SYNTHETIC TEAR DROPS, AND USES THEREOF

Field of the Invention

The present invention relates to method for producing a synthetic tear drop. Also contemplated is the use of a synthetic tear drop to form a liquid filmon the eye of a subject.

Background to the Invention

Ocular conditions such as short-sightedness (myopia), far-sightedness (hyperopia), and astigmatism are suitable for various types of corrective treatment, including wearing corrective glasses, corrective contact lenses, laser eye surgery, and in some cases drug therapy. Laser eye therapy, while a successful treatment, is not suitable for all forms of sight defects, and is expensive and sometime painful for the patient. Many patients do not like wearing glasses, due to the inconvenience (especially during physical activities) and vanity. Many patients who do not like wearing glasses, use contact lenses instead. These are small lenses made of hydrogel polymers of silicone hydrogels that are designed to sit on the tear film covering the cornea. Many patients find contact lenses uncomfortable, and do not like having to change the contact lenses regularly.

It is an object of the invention to overcome at least one of the above-referenced problems.

Summary of the Invention

The Applicant has addressed the problems of the prior art by providing a liquid contact lens that has a lipid phase/layer and an aqueous phase/layer, in which the aqueous layer has been modified by electrowetting to change the shape of the aqueous layer, for example to a shape suitable for correcting a refractive error in a wearer of the liquid contact lens. The liquid contact lens is produced by providing a liquid that is generally compositionally similar to a natural human tear, and providing a drop of the liquid suitably having a volume similar to a natural human tear drop. The drop of liquid will have two distinct layers, a lipid layer, an aqueous layer, with a meniscus between the aqueous layer and the lipid layer. The drop may also include a mucous layer. The drop is then treated, typically by an electrowetting process, to change the shape of the aqueous layer in the drop. This typically involves application of a voltage between the aqueous layer and a contact surface in contact with the meniscus that is suitably configured to change the contact angle between the meniscus and the surface, thereby changing the shape of the aqueous layer.

Electrowetting lenses, and methods for the production thereof, are described in the literature, and used for various applications, including telescopes and mirrors. The present invention comprises the application of electrowetting technology to drops of liquid, to modify the shape of the aqueous layer in the drop, so that when it is applied to a human eye, the film that coats the eye has an aqueous layer that alters vision and typically functions like a corrective contact lens.

In a first aspect, the invention provides a process for producing a synthetic tear drop (e.g. suitable for forming a liquid contact lens film), comprising the steps of: providing a drop of liquid comprising a lipid phase, an aqueous phase, optionally a mucous phase, and a meniscus between the lipid phase and the aqueous phase; and treating the drop of liquid by electrowetting to change the shape of meniscus and provide a synthetic tear drop (that is typically suitable for forming a liquid contact lens). The synthetic tear drop when applied to a corneal surface of a human eye forms a liquid film on the corneal surface. The liquid film can act as a liquid contact lens to alter the vision of the subject.

The lipid phase and aqueous phase generally have the same density.

In any embodiment, the drop of liquid comprises a mucous phase.

The details provided below enable a person skilled in the art manufacture a synthetic tear drop. In one embodiment, the synthetic tear drop is compositionally similar to a natural human tear (generally basal tears).

In one embodiment, the synthetic tear drop is volumetrically similar to a natural human tear. For example, it may have a volume of 4 pi to 1000 mI, more preferably 4-1000 mI, more preferably about 5-50 mI, 5-40 mI, 5-30 mI, 5-20 mI or 5-10 mI.

The liquid contact lens film that forms on the corneal surface comprises at least two or three distinct layers, including an aqueous layer comprising of electrolytes, one or more surfactants (for example amino acids and/or proteins) that promotes the spreading of the tear film over the eye and helps control infections and osmotic regulation, an outer lipid layer that that coats the aqueous layer creating an envelope that prevents the tear from leaving the eye, and optionally a mucous layer in contact with the corneal surface (or a natural tear film on the corneal surface) that provides a hydrophilic layer allowing for even distribution of the tear on the corneal surface.

Using the basis of liquid lens technology, the lipid layer will act as the insulating fluid and the aqueous layer will act as the conducting fluid with the aid of the electrolytes. The shape of the aqueous layer will be altered by the electrowetting process that will lead to the change in the type of lens. Surfactants in the aqueous layer typically migrate during electrowetting to the interface between the aqueous and lipid layer to create a bond between the two layers, thereby maintaining the modified shape of the lens. The lens will typically keep its shape due to natural surfactants within the aqueous layer such as from the amides of the amino acids. When the shape of the lens is changed the surface area will increase allowing more surfactant to interact between the aqueous and lipid interface. Once the electrowetting process is finished and the change in voltage is removed the aqueous layer will not be able to return to its original shape due to the extra surfactant now attached to the lipid layer.

An illustration of the change in morphology of the synthetic tear drop during the electrowetting process is provided in Figure 1. In particular, it can be seen that the meniscus between the lipid and aqueous layers changes from being convex to being concave, which has the effect of altering the shape of the lens that is provided by the aqueous layer. The change in shape of the aqueous layer lens can be controlled by the electrowetting process, to provide a drop having an aqueous layer that when applied to the eye provides a liquid lens that can correct a defect in the eye.

The electrowetting process may be carried out in a chamber configured to hold the drop of liquid, and having an electrode arrangement configured for application of a voltage between the aqueous phase of the drop and a surface in contact with the meniscus forming the interface between the lipid and aqueous layers. The electrode arrangement may comprise a first electrode in contact with a periphery of the aqueous layer, and a second electrode in contact with a sidewall of the chamber. Such chambers for producing electrowetting lenses are described on the Comsol webste (www.comsol.com) in the section entitled “Focussing on an electrowetting lens”, and on the Researchgate website

(https://www.researchgate.net/fiqure/Schematic-of-an-elec trowetting-tvpe-liquid- lens-ln-absence-of-applied-voltage-the fig2 288827613).

The electrowetting step suitable employs a voltage of 1 K to 10K, preferably about 3K to 7K, ideally about 5K, volts. The voltage is applied to the drop for a short period of time, for example 0.1 to 10 seconds, generally 0.5 to 2, or 0.5 to 1.5, or about 1 second. The current applied is generally direct current. The current is generally less than 1.0, 0.1, 0.11 amp, for example 0.001 to 0.01 amps.

In another aspect, the invention provides a device for generating a synthetic tear drop according to the process of the invention.

In another aspect, the invention provides a synthetic tear drop having a lipid phase, an aqueous phase, optionally a mucous phase, and a meniscus between the lipid phase and the aqueous phase, wherein the shape of the aqueous phase has been modified by electrowetting.

In any embodiment, the volume of the aqueous phase is less than the volume of the lipid phase. In any embodiment a volumetric ratio of lipid phase to aqueous phase in the drop of liquid is 1 :3 to 3:1, typically 3:1 to 1 : 1 , and ideally about 1.5: 1 to 2.5 to 1.

In any embodiment, the volume of the lipid phase of the tear drop is configured to provide a film on the surface of the cornea having a lipid layer of about 0.5 to 1.5 pm, more preferably about 0.1 pm.

In any embodiment, the volume of the aqueous phase of the tear drop is configured to provide a film on the surface of the cornea having an aqueous layer of about 5 to 15 pm, more preferably about 8-12 pm and ideally about 10 pm.

In any embodiment, the volume of the mucous phase of the tear drop is configured to provide a film on the surface of the cornea having a mucous layer of about 10 to 50 pm, more preferably about 40-60 pm and ideally about 50 pm.

Typically the mucous phase is highly hydrated and semi-solid.

In any embodiment, the modified tear drop is compositionally similar to a natural human tear (generally basal tears). The composition of human tears is described in: Cwiklik et al (Biochimica et Biophysica Acta (BBA) - Biomembranes; Vol. 1858, Issue 10, Oct 2016);

Gillan et al (S. Afr. Opinion 2010; 69)2); 100-106);

Dartt et al (Exp Eye Res 2013 Dec; 117: 1-3);

Badgujar 9tear Film Dynamics https://www.slideshare.net/ashishbadquiar/tear-film- dynamics-57229751.

In any embodiment, the synthetic tear drop has a pH of about 7.3. To 7.7. In any embodiment, the synthetic tear drop has an osmotic pressure of about 0.9 to 0.95 NaCI solution.

In any embodiment, the synthetic tear drop comprises water, salts, lipids, surfactant (e.g. protein and/or amino acids) and optionally one or more metabolites. Typically the tear comprises about 98% water and about 1.5-2.0% dissolved solids. Typically the synthetic tear drop comprises about 0.6 to 2.0% protein. Proteins may include IGG, ALB, transferrin, Alpha-1 antitrypsin, Alpha-1 chymotrypsin, beta-2 microglobulin, lysozyme, lactoferring and IGA, and optionally ceruloplasmin, haptoglobins, ZN-alpha 2 glycoprotein,. Albumin may make up about 60% of total protein.

One or more metabolites may be present in the following composition:

Glucose - about 1/10th the composition of blood (i.e 3-10 mg/ml);

Lactate - 1-5 mmol/l (higher than blood);

Pyruvate - approx same as blood; and/or Urea - 0.004 mg/100ml

Electrolites may be present in the following composition:

Na - 142 mEq/l Cl - 120-135 mEq/l HC03 - 26 mEq/l Ca - 2.29 mg/100ml The mucous phase generally comprises a plurality of tear film mucins, for example one or more of the mucins described in Hosseini et al. (Tetrahedron. 2014 Oct 21 ;0(42)). The

The aqueous phase generally comprises water, electrolytes, surfactant (e.g. one or more amino acids or modified amino acids that will act as surfactants). The amino acid may be a charged amino acid such as arginine or derived from a charged amino acid. The surfactant may be an amino acid surfactant (Lidia Pinheiro and Celia Faustino (July 5th 2017). Amino Acid-Based Surfactants for Biomedical Applications, Application and Characterization of Surfactants, Reza Najjar, IntechOpen, DOI: 10.5772/67977. Available from: https://www.intechopen.com/books/application-and-characteriz ation-of- surfactants/amino-acid-based-surfactants-for-biomedical-appl ications).

The aqueous phase may include one or more metabolites. Examples of amino acids and metabolites include1-Methylhistidine/3-Methylhistidine, Arginine, Asymmetric, Asymmetric dimethylarginine/Symmetric dimethylarginine, Citrulline, Creatine, Glutamine, Homoarginine, Hydroxyproline, Phenylalanine, Proline, Pyroglutamic acid, Serine, Taurine, Theonine, Tryptophan, Tyrosine, Urocanic acid, Valme), Amino Alcohols (Panthenol); Amino Ketones (Allantoin, Creatine), Aromatic Acids (Cinnamic acid, o-Coumaric acid/m-Coumaric acid/p-Coumaric acid), Carbohydrates (N-Acetylneuraminic acid), Carnitines (Acetylcarnitine, Carnitine, hexanoylcarnitine, Palmitoylcarnitine); Cyclic Amines (Niacinamide); Dicarboxylic Acids (Fumaric acid/ Maleic acid), Nucleosides (1-Methyladenosine, Adenosine, Cytidine, Guanosine, Inosine, S-Adenosyl-homocysteine, S-Adenosylmethionine, Uridine, and Xanthosine), Nucleotides (ADP, AMO, CMP, Cytidine diphosphate choline, GMP, IMP, UDP, UMP, UDP-N-acetylgalactosamine/UDP-N- acetylglucosamine), Peptides (Oxidized glutathione), Phospholipids (1-Palmitoyl- lysophosphatidylcholine), Purines and derivatives (Hypoxanthine, Theobromine,

Uric acid, Xanthine), Purines and derivatives (4-Pyridoxic acid), Quaternary Amines (Acetylcholine, Glycerophosphocholine, Phosphocholine), and Tricarboxylic Acids (Citric acid)--and other substances such as proteins (e.g., antibodies, lipocalin, lactoferrin, lysozyme, and lacritin)"

The lipid layer (also known as “tear film lipid layer” or “TFLL”) reduces surface tension of the tear film and helps with the film re-speading after blinking. The lipid layer typically comprises a mixture of polar and non-polar lipids. The composition of the lipid layer of natural tears is described in Cwiklik et al (Biochimica et Biophysica Acta (BBA) - Biomembranes; Vol. 1858, Issue 10, Oct 2016) - especially Figure 3 - and Millar et al (Exp. Eye. Res. 137 (2105); page 125-138). The on-polar lipids of TFLL secreted by meibomian glands contain 30-45 mol% of cholesterol esters (CE) with long acyl chains (C22: 1 — C34: 1 ), ~ 30-50 mol% of wax esters (WE) with a high representation of C18: 1 fatty acid chains mixed with C18-C30 alcohol chains. Moreover, up to 4 mol% of OAHFAs was found. Regarding polar lipids of non- meibomian origin, ~ 13 mol% of phospholipids (PLs) is present, mainly glycerophospholipids, lysophospholipids, and sphingomyelins. Most of phospholipids are phosphatidylcholines (PCs, > 60 mol%) with a smaller amount of phosphatidylethanolamines (PEs, ~ 15%). Moreover, small quantities (< 5%) of ceramides (Cer) and sphingomyelins (SM) were found. The lipid layer may include a thickener or stabiliser. The lipid layer may include carboxymethyl cellulose.

In any embodiment, the synthetic tear drop is volumetrically similar to a natural human tear. For example, it may have a volume of 20 pi to 1000 mI, more preferably 20-500 mI, more preferably 20-200 mI. In any embodiment, the volume of the synthetic tear drop is configured to provide a film on the surface of the cornea having a lipid layer of about 0.5 to 1.5 pm, more preferably about 0.1 pm.

In another aspect, the invention provides a method comprising the step of application of a synthetic tear drop according to the invention (or produced according to a method of the invention) to a corneal surface of a human eye of a subject where the synthetic tear drop spreads out on the corneal surface to provide a liquid film (e.g. liquid contact lens film) on the surface of the eye. In one embodiment, the method is a method of correcting an ocular condition in the subject by corrective lens therapy, in which the aqueous layer of the film acts as a corrective lens for the ocular condition.

In another aspect, the invention provides a device for generating and dispensing a modified tear drop according to the invention.

In another aspect, the invention provides a device for generating and dispensing a synthetic tear drop onto a corneal surface of the eye, comprising: an electrowetting module comprising a chamber configured to hold a drop of liquid and an electrode arrangement configured for application of a voltage to the tear drop to change the shape of the aqueous phase; a dispensing module configured to receive the modified tear drop from the chamber of the electrowetting module and comprising means for delivering the drop to the eye (i.e.an eye dropper); and valve means actuable to transfer the drop from the chamber of the electrowetting module to the dispensing module.

The electrode arrangement may be configured for application of a voltage between the aqueous phase of the drop and an insulated surface in contact with the meniscus forming the interface between the lipid and aqueous layers. A first electrode may be disposed to directly contact the aqueous phase. A second electrode may be configured to contact the lipid phase via an insulator, part of the lipid and aqueous phase via an insulator. The first electrode may be an anode and the second electrode may be a cathode. Two or more first electrodes and second electrodes may be provided, for example one first electrode on one side of the aqueous phase and another first electrode on an opposite side of the aqueous layer and/or one second electrode on one side of the lipid phase or meniscus and another second electrode on an opposite side of the lipid layer or meniscus. The drop of liquid generally has a lipid layer, an aqueous layer, optionally a mucous layer, with a meniscus between the aqueous layer and the lipid layer,

In one embodiment, the device comprises a reservoir chamber for holding a reservoir of liquid and having an outlet in fluid communication with the chamber of the electrowetting module, and a metering module configured to transfer a drop of fluid from the reservoir chamber to the electrowetting chamber upon actuation.

In one embodiment, the valve means is configured to open and close the electrowetting chamber to allow the drop of liquid pass into the dispensing chamber under the force of gravity.

Other aspects and preferred embodiments of the invention are defined and described in the other claims set out below.

Brief Description of the Figures

FIG. 1 is an illustration of the changes in a tear drop during an electrowetting process.

FIG 2 is an illustration of an electrowetting chamber suitable for use in the method of the invention.

FIG 3 is an illustration of a device for forming and dispensing a modified tear drop according to the invention.

FIG 4A is an illustration of a further electrowetting chamber suitable for use in the method of the invention showing the drop of liquid prior to the electrowetting step. FIG 4B is an illustration of the electrowetting chamber of FIG. 4A showing the drop of liquid after the electrowetting step in which the shape of the aqueous phase has been altered changing the focal length of the aqueous phase when light is shone through the drop of liquid..

Detailed Description of the Invention

All publications, patents, patent applications and other references mentioned herein are hereby incorporated by reference in their entireties for all purposes as if each individual publication, patent or patent application were specifically and individually indicated to be incorporated by reference and the content thereof recited in full.

Definitions and general preferences

Where used herein and unless specifically indicated otherwise, the following terms are intended to have the following meanings in addition to any broader (or narrower) meanings the terms might enjoy in the art:

Unless otherwise required by context, the use herein of the singular is to be read to include the plural and vice versa. The term "a" or "an" used in relation to an entity is to be read to refer to one or more of that entity. As such, the terms "a" (or "an"), "one or more," and "at least one" are used interchangeably herein.

As used herein, the term "comprise," or variations thereof such as "comprises" or "comprising," are to be read to indicate the inclusion of any recited integer (e.g. a feature, element, characteristic, property, method/process step or limitation) or group of integers (e.g. features, element, characteristics, properties, method/process steps or limitations) but not the exclusion of any other integer or group of integers. Thus, as used herein the term "comprising" is inclusive or open- ended and does not exclude additional, unrecited integers or method/process steps.

As used herein, the term “disease” is used to define any abnormal condition that impairs physiological function and is associated with specific symptoms. The term is used broadly to encompass any disorder, illness, abnormality, pathology, sickness, condition or syndrome in which physiological function is impaired irrespective of the nature of the aetiology (or indeed whether the aetiological basis for the disease is established). It therefore encompasses conditions arising from infection, trauma, injury, surgery, radiological ablation, age, poisoning or nutritional deficiencies.

As used herein, the term "treatment" or "treating" refers to an intervention (e.g. the administration of an agent to a subject) which cures, ameliorates or lessens the symptoms of a disease or removes (or lessens the impact of) its cause(s) (for example, the reduction in accumulation of pathological levels of lysosomal enzymes). In this case, the term is used synonymously with the term “therapy”.

Additionally, the terms "treatment" or "treating" refers to an intervention (e.g. the administration of an agent to a subject) which prevents or delays the onset or progression of a disease or reduces (or eradicates) its incidence within a treated population. In this case, the term treatment is used synonymously with the term “prophylaxis”.

As used herein, an effective amount or a therapeutically effective amount of an agent defines an amount that can be administered to a subject without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio, but one that is sufficient to provide the desired effect, e.g. the treatment or prophylaxis manifested by a permanent or temporary improvement in the subject's condition. The amount will vary from subject to subject, depending on the age and general condition of the individual, mode of administration and other factors. Thus, while it is not possible to specify an exact effective amount, those skilled in the art will be able to determine an appropriate "effective" amount in any individual case using routine experimentation and background general knowledge. A therapeutic result in this context includes eradication or lessening of symptoms, reduced pain or discomfort, prolonged survival, improved mobility and other markers of clinical improvement. A therapeutic result need not be a complete cure. Improvement may be observed in biological / molecular markers, clinical or observational improvements. In a preferred embodiment, the methods of the invention are applicable to humans, large racing animals (horses, camels, dogs), and domestic companion animals (cats and dogs).

In the context of treatment and effective amounts as defined above, the term subject (which is to be read to include "individual", "animal", "patient" or "mammal" where context permits) defines any subject, particularly a mammalian subject, for whom treatment is indicated. Mammalian subjects include, but are not limited to, humans, domestic animals, farm animals, zoo animals, sport animals, pet animals such as dogs, cats, guinea pigs, rabbits, rats, mice, horses, camels, bison, cattle, cows; primates such as apes, monkeys, orangutans, and chimpanzees; canids such as dogs and wolves; felids such as cats, lions, and tigers; equids such as horses, donkeys, and zebras; food animals such as cows, pigs, and sheep; ungulates such as deer and giraffes; and rodents such as mice, rats, hamsters and guinea pigs. In preferred embodiments, the subject is a human. As used herein, the term “equine” refers to mammals of the family Equidae, which includes horses, donkeys, asses, kiang and zebra.

As used herein, the term “mucous phase” refers to the phase of the tear drop that contains a plurality of tear film mucins, such as the mucins described in Hosseini et al. Tetrahedron. 2014 Oct 21 ;0(42)) and Spurr-Michaud et al (Exp Eye Res 2007 May; 84(5)).

As used herein, the term “aqueous phase” (or “aqueous layer”) refers to the phase of the tear drop that contains water, electrolytes, surfactant (e.g. one or more amino acids that will act as surfactants) and optionally one or more metabolites. Examples of amino acids and metabolites include: Amino Acids (1 -Methylhistidine/3- Methylhistidine, Arginine, Asymmetric, Asymmetric dimethylarginine/Symmetric dimethylarginine, Citrulline, Creatine, Glutamine, Flomoarginine, Flydroxyproline, Phenylalanine, Proline, Pyroglutamic acid, Serine, Taurine, Theonine, Tryptophan, Tyrosine, Urocanic acid, Valme), Amino Alcohols (Panthenol); Amino Ketones (Allantoin, Creatine), Aromatic Acids (Cinnamic acid, o-Coumaric acid/m-Coumaric acid/p-Coumaric acid), Carbohydrates (N-Acetylneuraminic acid), Carnitines (Acetylcarnitine, Carnitine, hexanoylcarnitine, Palmitoylcarnitine); Cyclic Amines (Niacinamide); Dicarboxylic Acids (Fumaric acid/ Maleic acid), Nucleosides (1- Methyladenosine, Adenosine, Cytidine, Guanosine, Inosine, S-Adenosyl- homocysteine, S-Adenosylmethionine, Uridine, and Xanthosine), Nucleotides (ADP, AMO, CMP, Cytidine diphosphate choline, GMP, IMP, UDP, UMP, UDP-N- acetylgalactosamine/UDP-N-acetylglucosamine), Peptides (Oxidized glutathione), Phospholipids (1-Palmitoyl-lysophosphatidylcholine), Purines and derivatives (Hypoxanthine, Theobromine, Uric acid, Xanthine), Purines and derivatives (4- Pyridoxic acid), Quaternary Amines (Acetylcholine, Glycerophosphocholine, Phosphocholine), and Tricarboxylic Acids (Citric acid)--and other substances such as proteins (e.g., antibodies, lipocalin, lactoferrin, lysozyme, and lacritin)"

As used herein, the term “lipid phase” or “lipid layer” should be understood to mean a phase of the drop of liquid that is separate from the aqueous phase and which contains lipid or a polyol such as glycerine. The lipid phase functions to reduce surface tension of the tear film and helps the film re-spread on the corneal surface following blinking. The lipid layer typically comprises a mixture of polar and non polar lipids. The lipid layer may comprise glycerin (or another polyol), mineral oil, light mineral oil, or any combination thereof. The lipid phase may be compositionally similar to natural tears composition of the lipid layer of natural tears is described in Cwiklik et al (Biochimica et Biophysica Acta (BBA) - Biomembranes; Vol. 1858, Issue 10, Oct 2016) - especially Figure 3 - and Millar et al (Exp. Eye. Res. 137 (2105); page 125-138). The non-polar lipids of TFLL secreted by meibomian glands contain 30-45 mol% of cholesterol esters (CE) with long acyl chains (C22: 1— C34: 1 ), ~ 30-50 mol% of wax esters (WE) with a high representation of C18: 1 fatty acid chains mixed with C18-C30 alcohol chains. Moreover, up to 4 mol% of OAHFAs was found. Regarding polar lipids of non- meibomian origin, ~ 13 mol% of phospholipids (PLs) is present, mainly glycerophospholipids, lysophospholipids, and sphingomyelins. Most of phospholipids are phosphatidylcholines (PCs, > 60 mol%) with a smaller amount of phosphatidylethanolamines (PEs, ~ 15%). Moreover, small quantities (< 5%) of ceramides (Cer) and sphingomyelins (SM) were found. The lipid layer may include an emulsifier or stabiliser. The lipid layer may include carboxymethyl cellulose.

Exemplification

The invention will now be described with reference to specific Examples. These are merely exemplary and for illustrative purposes only: they are not intended to be limiting in any way to the scope of the monopoly claimed or to the invention described. These examples constitute the best mode currently contemplated for practicing the invention.

Referring to the drawings, and initially to Figure 1 , a process for producing a modified tear drop suitable for forming a liquid contact lens film is described. In Figure 1 A, a synthetic tear drop is shown, having a mucous layer 1 , lipid layer 2 and aqueous layer 3. The drop is resting on a support surface 4, and therefore has a flat base and convex upper surface 5 defined by the lipid layer. It can be seen that the interface between the aqueous and lipid layers (meniscus 6) is convex. In Figure 1 B, the drop is shown after an electrowetting treatment, and it can be seen that the angle of the meniscus has changed, with the meniscus is now concave in shape, and the aqueous layer resultantly has a different shape. In Figure 1C, the modified drop with the modified aqueous phase is shown in a dispenser 10 having a dropper 11 configured to dispense the modified tear drop into an eye of a patient. Referring to Figure 2, an electrowetting chamber 10 is illustrated having a first electrode 12 (anode) directly in contact with the aqueous phase of the drop and a second electrode 13 (cathode) in contact with an insulated section of the chamber wall 14 where the meniscus 6 subtends to the wall. In Figure 2B, a voltage has been applied between the aqueous phase and the insulated section of the wall of the chamber, causing the meniscus to change in shape, changing the shape of the aqueous layer 3.

Referring to Figure 3, a dispensing device for dispensing modified synthetic tear drops is described, in which parts described previously are assigned the same reference numerals. The device 20, comprises a reservoir chamber 21 for receiving a liquid, an electrowetting chamber 23 in fluid communication with the reservoir chamber 21 via a metering device 24 configured upon activation to meter a drop of the liquid into the electrowetting chamber 23, an electrode arrangement 25 coupled to the electrowetting chamber 25 for performing an electrowetting treatment on the drop of liquid in the chamber 23, and a dropper 26 fluidically coupled to the electrowetting chamber 23 by a valving arrangement 27 configured to dispense the drop into the dropper 26 upon actuation. In use, a synthetic tear drop liquid composition is dispensed into the reservoir chamber, for example 5 to 10 ml. When a user wishes to use the device to generate a modified tear drop, the metering device is actuated to dispense a drop of synthetic tear fluid from the reservoir 21 into the electrowetting chamber 23. The users then actuates the electrodes arrangement (which includes electrodes similar to that described in Figure 2, a battery, and a switch) to apply an electrowetting treatment to the synthetic tear drop in the electrowetting chamber, to change the shape of the aqueous layer in the drop as described previously, and then the valving arrangement 27 is actuated to dispense the modified tear drop to the eye of a patient through the dropper 26. The device may also include a processor configured to perform a number of different electrowetting treatments to a drop, having different voltages, and voltage application times. The different treatment may be stored on the processor. The device may also include a display to indicate the different electrowetting treatments available. Figures 4A and 4B show an elongated electrowetting chamber including a drop of liquid having an aqueous phase and a lipid phase separated by a meniscus. The left hand side of the chamber includes a metal anode at each end of the chamber in direct contact with the aqueous phase, and the right hand side of the chamber includes a metal cathode at each end, covered by a layer of insulation, and in contact via the insulation with the lipid phase and the mesiscus and part of the lipid phase. Figure 4A shows the drop prior to electrowetting, with the aqueous phase convex shape and also showing the focal length of the of the aqueous phase.

Figure 4B shows the drop after it has been electrowetted, and shows how the application of voltage changes the shape of the aqueous phase from a convex shape to a concave shape, and how this changes the focal length of the aqueous phase.

Example 1

Aqueous phase: The aqueous phase consists of distilled water, sodium chloride; dipotassium phosphate, hydroxyethylcellulose, potassium phosphate; methyl 4- hydroxybenzoate sodium salt and arginine. GSE eye drops (https://www.farmando.it/it/gse-eye-drops-click-gocce- 10x5ml.php?utm source=google&utm medium=ppc&utm campaign=google- shopping&msclkid=d03c3075d1 dfi cd049726fb0e146b01 d) were employed as the base, and arginine was added to the base to provide an aqueous phase with a concentration of 25% arginine w/v).

Lipid Phase: Glycerol (99% by volume), Light mineral oil (0.5% by volume) and mineral oil (0.5% by volume( were combined. WERE THEY MIXED, VORTEXED ?

0.5 ml of aqueous phase was applied as a drop on to a plastic slide. An electrode is attached to the aqueous phase. 1.0 ml of lipid phase is then applied to the drop of aqueous phase to form a drop of liquid with an aqueous phase and a lipid phase. A second electrode is attached to the lipid phase, not touching the aqueous phase. A voltage is passed between the electrodes (5kV for 1 second) to form a synthetic tear drop.

Example 2

As per Example 1 except that the lipid phase consists of glycerin (0.9% by volume), carboxymethyl cellulose (1.0% by volume) and mineral oil (98.1% by volume).

Example 3

The modified tear drop produced in Example 1 is applied to the eye of a human subject. The drop spreads out on the corneal surface of the eye, forming a film. The vision of the subject from the treated eye was altered by the presence of the film on the corneal surface of the eye.

Equivalents

The foregoing description details presently preferred embodiments of the present invention. Numerous modifications and variations in practice thereof are expected to occur to those skilled in the art upon consideration of these descriptions. Those modifications and variations are intended to be encompassed within the claims appended hereto.