HK40120036A - Isoxazoline parasiticide formulations and methods for treating blepharitis - Google Patents

Description

Isoxazoline anthelmintic preparations and methods for treating blepharitis

Priority requirements

This application is a divisional application of Chinese Patent Application No. 201880088176.3, and claims the benefit of any of the non-provisional applications of U.S. Provisional Application No. 62/599,213, filed December 15, 2017; No. 62/615,855, filed January 10, 2018; No. 62/626,612, filed February 5, 2018; No. 62/689,787, filed June 25, 2018; and No. 62/746,498, filed October 16, 2018, each of which is incorporated herein by reference in its entirety.

Background of the Invention

Blepharitis, or inflammation of the eyelid, is a common, often chronic condition that can be challenging to treat and affects people of all ages. Blepharitis can occur on the anterior (where the outer surface of the eyelid, where eyelashes are attached) and/or on the posterior (where the inner surface of the eyelid is affected). Blepharitis can be associated with systemic diseases including rosacea and seborrheic dermatitis, and with other ophthalmic conditions including meibomian gland cysts, conjunctivitis, keratitis, and dry eye.

Demodex folliculorum and Demodex brevis are microscopic, obligate, slender mites that are among the most common permanent endodermal parasites, inhabiting the hair follicles and sebaceous glands of humans and animals. A total of 65 species of Demodex mites have been described, parasitizing 11 orders of mammals and belonging to the class Arachnida, order Acarina, and family Demodicidae. Mating occurs in the opening of the hair follicle, and the eggs are placed within the hair follicle or sebaceous gland. The six-legged larvae hatch after 3–4 days, and develop into adults after about 7 days. The lifespan of Demodex mites is approximately 14 days. The total lifespan of Demodex mites is several weeks. Dead mites decompose within the hair follicle or sebaceous gland.

Demodex mites can be found on the face, including cheeks, nose, chin, forehead, temples, eyelashes, and eyebrows, as well as the scalp, neck, and ears. They can also infect other seborrheic sites, such as the nasolabial folds, periorbital region, and less commonly the upper and middle areas of the chest and back. Demodex mites can also be found in ectopic sebaceous glands on the penis, pubic area, buttocks, and oral mucosa. In some cases, a mite density of more than 5 mites/ ^cm² in a follicular sebaceous unit or 5 or more mites per follicle is associated with Demodex mite infection.

Of the numerous reported species, only two have been found parasitizing human surfaces: *Demodex folliculorum* and *Demodex brevis*. *Demodex folliculorum* has been found, for example, on eyelash follicles, while *Demodex brevis* has been found, for example, on the meibomian glands surrounding the sebaceous glands near the eyes and skin. The meibomian glands are holosecretive exocrine glands located on the inner edge of the eyelid, responsible for supplying meibomian lipids—an oily substance that prevents the evaporation of the tear film. Meibomian lipids prevent tears from overflowing onto the cheeks, trapping them between the oily edge and the eyeball, and keeping the closed lid airtight. There are approximately 50 glands on the upper eyelid and 25 on the lower eyelid. Symbiotic bacteria on the mites can also contribute to pathology. Increased sebum secretion and an increased number of sebaceous glands can provide a favorable habitat for the mites. Although some levels of Demodex mites can be asymptomatic, high-density proliferation and/or concurrent immune imbalances often lead to skin lesions. A growing body of literature suggests the presence of Demodex mites in both anterior and posterior blepharitis. For example, Demodex mites are involved in 45% of blepharitis cases. The estimated prevalence of ocular surface diseases is approximately 30 million; of these, 19 million suffer from meibomian gland dysfunction/posterior blepharitis; 9 million have Demodex mite infestations, and 4 million show obvious signs of Demodex. Blepharitis is an important diagnosis, yet there are currently no approved treatments in the United States. Safe and effective treatments are needed for blepharitis and other ophthalmic and dermatological conditions.

Invention Overview

In some embodiments, this document discloses topical therapeutic agents, including but not limited to topical agents comprising one or more isoxazoline anthelmintics, formamiditin anthelmintics, phenylpyrazole anthelmintics, drugs commonly used to treat Alzheimer's disease (e.g., galantamine, etc.), and other agents used to treat various ophthalmic and dermatological conditions.

In some configurations, this document discloses a method for treating blepharitis in patients, comprising direct topical administration of an effective amount of isoxazoline insecticide, formulated into an ophthalmic composition, to the ophthalmic surface of one or more eyes of a patient requiring treatment, the ophthalmic composition further comprising a pharmaceutically acceptable carrier.

In some formulations, the ophthalmic composition is sterile and non-irritating to the eyes.

In some formulations, isoxazoline anthelmintics may be the sole active ingredient in the ophthalmic composition.

In some formulations, isoxazoline anthelmintics are administered at a rate of about 0.01% to about 1% of the total weight of the composition.

In some formulations, about 0.03% by weight of isoxazoline anthelmintic is administered relative to the total weight of the composition.

In some formulations, about 0.10% by weight of isoxazoline anthelmintic is administered relative to the total weight of the composition.

In some formulations, the ophthalmic composition contains eye drops.

In some formulations, the ophthalmic composition does not contain any essential oils.

In some formulations, the isoxazoline insecticide is selected from: fluralaner, sarolaner, lotilaner, afoxolaner, and fluxametamide.

In some configurations, the ocular surface comprises at least one of the conjunctiva or cornea of one or more of the patient's eyes.

In some formulations, the ophthalmic composition contains polysorbate.

In some configurations, this document discloses a method of treating blepharitis in a patient, comprising directly and topically administering an effective amount of isoxazoline anthelmintic to one or more of the eyes, eyelids, or eyelashes of a patient requiring treatment, which is formulated into an ophthalmic composition further comprising a pharmaceutically acceptable medium, wherein the ophthalmic composition is sterile and non-irritating to the eyes, and wherein the isoxazoline anthelmintic is the sole active ingredient of the ophthalmic composition.

In some configurations, after topical administration of the ophthalmic composition, the patient's eye is closed, allowing the composition to come into contact with the patient's meibomian gland openings and the outer edge of the patient's eyelid.

In some configurations, the method also includes applying the composition to the eyelashes and the hair follicles of the eyelashes.

In some configurations, the method also includes applying the composition to the eyelashes and eyelash follicles using an applicator.

In some formulations, approximately 0.001% to approximately 1% of isoxazoline anthelmintic is administered.

In some formulations, approximately 0.001% to approximately 1% of isoxazoline anthelmintic is administered.

In some configurations, the method also includes topical application of the ophthalmic composition at least once daily for at least approximately two weeks.

In some configurations, the method also includes topical application of the ophthalmic composition at least once daily for at least approximately 4 weeks.

In some configurations, this document discloses a method for treating ocular Demodex mite infestation in a patient, comprising direct topical administration of an effective amount of isoxazoline anthelmintic to one or more of the eyes, eyelids, or eyelashes of one or more eyes of a patient requiring treatment, wherein the isoxazoline anthelmintic is formulated into an ophthalmic composition further comprising a pharmaceutically acceptable medium, wherein the ophthalmic composition is sterile and non-irritating to the eyes, and wherein the isoxazoline anthelmintic is the sole active ingredient of the ophthalmic composition.

In some configurations, the method also includes receiving a first assessment of the amount of Demodex mites on the patient's anatomy, and topically administering an ophthalmic composition if the amount of Demodex mites is greater than a predetermined value.

In some formulations, ophthalmic preparations cause the abdomen and tail of the Demodex mites on the patient to stop moving more quickly than the cephalothorax of the Demodex mites.

In some configurations, this article discloses a method for treating blepharitis and/or rosacea, comprising the topical application of an isoxazoline anthelmintic near one or more eyelashes, wherein the topical application is therapeutically effective and preferentially absorbed by the body of the Demodex mite relative to the ingestion of the Demodex mite, sufficient to cause a reduction in the movement of the body of the Demodex mite relative to the head of the Demodex mite, the method being sufficient to reduce or eliminate Demodex mites near the eyelashes, resulting in improvement of the blepharitis and/or rosacea presentation.

In some configurations, this document discloses a topical ophthalmic preparation for treating blepharitis in patients, comprising an effective amount of isoxazoline anthelmintic and a pharmaceutically acceptable carrier, wherein the ophthalmic composition is sterile and non-irritating to the eyes, and wherein the isoxazoline anthelmintic is the sole active ingredient of the ophthalmic composition.

In some formulations, isoxazoline anthelmintics are administered at a rate of about 0.01% to about 1% of the total weight of the composition.

In some formulations, about 0.03% by weight of isoxazoline anthelmintic is administered relative to the total weight of the composition.

In some formulations, about 0.10% by weight of isoxazoline anthelmintic is administered relative to the total weight of the composition.

In some formulations, the ophthalmic composition contains eye drops.

In some formulations, the ophthalmic composition does not contain any essential oils.

In some formulations, the isoxazoline insecticide is selected from: fleranal, salorananal, loteranana, afolanana, and fluoxazolamide.

In some configurations, this document discloses a topical formulation for treating ocular surface diseases comprising: isoxazoline anthelmintic; at least one of Pemulen and HPMC; polysorbate 80; glycerin; a buffer; and lorazepam, wherein said formulation is therapeutically effective in reducing or eliminating Demodex mites near the eyelashes, resulting in improvement of blepharitis and/or erythematous acne manifestations.

In some formulations, the preparation is used to treat blepharitis.

In some formulations, the preparation is used to treat anterior blepharitis.

In some formulations, the preparation is used to treat posterior blepharitis.

In some formulations, the preparation is used to treat ocular rosacea.

In some configurations, this document discloses a method for treating blepharitis in patients, comprising directly and topically administering an effective amount of amitraz anthelmintic to the ocular surface of one or more eyes of a patient requiring treatment, the amitraz anthelmintic being formulated into an ophthalmic composition, the ophthalmic composition further comprising a pharmaceutically acceptable carrier, wherein the ophthalmic composition is sterile and non-irritating to the eyes, and wherein the amitraz anthelmintic is the sole active ingredient of the ophthalmic composition.

In some formulations, a formamidine anthelmintic is administered at a concentration of about 0.01% to about 1% of the total weight of the composition.

In some formulations, approximately 0.03% by weight of formamidin anthelmintic is administered relative to the total weight of the composition.

In some formulations, approximately 0.10% by weight of formamidine is administered relative to the total weight of the composition.

In some formulations, the ophthalmic composition contains eye drops.

In some formulations, the ophthalmic composition contains an ointment or cream.

In some formulations, the ophthalmic composition does not contain any essential oils.

In some formulations, the formamidin is selected from: amitraz, N-(2,4-dimethylphenyl)-N-methylformamidin (DPMF) and 2,4-dimethylaniline.

In some configurations, the ocular surface comprises at least one of the conjunctiva or cornea of one or more of the patient's eyes.

In some formulations, the ophthalmic composition contains polysorbate.

In some configurations, this document discloses a method of treating blepharitis in patients, comprising directly and topically administering an effective amount of amitraz anthelmintic to one or more of the eyes, eyelids, or eyelashes of a patient requiring treatment, which is formulated into an ophthalmic composition further comprising a pharmaceutically acceptable medium, wherein the ophthalmic composition is sterile and non-irritating to the eyes, and wherein the amitraz anthelmintic is the sole active ingredient of the ophthalmic composition.

In some configurations, after topical administration of the ophthalmic composition, the patient's eye is closed, allowing the composition to come into contact with the patient's meibomian gland openings and the outer edge of the patient's eyelid.

In some configurations, the method also includes applying the composition to the eyelashes and the hair follicles of the eyelashes.

In some configurations, the method also includes applying the composition to the eyelashes and eyelash follicles using an applicator.

In some formulations, approximately 0.001% to approximately 1% of formamidin is administered.

In some formulations, approximately 0.001% to approximately 1% of formamidin is administered.

In some configurations, the method also includes topical application of the ophthalmic composition at least once daily for at least approximately two weeks.

In some configurations, the method also includes topical application of the ophthalmic composition at least once daily for at least approximately 4 weeks.

In some configurations, this document discloses a method for treating ocular Demodex mite infestation in a patient, comprising direct topical administration of an effective amount of amitraz anthelmintic to one or more of the eyes, eyelids, or eyelashes of one or more eyes of a patient requiring treatment, wherein the amitraz anthelmintic is formulated into an ophthalmic composition further comprising a pharmaceutically acceptable medium, wherein the ophthalmic composition is sterile and non-irritating to the eyes, and wherein the amitraz anthelmintic is the sole active ingredient of the ophthalmic composition.

In some configurations, the method also includes receiving a first assessment of the amount of Demodex mites on the patient's anatomy, and topically administering an ophthalmic composition if the amount of Demodex mites is greater than a predetermined value.

In some formulations, ophthalmic preparations cause the abdomen and tail of the Demodex mites on the patient to stop moving more quickly than the cephalothorax of the Demodex mites.

In some configurations, this article discloses a method for treating blepharitis and/or rosacea, comprising the topical application of a formamidin anthelmintic near one or more eyelashes, wherein the topical application is therapeutically effective and preferentially absorbed by the body of the Demodex mite relative to the ingestion of the Demodex mite, sufficient to cause a reduction in the movement of the body of the Demodex mite relative to the head of the Demodex mite, the method being sufficient to reduce or eliminate the Demodex mites near the eyelashes, resulting in improvement of the blepharitis and/or rosacea presentation.

In some configurations, this document discloses a topical ophthalmic preparation for treating blepharitis in patients, comprising an effective amount of amitraz anthelmintic and a pharmaceutically acceptable carrier, wherein the ophthalmic composition is sterile and non-irritating to the eyes, and wherein the amitraz anthelmintic is the sole active ingredient of the ophthalmic composition.

In some formulations, a formamidin anthelmintic is administered at about 0.01% to about 1% of the total weight of the composition.

In some formulations, approximately 0.03% by weight of formamidin anthelmintic is administered relative to the total weight of the composition.

In some formulations, approximately 0.10% by weight of formamidine is administered relative to the total weight of the composition.

In some formulations, ophthalmic compositions comprise eye drops, creams, or ointments.

In some formulations, the ophthalmic composition does not contain any essential oils.

In some formulations, the formamidin is selected from: amitraz, N-(2,4-dimethylphenyl)-N-methylformamidin (DPMF) and 2,4-dimethylaniline.

In some configurations, this document discloses a method for treating symptoms of blepharitis and/or ocular erythema in the eye, the symptoms being selected from: burning sensation in the eye, stinging sensation in the eye, dryness in the eye, increased sensitivity to light, blurred vision, and complications of ocular erythema in the cornea, the method comprising directly and topically administering, to the conjunctiva and/or cornea of the eye of the individual requiring such treatment, an effective amount of a formamidin anthelmintic formulated into an eyewash composition having a pharmaceutically acceptable medium, the eyewash composition being sterile, non-irritating, and compatible with ocular tissues.

In some formulations, 0.001% to 10% by weight of formamidine is administered relative to the total weight of the composition.

In some formulations, 0.01% to 5% of formamidin anthelmintic is administered relative to the total weight of the composition.

In some formulations, 0.03% by weight of formamidine anthelmintic is administered relative to the total weight of the composition.

In some formulations, 0.10% by weight of formamidine anthelmintic is administered relative to the total weight of the composition.

In some configurations, this article discloses a method for treating blepharitis and/or rosacea by orally or topically administering a formamidin anthelmintic at a dose sufficient to fill and eliminate Demodex mites at one or more anatomical locations, resulting in cessation of the manifestations of blepharitis and/or rosacea.

In some formulations, the formamidin anthelmintic is administered in doses repeated approximately 2 to 4 times, with intervals of 3 to 7 days.

In some formulations, the topical formamidin anthelmintic is prepared as a carrier lotion, cream, or gel.

In some formulations, the concentration of formamidin in the topical lotion, cream, or gel is approximately 1% to 5% by weight.

In some configurations, the topical formamidin anthelmintic is applied to the eyelids.

In some configurations, the topical formamiditin is applied to the affected skin area at least once and no more than twice daily for approximately two to four weeks.

In some formulations, the topically applied formamidin anthelmintic is encapsulated in microliposomes before being formulated into the carrier lotion, cream, or gel.

In some configurations, this document discloses compositions for treating blepharitis and/or rosacea, comprising an oral or topical drug preparation, amitraz, in a dose sufficient to eliminate Demodex mites at one or more anatomical locations, resulting in cessation of the manifestations of blepharitis and/or rosacea.

In some configurations, this document discloses a method for treating cylindrical eyelash dandruff associated with blepharitis and/or ocular erythema, the method comprising directly and topically administering, to the conjunctiva and/or cornea of the eye of the individual requiring such treatment, an effective amount of a formamidin anthelmintic formulated with a pharmaceutically acceptable mediator, said formamidin anthelmintic being sterile, non-irritating, and compatible with ocular tissues.

In some formulations, 0.001% to 10% by weight of formamidin anthelmintic is administered relative to the total weight of the composition.

In some formulations, 0.01% to 5% of formamidin anthelmintic is administered relative to the total weight of the composition.

In some formulations, 0.03% by weight of formamidine anthelmintic is administered relative to the total weight of the composition.

In some formulations, 0.10% by weight of formamidine anthelmintic is administered relative to the total weight of the composition.

In some configurations, this article discloses a method for treating blepharitis and/or rosacea by orally or topically administering a formamidin anthelmintic at a dose sufficient to fill and eliminate Demodex mites at one or more anatomical locations, resulting in cessation of the manifestations of blepharitis and/or rosacea.

In some formulations, the formamidin anthelmintic is administered in doses repeated approximately 2 to 4 times, with intervals of 3 to 7 days.

In some formulations, the topical formamidin anthelmintic is prepared as a carrier lotion, cream, or gel.

In some formulations, the concentration of formamidin in the topical lotion, cream, or gel is about 1% to 5% by weight.

In some configurations, the topical formamidin anthelmintic is applied to the eyelids.

In some configurations, the topical formamiditin is applied to the affected skin area at least once and no more than twice daily for approximately two to four weeks.

In some formulations, the topically applied formamidin anthelmintic is encapsulated in microliposomes before being formulated into the carrier lotion, cream, or gel.

In some configurations, this document discloses compositions for treating blepharitis and/or rosacea, comprising an oral or topical drug preparation, amitraz, in a dose sufficient to eliminate Demodex mites at one or more anatomical locations, resulting in cessation of the manifestations of blepharitis and/or rosacea.

In some configurations, this document discloses a method for treating symptoms of blepharitis and/or ocular erythema in the eye, the symptoms being selected from: burning sensation in the eye, stinging sensation in the eye, dryness in the eye, increased sensitivity to light, blurred vision, and complications of ocular erythema in the cornea, the method comprising directly and topically administering, to the conjunctiva and/or cornea of the eye of the individual requiring such treatment, an effective amount of a formamidin anthelmintic formulated as an eyewash composition having a pharmaceutically acceptable medium, the eyewash composition being sterile, non-irritating, and compatible with ocular tissues.

In some formulations, 0.001% to 10% by weight of formamidin anthelmintic is administered relative to the total weight of the composition.

In some formulations, 0.01% to 5% of formamidin anthelmintic is administered relative to the total weight of the composition.

In some formulations, 0.03% by weight of formamidine anthelmintic is administered relative to the total weight of the composition.

In some formulations, 0.10% by weight of formamidine anthelmintic is administered relative to the total weight of the composition.

In some configurations, this article discloses a method for treating blepharitis and/or rosacea by orally or topically administering a formamidin anthelmintic at a dose sufficient to fill and eliminate Demodex mites at one or more anatomical locations, resulting in cessation of the manifestations of blepharitis and/or rosacea.

In some formulations, the formamidin anthelmintic is administered in doses repeated approximately 2 to 4 times, with intervals of 3 to 7 days.

In some formulations, the topical formamidin anthelmintic is prepared as a carrier lotion, cream, or gel.

In some formulations, the concentration of formamidin in the topical lotion, cream, or gel is about 1% to 5% by weight.

In some configurations, the topical formamidin anthelmintic is applied to the eyelids.

In some configurations, the topical formamiditin is applied to the affected skin area at least once and no more than twice daily for approximately two to four weeks.

In some formulations, the topically applied formamidin anthelmintic is encapsulated in microliposomes before being formulated into the carrier lotion, cream, or gel.

In some configurations, this document discloses compositions for treating blepharitis and/or rosacea, comprising an oral or topical drug preparation, amitraz, in a dose sufficient to eliminate Demodex mites at one or more anatomical locations, resulting in cessation of the manifestations of blepharitis and/or rosacea.

In some configurations, this document discloses a method for treating cylindrical eyelash scales associated with blepharitis and/or ocular erythema, the method comprising directly and topically administering, to the conjunctiva and/or cornea of the eye of an individual requiring such treatment, an effective amount of a formamidin anthelmintic formulated as an eyewash composition having a pharmaceutically acceptable medium, said eyewash composition being sterile, non-irritating and compatible with ocular tissues.

In some formulations, 0.001% to 10% by weight of formamidin anthelmintic is administered relative to the total weight of the composition.

In some formulations, 0.01% to 5% of formamidin anthelmintic is administered relative to the total weight of the composition.

In some formulations, 0.03% by weight of formamidine anthelmintic is administered relative to the total weight of the composition.

In some formulations, 0.10% by weight of formamidine anthelmintic is administered relative to the total weight of the composition.

In some configurations, this article discloses a method for treating blepharitis and/or rosacea by orally or topically administering a formamidin anthelmintic at a dose sufficient to fill and eliminate Demodex mites at one or more anatomical locations, resulting in cessation of the manifestations of blepharitis and/or rosacea.

In some formulations, the formamidin anthelmintic is administered in doses repeated approximately 2 to 4 times, with intervals of 3 to 7 days.

In some formulations, the topical formamidin anthelmintic is prepared as a carrier lotion, cream, or gel.

In some formulations, the concentration of formamidin in the topical lotion, cream, or gel is about 1% to 5% by weight.

In some configurations, the topical formamidin anthelmintic is applied to the eyelids.

In some configurations, the topical formamiditin is applied to the affected skin area at least once and no more than twice daily for approximately two to four weeks.

In some formulations, the topically applied formamidin anthelmintic is encapsulated in microliposomes before being formulated into the carrier lotion, cream, or gel.

In some configurations, this document discloses compositions for treating blepharitis and/or rosacea, comprising an oral or topical drug preparation, amitraz, in a dose sufficient to eliminate Demodex mites at one or more anatomical locations, resulting in cessation of the manifestations of blepharitis and/or rosacea.

In some configurations, this document discloses methods for treating symptoms of blepharitis and/or ocular erythema in the eye, the symptoms being selected from: burning sensation in the eye, stinging sensation in the eye, dryness in the eye, increased sensitivity to light, blurred vision, and complications of ocular erythema in the cornea, the methods comprising directly and topically administering, thus effectively, an eyewash composition formulated with a pharmaceutically acceptable medium to the conjunctiva and/or cornea of the eye of the individual requiring such treatment, the eyewash composition being sterile, non-irritating, and compatible with ocular tissues.

In some formulations, 0.001% to 10% by weight of phenylpyrazole insecticide is administered relative to the total weight of the composition.

In some formulations, 0.01% to 5% of a phenylpyrazole insecticide is administered relative to the total weight of the composition.

In some formulations, 0.03% by weight of phenylpyrazole insecticide is administered relative to the total weight of the composition.

In some formulations, 0.10% by weight of phenylpyrazole insecticide is administered relative to the total weight of the composition.

In some configurations, this article discloses a method for treating blepharitis and/or rosacea by orally or topically administering a phenylpyrazole anthelmintic at a dose sufficient to fill and eliminate Demodex mites at one or more anatomical locations, resulting in cessation of the manifestations of blepharitis and/or rosacea.

In some formulations, the dose of the phenylpyrazole insecticide is repeated approximately 2 to 4 times, with intervals of 3 to 7 days.

In some formulations, the topical phenylpyrazole insect repellent is formulated as a carrier lotion, cream, or gel.

In some formulations, the concentration of phenylpyrazole insect repellent in the topical lotion, cream, or gel is about 1% to 5% by weight.

In some configurations, the topical phenylpyrazole insect repellent is applied to the eyelids.

In some formulations, the topical phenylpyrazole insect repellent is applied to the affected skin area at least once and no more than twice daily for approximately two to four weeks.

In some formulations, the topically applied phenylpyrazole insect repellent is encapsulated in microliposomes before being formulated into the carrier lotion, cream, or gel.

In some configurations, this document discloses compositions for treating blepharitis and/or rosacea, comprising an oral or topical pharmaceutical preparation, phenylpyrazole anthelmintic, in a dose sufficient to eliminate Demodex mites at one or more anatomical locations, resulting in cessation of the manifestations of blepharitis and/or rosacea.

In some configurations, this document discloses a method for treating cylindrical eyelash scales associated with blepharitis and/or ocular erythema, the method comprising directly and topically administering, thus effectively, an eyewash composition formulated with a pharmaceutically acceptable medium to the conjunctiva and/or cornea of the eye of an individual requiring such treatment, said eyewash composition being sterile, non-irritating, and compatible with ocular tissues.

In some formulations, 0.001% to 10% by weight of phenylpyrazole insecticide is administered relative to the total weight of the composition.

In some formulations, 0.01% to 5% of a phenylpyrazole insecticide is administered relative to the total weight of the composition.

In some formulations, 0.03% by weight of phenylpyrazole insecticide is administered relative to the total weight of the composition.

In some formulations, 0.10% by weight of phenylpyrazole insecticide is administered relative to the total weight of the composition.

In some configurations, this article discloses a method for treating blepharitis and/or rosacea by orally or topically administering a phenylpyrazole anthelmintic at a dose sufficient to fill and eliminate Demodex mites at one or more anatomical locations, resulting in cessation of the manifestations of blepharitis and/or rosacea.

In some formulations, the dose of the phenylpyrazole insecticide is repeated approximately 2 to 4 times, with intervals of 3 to 7 days.

In some formulations, the topical phenylpyrazole insect repellent is formulated as a carrier lotion, cream, or gel.

In some formulations, the concentration of phenylpyrazole insect repellent in the topical lotion, cream, or gel is about 1% to 5% by weight.

In some configurations, the topical phenylpyrazole insect repellent is applied to the eyelids.

In some formulations, the topical phenylpyrazole insect repellent is applied to the affected skin area at least once and no more than twice daily for approximately two to four weeks.

In some formulations, the topically applied phenylpyrazole insect repellent is encapsulated in microliposomes before being formulated into the carrier lotion, cream, or gel.

In some configurations, this document discloses compositions for treating blepharitis and/or rosacea, comprising an oral or topical pharmaceutical preparation, phenylpyrazole anthelmintic, in a dose sufficient to eliminate Demodex mites at one or more anatomical locations, resulting in cessation of the manifestations of blepharitis and/or rosacea.

In some configurations, this document discloses a method for treating symptoms of blepharitis and/or ocular erythema in the eye, the symptoms being selected from: burning sensation in the eye, stinging sensation in the eye, dryness in the eye, increased sensitivity to light, blurred vision, and complications of ocular erythema in the cornea. The method comprises directly and topically administering, to the conjunctiva and/or cornea of the eye of the individual requiring such treatment, an effective amount of a drug for treating Alzheimer's disease, the administered drug being formulated into an eyewash composition having a pharmaceutically acceptable mediator, the eyewash composition being sterile, non-irritating, and compatible with ocular tissues.

In some formulations, 0.001% to 10% by weight of a drug for treating Alzheimer's disease is administered relative to the total weight of the composition.

In some formulations, 0.01% to 5% of a drug for treating Alzheimer's disease is administered relative to the total weight of the composition.

In some formulations, 0.03% by weight of a drug for treating Alzheimer's disease is administered relative to the total weight of the composition.

In some formulations, 0.10% by weight of a drug for treating Alzheimer's disease is administered relative to the total weight of the composition.

In some configurations, this document discloses a method for treating blepharitis and/or rosacea by orally or topically administering a drug for the treatment of Alzheimer's disease in a dose sufficient to fill and eliminate Demodex mites at one or more anatomical locations, resulting in the cessation of the manifestations of blepharitis and/or rosacea.

In some configurations, the dosage of the drug used to treat Alzheimer's disease is repeated approximately 2 to 4 times, with intervals of 3 to 7 days.

In some configurations, the topical medication for treating Alzheimer's disease is formulated as a carrier lotion, cream, or gel.

In some formulations, the concentration of the drug for treating Alzheimer's disease in the topically applied lotion, cream, or gel is about 1% to 5% by weight.

In some configurations, the topical medication for treating Alzheimer's disease is applied to the eyelids.

In some configurations, the topical medication for treating Alzheimer's disease is applied to the affected skin area at least once and no more than twice daily for approximately 2 to 4 weeks.

In some configurations, the topical medication for treating Alzheimer's disease is encapsulated in microliposomes before being formulated into the carrier lotion, cream, or gel.

In some configurations, this document discloses compositions for treating blepharitis and/or rosacea, comprising an oral or topical pharmaceutical preparation for treating Alzheimer's disease, in a dose sufficient to eliminate Demodex mites at one or more anatomical locations, resulting in cessation of the manifestations of blepharitis and/or rosacea.

Attached Figure Description

Figures 1A-B schematically illustrate the application of ophthalmic preparations in eyes infected with Demodex mites.

Figure 2 shows data demonstrating the activity of selected Demodex mite anatomy structures after treatment with topical formulations.

Figures 3A-3B show examples of formulations containing dimethylamic acid and fluranal.

Figures 4A-4C illustrate implementation schemes for various Demodex mite diagnostic techniques that do not necessarily require hair removal.

Invention Details

In some embodiments, this document discloses topical therapeutic agents, including but not limited to topical agents comprising one or more isoxazoline anthelmintics, formamidin anthelmintics, agents for the treatment of Alzheimer's disease, and other agents as disclosed herein for the treatment of various ophthalmic and dermatological conditions. This document also discloses methods for treating blepharitis, ocular rosacea, and Demodex mite infestations in patients in need. In some embodiments, patients in need can be treated with active agents from the isoxazoline anthelmintic chemical family, including but not limited to isoxazoline-substituted benzamide derivatives. Without being theoretically limited, isoxazoline anthelmintics can act as GABA-chlorine antagonists to selectively target certain organisms, including but not limited to the nervous system of Demodex mites. GABA-mediated chloride influx can cause hyperpolarization of the cell membrane and generate inhibitory postsynaptic potentials, which reduce the probability of action potentials and cause paralysis and eventual death of Demodex mites. Isoxazoline anthelmintics may include, for example, fleranal, saloranal, loteranal, afolanal, and/or fluoxazolamide, including derivatives, analogs, and L- and D-isomers of the above, including but not limited to enantiomers, compositions comprising racemic mixtures, and any one or more optically pure compositions. In some embodiments, the isoxazoline anthelmintics, formamidin anthelmintics, or other active ingredients disclosed herein are the sole active ingredient used in the formulation and/or method. In some embodiments, the isoxazoline anthelmintics are isoxazoline-substituted benzamide derivatives. In some embodiments, the isoxazoline anthelmintics have one, two, three, or more fluorine groups, such as trifluoro groups (e.g., R- _CF3 ), in their chemical structure.

Isoxazoline anthelmintics have been routinely used in veterinary applications, including chewable and non-ophthalmic topical "pouron" solutions, but to the inventors' knowledge, no human formulations have been developed. Non-limiting examples of isoxazoline anthelmintics can be found, for example, in U.S. Patent No. 7,662,972 to Mita et al., U.S. Patent No. 8,466,115 to Curtis et al., U.S. Patent No. 7,964,204 to Lahm et al., and U.S. Patent No. 8,383,659 to Nanchen et al., each of which is incorporated herein by reference in its entirety. Additionally, U.S. Publication No. 2010/0254960A1, PCT Publication No. WO 2007/070606A2, PCT Publication No. WO 2007/123855 A2, PCT Publication No. WO 2010/003923A1, U.S. Patent No. 7,951,828, U.S. Patent No. 7,662,972, U.S. Publication No. 2010/0137372A1, and others... U.S. Publications 2010/0179194A2, 2011/0086886A2, 2011/0059988A1, US2010/0179195 A1, PCT Publication WO2007/075459A2, and U.S. Patent No. 7,951,828 describe various other isoxazoline insecticides, all of which are incorporated herein by reference in their entirety. Veterinary oral formulations, such as chewables, result in first-pass hepatic metabolism and systemic effects, which may be undesirable for targeted local application in some cases. A significant challenge is that the fluoridated and/or chlorinated groups of certain isoxazoline anthelmintics result in these molecules being highly insoluble in any drug-based solution, including oil-based and aqueous solutions, and having solubility of less than about 1 mg/kg, or 1 mg/mL in aqueous solutions, or even lower. Topical veterinary solutions of isoxazoline anthelmintics include, for example, dimethylacetamide, glycofurol, diethyltoluamide, and/or acetone. However, such solutions are only indicated as a “sprinkle” solution for the back of the neck of animals such as cats or dogs, are not suitable for ophthalmic use (and are potentially toxic), and include instructions not to administer the solution into or around the eyes. This “sprinkle” solution is absorbed systemically by the animal and does not result in targeted local activity. To the inventors’ knowledge, no topical ophthalmic formulations of isoxazoline or formamidin anthelmintics have previously been developed. For example, there is a need for therapeutic formulations that are safe, non-toxic, and sufficiently soluble for ocular use to be therapeutically effective in treating ocular demodicosis and related conditions such as blepharitis.

It has now been determined that compounds of the families of isoxazoline anthelmintics, metamidin anthelmintics, agents for the treatment of Alzheimer's disease, and/or other agents as disclosed elsewhere herein are suitable for the treatment of ophthalmic conditions of any origin, particularly those caused by Demodex folliculorum, and more particularly blepharitis and/or ocular erythema. Other conditions that can be treated with the formulations and methods disclosed herein include, for example, rosacea, pityriasis folliculitis, rosacea-like demodicosis and severe demodicosis, nonspecific facial dermatitis, steroid rosacea, androgenetic alopecia, madarosis, disseminated lupus miliaris, anatomical folliculitis, perioral dermatitis, acarica blepharoconjuncitivitis, papulopustular scalp eruptions, eosinophilic folliculitis, pustular folliculitis, Grover's disease, and demodicosis abscess.

Ivermectin is another drug already used to treat Demodex mites and is generally more soluble in solution than isoxazoline anthelmintics. However, no known formulations are approved for ocular use (e.g., for blepharitis), and more effective therapeutic agents are needed. In some embodiments, the formulation and/or method do not involve ivermectin, such as ivermectin or other macrolide derivatives. However, in other embodiments, the formulation may include ivermectin.

This document discloses various embodiments of systems, methods, and preparations for treating various ocular conditions, including but not limited to blepharitis and Demodex mite infestations (e.g., on the eyelids of a subject such as a human). Embodiments may include any one or more of the features disclosed herein. Some embodiments do not include dimethylacetamide, tetrahydrofuran polyethylene glycol ether, diethyltoluamide, and/or acetone, and in some cases, at least some of these may be toxic or irritating to the eyes.

This article also discloses the use of topical isoxazoline anthelmintics, formamidin anthelmintics, reagents for treating Alzheimer's disease, and/or other reagents as disclosed elsewhere herein for treating blepharitis in patients in need, as well as methods for treating Demodex mite infestations and blepharitis in patients in need.

Also disclosed are topical isoxazoline anthelmintics, amitraz anthelmintics, agents for treating Alzheimer's disease, and/or other agents (e.g., from the isoxazoline anthelmintic chemical family) for treating erythematous acne and/or ocular erythematous acne in patients in need, as well as methods for treating Demodex mite infestations and erythematous acne and/or ocular erythematous acne in patients in need. Formulations and methods for reducing Demodex mite counts and cylindrical eyelash scales near the eyes of patients are also disclosed.

This article also discloses topical isoxazoline anthelmintics, methamphetamine anthelmintics, agents for treating Alzheimer's disease, and/or other agents as disclosed elsewhere herein, for treating erythematous acne and/or ocular erythematous acne in patients in need, as well as for treating Demodex mite infestation and erythematous acne and/or ocular erythematous acne in patients in need.

According to some embodiments, the pharmaceutical composition may include at least one, two or more compounds selected from the isoxazoline anthelmintic family, including, for example, fleranal, saloranal, loteranal, afolanal and/or fluoxazolamide, which are given specifically for the treatment of conjunctivitis, blepharitis, ocular erythema or other indications, including other ocular surface diseases such as meibomian gland dysfunction or dry eye disease.

Some embodiments may include derivatives or analogs of isoxazoline anthelmintics, formamidin anthelmintics, or other active therapeutic agents as disclosed elsewhere herein, as well as L-isomers and D-isomers, including but not limited to enantiomers, compositions comprising racemic mixtures, and optically pure compositions.

In some embodiments, it may be surprising to use a dose of isoxazoline anthelmintics, methamphetamine anthelmintics, agents for treating Alzheimer's disease, and/or other agents as disclosed elsewhere herein, at a dose lower than, or including, clinically effective doses (e.g., concentrations in the range of 1-10 nM or 100 pM-1 nM) that act via systemic absorption through local rinsing or washing in veterinary medicine, or a range including any two of the foregoing values. These lower effective concentrations may be due to, but are not limited to, the fact that the mite's abdomen (~2 μm) is thinner and more likely to absorb the drug than its cephalothorax (~0.5 μm) because the mite absorbs the drug directly rather than ingests it. In some embodiments, direct absorption of the drug by the mite may be a mechanism resulting in at least about 50%, 60%, 70%, 80%, 90%, or more of the total drug uptake by the mite.

In some implementations, daily and local treatment is given, rather than large, long-acting systemic doses (such as those administered monthly, every 8 weeks, every 12 weeks, every 16 weeks, or less in veterinary medicine). However, in other implementations, long-acting systemic or local doses may be used.

In some embodiments, administration may be, for example, about 1, 2, 3, 4, 5, 6, 7, 8 or more times daily, such as 1-2 times daily. In some embodiments, treatment may also be weekly, a single dose, or a limited course of treatment. In some embodiments, the formulation may preferably be used in the morning, at night, or only at night to target exposed mites during mating.

In some implementations, the formulation may be advantageous, partly due to the slow elimination rate of molecules such as isoxazoline anthelmintics; however, small local doses allow for repeated and frequent administration, which may be beneficial in disrupting the Demodex mite life cycle by affecting more susceptible juvenile forms without the associated systemic risks and side effects.

In some embodiments, the active molecule may preferably be hydrophobic, such that it is concentrated in areas with sebum or meibomian oil (e.g., eyelash follicles and/or meibomian glands). The formulation may preferably be water-based to facilitate the delivery of hydrophilic chitosan to and absorption by the hydrophilic chitosan on the exterior of the Demodex mite.

In some embodiments, the therapeutic agent may be delivered in the form of drops, creams, ointments, eye washes, liniments, ointments, gels, or either an immediate-release or sustained-release formulation. In some embodiments, the therapeutic agent may be delivered in the form of punctal plugs or canaliculus plugs or emulsions. In some cases, oily, gel-like, or viscous ointments may also prevent Demodex mites from moving across the skin surface during mating.

In some implementations, isoxazoline anthelmintics, formamidin anthelmintics, agents for treating Alzheimer's disease, and/or other agents as disclosed elsewhere herein may have preferential selectivity for insect/mite/tick receptors relative to vertebrate/mammal/human receptors.

In some embodiments, the active agent is delivered in an oral formulation (e.g., tablets, capsules, solutions, etc.), and very small doses can be delivered to avoid significant systemic or non-local skin exposure (as taught in veterinary medicine). However, in some embodiments, the active agent is delivered in a non-oral formulation, such as a topical ophthalmic formulation.

In some embodiments, the dosage is, for example, 1 microgram to 1 mg/ml or 0.0001% to 1% by weight of the active agent (e.g., isoxazoline anthelmintics, formamiditin anthelmintics, agents for treating Alzheimer's disease, and/or other agents as disclosed elsewhere herein), or about 0.01% to 10% by weight, about 0.05% to about 0.5% by weight, or about 0.01%, 0.015%, 0.02%, 0.025%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.10%, 0.15%, 0.20%, 0.25%, 0.30%, 0.35%, 0.40%, 0.45%, 0.50%, 0.55%. %, 0.60%, 0.65%, 0.70%, 0.75%, 0.80%, 0.85%, 0.90%, 0.95%, 1.00% or a range including any two of the above values, or 1 ng to 1 microgram/ml or 0.0000001% to 0.0001% by weight of an active agent (e.g., isoxazoline anthelmintics, formamiditin anthelmintics, reagents for treating Alzheimer's disease and/or other reagents as disclosed elsewhere herein), or 1 mg/ml to 100 mg/ml or 0.1% to 10% by weight of an active agent (e.g., isoxazoline anthelmintics, formamiditin anthelmintics, reagents for treating Alzheimer's disease and/or other reagents as disclosed elsewhere herein), or a range including any one of the foregoing values. In some implementations, isoxazoline anthelmintics, formamidin anthelmintics, agents for treating Alzheimer's disease, or other agents as disclosed elsewhere herein are the sole active agents.

In some embodiments, the ophthalmic preparation may be formulated for direct delivery onto the surface of the eye, including but not limited to the conjunctiva and/or cornea. In some embodiments, the ophthalmic preparation may be formulated for direct or indirect delivery onto any one or more of the anterior or posterior eyelids, eyelashes, or eyebrows. In some embodiments, the ophthalmic preparation is not directly delivered to any one or more of the conjunctiva, cornea, anterior or posterior eyelids, eyelashes, or eyebrows.

Eye drops can be engineered to specifically and simultaneously treat blepharitis and Demodex mites in the eyelash follicles and/or meibomian glands, but are not limited to delivery tools such as mascara brushes or application sites due to their oily additives, emulsions, ointment-based or cream-based formulations. In some implementations, the “Drop and Coat the Lashes” (DACTL) technique can be used. The patient can be instructed to administer the medication to a closed eye, allowing the preparation to come into contact with the meibomian gland openings on the eyelid margin and accumulate on the outer side of the eyelid margin. The patient can then use their finger or applicator to apply the accumulated preparation to the hair follicles of the eyelashes and/or lower and/or upper eyelashes. Without being theoretically limited, since Demodex mites are present in both eyelash follicles and meibomian glands, direct application of the eye drops to one or both of these sites may be advantageous. Because the combination of these two targets is unique for this condition, the therapeutic agent can be delivered to these sites simultaneously. The meibomian gland openings are located on the upper and lower surfaces of the lower and upper eyelids, respectively. Therefore, eye drops placed directly on the ocular surface allow for direct delivery of the formulation to the upper and lower meibomian gland openings.

Methods for treating blepharitis and/or Demodex mite infestation may include the specific delivery of a formulation/treatment (or similar) by applying drops into the eye followed by application to the base of hair follicles in the upper and/or lower eyelids using a finger or instrument (e.g., an eyelash brush). In some embodiments, desirable characteristics of the formulation may include maximizing drug water solubility to increase bioavailability (in solutions and suspensions), using polymers/viscosities to improve the residence time of the drug product in the eye, and achieving any one or more of acceptable visual acuity and comfort.

In some embodiments, the viscosity of the formulation may be high enough to cause the formulation to coat the meibomian gland openings on the margins of the upper and/or lower eyelids when the eyes blink or close.

In some cases, the viscosity can be high enough to slow the expulsion of the formulation through the tear duct for at least 5, 10, 20, 30 or longer seconds to enhance the contact time between the formulation and the meibomian gland opening and to allow the formulation to spill over the eyelid margin to a location that can be accessed for delivery to the eyelash follicle (e.g., by runoff and/or by applying the formulation with a finger and/or an instrument).

The formulation ingredients can be selected to allow the active agent to dissolve in solution, but with a low concentration of organic solvent by weight, such as ≤50%, 20%, 10%, 5%, 2%, or 1% by weight, or less or more organic solvent. This can be achieved, at least in part, by using surfactants such as, for example, polysorbate-80 or polysorbate-20. In some cases, a low concentration of polysorbate-80 may be preferred because higher concentrations can cause hydrolysis of the isoxazoline insecticide (e.g., 0.001%–0.1% polysorbate-80 by weight).

In some cases, this can also be achieved by using organic solvents such as propylene glycol to enhance the solubility of isoxazoline insecticides.

Solubility and viscosity can be enhanced simultaneously by selecting appropriate additives, thereby minimizing osmotic pressure, such as using polyvinyl alcohol, carboxymethyl cellulose, etc.

The formulation components can be selected to allow the active agent (e.g., isoxazoline anthelmintic or other active agents) to dissolve in solution, and formulation components that are stable to hydrolysis for 1, 1.5, 2 years or longer can be selected to achieve commercial shelf life, for example, with an optimal pH range of neutral to slightly alkaline (e.g., pH 7-10, 7-7.5 or pH 5-7 in other embodiments).

In some cases, the buffer concentration required to reach the desired pH can be minimized, thereby slowing down the hydrolysis rate (e.g., phosphate buffer concentration of 0.01–0.1 M). This can also be achieved using organic solvents and surfactants within the aforementioned concentration range.

Cationic surfactants can also benefit from slowing down the hydrolysis rate by generating cationic micelles.

Emulsions and emulsifiers can be mixed with water to prevent isoxazoline anthelmintics, formamidite anthelmintics, agents for treating Alzheimer's disease, and/or other agents and/or other active agents from contacting water in oil-in-water droplets, for example, by mixing with carbodiimide additives to prolong stability by forming more complex anhydrous micelles.

Water scavengers such as Stabaxol (bis-2,6-diisopropylphenylcarbodiimide) can be added to achieve long-lasting oil-based formulations to remove solvents from water.

In some embodiments, the pharmaceutical composition may comprise at least one compound selected from isoxazoline anthelmintics, formamiditin anthelmintics, agents for treating Alzheimer's disease, and/or other agents and/or other active agents, which is particularly suitable for treating ophthalmic symptoms selected from the following: burning or stinging sensation or perception of the eyes, sensation or perception of a foreign body in the eyes, sensation or perception of dry eyes, increased sensitivity to light, blurred vision, telangiectasia of the eyelid margin, blepharitis, chalazion, conjunctival hyperemia, and papillary conjunctivitis.

The term “treatment” can include treatment in humans and/or other animals.

Pharmaceutical compositions according to some embodiments of the present invention can be used for topical, oral, parenteral, or rectal treatment of the eyes.

Topical application is the most common method of administering ophthalmic medications. The topical route makes it possible to instill drops into the eye, or to apply solutions, eye washes, suspensions, ointments, creams, gels, sprays, foams, powders, lotions, viscoelastic solutions to the eye, and/or to the surface of the eye in solid forms, impregnated pads, synthetic agents, or wipes.

Some formulations may also be provided as suspensions of microspheres or nanospheres, or as vesicles or polymer patches and hydrogels formed from lipids or polymers that enable controlled release. These compositions for topical application may be provided in anhydrous, aqueous, or emulsion forms.

Pharmaceutical compositions for topical application are preferably non-irritating and compatible with ocular tissues. Solutions may be sterile preparations and may not contain all particles. Suspensions may be sterile preparations and may include solid particles in a liquid medium suitable for ocular instillation. Ointments may be semi-solid and sterile preparations.

Orally, the pharmaceutical composition may be provided in liquid, paste, or solid form, in powder form, and more particularly in tablet form, including sugar-coated tablets, hard gelatin capsules, syrups, suspensions, solutions, powders, granules, emulsions, microspheres or nanospheres, or vesicles formed of lipids or polymers that enable controlled release. Parenterally, the composition may be provided in the form of a solution or suspension for infusion or injection. Rectally, the composition may be provided in the form of suppositories. In some cases, the pharmaceutical composition is a topical ophthalmic composition, rather than an oral or rectal composition.

In some embodiments, the composition may comprise 0.001% to 10% by weight of at least one compound selected from isoxazoline anthelmintics, formamidin anthelmintics, agents for treating Alzheimer's disease, and/or other families of agents disclosed herein. In some embodiments, the composition according to the invention comprises 0.01% to 5% by weight of at least one compound selected from the isoxazoline anthelmintics family.

In some embodiments, the compositions according to the invention are provided in the form of eye washes or eye drops. The term "eye wash" refers to a liquid preparation particularly suitable for administration to the conjunctiva and cornea of the eye. Eye washes may comprise, for example, drops of about 25-50 microliters in volume. In some embodiments, the compositions are provided as kits, such as eye drops and shampoos, and may be used with sterilizing agents such as tea tree oil and its derivatives, as well as hypochlorous acid, which have also been shown to have Demodex mite activity, or in some cases may not include tea tree oil or other oils.

As shown above, in some embodiments, the composition may meet specific conditions for application to the eyes. Such conditions include, in particular, sterility, non-irritation, and biocompatibility with ocular tissues. The latter criterion is more difficult to obtain than that for compositions intended for skin; in particular, compounds such as ethanol or ethylene glycol, which are formulated into compositions for skin application, cannot be included in compositions intended for ocular use in some cases.

Topical compositions enable the direct and specific treatment of symptoms of diseases in the eyes and eyelids through local action; in particular, better results can be expected because they target only the eyes.

In some implementations, the formulation may be a solution, suspension, cream, ointment, or other form.

Liquid compositions formulated for topical ophthalmic use are formulated to allow for topical administration to the eye. Comfort is maximized as much as possible, although sometimes formulation considerations (such as drug stability) may necessitate a lower level of comfort than optimal. Where maximizing comfort cannot be achieved, the liquid can be formulated tolerable for topical ophthalmic use in patients. Additionally, ophthalmologically acceptable liquids may be packaged for single use or contain preservatives to prevent contamination during repeated use.

For ophthalmic applications, physiological saline solutions are typically used as the primary medium for preparing solutions or medications. These mediums include, but are not limited to, polyvinyl alcohol, povidone, hydroxypropyl methylcellulose, poloxamer, carboxymethyl cellulose, hydroxyethyl cellulose, and purified water. Ophthalmic solutions are preferably maintained at a comfortable pH using an appropriate buffer system. Formulations may also contain pharmaceutically acceptable preservatives, stabilizers, and surfactants.

In some implementations, the topical formulation does not include a skin penetration enhancer, which can increase systemic absorption and, in some cases, is contrary to the intention of maintaining the formulation locally at or near the application site. In some embodiments, the formulation does not include any skin penetration enhancers such as one or more of the following: laurocapram and laurocapram derivatives, such as 1-alkylazacycloheptan-2-one, and oleic acid and its ester derivatives, such as methyl, ethyl, propyl, isopropyl, butyl, vinyl and glyceryl monooleate, and sorbitan esters, such as sorbitan monolaurate and sorbitan monooleate, and other fatty acid esters, such as isopropyl laurate, isopropyl myristate, isopropyl palmitate, diisopropyl adipate, propylene glycol monolaurate and propylene glycol monooleate, and long-chain alkyl esters of 2-pyrrolidone, particularly 1-lauryl, 1-hexyl and 1-(2-ethylhexyl) esters of 2-pyrrolidine, and those skin penetration enhancers such as (N,N-dimethylamino)acetic acid dodecyl ester and (N,N-dimethylamino)propionate dodecyl ester and 2-n-nonyl-1-3-dioxolane. However, some implementations of the formulation may include one or more skin penetration enhancers.

In some embodiments, the topical formulation may include one or more gelling agents. The gelling agent may be a copolymer, such as Pemulen ^™ TR1 and/or TR2 polymeric emulsifiers (Lubrizol Corp., Wickliffe, OH), which are high molecular weight copolymers of acrylic acid and C10-C30 alkyl acrylates crosslinked with allyl pentaerythritol. They are fluffy white powders and are primarily used to form stable oil-in-water emulsions. Pemulen polymers include intramolecular hydrophilic and hydrophobic portions. The hydrophobic portion of the polymer adsorbs at the oil-water interface, and the hydrophilic portion swells in water, forming a gel network around the oil droplets to provide emulsion stability. Pemulen polymers can form stable oil-in-water emulsions without the need for any additional surfactants. Therefore, for example, they can be advantageous for developing low-irritant lotions and creams. Pemulen polymers provide viscosity build-up and high yield values to allow for the suspension and stability of insoluble substances and particles. In some embodiments, the gelling agent may not be present in the formulation at about 0.001% to about 1%, about 0.01% to about 0.10%, or about 0.001%, 0.005%, 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.10%, 0.15%, 0.20%, 0.25%, 0.30%, 0.35%, 0.40%, 0.45%, 0.50% w/w, or a range including any two of the foregoing values.

In some embodiments, oil-based formulations such as creams, ointments, or emulsions may include, for example, one or more of mineral oil, castor oil, or petrolatum, for example, about 20% to about 80% of the formulation, or about 30% to about 70% w/w. The formulation may also include cyclodextrin as a carrier molecule to promote dissolution.

In some embodiments, the topical formulation may include one or more thickeners, including polysaccharide thickeners such as hydroxypropyl methylcellulose (HPMC) and sodium CMC. In some embodiments, the thickener may be present at about 0% to about 2%, about 0.10% to about 1.00%, about 0.25% to about 1.00%, or about 0.10%, 0.20%, 0.25%, 0.30%, 0.35%, 0.40%, 0.50%, 0.60%, 0.70%, 0.80%, 0.90%, 1.00% w/w, or a range including any two of the foregoing values, such as about 0.1% to about 0.5%. In some embodiments, the formulation may have a viscosity of about 50 cp to about 100 cp to increase the residence time of the formulation in the eye. In some embodiments, the formulation may include a viscosity, for example, equal to or greater than 5 cP, or 20 cP, or 40 cP, or 100 cP, or 250 cP, or 400 cP, or 1000 cP, or a range including any two of the foregoing values. In some cases, the formulation is formulated to have a residence time in the eye of about 90 seconds to about 10 minutes, or a residence time of about or at least about 60 seconds, 90 seconds, 120 seconds, 180 seconds, 240 seconds, 300 seconds, 6 minutes, 7 minutes, 8 minutes, 9 minutes, 10 minutes, or a range including any two of the foregoing values.

In some embodiments, the topical formulation may include one or more solubilizers and/or surfactants, including nonionic surfactants such as polysorbates, such as polysorbate 80, polysorbate 65, polysorbate 60, polysorbate 40, or polysorbate 20. In some embodiments, polysorbate 80 has been found to unexpectedly increase the solubility of isoxazoline insecticides relative to other polysorbates. Other surfactants, such as fluorinated surfactants, may be used in addition to nonionic surfactants. In some embodiments, the solubilizer and/or surfactant may be present at about 0% to about 5%, about 0.10% to about 4%, about 0.50% to about 4%, or about 0.50%, 0.75%, 1.00%, 1.25%, 1.50%, 1.75%, 2.00%, 2.25%, 2.50%, 2.75%, 3.00%, 3.25%, 3.50%, 3.75%, 4.00%, 4.25%, 4.50%, 4.75%, 5.00% w/w, or a range including any two of the foregoing values. Polysorbate 80 may also be replaced by up to 5%, such as about 1%, 2%, 3%, 4%, or 5%, or about 1% to 5%, or a range including any two of the foregoing values, of FDA-approved Cremphor EL (hydrogenated castor oil) to promote higher drug concentrations.

In some embodiments, the formulation (including, but not limited to, eye drops, creams, ointments, or other forms as disclosed elsewhere herein) may include castor oil (e.g., meta-hydrogenated castor oil) and a polysaccharide thickener such as HPMC or sodium CMC. In some cases, the combination can advantageously and unexpectedly form a durable film.

In some embodiments, for example, the topical formulation may include one or more tensile agents, such as glycerin, dextran, mannitol, potassium chloride, and/or sodium chloride. In some embodiments, the tensile agent may be present at about 0% to about 5%, about 0.10% to about 4%, about 0.50% to about 4%, or about 0.50%, 0.75%, 1.00%, 1.25%, 1.50%, 1.75%, 2.00%, 2.25%, 2.50%, 2.75%, 3.00%, 3.25%, 3.50%, 3.75%, 4.00%, 4.25%, 4.50%, 4.75%, 5.00% w/w, or a range including any two of the foregoing values.

In some embodiments, the topical formulation may include one, two, or more buffers. Buffers may include, for example, acetate buffers, citrate buffers, phosphate buffers, and borate buffers. The pH of these formulations may be adjusted using an acid or base as needed. Buffers may be one or more of the following: sodium bicarbonate buffer, calcium bicarbonate buffer, tris(hydroxymethyl)aminomethane (Tris or THAM), MOPS (3-(N-morpholino)propanesulfonic acid) buffer, HEPES (N-(2-hydroxyethyl)piperazine-N'-(2-ethanesulfonic acid) buffer, ACES (2-[(2-amino-2-oxoethyl)amino]ethanesulfonic acid) buffer, ADA (N-(2-acetamido)-2-iminodiacetic acid) buffer, AMPSO (3-[(1,1-dimethyl-2-hydroxyethyl)amino]-2-propanesulfonic acid) buffer. Acid) buffer, BES (N,N-bis(2-hydroxyethyl)-2-aminoethanesulfonic acid) buffer, diglycine (N,N-bis(2-hydroxyethylglycine) buffer, bis-tris(bis-(2-hydroxyethyl)imino-tris(hydroxymethyl)methane buffer, CAPS (3-(cyclohexylamino)-1-propanesulfonic acid) buffer, CAPSO (3-(cyclohexylamino)-2-hydroxy-1-propanesulfonic acid) buffer, CHES (2-(N-cyclohexylamino)ethanesulfonic acid) buffer, DIPSO (3-[N,N-bis(2-hydroxyethyl)amino]-2-hydroxy-propanesulfonic acid) buffer Buffers, HEPPS (N-(2-hydroxyethylpiperazine)-N'-(3-propanesulfonic acid) buffer, HEPPSO (N-(2-hydroxyethyl)piperazine-N'-(2-hydroxypropanesulfonic acid) buffer, MES (2-(N-morpholino)ethanesulfonic acid) buffer, triethanolamine buffer, imidazole buffer, glycine buffer, ethanolamine buffer, phosphate buffer, MOPSO (3-(N-morpholino)-2-hydroxypropanesulfonic acid) buffer, PIPES (piperazine-N,N'-bis(2-ethanesulfonic acid) buffer, POPSO (piperazine-N,N'-bis(2-hydroxypropanesulfonic acid) buffer, POPSO (piperazine-N,N'-bis(2-hydroxypropanesulfonic acid) buffer) The buffers include: TAPS (N-tris(hydroxymethyl)methyl-3-aminopropanesulfonic acid) buffer, TAPSO (3-[N-tris(hydroxymethyl)methylamino]-2-hydroxy-propanesulfonic acid) buffer, TES (N-tris(hydroxymethyl)methyl-2-aminoethanesulfonic acid) buffer, zwitterionic buffer (N-tris(hydroxymethyl)methylglycine buffer), 2-amino-2-methyl-1,3-propanediol buffer, and 2-amino-2-methyl-1-propanol buffer, as well as combinations thereof. In some embodiments, the buffers are Tris and/or _disodium hydrogen phosphate ( _Na₂HPO₄ ) and sodium dihydrogen phosphate heptahydrate ( _{NaH₂PO₄ ·} 7H₂O _). In some embodiments, the buffer may be present at about 0% to about 2%, about 0.01% to about 1%, about 0.01% to about 0.75% of the formulation, or about 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.10%, 0.11%, 0.12%, 0.13%, 0.14%, 0.15%, 0.20%, 0.25%, 0.30%, 0.35%, 0.40%, 0.45%, 0.5% of the formulation. The concentrations are 0%, 0.55%, 0.60%, 0.65%, 0.70%, 0.75%, 0.80%, 0.85%, 0.90%, 0.95%, 1.00% w/w, or a range including any two of the foregoing values. A therapeutically effective amount of buffer may be selected such that the pH of the pharmaceutical composition can be, for example, about 7.35 to about 7.65, about 7.45 to 7.55, or about 7.30, 7.35, 7.40, 7.45, 7.50, 7.55, 7.60, or a range including any two of the foregoing values.

In some embodiments, the topical formulation may include one or more preservatives, including but not limited to lorazepam and benzalkonium chloride. Other preservatives may include, for example, PHMB, chlorobutanol, thimerosal, phenylmercuric acid, acetate, and phenylmercuric acid nitrate. In some embodiments, the preservative may be present in the topical formulation at about 0.001% to about 0.1%, about 0.001% to about 0.01%, or about 0.001%, 0.002%, 0.003%, 0.004%, 0.005%, 0.006%, 0.007%, 0.008%, 0.009%, 0.010% w/w, or a range including any two of the foregoing values.

Pharmaceutical compositions according to some embodiments of the present invention may additionally comprise inert additives or combinations thereof, such as: wetting agents, emollients; agents for improving flavor; preservatives; stabilizers; agents for adjusting moisture content; pH adjusters; buffers; agents for adjusting osmotic pressure; emulsifiers; agents for increasing viscosity; and antioxidants. Ophthalmologically acceptable antioxidants include, but are not limited to, sodium metabisulfite, sodium thiosulfate, acetylcysteine, butylated hydroxyanisole, and butylated hydroxytoluene. Other excipient components that may be included in ophthalmic formulations are chelating agents. A usable chelating agent is disodium ethylenediaminetetraacetate (EDTA), although other chelating agents may also be used suitably or in combination with it.

In some embodiments, the pharmaceutical composition may include tocopherol. In some cases, tocopherol can effectively prevent the degradation of isoxazoline in water. In some cases, vitamin E is tocopherol; in other embodiments, the tocopherol is α-tocopherol or γ-tocopherol; more preferably, α-tocopherol. In some embodiments, the pharmaceutical composition does not include tocopherol.

In some embodiments, the pharmaceutical preparation does not include any essential oils such as tea tree oil, α-terpineol, cardinene, d-carvone, 1-carvone, γ-terpinene, α-terpinene, 1,8-cineole, α-terpineol, para-cimene, α-pinene, limonene, α-Thugene, eucalyptol, (+)-ledene, cumene, or myrcene. However, some embodiments may include one or more of the aforementioned essential oils.

In some embodiments, one or more optional compounds may be added to these compositions such that the advantageous properties inherent to some embodiments of the invention are unaffected or substantially unaffected by the contemplated addition, such as tetracycline or omega-3 fatty acids, which may have a beneficial effect in blepharitis.

In some embodiments, isoxazoline anthelmintics are administered orally to patients suffering from blepharitis, rosacea, or other conditions disclosed elsewhere herein. Because the target organism, Demodex folliculorum (and/or Demodex brevis), is an ectoparasite of the Mite family, effective treatment in some cases involves the therapeutic eradication of this microscopic insect throughout its entire life cycle, including the egg, larval, and adult stages. For this purpose, some embodiments treat patients with blepharitis and/or rosacea with at least two timed doses, spaced approximately 3 to approximately 7 days apart. This interval allows time for the Demodex eggs to hatch into immature mites, which are then killed before they can mature into oviparous adults. In some embodiments, one, two, three, four, or more doses may be administered, spaced three to seven days apart. Following the acaricidal activity of isoxazoline anthelmintics or other active agents against Demodex folliculorum (and/or Demodex brevis) organisms, as disclosed herein, the inflammatory response to them begins to decrease. However, residual dead mites still cause some redness and lesion formation until the body's clearance process removes them, which in some cases takes 6-8 weeks. During this initial administration phase, other medications such as oral tetracyclines and topical metronidazole, and/or anti-inflammatory agents such as NSAIDs and/or steroids may be used to suppress early flare-ups and provide an early clinical response. However, in some embodiments, the formulation or method does not involve tetracyclines or other antibiotics, steroids, and/or metronidazole. Treatment can be repeated if classic signs begin to reappear after a prolonged symptom-free period.

In alternative embodiments, isoxazoline anthelmintics can be formulated as cosmetically acceptable topical lotions, creams, or gels and applied to the skin, eyelids, eyelashes, meibomian glands, or other anatomical sites as shown elsewhere herein. In some cases, such a treatment route may require once- or twice-daily application for up to four weeks to achieve adequate follicular penetration and effective acaricidal activity. In some cases, topical formulations that achieve this effect may contain, for example, about 0.01% to 5% of the active ingredient, and if the active agent is encapsulated in microliposomes, penetration may be enhanced. This topical treatment may require more frequent repetition than the preferred oral regimen, but disease-free intervals should be maintained with each course of treatment.

In some embodiments, pharmaceutical formulations, including any of the pharmaceutical formulations disclosed herein, can be formulated to advantageously allow the preferential absorption of the pharmaceutical formulation via the mite's exoskeleton (e.g., abdomen or opisthsoma) rather than mite ingestion of the pharmaceutical formulation (e.g., by ingestion of skin cells, sebum, and other sites that may absorb a certain amount of the active agent via systemic absorption) to eradicate mites near eyelashes. Not limited by theory, Demodex mites have a hydrophobic chitinous exoskeleton and a relatively thin exoskeleton (about 0.5 μm, compared to about 2.0 μm in the cephalothorax) in the abdominal/opisthsoma region, which surprisingly allows for more rapid absorption of the formulation via the abdomen, rather than primarily via ingestion (as in previous veterinary formulations of isoxazoline anthelmintics). Figures 1A-B schematically illustrate the application of formulation 120 to an eye 140 having an iris/pupil 142. The eyelids surrounding the eye 140 may include hair follicles 180 of eyelashes 186, and hair follicles 180 may include sebum 182. The eyelid may include meibomian glands 160 with meibomian oil 162. As shown in Figures 1A-B, the “face-down” orientation of mites (e.g., Demodex folliculorum 164, Demodex brevis 184) relative to hair follicles 180 or meibomian glands 160 (where the mite body points toward the opening of hair follicle 180 or gland 160) can facilitate the absorption of formulation 120 through the preferential abdominal region 190 of the abdomen/posterior body region. In in vitro studies, it has been surprisingly observed that after delivery of certain pharmaceutical formulations as disclosed herein, the abdomen and tail of the Demodex mites cease movement more quickly than the cephalothorax (Figure 2), indicating that Demodex mites are particularly sensitive to topical ophthalmic formulations as disclosed herein.

In some embodiments, the compositions and methods disclosed herein may be used topically or otherwise, alone or in combination with any one or more of the following agents, which can be formulated into a formulation having parameters including, but not limited to, concentration, excipients, and other characteristics, or the absence of other characteristics as disclosed elsewhere herein: albendazole, canbendazole, fenbendazole, flubendazole, mebendazole, oxifendazole, p-bendazole, thiabendazole, trichlorobenzazole, amitraz, demiditraz, clorsulon, closantel, oxyclonazide, rifenidone, deltamethrin, flufenoxuron, permethrin, promazine, derquantel, difenoconazole, dixinil, dinotefuran, imidacloprid, acetamiprid, thiamethoxam, abamectin, doramectin Emnnomectin, ivermectin, moxicillin, selamectin, milbemycin oxime, emodepside, epsiprantel, fipronil, fluazuron, fluhexafon, indoxacarb, levamisole, lufenuron, cyanflufenicol, methoprene, morantal, niclosamide, nitrothion, nitroisothion, novaluron, octyl, praziquantel, pyranopyridine, pyrprole, sisaproml, spinosad, ethyl spinosad, lindane, picrotoxin, dieldrin, endothelium sulfide, and/or triflumezopyrim. In some embodiments, the composition and method may include m-diamids (e.g., broflanilide), cyclodienes, and/or macrolides (including avermectin and milbemycin). In some embodiments, the Alzheimer's disease drug may be an active agent, such as galantamine, donepezil and other piperidine analogs, rivastigmine and other carbamate analogs, tacrine, 7-methoxytacrine, other pyridine analogs, huperazine A and other alkaloid analogs, which may also have anti-Demodex mite activity. For example, galantamine is a selective, competitive, rapidly reversible acetylcholinesterase inhibitor with an anionic substrate and an aromatic valley, as well as an allosteric ligand/activator at the nicotinic cholinergic receptor, thereby increasing GABA activity. Other acetylcholinesterase inhibitors may also be used in some cases. Derivatives, analogs, and L- and D-isomers may also be used, including but not limited to enantiomers, compositions comprising racemic mixtures, and optically pure compositions of any of the above listed in this paragraph. In some embodiments, the formulation does not include any one or more of the reagents listed in this paragraph.

In some embodiments, dermatological and/or ophthalmic preparations may include active therapeutic agents of formamidin anthelmintics, in addition to or besides the isoxazoline anthelmintics disclosed above. Formamidin anthelmintics may be, for example, amitraz, which can act as an octopamine receptor modulator. N-(2,4-dimethylphenyl)-N-methylformamidin (DPMF)—a metabolite of amitraz—is considered an active agent that exerts acaricidal and insecticidal effects by acting as an agonist of octopamine receptors, and may be another active therapeutic agent, alone or in addition. 2,4-Dimethylaniline is a hydrolytic metabolite of DPMF and may also be an active therapeutic agent in other embodiments. Derivatives, analogs, and L- and D-isomers thereof may also be used, including but not limited to enantiomers, compositions comprising racemic mixtures, and optically pure compositions. In some embodiments, dermatological and/or ophthalmic preparations may include active therapeutic agents of phenylpyrazole insecticides, in addition to or besides the isoxazoline or formamid insecticides disclosed above. The chemical structure of these insecticides is characterized by a central pyrazole ring having a phenyl group bonded to one of the nitrogen atoms of the pyrazole. Some non-limiting examples of phenylpyrazole insecticides include, for example, acetamiprid, acetamiprid, fipronil, butenpyram, pyrazophos, pifraporthium, pyriprole, pyrolan, and vaniliprole.

To further illustrate some implementation schemes and their advantages, Table 1 below lists several non-limiting specific examples of topical isoxazoline anthelmintic formulations, which are for illustrative purposes only. All ingredients are listed as % w/w or g/100 g of formulation, and Figures 3A-3B show examples of formulations containing amitraz and fleranal.

An exemplary embodiment of a dimethylamidine solution comprises 0.100% w/w dimethylamidine in 99.9% light mineral oil. Another example of a dimethylamidine ointment may comprise 0.100% w/w dimethylamidine and 29.9% mineral oil and 70.0% petrolatum.

Table 1

Element Solution 1 Solution 2 Suspension 1 Freranar 0.0100 0.0250 0.500 Pemulen TR1 0 0 0.050 HPMC 0.50 0.50 0 Polysorbate 80 2.0 2.0 2.0 Glycerol 2.5 2.5 2.5 TRIS 0 0 0.050 <![CDATA[NaH₂PO₄7H₂O]]> 0.44 0.44 0 <![CDATA[Na₂HPO₄]]> 0.045 0.045 0 pH 7.5 7.5 7.5 lorazepam 0.0050 0.0050 0.0050 water q.s.ad 100% q.s.ad 100% q.s.ad 100%

In some embodiments, the topical ophthalmic preparation may include the following instructions for use. Before administering the study drug, the patient may be instructed to shower or bathe first and wash their hands before administering the study drug. A unit dose, such as a single drop, may be administered directly into each eye once or twice daily, for example, once in the morning and once in the evening. After delivering the drops to the conjunctiva and/or cornea of the eye, the patient may close their eyes and apply gentle pressure to the upper eyelid to squeeze the medication through the margins of their upper and lower eyelids. The preparation can then be allowed to dry without wiping with a tissue. The preparation can then be stored at room temperature in a climate-controlled environment (15–30°C), avoiding extreme heat or cold. In some embodiments, the patient is instructed not to administer any other topical ophthalmic medications during specific periods, such as one hour before and one hour after administering the study drug.

In some embodiments, the system and method include a qualitative and/or quantitative assessment of Demodex mites in anatomical locations of the patient, such as on the eyelashes and/or within glands. In some embodiments, the method may include receiving a first assessment of the amount of Demodex mites on the patient's anatomical structures, and initiating topical administration of a dermatological and/or ophthalmic composition when the amount of Demodex mites is greater than a predetermined value, such as greater than about 1, 1.5, 2, 2.5, 3, 4, 5, or more mites (or mites/eyelashes) per square centimeter of skin. In some embodiments, the method may include receiving a second assessment of the number of Demodex mites after treatment to quantitatively assess improvement, and continuing, modifying (via increases or decreases in dosage, frequency, formulation, etc.) or discontinuing treatment based on the second assessment, which may be about, no more than, or at least about 1 day, 2 days, 3 days, 5 days, 7 days, 10 days, 14 days, 21 days, 28 days, 30 days, or more or fewer days after the first assessment. In some implementations, the treatment results in a reduction of approximately or at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% of the Demodex mites at the anatomical location.

The presence of cylindrical scales, also known as cylindrical casts, refers to the formation of transparent scales that encase the base of the eyelashes. Cylindrical scales on eyelashes are generally considered characteristic of Demodex mite infestations and can be diagnosed by hair removal and observation under a slit-lamp microscope, followed by automated or manual counting. Surface skin biopsy (SSB) with cyanoacrylate adhesion is a commonly used method for measuring Demodex mite density. It allows collection of the surface portion of the stratum corneum and the contents of the hair follicle sebaceous gland. Other sampling methods used for microscopic assessment of Demodex mite presence include adhesive tape, skin scraping, skin impressions, expression of follicular contents, comedo extraction, hair removal, and perforated biopsy.

In some implementations, systems and methods for detecting Demodex mites in subjects are disclosed that do not necessarily require hair removal. This measurement for diagnosing Demodex mites may be advantageous because detecting and quantifying Demodex mites, particularly Demodex brevis, via hair removal is challenging. Furthermore, many patients are opposed to hair removal due to discomfort. Additionally, treatment can be initiated earlier and based on objective criteria.

For example, a device such as a disposable hydrogel contact lens can be used to collect tears from an object. This device, such as the contact lens, is then sent to a laboratory for detection and potential quantification of Demodex mite DNA via PCR or other methods. The genomes of Demodex folliculorum and Demodex brevis have been sequenced. A “diagnostic” contact lens can be placed on the eye and removed after a short, fixed time, such as about or less than about 30, 20, 15, 10, or 5 minutes. Such a contact lens can be made of a hydrogel with relatively high affinity for Demodex mite biomarkers, including DNA.

In some implementations, as shown in Figure 4A, tear sampling can be performed using a device including a capillary glass tube to collect tears from the meniscus of the lower eyelid. This method can be particularly useful when a small, quantitative volume is required. Additionally, evaporation can be easily eliminated by sealing both ends of the tube, if it is advantageous to do so.

Some implementations also include non-contact lens skin and tear sampling methods, such as litmus paper or core-absorbing paper implementations similar to the Schirmer test (Figure 4B), or eyelash brush sampling techniques (Figure 4C). In some implementations, chitin, deacetylated chitosan, or other Demodex mite-specific biomarkers can be detected and quantified to correlate with mite populations.

Demodex mite DNA can be quantified as, for example, the density of DNA copies encoding a specific Demodex mite target sequence (e.g., 18S rRNA, as a non-limiting example). In some embodiments, if the density of Demodex mites (defined as the number of DNA copies encoding the target region of Demodex mite per ng of human gDNA ( ^x10⁻⁶ )) is greater than about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or more, can be a threshold for initiating treatment.

Infections can be further classified based on the pathogenic species of the Demodex mites (e.g., Demodex folliculorum vs. Demodex brevis). Demodex brevis is primarily located within the meibomian glands and sebaceous glands. Treatments can be improved, enhanced, or targeted based on the dominant species, for example, by increasing the delivery of therapeutic agents to selected glands.

Based on the foregoing teachings, various other modifications, adjustments, and alternative designs are of course possible. Therefore, it should be understood that the invention can be practiced in ways different from those specifically described herein within the scope of the appended claims. It is conceivable that various combinations or sub-combinations of the specific features and aspects of the disclosed embodiments can be made, and such combinations or sub-combinations still fall within one or more scopes of the invention. Furthermore, any particular feature, aspect, method, characteristic, feature, quality, attribute, element, etc., disclosed herein with respect to embodiments can be applied to all other embodiments shown herein. Therefore, it should be understood that various features and aspects of the disclosed embodiments can be combined or substituted with each other to form variations of the disclosed invention. Therefore, the scope of the invention disclosed herein is not intended to be limited to the specifically disclosed embodiments above. Furthermore, while the invention is readily adaptable to various modifications and alternatives, specific examples of which have been shown in the drawings and described in detail herein. However, it should be understood that the invention is not limited to the specific forms or methods disclosed, but rather, the invention covers all modifications, equivalents, and substitutions falling within the spirit and scope of the various embodiments described and the appended claims. Any method disclosed herein need not be performed in the order described. The methods disclosed herein include certain actions taken by practitioners; however, they may also include any third-party instructions regarding those actions, whether explicit or implicit. For example, an action such as “apply isoxazoline insecticide to the eyes” includes “instructing the application of isoxazoline insecticide to the eyes.” The scope of this disclosure also includes any and all overlapping, sub-scopes, and combinations thereof. Languages such as “up to,” “at least,” “greater than,” “less than,” “between,” etc., include the enumerated numbers. Numbers preceding terms such as “approximately,” “about,” and “substantially” as used herein include the stated number (e.g., about 10% = 10%) and also indicate quantities close to the stated amount that still perform the desired function or achieve the desired result. For example, the terms “approximately,” “about,” and “substantially” may refer to amounts less than 10%, less than 5%, less than 1%, less than 0.1%, and less than 0.01% of the stated amount.

This application also relates to the following implementation schemes:

Implementation Plan 1. Methods for treating the patient's blepharitis, including:

An effective amount of isoxazoline anthelmintic, formulated as an ophthalmic composition, is administered directly and topically to the ocular surface of one or more eyes of a patient requiring treatment. The ophthalmic composition further comprises a pharmaceutically acceptable carrier.

The ophthalmic composition described herein is sterile and non-irritating to the eyes.

The isoxazoline insect repellent is the sole active ingredient in the ophthalmic composition.

Implementation Scheme 2. The method as described in Implementation Scheme 1, wherein about 0.01% to about 1% of isoxazoline anthelmintic is administered relative to the total weight of the composition.

Implementation Scheme 3. The method as described in Implementation Scheme 1, wherein about 0.03% by weight of isoxazoline anthelmintic is administered relative to the total weight of the composition.

Implementation Scheme 4. The method as described in Implementation Scheme 1, wherein about 0.10% by weight of isoxazoline anthelmintic is administered relative to the total weight of the composition.

Implementation Scheme 5. The method of Implementation Scheme 1, wherein the ophthalmic composition comprises eye drops.

Implementation Scheme 6. The method as described in Implementation Scheme 1, wherein the ophthalmic composition does not contain any essential oils.

Implementation Scheme 7. The method of Implementation Scheme 1, wherein the isoxazoline anthelmintic is selected from: fluralaner, sarolaner, lotilaner, afoxolaner, and fluxametamide.

Implementation Scheme 8. The method of Implementation Scheme 1, wherein the ocular surface comprises at least one of the conjunctiva or cornea of one or more of the patient's eyes.

Implementation Scheme 9. The method of Implementation Scheme 1, wherein the ophthalmic composition comprises polysorbate.

Implementation Plan 10. Methods for treating blepharitis in patients, including:

An effective amount of isoxazoline anthelmintic is administered directly and topically to one or more of the eyes, eyelids, or eyelashes of a patient requiring treatment. This is formulated as an ophthalmic composition further comprising a pharmaceutically acceptable carrier, wherein the ophthalmic composition is sterile and non-irritating to the eyes.

The isoxazoline insect repellent is the only active ingredient in the ophthalmic composition.

Implementation Scheme 11. The method of Implementation Scheme 10, wherein after topical administration of the ophthalmic composition, the patient's eye is closed such that the composition comes into contact with the patient's meibomian gland openings and the outer edge of the patient's eyelid margin.

Implementation Scheme 12. The method of Implementation Scheme 11 further includes applying the composition to eyelashes and eyelash follicles.

Implementation Scheme 13. The method of Implementation Scheme 11 further includes applying the composition to the eyelashes and eyelash follicles using an applicator.

Implementation Scheme 14. The method as described in Implementation Scheme 10, wherein about 0.001% to about 1% of isoxazoline anthelmintic is administered.

Implementation Scheme 15. The method as described in Implementation Scheme 10, wherein about 0.001% to about 1% of isoxazoline anthelmintic is administered.

Implementation Scheme 16. The method as described in Implementation Scheme 10, comprising applying the ophthalmic composition topically at least once daily for at least about 2 weeks.

Implementation Scheme 17. The method as described in Implementation Scheme 10, comprising applying the ophthalmic composition topically at least once daily for at least about 4 weeks.

Implementation Plan 18. Methods for treating ocular Demodex mite infection in patients, including:

An effective amount of isoxazoline anthelmintic, formulated as an ophthalmic composition further comprising a pharmaceutically acceptable mediator, is administered directly and topically to one or more eyes, eyelids, or eyelashes of a patient requiring treatment.

The ophthalmic composition described herein is sterile and non-irritating to the eyes.

The isoxazoline insect repellent is the sole active ingredient in the ophthalmic composition.

Implementation Scheme 19. The method of Implementation Scheme 18 further includes receiving a first assessment of the amount of Demodex mites on the patient's anatomical structures, and topically administering the ophthalmic composition when the amount of Demodex mites is greater than a predetermined value.

Implementation Scheme 20. The method of Implementation Scheme 18, wherein the ophthalmic preparation causes the abdomen and tail of the Demodex mite on the patient to stop moving more quickly relative to the cephalothorax of the Demodex mite.

Implementation Plan 21. Methods for treating blepharitis and/or rosacea, including:

Topical application of isoxazoline anthelmintics near one or more eyelashes is therapeutically effective and preferentially absorbed by the Demodex mite's body relative to the mite's ingestion, sufficient to reduce the movement of the mite's body relative to its head. This method is sufficient to reduce or eliminate Demodex mites near the eyelashes, resulting in improved presentation of blepharitis and/or erythematous acne.

Implementation Plan 22. A topical ophthalmic preparation for treating blepharitis in patients, comprising:

An effective amount of isoxazoline anthelmintic and a pharmaceutically acceptable vector.

The ophthalmic composition described herein is sterile and non-irritating to the eyes.

The isoxazoline insect repellent is the sole active ingredient in the ophthalmic composition.

Implementation Scheme 23. A topical ophthalmic preparation as described in Implementation Scheme 22, wherein an isoxazoline anthelmintic is administered at about 0.01% to about 1% of the total weight of the composition.

Implementation Scheme 24. A topical ophthalmic preparation as described in Implementation Scheme 22, wherein about 0.03% by weight of isoxazoline anthelmintic is administered relative to the total weight of the composition.

Implementation Scheme 25. A topical ophthalmic preparation as described in Implementation Scheme 22, wherein about 0.10% by weight of isoxazoline anthelmintic is administered relative to the total weight of the composition.

Implementation Scheme 26. A topical ophthalmic preparation as described in Implementation Scheme 22, wherein the ophthalmic composition comprises eye drops.

Implementation Scheme 27. A topical ophthalmic preparation as described in Implementation Scheme 22, wherein the ophthalmic composition does not contain any essential oils.

Implementation Scheme 28. A topical ophthalmic preparation as described in Implementation Scheme 22, wherein the isoxazoline anthelmintic is selected from: fleranal, saloranal, loteranal, afolanal and fluoxazolamide.

Implementation Scheme 29. A topical preparation for treating ocular surface diseases, comprising:

Isoxazoline insecticide;

At least one of Pemulen and HPMC;

Polysorbate 80;

glycerin;

Buffer; and

lorazepam,

The aforementioned preparation effectively reduces or eliminates Demodex mites near the eyelashes, leading to improvement in blepharitis and/or rosacea.

Implementation Scheme 30. A topical preparation as described in Implementation Scheme 29, used for the treatment of blepharitis.

Implementation Scheme 31. A topical preparation as described in Implementation Scheme 29, used for the treatment of anterior blepharitis.

Implementation Scheme 32. A topical preparation as described in Implementation Scheme 29, used for the treatment of posterior blepharitis.

Implementation Scheme 33. A topical preparation as described in Implementation Scheme 29, used for the treatment of ocular rosacea.

Implementation Plan 34. Methods for treating blepharitis in patients, including:

An effective amount of amitraz anthelmintic is administered directly and topically to the ocular surface of one or more eyes of a patient requiring treatment. This is formulated as an ophthalmic composition, which further comprises a pharmaceutically acceptable carrier.

The ophthalmic composition described herein is sterile and non-irritating to the eyes.

The formamidin is the sole active ingredient in the ophthalmic composition.

Implementation Scheme 35. The method as described in Implementation Scheme 34, wherein about 0.01% to about 1% of a formamidin anthelmintic is administered relative to the total weight of the composition.

Implementation Scheme 36. The method of Implementation Scheme 34, wherein about 0.03% by weight of a formamidin anthelmintic is administered relative to the total weight of the composition.

Implementation Scheme 37. The method as described in Implementation Scheme 34, wherein about 0.10% by weight of a formamidin anthelmintic is administered relative to the total weight of the composition.

Implementation Scheme 38. The method of Implementation Scheme 34, wherein the ophthalmic composition comprises eye drops.

Implementation Scheme 39. The method of Implementation Scheme 34, wherein the ophthalmic composition comprises an ointment or cream.

Implementation Scheme 40. The method of Implementation Scheme 34, wherein the ophthalmic composition does not contain any essential oils.

Implementation Scheme 41. The method of Implementation Scheme 34, wherein the formamidin is selected from: amitraz, N-(2,4-dimethylphenyl)-N-methylformamidin (DPMF) and 2,4-dimethylaniline.

Implementation Scheme 42. The method of Implementation Scheme 34, wherein the ocular surface comprises at least one of the conjunctiva or cornea of one or more of the patient's eyes.

Implementation Scheme 43. The method of Implementation Scheme 34, wherein the ophthalmic composition comprises polysorbate.

Implementation Plan 44. Methods for treating blepharitis in patients, including:

An effective amount of amitraz anthelmintic is administered directly to one or more of the eyes, eyelids, or eyelashes of a patient requiring treatment. The anthelmintic is formulated as an ophthalmic composition further comprising a pharmaceutically acceptable carrier, wherein the ophthalmic composition is sterile and non-irritating to the eyes.

The formamidin is the sole active ingredient in the ophthalmic composition.

Implementation Scheme 45. The method of Implementation Scheme 44, wherein after topical administration of the ophthalmic composition, the patient's eye is closed such that the composition comes into contact with the patient's meibomian gland openings and the outer edge of the patient's eyelid margin.

Implementation Scheme 46. The method of Implementation Scheme 44 further includes applying the composition to eyelashes and eyelash follicles.

Implementation Scheme 47. The method of Implementation Scheme 44 further includes applying the composition to the eyelashes and eyelash follicles using an applicator.

Implementation Scheme 48. The method as described in Implementation Scheme 44, wherein about 0.001% to about 1% of formamidin is administered.

Implementation Scheme 49. The method as described in Implementation Scheme 44, wherein about 0.001% to about 1% of amitraz anthelmintic is administered.

Implementation Scheme 50. The method as described in Implementation Scheme 44, comprising applying the ophthalmic composition topically at least once daily for at least about 2 weeks.

Implementation Scheme 51. The method as described in Implementation Scheme 44, comprising applying the ophthalmic composition topically at least once daily for at least about 4 weeks.

Implementation Plan 52. Methods for treating ocular Demodex mite infection in patients, including:

An effective amount of amitraz anthelmintic, formulated to also contain a pharmaceutically acceptable carrier, is administered directly and topically to one or more of the eyes, eyelids, or eyelashes of a patient requiring treatment.

The ophthalmic composition described herein is sterile and non-irritating to the eyes.

The formamidin is the sole active ingredient in the ophthalmic composition.

Implementation Scheme 53. The method of Implementation Scheme 52 further includes receiving a first assessment of the amount of Demodex mites on the patient's anatomical structures, and topically administering the ophthalmic composition when the amount of Demodex mites is greater than a predetermined value.

Implementation Scheme 54. The method of Implementation Scheme 52, wherein the ophthalmic preparation causes the abdomen and tail of the patient's Demodex mites to stop moving more quickly relative to the cephalothorax of the Demodex mites.

Implementation Plan 55. Methods for treating blepharitis and/or rosacea, including:

Topical application of amitraz near one or more eyelashes is therapeutically effective in being preferentially absorbed by the body of the Demodex mites relative to their ingestion, sufficient to cause a reduction in the movement of the Demodex mite's body relative to its head. This method is sufficient to reduce or eliminate Demodex mites near the eyelashes, resulting in improvement in blepharitis and/or erythematous acne.

Implementation Plan 56. A topical ophthalmic preparation for treating blepharitis in patients, comprising:

An effective amount of formamiditin and a pharmaceutically acceptable medium.

The ophthalmic composition described herein is sterile and non-irritating to the eyes.

The formamidin is the sole active ingredient in the ophthalmic composition.

Implementation Scheme 57. A topical ophthalmic preparation as described in Implementation Scheme 56, wherein a formamidin anthelmintic is administered at about 0.01% to about 1% of the total weight of the composition.

Implementation Scheme 58. A topical ophthalmic preparation as described in Implementation Scheme 56, wherein about 0.03% by weight of a formamidin anthelmintic is administered relative to the total weight of the composition.

Implementation Scheme 59. A topical ophthalmic preparation as described in Implementation Scheme 56, wherein about 0.10% by weight of a formamidin anthelmintic is administered relative to the total weight of the composition.

Implementation Scheme 60. A topical ophthalmic preparation as described in Implementation Scheme 56, wherein the ophthalmic composition comprises eye drops, cream, or ointment.

Implementation Scheme 61. A topical ophthalmic preparation as described in Implementation Scheme 56, wherein the ophthalmic composition does not contain any essential oils.

Implementation Scheme 62. The topical ophthalmic preparation as described in Implementation Scheme 56, wherein the formamidin is selected from: amitraz, N-(2,4-dimethylphenyl)-N-methylformamidin (DPMF) and 2,4-dimethylaniline.

Claims (10)

1. Treatment methods for blepharitis include: An effective amount of isoxazoline anthelmintic, formulated as an ophthalmic composition, is administered directly and topically to the ocular surface of one or more eyes of a patient requiring treatment. The ophthalmic composition further comprises a pharmaceutically acceptable carrier. The ophthalmic composition described herein is sterile and non-irritating to the eyes. The isoxazoline insect repellent is the only active ingredient in the ophthalmic composition. 2. Treatment methods for blepharitis include: An effective amount of isoxazoline anthelmintic is administered directly and topically to one or more of the eyes, eyelids, or eyelashes of a patient requiring treatment. This is formulated as an ophthalmic composition further comprising a pharmaceutically acceptable carrier, wherein the ophthalmic composition is sterile and non-irritating to the eyes. The isoxazoline insect repellent is the only active ingredient in the ophthalmic composition. 3. Treatment methods for patients with ocular Demodex mite infection include: An effective amount of isoxazoline anthelmintic, formulated as an ophthalmic composition further comprising a pharmaceutically acceptable mediator, is administered directly and topically to one or more eyes, eyelids, or eyelashes of a patient requiring treatment. The ophthalmic composition described herein is sterile and non-irritating to the eyes. The isoxazoline insect repellent is the only active ingredient in the ophthalmic composition. 4. Treatment methods for blepharitis and/or rosacea include: Topical application of isoxazoline anthelmintics near one or more eyelashes is therapeutically effective and preferentially absorbed by the Demodex mite's body relative to the mite's ingestion, sufficient to reduce the movement of the mite's body relative to its head. This method is sufficient to reduce or eliminate Demodex mites near the eyelashes, resulting in improved presentation of blepharitis and/or erythematous acne. 5. A topical ophthalmic preparation for treating blepharitis in patients, comprising: An effective amount of isoxazoline anthelmintic and a pharmaceutically acceptable vector. The ophthalmic composition described herein is sterile and non-irritating to the eyes. The isoxazoline insect repellent is the sole active ingredient in the ophthalmic composition. 6. Topical preparations for treating ocular surface diseases, comprising: Isoxazoline insecticide; At least one of Pemulen and HPMC; Polysorbate 80; glycerin; Buffer; and lorazepam, The aforementioned formulation is therapeutically effective in reducing or eliminating Demodex mites near the eyelashes, leading to improvement in blepharitis and/or rosacea. 7. Treatment methods for blepharitis include: An effective amount of amitraz anthelmintic is administered directly and topically to the ocular surface of one or more eyes of a patient requiring treatment. This is formulated as an ophthalmic composition, which further comprises a pharmaceutically acceptable carrier. The ophthalmic composition described herein is sterile and non-irritating to the eyes. The formamidin is the sole active ingredient in the ophthalmic composition. 8. Treatment methods for blepharitis include: An effective amount of amitraz anthelmintic is administered directly to one or more of the eyes, eyelids, or eyelashes of a patient requiring treatment. The anthelmintic is formulated as an ophthalmic composition further comprising a pharmaceutically acceptable carrier, wherein the ophthalmic composition is sterile and non-irritating to the eyes. The formamidin is the sole active ingredient in the ophthalmic composition. 9. Treatment methods for patients with ocular Demodex mite infection include: An effective amount of amitraz anthelmintic, formulated to also contain a pharmaceutically acceptable carrier, is administered directly and topically to one or more of the eyes, eyelids, or eyelashes of a patient requiring treatment. The ophthalmic composition described herein is sterile and non-irritating to the eyes. The formamidin is the sole active ingredient in the ophthalmic composition. 10. Treatment methods for blepharitis and/or rosacea include: Topical application of amitraz near one or more eyelashes is therapeutically effective in being preferentially absorbed by the body of the Demodex mites relative to their ingestion, sufficient to cause a reduction in the movement of the Demodex mite's body relative to its head. This method is sufficient to reduce or eliminate Demodex mites near the eyelashes, resulting in improvement in blepharitis and/or erythematous acne.