In healthy eyes, blinking induces the formation of tears which form a thin film which spreads over the corneal surface of the eye, making the surface smooth and optically clear, thereby enabling good vision. Said tear film is formed of three layers: an oil layer (lipids), a water (aqueous) layer, and a layer of mucus. The outermost layer is the lipid layer; its purpose is to smooth the tear surface and reduce evaporation of the eye's natural lubricants. The middle layer is the water layer; its purpose is to cleanse the eye and wash away any foreign particles or irritants. The innermost layer is the mucus layer; the mucus allows the water layer to spread evenly over the surface of the eye. Without the mucus layer, tears would not adhere to the eye.
Tears are produced by the Lacrimal Glands, located under the eyelids. “Dry Eye” is a condition caused by tear film instability and consequent ocular surface degeneration. Dry Eye may occur when the Lacrimal tear gland produces insufficient natural tears, in some instances as a normal consequence of the aging process during which lacrimal tissue may deteriorate and the lacrimal glands may shrink. Alternatively, dysfunction of the Meibomain gland may destabilize the tear film, or a blockage may occur in the execratory ducts of the lacrimal gland. Early signs and symptoms of Dry Eye include redness, burning, light sensitivity, gritty sensation, and watery eyes. As the normal base line tear production decreases, the eyes become dry and irritated. This may result in increased symptoms, including pain, redness blurred vision and infection. Over time, the reduced production of natural tears leads to dissipation of the lipid and mucous tear film layers. This in turn allows for evaporation of the aqueous layer, causing dry spots on the surface of the eye. The resulting impaired cellular surface leads to an unstable tear film, and a pathologically short tear break-up time (TBUT). If untreated, this condition will eventually exacerbate the symptoms noted above and result in ocular surface damage.
The present invention relates to a composition for a unique clear topical ophthalmic gel-forming liquid, delivering in a clear colloidal form for the first time submicron sized particles of clear colloidal oil droplets of polar nanolipids (Nanopids™), emulsifiers, and multiple aqueous tearlike ingredients (aqueous lubricants and/or aqueous polymers). The subject composition is uniquely designed to protect the three (3) layers of corneal film from dryness, deliver advanced eye lubricants, and to deliver a unique system of Dry Eye treatment that addresses and treats all three layers of corneal tear film. The size distribution of the clear colloidal polar lipids is in the range of 1.0 nanometers to 200.0 nanometers, with a preferred upper limit of 50 nanometers. The preferred mean average particle size is 13.0 nanometers (standard deviation of 3.2 nanometers) with a population distribution range of 6.0 nanometers to 22.0 nanometers. The size distribution of the aqueous colloidal particles is in the range of 3.0 nanometers to 200.0 nanometers. The preferred mean average particle size is 30.0 nanometers (standard deviation of 15.0 nanometers) with a particle size distribution range of 3 nanometers to 150 nanometers.
The subject composition also contains a unique gelling agent (anionic heteropolysachharide) which after introduction into the eye and upon contact with the cations naturally present in the pre-corneal tear film forms a clear gel. The composition allows the delivery of colloidal polar nanolipids in a clear gel form, and the additional benefits derived therefrom.
The clear (transparent) nature of the composition is a significant advantage of the invention. Conventional ophthalmic gel preparations, ophthalmic ointments and ophthalmic emulsions are uniformly cloudy or opaque. For example, the compositions of such conventional ophthalmic emulsions consist of large particle sizes that are generally greater than 1 micron, and can exceed 24 microns (e.g., Soothe). When such conventional preparations are instilled in the eye, the result is prolonged blurred vision. Prolonged blurriness has a negative impact on patient acceptance of such ophthalmic preparations, and negatively impacts on patient compliance with the use of such products as directed. While adjustments in the viscosity of such conventional ophthalmic preparations may make the resultant formula less viscous, such will not resolve patient complaints of blurriness due to the cloudy/opaque nature of such preparations. In contrast, the clear nature of the subject composition will result in superior acceptance by patients, and a superior overall patient experience.
The present invention contemplates a unique clear ophthalmic gel-forming liquid designed to remedy the inability of Dry Eye patient's eyes to lubricate themselves through the natural replenishment of the tear film. The clear polar nanolipids play a major role in restoring and maintaining a healthy outer lipid layer of the tear film. The size, concentration and clarity of the colloidal polar nanolipids are particularly important for the subject composition. Conventional ophthalmic emulsions containing oil or lipids are cloudy due to the particle size. The particle size of these emulsions is greater than 1000 nanometers (greater than 1 micron). Some of these ophthalmic emulsions contain non-polar mineral oil with an oil droplet particle size greater than 10,000 nanometers (10 microns), in some cases with a particle size exceeding 24,000 nanometers (24 microns). Such formulations cause blurring in the eyes of users, negatively impacting on clarity of vision. Additionally, since they are non-viscous liquid emulsions, a large percentage of such preparations are blinked away during administration into the eye. As a result, only a small fraction of the dose remains in contact with the cornea. Conventional ophthalmic gel preparations and ophthalmic ointments present similar issues related to cloudiness and loss of the preparations due to their particle size. By contrast the subject composition containing the submicron sized nanoparticles, which in addition to allowing for the formation of a clear gel, results in a composition which is more effective in lubricating the eye and maintaining the tear film layers. First, the submicron sized particles of colloidal oil droplets of polar nanolipids comprising the subject composition are not lost as a result of blinking, resulting in prolonged eye exposure to the composition and any pharmaceutically active compounds present. Second, as the composition remains in colloidal liquid for until instilled into the eye, it is easier to administer to the eye, as compare to conventional ophthalmic emulsions, gel and/or ointment preparations.
The subject composition's formation of a clear viscous gel once administered into the eye further prolongs the delivery of nanolipids and nano-sized aqueous lubricants into the lacrimal fluid. As a result, the amount delivered is sustained over an extended time, providing a controlled bioavailability vehicle for delivery of the nanolipids and nano-sized aqueous lubricants to support the tear film. The subject colloidal liquid composition also contains a polysaccharide which undergoes a liquid-gel phase transition under the effect on an increase in cationic strength, and as such is diluted less rapidly which in turn provides for sustained delivery of the nanoparticles suspended in the subject composition. The prolonged exposure time provided by the subject composition results in delivery of a more effective concentration of the nanolipids and nano-lubricants to the lacrimal fluid.
The dissipation of the lipid and mucous layers experienced by Dry Eye patients results in evaporation of the aqueous watery layer, causing dry spots. The resulting impaired ocular surface leads to an unstable tear film and a pathologic short tear break-up time (TBUT), which eventually results in ocular surface damage. Normal tear break-up time is approximately ten (10) seconds. A TBUT shorter than ten (10) seconds indicates a Dry Eye condition. If the tear film breaks up before a blink occurs, some portion of the eye will be exposed to desiccating elements. Through prolonged exposure to the air and environmental particulate matter, the unprotected ocular cells become desiccated and die. Eventually, the mucins will not be able to form a smooth ocular surface across the eye. As a result, the ability of the eye's naturally forming tears to adhere to the corneal epithelia is compromised, further shortening the tear break-up time and intensifying surface exposure.
A clinical study was performed on the composition that is the subject of the present invention. Clinical observation and testing of the composition as used by Dry Eye patients demonstrated a considerable improvement in the normal tear break-up time. The data showed a significant trend of increased tear break-up time, increasing from a 7.68 second TBUT baseline (prior to use of the subject invention) to 11.27 seconds after one (1) month of use of the composition. This measurable increase of over 3.5 seconds in TBUT is remarkable from a clinical perspective, since the duration of the study was only one (1) month and the composition was administered in a minimal dosage (2 times per day). Additionally, the composition significantly improved conjunctival staining after one (1) month of use. It also statistically improved ‘Dry Eye’ symptoms such as redness, dryness, headaches, feelings of grittiness or sandiness, scratchiness, and blurred vision. After installation of the subject composition such symptoms resolved in one (1) hour in eighty percent (80%) of the study subjects; a full one hundred percent (100%) of study subjects reported relief for thirty (30) minutes or more. This is a statistically significant improvement compared to the study baseline. Finally, the reported duration of the relief combined with the quality of vision results suggest that the subject composition provides a significant duration of relief of symptoms without compromising visual quality and acuity.