HK1234605B - Methods for treating and preventing ocular diseases, disorders, and conditions with melanin - Google Patents

Description

FIELD OF THE INVENTION

The invention relates to compositions for use in methods for treating and preventing ocular diseases, disorders, and conditions, the compositions comprising a therapeutically effective amount of melanin. More specifically, the invention relates to melanin-containing compositions for use in methods for treating and preventing leukoplakia and compositions for use in methods for treating ocular hyperemia.

BACKGROUND OF THE INVENTION

Melanin is ubiquitous in nature, and is composed of nitrogen, oxygen, hydrogen, and carbon. For many years, melanin had no biological or physiological function attributed to it, other than it being considered a simple sunscreen. Because melanin was able to absorb all wavelengths of electromagnetic energy, but did not seem to emit any energy, it was considered the darkest molecule. This characteristic was unique to melanin, and contradicted thermodynamic laws, because other compounds capable of absorbing energy, particularly pigments, emit at least a portion of the energy absorbed. Thus, the electronic properties of melanin have been the focus of attention for quite some time. However, melanin is one of the most stable compounds known to man, and for a long time, it seemed that melanin was unable to catalyze any chemical reaction, or have any other biological or physiological function.

Recently, the intrinsic ability of melanin to split the water molecule into hydrogen and oxygen upon absorption of electromagnetic energy, such as light energy, has previously been reported in U.S. Patent No. 8,455,145 . It is believed that upon the absorption of electromagnetic energy, such as light energy (visible or invisible), melanin catalyzes the dissociation of water into diatomic hydrogen (H₂), diatomic oxygen (O₂), and electrons. Although the splitting of water into hydrogen and oxygen consumes energy, the reaction is reversible, and in the reverse process, the reduction of oxygen atoms with diatomic hydrogen reforms water molecules and liberates energy.

It has also recently been demonstrated that nicotine can increase the release or activity of α-melanocyte stimulating hormone (a-MSH) in a subject, which is believed to be efficacious in treating different disorders by inducing "human photosynthesis" in the subject (see, e.g., U.S. Patent Application Publication No. 2012/0270907 ). Although the mechanism is not fully understood, it is hypothesized that the increased release or activity of a-MSH increases the synthesis of melanin.

Despite the growing knowledge regarding the biological functions of melanin, the therapeutic effects of direct administration of melanin have only been explored in a limited capacity. For example, melanin has been shown to be a simple sunscreen with a low protection factor equivalent to that of a 2% copper sulfate solution. Direct injection of a melanin solution into the anterior chamber of the eye in rabbits was shown to increase both the clearance period of hyphema and the incidence of rebleeds, suggesting that injection of melanin into the eye has a negative effect on the treatment of hyphema. Lai et al. "Effect of Melanin on Traumatic Hyphema in Rabbits" Arch. Ophthalmol. (1999) 177, 789-93. However, as far as the inventor is aware, the effect of direct administration of melanin as a therapeutic agent has not yet been fully explored.

WO 2007/102724 A2 discloses the topical use of melanin for the treatment or prophylaxis of corneal ectasias such as keratoconus, astigmatism, or of corneal problems after laser-assisted in situ keratomileusis (LASIK), or of other ocular disorders such as inflammation of the conjunctiva, hyperaemia, conjunctivitis, infections of the cornea or conjunctiva. WO 2007/102724 A2 teaches that melanin can be administered in liquid or solid form, or in gel form. For treatment of the eye, WO 2007/102724 A2 discloses a 10% solution of melanin.

US 2003/0096735 A1 discloses the use of melanin or melanin-promoting compounds for inhibiting corneal angiogenesis and for treating diseases, e. g. diseases related to corneal revascularization such as macular degeneration, keratoconjunctivitis, glaucoma or diabetic retinopathy. According to US 2003/0096735 A1 , melanin is placed in pharmaceutically acceptable formulations using formulation methods known to those of ordinary skill in the art, and the formulations can be administered by standard routes. The melanin formulations also include those suitable for ophthalmic administration.

BRIEF SUMMARY OF THE INVENTION

It is now discovered that the application of melanin to an eye of a subject has beneficial therapeutic effects in treating and preventing leukoplakia, or in treating hyperemia of the eye in a human subject.

In accordance with claim 1, the invention relates to a composition comprising a therapeutically effective amount of melanin for use in a method of treating and preventing an ocular disease, disorder, or condition in a subject, the method comprising administering the composition to an eye of the subject to treat or prevent the ocular disease, disorder, or condition, wherein the ocular disease, disorder, or condition is leukoplakia.

In accordance with claim 17, the invention further relates to an aqueous composition comprising 3% (w/v) of melanin for use in a method of treating hyperemia of the eye in a human subject, the method comprising topically administering the aqueous composition to an eye of the subject in need of the treatment to treat hyperemia.

In preferred embodiments of the invention, the composition is administered as eye drops.

In other preferred embodiments of the invention, the composition administered to the eye of the subject for treating or preventing leukoplakia comprises 1.5% to 10% (w/v) of melanin.

The composition administered to the eye of the subject may comprise synthetic melanin or natural melanin as the aforementioned melanin.

BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS

The foregoing summary, as well as the following detailed description of the invention, will be better understood when read in conjunction with the appended drawings. For the purpose of illustrating the invention, there are shown in the drawings embodiments which are presently preferred. It should be understood, however, that the invention is not limited to the precise arrangements and instrumentalities shown in the drawings and described in the following detailed description of the invention. In the drawings:

FIGS. 1A and 1B show photographic images of a right eye of a male patient (age 30) having a small white plaque growing on the surface of the eye (leukoplakia) and hyperemia (redness), before and after treatment with melanin; the images shown from top to bottom are photographs taken of the same view with increasing magnification, and the arrow indicates the position at which the growth of a small white plaque was observed; FIG. 1A: photographic images of the eye prior to treatment with melanin; FIG. 1B: photographic images of the eye three and a half months after topical treatment with a 3% aqueous solution of melanin.

DETAILED DESCRIPTION OF THE INVENTION

The invention is defined by the claims. Any subject-matter falling outside the scope of the claims is provided for information only. Discussion of documents, acts, materials, devices, articles or the like which have been included in the present specification is for the purpose of providing context for the invention.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art to which this invention pertains. Otherwise, certain terms used herein have the meanings as set forth in the specification.

It must be noted that as used herein and in the appended claims, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise.

According to the invention, a composition for use in the methods described above and defined in the claims comprises melanin. The composition also optionally comprises one or more pharmaceutically acceptable excipients. In a disclosure the pH of the composition is near physiological pH, and is about pH 7.0 to pH 7.4

According to the invention, the composition for use in the above-mentioned methods comprises melanin. The melanin used can be natural melanin or synthetic melanin. "Natural melanin" is intended to refer to melanin that is isolated from a natural source, such as a plant or animal. "Synthetic melanin" is intended to refer to melanin that is chemically synthesized.

As used herein, the term "subject" refers to any animal, preferably a mammal, and most preferably a human, to whom has been or will be administered melanin. Examples of mammals include humans, cows, dogs, cats, horses, pigs, monkeys, sheep, and rodents. Examples of rodents include rats, mice, rabbits, and guinea pigs. Preferably, the subject is a human.

The above-mentioned aqueous composition comprising 3% (w/v) of melanin for use in a method of treating hyperemia of the eye is a composition for use in the treatment of a human subject.

The etiology of the above-mentioned leukoplakia or hyperemia is not limited, and can arise from an infection, allergy or allergic reaction, a degenerative disorder, inflammatory disease, trauma, surgery, radiation, irritation (e.g., from medications or contact lenses), autoimmune disease, or a proliferative disorder. The leukoplakia or hyperemia can be acute or chronic.

Leukoplakia is characterized by the formation of white plaques.

As used herein, "hyperemia" generally refers to an increase in blood flow to a tissue, resulting in redness of the tissue experiencing increased blood flow. According to embodiments of the invention, hyperemia refers to increased blood flow to the eye, in chronic and acute form, resulting in increased redness of the eye. Hyperemia of the eye can occur on its own (primary), or it can be a symptom associated with one or more other ocular diseases, disorders, or conditions (secondary). Hyperemia can also be acute or chronic.

As used herein, the term "leukoplakia" refers to a disorder of mucous membranes that manifests as small white plaques or patches on the surface of the mucous membrane. Leukoplakia is often associated with an increased risk of proliferative disorders, e.g., cancer, or uncontrolled cell or tissue growth in the affected area. Leukoplakia most commonly occurs in the part of the eye where one type of epithelium tissue transitions into another type of epithelium tissue, e.g., in the area the conjunctiva transitions into the corneal epithelium, known as the cornea-scleral limbus.

As used herein, a "therapeutically effective amount" refers to an amount of a therapeutically active ingredient needed to elicit the desired biological or clinical effect. In one embodiment of the invention, a "therapeutically effective amount" is the amount of melanin needed to treat leukoplakia or hyperemia. In another embodiment of the invention, a "therapeutically effective amount" is the amount of melanin needed to prevent leukoplakia, disorder, or condition.

As used herein, the terms "treat," "treating," and "treatment" refer to administering a therapeutically effective amount of melanin in order to reduce, alleviate, or slow the progression or development of leukoplakia or hyperemia. In another embodiment, "treat," "treating," and "treatment" refer to reducing, slowing the progression of, or ameliorating one or more signs or symptoms of leukoplakia or hyperemia. In particular embodiments of the invention, "treat," "treating," and "treatment" refer to reducing redness in the eye; and to reducing or eliminating white plaques associated with leukoplakia.

As used herein, the terms "prevent," "preventing," and "prevention" refer to administering a therapeutically effective amount of melanin before the onset of leukoplakia, such that the leukoplakia is prevented altogether, time-delayed as to its occurrence, or still occurs, but to a lesser extent, than in the absence of administration of melanin.

According to embodiments of the invention, a composition for use in the treatment of leukoplakia can be administered to an eye of a subject by any method known in the art including, but not limited to, topical application and injection. Injection can be subconjunctival injection (i.e., under the conjunctiva) or intraocular injection. In a preferred embodiment, the composition is topically administered, e.g., by eye drops or by swabbing.

A composition for use in a method of the invention can be in any form suitable for application to the eye. Compositions suitable for injection include, but are not limited to, liquid compositions such as solutions and suspensions. Compositions suitable for topical application include, but are not limited to, solutions, suspensions, eye drops, spray formulations, gels, ointments, creams, and emulsions. In a preferred embodiment of the invention, the composition is a solution, and is more preferably an aqueous solution. An aqueous solution for use in a method according to the invention can be made by, for example, mixing melanin with water. Melanin and water can be mixed together to form a homogenous aqueous solution. In certain embodiments, an aqueous solution for use in a method of the invention contains only melanin and water.

In a preferred embodiment of the invention, the composition is formulated for topical application to the eye. In a particularly preferred embodiment of the invention, the composition is an aqueous solution that is topically administered as eye drops.

According to embodiments of the invention, the composition can be applied to any part of the eye, and is preferably applied to the affected portion of the eye, e.g., cornea, conjunctiva, eyelids, etc..

In the embodiment of the invention which relates to the treatment of hyperemia in a human subject, an aqueous composition comprising 3% (w/v) of melanin is administered topically to an eye of the subject to be treated.

The concentration of melanin in a composition applied to an eye of a subject in a method of the invention can range from about 1.5% to about 10.0% (w/v), such as about 1.5%, 2.0%, 3.0%, 4.0%, 5.0%, 6.0%, 7.0%, 8.0%, 9.0%, or 10.0% (w/v). In a preferred embodiment, the concentration of melanin is 3% (w/v).

In the embodiment of the invention which relates to the treatment of hyperemia in a human subject, the concentration of melanin in the aqueous composition is 3% (w/v).

A composition according to the present invention comprising a therapeutically effective amount of melanin can be administered once, or it can be administered more than once. For example, the composition can be administered once daily, twice daily, once every week, or once every month. In severe cases, the composition can be administered every fifteen minutes, and once an improvement is noticed, the time between applications can be increased to every half hour, every hour, or every two hours, etc., as needed. Also, a composition according to the present invention can be administered prior to the onset of leukoplakia in order to prevent leukoplakia, or after the onset of leukoplakia or hyperemia in order to treat leukoplakia or hyperemia. Melanin is usually well tolerated. However, some side effects may occur, such as swelling, irritation, or inflammation of the eyelids, conjunctiva, or cornea, or subconjunctival bleeding.

The therapeutically effective amount of melanin in a composition according to the invention, the amount of the composition administered, and the frequency of administration can all vary depending on a variety of factors, such as the above-mentioned ocular disease, disorder, or condition to be treated or prevented, the severity of the above-mentioned ocular disease, disorder, or condition, the age and health of the subject to be administered the composition, etc. It is well within the purview of one of ordinary skill in the art to optimize each of these parameters in order to achieve the desired clinical outcome in view of the present disclosure.

For example, about 50 µL to 500 µL, preferably 50 µL to 200 µL, and more preferably 150 µL to 200 µL of a composition comprising 1.5% (w/v) to 10% (w/v) of melanin is administered per application. In particular, between one and five drops (about 50 µL per drop) of the composition is administered per application, such as one drop, two drops, three drops, four drops, or five drops.

As an illustrative and non-limiting example of a dosing regimen that can be followed in the methods for treating leukoplakia or hyperemia in a subject, about 50 µL to 100 µL of a 3% aqueous solution of melanin can be administered every thirty minutes at the start of treatment. Depending on the severity of the condition, the frequency of administration of the aqueous melanin solution can be adjusted to once every hour, once every two hours, etc. As another illustrative example, about 50 µL to 100 µL of a 3% aqueous solution of melanin can be administered four to six times daily to treat a chronic ocular disease, disorder, or condition, wherein the chronic ocular disease, disorder or condition is leukoplakia or hyperemia. The frequency of administration can again be adjusted depending on the severity of the condition.

The invention provides compositions - as defined in the claims - for use in a method of treating leukoplakia or hyperemia in a human subject comprising topically administering to an eye of the subject in need of the treatment an aqueous composition comprising a therapeutically effective amount of melanin. According to embodiments of the invention, the hyperemia can be primary or secondary hyperemia. The composition for use in a method of treating hyperemia of the eye in a human subject is an aqueous composition comprising 3% (w/v) of melanin.

Without wishing to be bound by any theories, one possible explanation for the efficacy of melanin in treating the above-mentioned ocular diseases, disorders, and conditions is that applying melanin to the eye enhances "human photosynthesis" in the eye. As explained above, melanin is believed to transform light energy into chemical energy, analogous to the process by which plants use the pigment chlorophyll to transform light energy into chemical energy during photosynthesis. By analogy, the conversion of light energy into chemical energy by melanin has been designated "human photosynthesis." Direct application of melanin to the eye is thus also thought to induce "human photosynthesis" in the eye, resulting in increased splitting and reformation of the water molecule, which results in an increased release of energy. The increased amount of energy made available to the surrounding cells is believed to fuel many important biological reactions that take place in the cell, such as those needed for cellular repair, etc.

Again without wishing to be bound by any theories, melanin is a relatively large biomolecule, which allows it to function as a chelating agent in certain circumstances. Thus, it is also believed that the ability of melanin to chelate or inactivate certain biological molecules and molecules of foreign origin that are often present in diseased tissue increases the purity of the tissue and improves the efficiency of water dissociation by melanin. This has the effect of further enhancing any beneficial therapeutic effects that result from increased "human photosynthesis."

This invention will be better understood by reference to the non-limiting examples that follow, but those skilled in the art will readily appreciate that the examples are only illustrative of the invention.

EXAMPLE Example 1: Topical treatment of leukoplakia and hyperemia of the eye with melanin.

A male patient, aged 30, had a small white plaque growing on the surface of his right eye (leukoplakia) and hyperemia (redness) (see FIG. 1A). The leukoplakia was hypothesized to be the result of excessive sun exposure and chemicals. The patient was initially treated with topical cortisone drops, and the cortisone treatment continued for two months. However, no improvement was observed with the topical cortisone drops, and cortisone treatment was thus stopped due to a lack of improvement.

One month subsequent to stopping cortisone treatment, the patient underwent treatment with a 3% aqueous solution of melanin (w/v) that was topically applied in the form of eye drops. The aqueous solution was produced by mixing water and chemically synthesized melanin (synthetic melanin). The aqueous solution did not contain any other components. Three to four drops (about 50 µL per drop) of the 3% aqueous melanin solution were administered for each application, and the solution was applied four times per day at approximately six hour intervals. After approximately three and a half months of treatment with the topical melanin solution, a dramatic improvement was observed. The same dosing regimen was used over the entire course of the treatment. In particular, the redness due to hyperemia was greatly reduced, and the small white plaque indicative of leukoplakia was no longer detectable by visual observation (see FIG. 1B).

The results of the above experiment indicate that topical application of melanin to the eye is effective in the treatment of hyperemia of the eye, particularly in humans. The results of the above experiment also indicate that topical application of melanin to the eye is effective in the treatment of leukoplakia, particularly in humans.

Claims (18)

1. A composition comprising a therapeutically effective amount of melanin for use in a method of treating or preventing an ocular disease, disorder, or condition in a subject, the method comprising administering the composition to an eye of the subject to treat or prevent the ocular disease, disorder, or condition, wherein the ocular disease, disorder, or condition is leukoplakia.
2. The composition for use according to claim 1, wherein the composition is administered topically or by injection.
3. The composition for use according to claim 1, wherein the composition comprises synthetic melanin or natural melanin.
4. The composition for use according to claim 1, wherein the composition is a topical composition selected from the group consisting of a solution, suspension, eye drops, spray formulation, ointment, gel, cream, and emulsion.
5. The composition for use according to claim 1, wherein the composition is an aqueous solution.
6. The composition for use according to claim 1, wherein the composition is administered as eye drops.
7. The composition for use according to claim 1, wherein the composition comprises 1.5% to 10% (w/v) of melanin.
8. The composition for use according to claim 1, wherein the subject is a human.
9. A composition comprising a therapeutically effective amount of melanin for use in a method of treating an ocular disease, disorder, or condition in a subject, the method comprising topically administering the composition to an eye of the subject in need of the treatment to treat the ocular disease, disorder, or condition, wherein the ocular disease, disorder, or condition is leukoplakia.
10. The composition for use according to claim 9, wherein the composition comprises 1.5% to 10% (w/v) of melanin.
11. The composition for use according to claim 9, wherein the composition is administered as eye drops.
12. The composition for use according to claim 9, wherein the composition comprises natural melanin or synthetic melanin.
13. An aqueous composition comprising a therapeutically effective amount of melanin for use in a method of treating leukoplakia in a human subject, the method comprising topically administering the aqueous composition to an eye of the subject in need of the treatment to treat leukoplakia .
14. The composition for use according to claim 13, wherein the aqueous composition is administered as eye drops.
15. The composition for use according to claim 13, wherein the aqueous composition comprises 1.5% to 10% (w/v) of melanin.
16. The composition for use according to any one of claims 7, 10 and 15, wherein the composition comprises 3% (w/v) of melanin.
17. An aqueous composition comprising 3% (w/v) of melanin for use in a method of treating hyperemia of the eye in a human subject, the method comprising topically administering the aqueous composition to an eye of the subject in need of the treatment to treat hyperemia.
18. The composition for use according to claim 17, wherein the aqueous composition is administered as eye drops.