Compositions for treating meibomian gland dysfunction

Abstract

A method for treating a meibomian gland dysfunction of an affected eye includes administering to the affected eye of a subject in need of such treatment a steroidal-androgen-free composition containing a therapeutically effective amount of a cyclic polysaccharide. A steroidal-androgen-free composition includes a cyclic polysaccharide as an active pharmaceutical ingredient for treating a meibomian gland dysfunction of an affected eye.

Description

FIELD OF THE INVENTION

The present invention relates to compositions and methods for treating a meibomian gland dysfunction (MGD) of an affected eye.

BACKGROUND OF THE INVENTION

Meibomian glands are a type of sebaceous gland located in the tarsal plate of the upper and lower eyelids. These glands are responsible for the supply of meibum, an oily substance that prevents evaporation of the eye's tear film, prevents tear evaporation, and makes the closed lids airtight. There are approximately 50 glands on the upper eyelids and 25 glands on the lower eyelids. Meibomian glands are distinguished by grape-like clusters of acini on the mucocutaneous lid junction and empty their lipid content (meibum) at this junction in order to coat the ocular surface via holocrine secretion. The glands are anchored by cells that produce both polar and nonpolar lipids, which are then stored in lysosomes that merge into larger storage granules. As these cells continue to enlarge with lipid, they eventually commit apoptosis and rupture to release the meibum into the meibomian gland opening and spill the meibum over the ocular surface. Meibum is fluid at the temperature of ocular surface, and distributed over the ocular surface in a thin, smooth film on top of the aqueous layer. This lipid layer prevents evaporation of the aqueous layer. Alterations in the meibum composition, property and level can have a profound effect on the health of the eyelid margins and ocular surface. Meibomian gland dysfunction in the general population is pretty high with some estimates as high as 39% with an increase in incidence in contact lens wearers.

Meibomian gland secretions form the lipid layer of tears and consist of polar and nonpolar lipids. The lipid composition of the meibum can affect tear parameters like initial formation of a composite monolayer with polar and nonpolar phases, adequate fluidity near body temperature, and the ability to undergo compression and expansion during blinking. These properties are very important for effective polar lipid structuring and fluidity (melted physical state) at normal body temperature. Any alterations in the saturation of the fatty acids can lead to instability of tears.

MGD patients usually have normal production of aqueous tears by their lacrimal glands, their meibomian glands can atrophy and this is frequently accompanied by metaplasia of the ductal epithelium of these glands. Anterior erosion of the mucocutaneous junction of the eyelid is often noted, as well as eyelid and conjunctival infection, eyelid margin irregularity, corneal epithelial changes, and corneal vascularization. In some cases, abnormal overproduction of meibum can also cause the same problems.

As meibomian glands lining the eyelids produce lipids that promote the stability of the tears and reduce evaporation of the tear film, dysfunction of the meibomian glands can lead to lipid insufficiency that destabilizes the tear film and causes decreases in tear film break-up time and evaporative dry eye.

MGD may also be characterized by increased melting point of the lipids, causing solidification of the lipids and obstruction of the meibomian gland secretion. This can result in cysts, infections and decreased lipid content in the tears. MGD is also characterized by excess, abnormally turbid secretion that gets inspissated and plugs the meibomian orifices. This is followed by metaplasia of the meibomian ducts (abnormal hyper-keratinization). Blockage and resistance to flow results in inflammation and vascularization (redness) of tissues around the orifice. Inflammatory mediators accumulate in the tear film leading to damage of ocular surface. Sequalae of all these events is inflammatory scarring of the duct leading to stenosis. Initially glands swell and eventually atrophy.

Common complaints of MGD patients include blurred or filmy vision, light sensitivity or photophobia, burning or foreign body sensations in the eye, excessive tearing, intolerance to contact lens and pain.

Light sensitivity is an intolerance of sunlight, fluorescent light or incandescent light. It is one of the symptoms of MGD and is associated with other conditions such as corneal abrasion, uveitis, meningitis, a detached retina, contact lens irritations, sunburn or refractive surgery.

Blurred vision is a lack of sharpness of vision, and may result from abnormalities such as nearsightedness, farsightedness, presbyopia, and astigmatism. It is also associated with MGD and other ocular surface conditions.

Currently, various lipid based artificial tears or lubricants are used to alleviate the symptoms of MGD. Physical treatments, such as maintaining good hygiene, heating, and massage, are often used as well. However, these treatments do not cure the disease. There is a need for an effective and safe treatment for MGD.

SUMMARY OF THE INVENTION

In one embodiment, the present invention provides a method for treating a meibomian gland dysfunction of an affected eye. The method includes administering to the affected eye of a subject in need of such treatment a steroidal-androgen-free composition containing a therapeutically effective amount of a cyclic polysaccharide.

In another embodiment, the steroidal-androgen-free composition is administered topically to the affected eye, topically onto a surrounding skin of the affected eye, or orally to the subject.

In another embodiment, the cyclic polysaccharide is a cyclodextrin selected from the group consisting of alpha-cyclodextrin, beta-cyclodextrin, 2-hydroxypropyl-beta-cyclodextrin, methyl-beta-cyclodextrin, 2,6-di-O-methyl-beta-cyclodextrin, sulfobutylether beta-cyclodextrin, branched beta-cyclodextrin, glucosyl-beta-cyclodextrin, maltosyl-beta-cyclodextrin, gamma-cyclodextrin, 2-hydroxypropyl-gamma-cyclodextrin, 2-hydroxypropyl-alpha-cyclodextrin, epichlorohydrin-carboxymethyl-alpha-cyclodextrin, epichlorohydrin-beta-cyclodextrin and a combination thereof.

In another embodiment, the cyclic polysaccharide is present in the composition at a concentration of 0.1% w/w to 30% w/w, 0.5% w/w to 25% w/w, 1% w/w to 20% w/w, 5% w/w to 15% w/w, 8% w/w to 12% w/w, about 10% w/w, or 10% w/w.

In another embodiment, the steroidal-androgen-free composition does not include an androgen with a steroidal chemical structure, testosterone, or precursors of testosterone.

In another embodiment, the method further includes maintaining effects of treating the meibomian gland for a period of time post administering.

In another embodiment, the period of time post administering is 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months or 12 months.

In another embodiment, the method further includes dissolving lipids crystals deposited at the opening of the meibomian gland of the affected eye.

In another embodiment, the method further includes reducing the sensation of a foreign body in the affected eye, hyperemia or redness of the affected eye and eyelid margin, plugging of a meibomian gland orifice of the affected eye, inflammation of ocular tissues, corneal staining of the affected eye, burning sensation in the affected eye, photophobia, blurred vision, pain in the affected eye, or itchiness in the affected eye; increasing tear film break up time (TBUT); decreasing the phase transition temperature of meibum; or improving clinical signs and symptoms of meibomian gland dysfunction (MGD). The ocular tissues are selected from the group consisting of meibomian glands, ducts, orifices, eye lids, cornea, and conjunctiva.

In one embodiment, the present invention provides a steroidal-androgen-free composition comprising a cyclic polysaccharide as an active pharmaceutical ingredient for treating a meibomian gland dysfunction of an affected eye.

In another embodiment, the cyclic polysaccharide is a sole active pharmaceutical ingredient for treating the meibomian gland dysfunction.

In another embodiment, the steroidal-androgen-free composition is an ophthalmic composition, a transdermal composition, or an oral composition.

In another embodiment, the cyclic polysaccharide is a cyclodextrin selected from the group consisting of alpha-cyclodextrin, beta-cyclodextrin, 2-hydroxypropyl-beta-cyclodextrin, methyl-beta-cyclodextrin, 2,6-di-O-methyl-beta-cyclodextrin, sulfobutylether beta-cyclodextrin, branched beta-cyclodextrin, glucosyl-beta-cyclodextrin, maltosyl-beta-cyclodextrin, gamma-cyclodextrin, 2-hydroxypropyl-gamma-cyclodextrin, 2-hydroxypropyl-alpha-cyclodextrin, epichlorohydrin-carboxymethyl-alpha-cyclodextrin, epichlorohydrin-beta-cyclodextrin, 6-monodeoxy-6-monoazido-beta-cyclodextrin, 6-monodeoxy-6-monoiodo-beta-cyclodextrin, 6-monodeoxy-6-monothio-beta-cyclodextrin, 6-monodeoxy-O-(p-toluenesulfonyl)-beta-cyclodextrin, 6-monodeoxy-6-monoazido-6-mono-O-(p-toluenesulfonyl)-beta-cyclodextrin, 6-monodeoxy-6-monobromo-beta-cyclodextrin, heptakis(2,3,6-tri-O-benzoyl)-beta-cyclodextrin, heptakis(2,3,6-tri-O-methyl)-beta-cyclodextrin, heptakis(2,6-di-O-methyl)-beta-cyclodextrin, heptakis(6-deoxy-6-azido)-beta-cyclodextrin, heptakis(6-deoxy-6-chloro)-beta-cyclodextrin, heptakis(6-deoxy-6-bromo)-beta-cyclodextrin, heptakis(6-deoxy-6-iodo)-beta-cyclodextrin, heptakis(6-deoxy-6-thio)-beta-cyclodextrin, sulfobutylated beta-cyclodextrin, acetyl beta-cyclodextrin, carboxymethyl-beta-cyclodextrin, succinyl-beta-cyclodextrin, (2-carboxyethyl)-beta-cyclodextrin, sulfobutylated beta-cyclodextrin, 6-monodeoxy-6-monoamino-beta-cyclodextrin, heptakis(6-deoxy-6-amino)-beta-cyclodextrin, (2-hydroxy-3-N,N,N-trimethylamino)propyl-beta-cyclodextrin, heptakis(2,3,6-di-O-methyl)-hexakis(6-O-methyl)-6-monodeoxy-6-monoamino ta-beta-cyclodextrin, 6-monodeoxy-6-monoamino-random-methyl-beta-cyclodextrin, (2-hydroxy-3-N,N,N-trimethylamino)propyl-beta-cyclodextrin, heptakis(6-sulfo)-beta-cyclodextrin, heptakis(2,3-di-O-acetyl-6-sulfo) beta cyclodextrin, heptakis(2,3-di-O-methyl-6-sulfo)-beta-cyclodextrin, heptakis(2,3-di-O-methyl-6-deoxy-6-amino)-b eta-cyclodextrin, heptakis(2,3-di-O-methyl-6-deoxy-6-azido)-beta-cyclodextrin, heptakis(6-deoxy-6-(2-carboxyethyl)thio)-beta-cyclodextrin, and a combination thereof.

In another embodiment, the cyclic polysaccharide is present in the steroidal-androgen-free composition at a concentration of 0.1% w/w to 30% w/w, 0.5% w/w to 25% w/w, 1% w/w to 20% w/w, 5% w/w to 15% w/w, 8% w/w to 12% w/w, about 10% w/w, or 10% w/w.

In another embodiment, the steroidal-androgen-free composition does not include an androgen with a steroidal chemical structure, testosterone, or precursors of testosterone.

In another embodiment, the steroidal-androgen-free composition further includes inactive ingredients selected from the group consisting of sodium phosphate monobasic monohydrate, sodium chloride, castor oil, Polysorbate 80, cremophor ELP, citric acid, sodium citrate, HPMC 2910, edetate disodium, and glycerin.

In another embodiment, the sodium phosphate monobasic monohydrate has a concentration of 0.10-0.30% w/w, and the sodium chloride has a concentration of 0.20-0.80% w/w.

In another embodiment, the castor oil has a concentration of 0.1-0.5% w/w, the Polysorbate 80 has a concentration of 0.1-1.0% w/w, the Cremophor ELP has a concentration of 0.1-1.0% w/w, the citric acid has a concentration of 0.010-0.30% w/w, the sodium citrate has a concentration of 0.030-0.060% w/w, the HPMC 2910 has a concentration of 0.01-1.0% w/w, and edetate disodium has a concentration of 0.01-0.5% w/w.

In another embodiment, the ophthalmic composition is selected from the group consisting of a solution, a suspension, an emulsion, a gel, an ointment, and a cream; the transdermal composition is selected from the group consisting of a solution, a suspension, an emulsion, a gel, an ointment, and a cream; and the oral composition is selected from the group consisting of a solution, a suspension, an emulsion, a tablet, and a capsule formulation.

It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory and are intended to provide further explanation of the invention as claimed.

BRIEF DESCRIPTION OF THE DRAWINGS

The accompanying drawings, which are included to provide a further understanding of the invention and are incorporated in and constitute a part of this specification, illustrate embodiments of the invention and together with the description serve to explain the principles of the invention.

In the drawings:

FIG. 1 shows the effects of 2-hydroxypropyl-beta-cyclodextrin (2-HP-β-CD) on sensitivity to light and blurred vision over a 24-week period in a Phase 2 clinical trial.

FIG. 2 shows the effects of 2-HP-β-CD on sensitivity to light and blurred vision over a 12-month period in a Phase 2 clinical trial.

FIG. 3 shows the overall average score of patients treated in the disease eye with a topical ocular drop of 2-hydropropyl-beta-cyclodextrin formulation at a concentration of 10% (w/w), 3 times daily for 4 weeks with subsequent continuous observations for 5 months in a Phase 2 clinical trial.

FIG. 4 shows the average ocular symptom score of the patients in a Phase 2 clinical trial.

FIG. 5 shows the average vision-related functioning score in a Phase 2 clinical trial.

FIG. 6 shows the average quality of life impact score of the patients in a Phase 2 clinical trial.

FIG. 7 shows ocular symptom score at each schedule visit for pterygium patients with dry eye or with no dry eye in a Phase 2 clinical trial.

FIG. 8 shows average change from baseline of ocular symptom score at each schedule visit for pterygium patients with dry eye or with no dry eye in a Phase 2 clinical trial.

FIG. 9 shows ocular symptom score at each schedule visit for pterygium patients with dry eye in a Phase 2 clinical trial.

FIG. 10 shows average change from baseline of ocular symptom score at each schedule visit for pterygium patients with dry eye in a Phase 2 clinical trial.

DETAILED DESCRIPTION OF THE ILLUSTRATED EMBODIMENTS

Reference will now be made in detail to embodiments of the present invention, example of which is illustrated in the accompanying drawings.

The present invention provides compositions and treatment methods for treating meibomian gland dysfunction. Without being bound by a particular theory, the methods utilize two important properties of the cyclodextrin compounds: 1) the ability to dissolve cholesterol and 2) the ability to inhibit immune activities such as macrophage activation. The first ability will help to remove excess lipids deposited near the orifice and help the flow of lipid and it will also modify the meibum composition to make it more fluid at the normal temperature of the ocular surface. The second ability will attenuate the abnormal immune activity present on the eyes of MGD patients. These patients suffer increased cytokines and immune cell activities, including macrophages, T-cells. Unlike the current treatments for MGD, this invention will have the potential to modify the disease in addition to improve symptoms such as light sensitivity and blurred vision.

U.S. Pat. No. 9,937,188 (Allergan, Inc) discloses the use of formulations comprising testosterone or related androgens for the treatment of keratoconjunctivitis sicca and meibomian gland disease. In this patent, cyclodextrin acts as a solubilizer for testosterone, the active ingredient, and is disclosed as one of the inactive excipients that also include castor oil, C10-30 alkyl acrylate crosspolymer and Polyoxyl 40 stearate. The methods of the present application are fundamentally different in that cyclodextrin is disclosed here as the active ingredient for the treatment of MGD, not an inactive excipient of a formulation as disclosed in U.S. Pat. No. 9,937,188. Importantly, the disclosed method does not use any steroidal androgen as disclosed in U.S. Pat. No. 9,937,188. This key difference will avoid many of the potential steroidal-related side effects, such as virilization for females and stimulation of the prostate for males. Androgens control the development, differentiation, and function of male reproductive and accessory sex tissues. Testosterone regulates the expression of thousands of genes in ocular tissues. Such gene regulations in meibomian gland provides the beneficial effects disclosed in U.S. Pat. No. 9,937,188, but since a very large number of genes' expression are changed, side effect potential is also high. ANDROGEL, containing 1% testosterone as an active ingredient, was approved for topical use as a replacement therapy in males for conditions associated with a deficiency or absence of endogenous testosterone. ANDROGEL product insert indicates the worsening of benign prostatic hyperplasia (BPH) and potential risk of prostate cancer for patients with BPH. ANDROGEL 1% should be avoided for unintentional exposure to women or children. Secondary exposure to testosterone can produce signs of virilization and ANDROGEL 1% should be discontinued until the cause of virilization is identified. Other observed side effects in the clinical trials of ANDROGEL 1% included azoospermia, edema with or without congestive heart failure, sleep apnea. Serum testosterone, prostate specific antigen, hemoglobin, hematocrit, liver function tests and lipid concentrations should be monitored periodically for patients treated with ANDROGEL 1%. The present application excludes the use of testosterone and uses cyclodextrin as the sole active ingredient. This avoids the side effect issues associated with testosterone.

As used herein, the “ophthalmic compositions” are useful for placement onto the surface of an eye of a human or animal. Such compositions are preferably administered into an eye of a patient in a fluid form. By administering the compositions as a fluid, the administration may occur without forming an incision in the eye.

As used herein, the “transdermal compositions” deliver a therapeutically effective amount of active ingredient across the skin of a patient. Transdermal compositions typically involve a carrier (such as a liquid, gel, or solid matrix, or a pressure sensitive adhesive) into which the active ingredient to be delivered is incorporated.

As used herein, an “active pharmaceutical ingredient” refers to therapeutic agents or substances used to treat a medical ophthalmic disease or condition of the eye and/or to otherwise beneficially affect a patient's eye, and “sole active pharmaceutical ingredient” refers to the one and only therapeutic agent or substance used to treat a medical ophthalmic disease or condition of the eye and/or to otherwise beneficially affect a patient's eye.

As used herein, the term “therapeutically effective amount” is intended to mean a nontoxic but sufficient concentration or amount of a cyclic polysaccharide, specifically, a cyclodextrin, and more specifically, alpha-cyclodextrin, beta-cyclodextrin, 2-hydroxypropyl-beta-cyclodextrin, methyl-beta-cyclodextrin, 2,6-di-O-methyl-beta-cyclodextrin, sulfobutylether beta-cyclodextrin, branched beta-cyclodextrin, glucosyl-beta-cyclodextrin, maltosyl-beta-cyclodextrin, gamma-cyclodextrin, 2-hydroxypropyl-gamma-cyclodextrin, 2-hydroxypropyl-alpha-cyclodextrin, epichlorohydrin-carboxymethyl-alpha-cyclodextrin, epichlorohydrin-beta-cyclodextrin and a combination thereof, to provide the desired therapeutic effects. The amount that is effective will vary from subject to subject, depending on the age and general condition of the individual, the cyclic polysaccharide, and the like. Thus, it is not always possible to specify an exact effective concentration or amount. However, an appropriate effective amount in any individual case may be determined by one of ordinary skill in the art using routine experimentation. Furthermore, the exact effective amount of a cyclic polysaccharide incorporated into a composition or dosage form of the present invention is not critical, so long as the concentration is within a range sufficient to permit ready application of the solution or formulation so as to deliver an amount of the cyclic polysaccharide inducing compound that is within a therapeutically effective range.

Cyclic polysaccharides (also known as cyclic oligosaccharide) are cyclic polymers composed of cyclic monomers (monosaccharides) typically joined by glycosidic linkages. Cyclodextrins are a family of cyclic oligosaccharides, consisting of a macrocyclic ring of glucose subunits joined by α-1,4 glycosidic bonds. Cyclodextrins may contain a number of glucose monomers ranging from six to eight units in a ring, creating a cone shape. Specifically, cyclodextrins used herein can be alpha-cyclodextrin, beta-cyclodextrin, 2-hydroxypropyl-beta-cyclodextrin, methyl-beta-cyclodextrin, 2,6-di-O-methyl-beta-cyclodextrin, sulfobutylether beta-cyclodextrin, branched beta-cyclodextrin, glucosyl-beta-cyclodextrin, maltosyl-beta-cyclodextrin, gamma-cyclodextrin, 2-hydroxypropyl-gamma-cyclodextrin, 2-hydroxypropyl-alpha-cyclodextrin, epichlorohydrin-carboxymethyl-alpha-cyclodextrin, epichlorohydrin-beta-cyclodextrin or a combination thereof.

2-Hydroxypropyl-beta-cyclodextrin (2-HP-β-CD) (CAS Number: 128446-35-5) is a modified cyclodextrin, and has the following formula.

2,6-Di-O-methyl-beta-cyclodextrin (also known as heptakis(2,6-di-O-methyl)-beta-cyclodextrin, CAS Number 51166-71-3) is a modified cyclodextrin, and has the following formula.

In a clinical trial to study a drug for treating pterygium, a surprising discovery was made that the vehicle (2-HP-β-CD Formulation I) reduced the symptom of foreign body sensation, pain, redness and in particular, light sensitivity and blurred vision in pterygia patients. The present invention was based on this unexpected observation. Pterygium is a common ocular disorder that causes several ocular symptoms that are also common in MGD. The meibomian glands in pterygium area are often dysfunctional. In this clinical trial, several common ocular symptoms including irritation, foreign body sensation, pain, light sensitivity and blurred vision, were assessed using questionnaires to the patients. Surprisingly, overall ocular symptom scores combining the scores of irritation, foreign body sensation, pain, light sensitivity and blurred vision have significantly reduced during cyclodextrin treatment when comparing to the prior treatment baseline. In particular, light sensitivity and blurred vision were significantly improved by the vehicle during the treatment compared to the prior treatment baseline. Even more surprising is that these symptom relief effects maintained for a prolong period of 5 months post vehicle treatment. The vehicle's main ingredient was 10% 2-HP-β-CD (w/w).

In certain embodiment, a method for treating MGD and improving MGD symptoms includes administering an ophthalmic composition containing a therapeutically effective amount of a cyclic polysaccharide to an affected eye of a subject. The cyclic polysaccharide is preferably a cyclodextrin, more preferably, 2-hydroxypropyl-beta-cyclodextrin.

In the ophthalmic composition, the cyclic polysaccharide is present at a concentration of 0.1% w/w to 30% w/w, 0.5% w/w to 25% w/w, 1% w/w to 20% w/w, 5% w/w to 15% w/w, 8% w/w to 12% w/w, about 10% w/w, or 10% w/w. The ophthalmic composition can be an aqueous composition and include inactive ingredients selected from the group consisting of hydroxypropyl guar, xantham gum, and trehalose or additional sugar molecules and derivatives. The ophthalmic composition can also include inactive ingredients selected from the group consisting of sodium phosphate monobasic monohydrate, sodium chloride, castor oil, Polysorbate 80, cremophor ELP, citric acid, sodium citrate, HPMC 2910, edetate disodium, and glycerin.

In certain embodiment, after administering the composition was ended, the beneficial effects remain for a period of time post administering. The period of time post administering can be 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 1 year.

Compositions and methods for treating symptoms are disclosed. The methods include administration of a suitable ocular formulation containing 2-Hydroxypropyl beta Cyclodextrin (2-HP-β-CD) to patients in need thereof. The disclosed methods are used for sustained improvements on the overall symptoms associated with MGD.

EXAMPLES

The invention is further described in the following representative examples, which do not limit the scope of the claimed invention.

Example 1: 2-HP-β-CD Formulation I

The formulation in this example includes 5%-20% (preferably, 10%) 2-HP-β-CD (w/w), 0.10-0.30% (preferably, 0.16%) sodium phosphate monobasic monohydrate (w/w), 0.20-0.80% (preferably, 0.52%) sodium chloride (w/w), and water. The formulation has a pH value of 4-9 (preferably, 7.4).

Example 2: Application of 2-HP-β-CD Formulation I

A Phase 2a Multicenter, Randomized, Vehicle-Controlled, Dose Escalating Study was carried out to evaluate the Safety, Efficacy and Pharmacokinetics of Nintedanib Ophthalmic Solution in Patients with Primary or Recurrent Pterygium. 2-HP-β-CD Formulation I was used as vehicle.

The multicenter, randomized, double-masked, vehicle-controlled, parallel study was conducted with 28 days three times a day (TID) repeat ocular dosing of vehicle and 0.2% nintedanib, followed by 5-month post-dosing observation.

Results:

In the clinical trial, pterygia patients were asked 15 questions on ocular sign, symptom and quality of life. Surprisingly, the 2-HP-β-CD Formulation I caused an unexpected improvement on light sensitivity and blurred vision. Table 1 shows that the two symptoms were statistically improved during treatment at weeks 2 and 4. A trend of effects also remained after the stop of treatment at weeks 8, 16, and 24. The results are shown in FIG. 1. The other questions didn't generate statistically significant effects.

TABLE 1
Effects of the 2-HP-β-CD Formulation
I on sensitivity to light and blurred vision
	Day
	1	Wk 2	Wk 4	Wk 8	Wk 16	Wk 24
Sensitivity to light
Mean veh (n = 23)	0.74	0.26	0.22	0.39	0.45	0.39
SD	1.14	0.45	0.42	0.72	0.96	0.72
TTEST vs baseline		0.031	0.015	0.148	0.167	0.175
Blurred vision
Mean veh (n = 23)	1.09	0.57	0.57	0.61	1.00	0.52
SD	1.31	1.20	0.95	1.03	1.23	0.51
TTEST vs baseline		0.004	0.025	0.086	0.776	0.039

Example 3: 2-HP-β-CD Formulation II

The formulation in this example includes 0.1-05% Castor Oil (w/w), 0.1-1.0% Polysorbate 80, super-refined (w/w), 0.1-1.0% Cremophor ELP (w/w), 5-20% 2-HP-β-CD (w/w), 0.010-0.30% Citric Acid (w/w), 0.030-0.060% Sodium Citrate (w/w), 0.01-1.0% HPMC 2910 (w/w), 0.01-0.5% Edetate Disodium (w/w), and water. The formulation has a pH value of 4.0-9.0. Glycerin is used to adjust the osmolality of the solution to 280-300 mOsm/kg.

Example 4: Application of 2-HP-β-CD Formulation II

A Phase 3 Multicenter, Randomized, Vehicle-Controlled, Dose Escalating Study was carried out to evaluate the Safety, Efficacy and Pharmacokinetics of Nintedanib Ophthalmic Solution in Patients with Primary or Recurrent Pterygium. 2-HP-β-CD Formulation II was used as vehicle.

The treatment time of the Phase 3 trial is longer than that of the Phase 2a trial. The results are shown in FIG. 2.

Example 5: Application of 2-HP-β-CD Formulation I

A Phase 2a Multicenter, Randomized, Vehicle-Controlled, Dose Escalating Study was carried out to evaluate the Safety, Efficacy and Pharmacokinetics of Nintedanib Ophthalmic Solution in Patients with Primary or Recurrent Pterygium. The multicenter, randomized, double-masked, vehicle-controlled, parallel study was conducted with 28 days three times a day (TID) repeat ocular dosing of vehicle and 0.2% nintedanib, followed by 5-month post-dosing observation. 2-HP-β-CD formulation listed in Example 1 was used as the vehicle.

Pterygium patients often have meibomian gland atrophy and clinical signs and symptoms of MGD, including ocular pain, itchy, foreign body sensation, redness, sensitivity to light and blue vision. In the Phase II clinical trial, pterygia patients were asked 15 questions on ocular symptom, vision-related functioning and quality of life via Pterygium Symptom and Life Quality (PSLQ) questionnaires.

Results:

PSLQ analyses were performed for 4 average category scores; Overall, Ocular Symptoms, Vision-Related Functioning, and Quality of Life Impact. Results of the analyses are summarized in Table 2 through Table 5. 2-HP-β-CD-treated group showed significant improvements in PSLQ scores when compared to the baseline. Statistically significant changes (improvements) from baseline were detected in the 2-HP-β-CD-treated group at Weeks 2, 4, and 8 for Overall PSLQ scores and at Weeks 2, 4 and 8 for Ocular Symptom scores, and at Week 2 for Quality of Life Impact scores and at Weeks 4 and 8 for the Vision-Related Functioning scores.

Surprisingly, the improvements on ocular symptoms and vision-related functioning were not only observed during 2-HP-β-CD treatment period at Weeks 2 and 4, but also continued after 2-HP-β-CD treatment period at Week 8.

TABLE 2
PSLQ: Overall Average Score - Baseline and Changes from Baseline
at Each Follow-up Visit: Modified Intent-to-Treat Population
Timepoint                       2-HP-β-CD
Statistic                       (N = 23)
Baseline Mean (SD)              0.70 (0.66)
Change from Baseline at Week 2  −0.28 (0.45)
Mean (SD)
p-value [a]                     0.007
Change from Baseline at Week 4  −0.35 (0.51)
Mean (SD)
p-value [a]                     0.004
Change from Baseline at Week 8  −0.30 (0.55)
Mean (SD)
p-value [a]                     0.016
Change from Baseline at Week 16 −0.20 (0.64)
Mean (SD)
p-value [a]                     0.164
Change from Baseline at Week 24 −0.22 (0.73)
Mean (SD)
p-value [a]                     0.158
[a] Within treatment group change from baseline p-value based on the one sample t-test.

TABLE 3
PSLQ: Average Ocular Symptom Score - Baseline and
Changes from Baseline at Each Follow-up Visit:
Modified Intent-to-Treat Population
Timepoint                       2-HP-β-CD
Statistic                       (N = 23)
Baseline Mean (SD)              0.88 (0.81)
Change from Baseline at Week 2  −0.36 (0.69)
Mean (SD)
p-value [a]                     0.019
Change from Baseline at Week 4  −0.46 (0.71)
Mean (SD)
p-value [a]                     0.005
Change from Baseline at Week 8  −0.39 (0.84)
Mean (SD)
p-value [a]                     0.035
Change from Baseline at Week 16 −0.29 (0.79)
Mean (SD)
p-value [a]                     0.102
Change from Baseline at Week 24 −0.33 (0.90)
Mean (SD)
p-value [a]                     0.090
[a] Within treatment group change from baseline p-value based on the one sample t-test.

TABLE 4
PSLQ: Average Vision-Related Functioning Score - Baseline and
Changes from Baseline at Each Follow-up Visit:
Modified Intent-to-Treat Population
Timepoint                       2-HP-β-CD
Statistic                       (N = 23)
Baseline Mean (SD)              0.57 (0.80)
Change from Baseline at Week 2  −0.27 (0.65)
Mean (SD)
p-value [a]                     0.067
Change from Baseline at Week 4  −0.48 (0.65)
Mean (SD)
p-value [a]                     0.003
Change from Baseline at Week 8  −0.43 (0.62)
Mean (SD)
p-value [a]                     0.004
Change from Baseline at Week 16 −0.23 (0.56)
Mean (SD)
p-value [a]                     0.08
Change from Baseline at Week 24 −0.11 (1.1)
Mean (SD)
p-value [a]                     0.617
[a] Within treatment group change from baseline p-value based on the one sample t-test.

TABLE 5
PSLQ: Average Quality of Life Impact Score - Baseline and
Changes from Baseline at Each Follow-up Visit:
Modified Intent-to-Treat Population
Timepoint                       2-HP-β-CD
Statistic                       (N = 23)
Baseline Mean (SD)              0.57 (0.92)
Change from Baseline at Week 2  −0.19 (0.39)
Mean (SD)
p-value [a]                     0.029
Change from Baseline at Week 4  −0.19 (0.50)
Mean (SD)
p-value [a]                     0.082
Change from Baseline at Week 8  −0.17 (0.52)
Mean (SD)
p-value [a]                     0.140
Change from Baseline at Week 16 −0.13 (0.68)
Mean (SD)
p-value [a]                     0.392
Change from Baseline at Week 24 −0.15 (0.59)
Mean (SD)
p-value [a]                     0.239
[a] Within treatment group change from baseline p-value based on the one sample t-test.

Further analysis was done to assess the potential therapeutic effect of 10% 2-hydroxypropyl beta-cyclodextrin on patients with symptoms of ocular pain, itchy, foreign body sensation, redness, sensitivity to light and blurred vision. These ocular symptoms are often observed in MGD patients. Scores of these symptoms were graded by patients as part of PSLQ questionnaires.

(1) Dry eye patients vs. Non-dry eye patients (based upon patients' medical history) with the combined nintedanib-treated and vehicle-treated groups. Results: Dry eye patients vs. Non-dry eye patients on Ocular Symptom Score as part of PSLQ: FIG. 7 shows mean PSLQ ocular symptom score at each schedule visit for pterygium patients with dry eye or with no dry eye and FIG. 8 shows average change from baseline of ocular symptom score at each schedule visit for pterygium patients with dry eye or with no dry eye.

The pterygium patients with dry eye condition was compared with pterygium patients with no dry eye condition. In this comparison, all pterygium patients with dry eye condition in the drug and vehicle treated group was combined and the same was done for pterygium patients with no dry eye condition. Number of data points for each group were N=17 for dry eye and N=18 for no dry eye. The data showed that statistically significant differences at Week 2 (p=0.042) and Week 4 (p=0.025) between dry eye group and no dry eye group. The mean differences in PSLQ ocular symptom reduction were 0.50 at Week 2 and 0.61 at Week 4. Pterygium patients with dry eye condition had higher baseline score and had bigger reduction from baseline of ocular symptom score during treatment period when compared to pterygium patients with no dry eye condition.

(2) Nintedanib vs. Vehicle for dry eye patients (based upon patients' medical history). Results: Nintedanib vs. Vehicle in Dry eye patients on Ocular Symptom Score as part of PSLQ: FIG. 9 shows mean PSLQ ocular symptom score at each schedule visit for pterygium patients with dry eye and FIG. 10 shows average change from baseline of ocular symptom score at each schedule visit for pterygium patients with dry eye.

Pterygium patients with dry eye condition in the drug treated group and vehicle treated group had similar responses for PSLQ ocular symptom. The change from baseline for PSLQ ocular symptom was similar during the treatment period and no statistically significant differences observed at any timepoints.

In conclusion: the evidences support that 10% 2-hydroxypropyl-beta-cyclodextrin had effects on PSLQ responses from pterygium patients with dry eye condition and pterygium patients with no dry eye condition. The magnitude of reduction in PSLQ ocular symptom score was statistically significant bigger in pterygium patients with dry eye condition than in pterygium patients with no dry eye condition.

On the contrary, when compared pterygium patients with dry eye condition that were treated with Nintedanib 0.2% or Vehicle, there was no statistically significant differences between two treatment groups. This indicates Nintedanib 0.2% was not the main cause for the reduction in PSLQ scores in pterygium patients with dry eye condition while 10% 2-hydroxypropyl-beta-cyclodextrin was the major factor that caused reduction in PSLQ scores in the pterygium patients with dry eye condition.

Example 6: Solubility of Cholesterol in Cyclodextrin

Solubility of cholesterol in the presence of cyclodextrin (CD) has been measured and reported (Nishijo, J., Moriyama, S. and Shiota S., Chem. Pharm. Bull., 51(11) 1253-1257, 2003). Solubility of Cholesterol in the Presence of CD Aliquots (7.0 ml) of CD aqueous solution of the appropriate concentration and excess cholesterol were placed in 20 ml L-type test tubes and the tubes were sealed. The test tubes were kept at 10, 25, 37 and 45° C., respectively, with shaking, for 1 week until solubility equilibrium was achieved. Then the solution was filtered through the membrane and 3.0 ml of color-producing reagent was added to 0.1 ml of the filtrate. Then the reaction mixture was heated for 5 min at 37° C. and the absorbance at 600 nm was measured using the calibration curve made in advance. Stability of cholesterol-CD complex was determined by a Shimadzu RF-503A fluorescence spectrophotometer at 25° C. Table 6 shows the increase in absorbance due to cholesterol dissolved by CDs in aqueous solution at 37° C.

TABLE 6
Increase in Absorbance Due to Cholesterol Dissolved
by CDs in Aqueous Solution at 37° C.
CD [a]      Absorbance (600 nm)
Without CD  0
Alpha-CD    0
Beta-CD     0
Gamma-CD    0
HP-beta-CD  0.01
DOM-beta-CD 0.336
[a] Concentration of CDs added is 1.0 × 10−2M.

As shown in Table 6, in the presence of alpha-CD, beta-CD and gamma-CD, the absorbances were zero, suggesting that these CDs do not form soluble complexes with cholesterol in aqueous solution. While only a slight increase in absorbance was observed in the presence of HP-beta-CD, a remarkable increase in absorbance was observed in the presence of DOM-beta-CD. These results suggest that DOM-beta-CD has a strong ability to form soluble complex with cholesterol in aqueous solution, but HP-beta-CD only a weak ability. Although soluble complex formations of cholesterol with alpha-CD, beta-CD and gamma-CD were not detected, insoluble complex formation might occur.

Example 7: Safety of 10% HP-β-CD (the Vehicle in the Phase 2 Clinical Trial)

This example demonstrates the safety of HP-β-CD in human. The data is derived from the stage 2 of the Phase 2 clinical trial in pterygium patients who are topically administered 10% HP-β-CD as the vehicle of the testing article. The patients were treated for 4 weeks with three-time a day dosing and then followed up for another 20 weeks after the stop of treatment. The safety evaluation included the 20 weeks of non-treatment period. The example will only show the vehicle results and not the testing article that is not relevant to this application.

All safety analyses are conducted on the safety population. MedDRA nomenclature was used to code adverse events. The number and percent of patients reporting adverse events are tabulated based on preferred terms and/or system organ class. Summary tables were generated for all adverse events regardless of causality as well as for treatment-related adverse events.

The mean duration of exposure to study treatment was 28 days with 96% of patients having a treatment duration of at least 28 days (Table 7).

TABLE 7
Extent of Exposure to Study Treatment Safety Population
           Vehicle
Exposure   (N = 25)
Treatment duration (days)
Mean       28.0
SD         0.0
Median     28.0
Min, Max   28, 28
n          24
Treatment duration, n (%)
>= 1 day   24 (96.0)
>= 14 days 24 (96.0)
>= 28 days 24 (96.0)
Missing    1 (4.0)

Adverse Events

A summary of adverse events is presented in Table 8. Ocular treatment-emergent adverse events (TEAEs) of any causality were reported in the study eyes of 16.0% ( 4/25) of patients in the Vehicle group. There were no study discontinuations due to AEs. No deaths or drug-related serious adverse events were reported in the study.

TABLE 8
Summary of Adverse Events Safety Population
Vehicle
(N = 25)
n (%)
All Ocular TEAEs
Study Eye                        4 (16.0)
Non-study Eye                    0
Treatment Related Ocular TEAEs
Study Eye                        1 (4.0)
Non-study Eye                    0
All Non-ocular TEAEs             7 (28.0)
Treatment Related Non-ocular TEAEs 0
Serious TEAEs                    1 (4.0)
Treatment-related Serious TEAEs  0
Discontinuation due to adverse events 0
Deaths                           0

In summary, 10% HP-β-CD as the vehicle in the Phase 2 pterygium clinical trial showed excellent safety profile, with only one treatment-related TEAE reported.

It will be apparent to those skilled in the art that various modifications and variations can be made in the present invention without departing from the spirit or scope of the invention. Thus, it is intended that the present invention cover the modifications and variations of this invention provided they come within the scope of the appended claims and their equivalents.

Claims

1. A topical ophthalmic composition consisting of a beta-cyclodextrin derivative, sodium chloride, water, and a buffer agent selected from the group consisting of sodium phosphate monobasic monohydrate, citric acid, and sodium citrate, wherein the beta-cyclodextrin derivative is methyl-beta-cyclodextrin.

2. A topical ophthalmic composition consisting of a beta-cyclodextrin derivative, sodium chloride, water, and a buffer agent selected from the group consisting of sodium phosphate monobasic monohydrate, citric acid, and sodium citrate, wherein the beta-cyclodextrin derivative is heptakis(2,6-di-O-methyl)-beta-cyclodextrin.