2014-02-13 Rohto Pharmaceut Co Ltd Aqueous ophthalmic composition
US9050369B2 (en) 2012-06-27 2015-06-09 Rohto Pharmaceutical Co., Ltd. Aqueous ophthalmic composition
US9345779B2 (en) 2012-06-27 2016-05-24 Rohto Pharmaceutical Co., Ltd. Aqueous ophthalmic composition
JP2016188259A (en) * 2012-06-27 2016-11-04 ロート製薬株式会社 Aqueous ophthalmic composition

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US20120093894A1 (en) 2012-04-19 application
US8828412B2 (en) 2014-09-09 grant

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