Isoxazoline insect repellant formulations and methods for treating blepharitis

Abstract

Disclosed herein are methods for treating or preventing ophthalmic and dermatological conditions in a patient, including ocular surface conditions such as blepharitis. The methods can include directly topically administering to the ocular surface of one or more eyes of a patient in need of treatment an effective amount of an isoxazoline insect repellant, a formamidine insect repellant, or other active ingredient formulated as an ophthalmic composition that further includes a pharmaceutically acceptable vehicle. Compositions are also disclosed.

Description

[0001] Priority claim

[0002] This application is a divisional application of Chinese patent application No. 201880088176.3, and claims the benefit of non-provisional applications of each of U.S. Provisional Application No. 62 / 599,213 filed on December 15, 2017, No. 62 / 615,855 filed on January 10, 2018, No. 62 / 626,612 filed on February 5, 2018, No. 62 / 689,787 filed on June 25, 2018, and No. 62 / 746,498 filed on October 16, 2018, each of which is hereby incorporated by reference in its entirety. Background of the Invention

[0004] Blepharitis, or eyelid inflammation, is a common, often chronic condition that can be challenging to treat and affects any age group. Blepharitis can be anterior (the outer surface of the eyelid, where the eyelashes are attached), and / or posterior (the inner surface of the eyelid). Blepharitis can be associated with systemic diseases including rosacea and seborrheic dermatitis, and with other ophthalmic diseases including chalazion, conjunctivitis, keratitis, and dry eyes.

[0005] Demodex folliculorum and Demodex brevis are microscopic, obligate, elongated mites that are the most common permanent endodermal parasites that inhabit the hair follicles and sebaceous glands of humans and animals. A total of 65 species of Demodex have been described, parasitizing 11 orders of mammals and belonging to the Demodicidae family of the Arachnida, Acarina order. Mating occurs in the opening of the hair follicle, and the eggs are placed in the hair follicle or sebaceous gland. The 6-legged larvae hatch after 3-4 days, and the larvae develop into adults after about 7 days. Demodex has a life cycle of about 14 days. The total life span of Demodex is several weeks. Dead mites decompose in the hair follicle or sebaceous gland.

[0006] Demodex mites can be found on the face, including the cheeks, nose, chin, forehead, temples, eyelashes, eyebrows, as well as on the scalp, neck, and ears. Other seborrheic sites may also be infested, such as the nasolabial folds, periorbital area, and less commonly, the upper and middle areas of the chest and back. Demodex mites can also be found in ectopic sebaceous glands in the penis, mons pubis, buttocks, and oral mucosa. In some cases, greater than 5 mites / cm2 may be present in a pilosebaceous unit. 2 Alternatively, a mite density of 5 or more mites per follicle was associated with Demodex infestation.

[0007] Among the species reported in large numbers, only two species, Demodex folliculorum and Demodex sebaceous, are found parasitizing the human body surface. Demodex folliculorum has been found, for example, on the eyelash follicles, while Demodex sebaceous has been found, for example, at the meibomian (tarsal) glands around the sebaceous glands near the eyes and skin. The meibomian gland is a holo-secreting exocrine gland located at the edge of the eyelid within the tarsal plate and is responsible for supplying meibum, an oily substance that prevents the tear film of the eye from evaporating. Meibum prevents tears from overflowing onto the cheeks, traps tears between the oiled edge and the eyeball, and makes the closed lid airtight. There are about 50 glands on the upper eyelid and 25 glands on the lower eyelid. Symbiotic bacteria on mites can also contribute to pathology. Increased sebum secretion and increased number of sebaceous glands can provide a favorable habitat for mites. Although a certain level of Demodex can be asymptomatic, the proliferation of Demodex to high density and / or simultaneous immune imbalances often lead to skin damage. There is a growing body of literature implicating Demodex in both anterior and posterior blepharitis. For example, Demodex is implicated in 45% of blepharitis cases. The prevalence of ocular surface disease is estimated to be approximately 30 million patients; of these, 19 million have meibomian gland dysfunction / posterior blepharitis; 9 million have Demodex infestation, and 4 million have overt signs of Demodex. Blepharitis is an important diagnosis with no currently approved therapies in the United States. Safe, effective therapies are needed to treat blepharitis and other ophthalmic and dermatologic conditions. SUMMARY OF THE INVENTION

[0009] In some embodiments, disclosed herein are topical therapeutic agents, including but not limited to topical agents, which include one or more isoxazoline anthelmintics, formamidine 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.

[0010] In some configurations, disclosed herein are methods of treating blepharitis in a patient comprising topically administering directly to the ocular surface of one or more eyes of the patient in need of treatment an effective amount of an isoxazoline insecticide formulated in an ophthalmic composition further comprising a pharmaceutically acceptable vehicle.

[0011] In some configurations, the ophthalmic compositions are sterile and non-irritating to the eye.

[0012] In some configurations, the isoxazoline repellent may be the sole active ingredient of the ophthalmic composition.

[0013] In some configurations, about 0.01% to about 1% of the isoxazoline anthelmintic is administered relative to the total weight of the composition.

[0014] In some configurations, about 0.03% by weight of the isoxazoline repellent is administered relative to the total weight of the composition.

[0015] In some configurations, about 0.10% by weight of the isoxazoline repellent is administered relative to the total weight of the composition.

[0016] In some configurations, the ophthalmic composition comprises eye drops.

[0017] In some configurations, the ophthalmic composition does not include any essential oils.

[0018] In some configurations, the isoxazoline repellent is selected from the group consisting of fluralaner, sarolaner, lotilaner, afoxolaner, and fluxametamide.

[0019] In some configurations, the ocular surface includes at least one of the conjunctiva or cornea of ​​one or more eyes of the patient.

[0020] In some configurations, the ophthalmic composition comprises a polysorbate.

[0021] In some configurations, disclosed herein are methods of treating blepharitis in a patient, comprising topically administering an effective amount of an isoxazoline insect repellent formulated into an ophthalmic composition further comprising a pharmaceutically acceptable vehicle directly to one or more of the eyes, eyelids, or eyelashes of the patient in need of treatment, wherein the ophthalmic composition is sterile and non-irritating to the eye, wherein the isoxazoline insect repellent is the sole active ingredient of the ophthalmic composition.

[0022] In some configurations, following topical administration of the ophthalmic composition, the patient's eye is closed such that the composition is in contact with the patient's meibomian gland openings and the exterior of the patient's lid margin.

[0023] In some configurations, the method further comprises applying the composition to the eyelashes and the follicles of the eyelashes.

[0024] In some configurations, the method further comprises applying the composition to the eyelashes and eyelash follicles with an applicator.

[0025] In some configurations, about 0.001% to about 1% of the isoxazoline anthelmintic is administered.

[0026] In some configurations, about 0.001% to about 1% of the isoxazoline anthelmintic is administered.

[0027] In some configurations, the method further comprises topically administering the ophthalmic composition at least once a day for at least about 2 weeks.

[0028] In some configurations, the method further comprises topically administering the ophthalmic composition at least once a day for at least about 4 weeks.

[0029] In some configurations, disclosed herein are methods of treating an ocular Demodex infestation in a patient, comprising topically administering an effective amount of an isoxazoline anthelmintic formulated in an ophthalmic composition further comprising a pharmaceutically acceptable vehicle directly to one or more of the eyes, eyelids, or eyelashes of one or more eyes of the patient in need of treatment, wherein the ophthalmic composition is sterile and non-irritating to the eye, wherein the isoxazoline anthelmintic is the sole active ingredient of the ophthalmic composition.

[0030] In some configurations, the method further includes receiving a first assessment of an amount of Demodex mites on the patient's anatomy, and topically administering the ophthalmic composition when the amount of Demodex mites is greater than a predetermined value.

[0031] In some configurations, the ophthalmic formulation causes the abdomen and tail of a Demodex mite on a patient to stop moving faster than the cephalothorax of a Demodex mite.

[0032] In some configurations, disclosed herein are methods of treating blepharitis and / or rosacea, comprising topically applying an isoxazoline repellent proximate one or more eyelashes, wherein the topical application is therapeutically effective to be preferentially absorbed by the body of the Demodex mite relative to ingestion by the Demodex mite, sufficient to cause a decrease in 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 mite proximate the eyelashes, resulting in an improvement in the manifestations of blepharitis and / or rosacea.

[0033] In some configurations, disclosed herein are topical ophthalmic formulations for treating blepharitis in a patient, comprising an effective amount of an isoxazoline insect repellent and a pharmaceutically acceptable vehicle, wherein the ophthalmic composition is sterile and non-irritating to the eye, wherein the isoxazoline insect repellent is the sole active ingredient of the ophthalmic composition.

[0034] In some configurations, about 0.01% to about 1% of the isoxazoline anthelmintic is administered relative to the total weight of the composition.

[0035] In some configurations, about 0.03% by weight of the isoxazoline repellent is administered relative to the total weight of the composition.

[0036] In some configurations, about 0.10% by weight of the isoxazoline repellent is administered relative to the total weight of the composition.

[0037] In some configurations, the ophthalmic composition comprises eye drops.

[0038] In some configurations, the ophthalmic composition does not include any essential oils.

[0039] In some configurations, the isoxazoline anthelmintic is selected from the group consisting of: fluralaner, sarolaner, lotiraner, afoxolaner, and fluoxazolamide.

[0040] In some configurations, disclosed herein is a topical formulation for treating an ocular surface disease comprising: an isoxazoline insect repellent; at least one of Pemulen and HPMC; polysorbate 80; glycerin; a buffer; and lauroxil chloride, wherein the formulation is therapeutically effective in reducing or eliminating Demodex mites proximate to the eyelashes, resulting in improvement in manifestations of blepharitis and / or rosacea.

[0041] In some configurations, the formulation is used to treat blepharitis.

[0042] In some configurations, the formulation is used to treat anterior blepharitis.

[0043] In some configurations, the formulation is used to treat posterior blepharitis.

[0044] In some configurations, the formulation is used to treat ocular rosacea.

[0045] In some configurations, disclosed herein are methods of treating blepharitis in a patient, comprising topically administering directly to the ocular surface of one or more eyes of a patient in need of treatment an effective amount of a formamidine anthelmintic formulated as an ophthalmic composition further comprising a pharmaceutically acceptable vehicle, wherein the ophthalmic composition is sterile and non-irritating to the eye, wherein the formamidine anthelmintic is the sole active ingredient of the ophthalmic composition.

[0046] In some configurations, about 0.01% to about 1% of the formamidine anthelmintic is administered relative to the total weight of the composition.

[0047] In some configurations, about 0.03% by weight of the formamidine anthelmintic is administered relative to the total weight of the composition.

[0048] In some configurations, about 0.10% by weight of the formamidine anthelmintic is administered relative to the total weight of the composition.

[0049] In some configurations, the ophthalmic composition comprises eye drops.

[0050] In some configurations, the ophthalmic composition comprises an ointment or a cream.

[0051] In some configurations, the ophthalmic composition does not include any essential oils.

[0052] In some configurations, the formamidine repellent is selected from the group consisting of amitraz, N-(2,4-dimethylphenyl)-N-methylformamidine (DPMF), and 2,4-dimethylaniline.

[0053] In some configurations, the ocular surface includes at least one of the conjunctiva or cornea of ​​one or more eyes of the patient.

[0054] In some configurations, the ophthalmic composition comprises a polysorbate.

[0055] In some configurations, disclosed herein are methods of treating blepharitis in a patient, comprising topically administering an effective amount of a formamidine anthelmintic directly to one or more of the eyes, eyelids, or eyelashes of a patient in need of treatment, formulated in an ophthalmic composition further comprising a pharmaceutically acceptable vehicle, wherein the ophthalmic composition is sterile and non-irritating to the eye, wherein the formamidine anthelmintic is the sole active ingredient of the ophthalmic composition.

[0056] In some configurations, following topical administration of the ophthalmic composition, the patient's eye is closed such that the composition is in contact with the patient's meibomian gland openings and the exterior of the patient's lid margin.

[0057] In some configurations, the method further comprises applying the composition to the eyelashes and the follicles of the eyelashes.

[0058] In some configurations, the method further comprises applying the composition to the eyelashes and eyelash follicles with an applicator.

[0059] In some configurations, about 0.001% to about 1% of the formamidine anthelmintic is administered.

[0060] In some configurations, about 0.001% to about 1% of the formamidine anthelmintic is administered.

[0061] In some configurations, the method further comprises topically administering the ophthalmic composition at least once a day for at least about 2 weeks.

[0062] In some configurations, the method further comprises topically administering the ophthalmic composition at least once a day for at least about 4 weeks.

[0063] In some configurations, disclosed herein are methods of treating an ocular Demodex infestation in a patient, comprising topically administering an effective amount of a formamidine anthelmintic formulated in an ophthalmic composition further comprising a pharmaceutically acceptable vehicle directly to one or more of the eyes, eyelids, or eyelashes of one or more eyes of the patient in need of treatment, wherein the ophthalmic composition is sterile and non-irritating to the eye, wherein the formamidine anthelmintic is the sole active ingredient of the ophthalmic composition.

[0064] In some configurations, the method further includes receiving a first assessment of an amount of Demodex mites on the patient's anatomy, and topically administering the ophthalmic composition when the amount of Demodex mites is greater than a predetermined value.

[0065] In some configurations, the ophthalmic formulation causes the abdomen and tail of the Demodex mite on the patient to cease movement more quickly than the cephalothorax of the Demodex mite.

[0066] In some configurations, disclosed herein are methods of treating blepharitis and / or rosacea, comprising topically applying a formamidine repellent proximate one or more eyelashes, wherein the topical application is therapeutically effective to be preferentially absorbed by the body of the Demodex mite relative to ingestion by the Demodex mite, sufficient to cause a decrease in 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 mite proximate the eyelashes, resulting in an improvement in the manifestations of blepharitis and / or rosacea.

[0067] In some configurations, disclosed herein are topical ophthalmic formulations for treating blepharitis in a patient, comprising an effective amount of a formamidine anthelmintic and a pharmaceutically acceptable vehicle, wherein the ophthalmic composition is sterile and non-irritating to the eye, wherein the formamidine anthelmintic is the sole active ingredient of the ophthalmic composition.

[0068] In some configurations, the formamidine anthelmintic is administered at about 0.01% to about 1% relative to the total weight of the composition.

[0069] In some configurations, about 0.03% by weight of the formamidine anthelmintic is administered relative to the total weight of the composition.

[0070] In some configurations, about 0.10% by weight of the formamidine anthelmintic is administered relative to the total weight of the composition.

[0071] In some configurations, the ophthalmic composition comprises eye drops, creams, or ointments.

[0072] In some configurations, the ophthalmic composition does not include any essential oils.

[0073] In some configurations, the formamidine repellent is selected from the group consisting of amitraz, N-(2,4-dimethylphenyl)-N-methylformamidine (DPMF), and 2,4-dimethylaniline.

[0074] In some configurations, disclosed herein are methods for treating symptoms of blepharitis and / or ocular rosacea in the eye, the symptoms selected from: burning sensation in the eye, stinging sensation in the eye, dryness of the eye, increased sensitivity to light, blurred vision, and complications of ocular rosacea in the cornea, the method comprising topically administering directly to the conjunctiva and / or cornea of ​​the eye of an individual in need of such treatment an effective amount of a formamidine repellent formulated in an eyewash composition having a pharmaceutically acceptable vehicle thereof, the eyewash composition being sterile, non-irritating, and compatible with ocular tissue.

[0075] In some configurations, 0.001% to 10% by weight of the formamidine anthelmintic is administered relative to the total weight of the composition.

[0076] In some configurations, 0.01% to 5% of the formamidine anthelmintic is administered relative to the total weight of the composition.

[0077] In some configurations, 0.03% by weight of the formamidine anthelmintic is administered relative to the total weight of the composition.

[0078] In some configurations, 0.10% by weight of the formamidine anthelmintic is administered relative to the total weight of the composition.

[0079] In some configurations, disclosed herein are methods of treating blepharitis and / or rosacea by orally administering or topically applying a formamidine anthelmintic in a dose sufficient to populate and eliminate Demodex mites at one or more anatomical locations, resulting in cessation of manifestations of blepharitis and / or rosacea.

[0080] In some configurations, the dosage of the formamidine anthelmintic is repeated about 2 to 4 times with intervals of 3 to 7 days therebetween.

[0081] In some configurations, the topically applied formamidine anthelmintic is formulated in a carrier lotion, cream, or gel.

[0082] In some configurations, the concentration of the formamidine repellent in the topically applied lotion, cream, or gel is about 1%-5% by weight.

[0083] In some configurations, the topically-administered formamidine repellent is applied to the eyelid.

[0084] In some configurations, the topically-administered formamidine anthelmintic is applied to the affected area of ​​skin at least once and no more than twice daily for a period of about two to four weeks.

[0085] In some configurations, the topically applied formamidine anthelmintic is encapsulated within microliposomes prior to formulation into the carrier lotion, cream, or gel.

[0086] In some configurations, disclosed herein are compositions for treating blepharitis and / or rosacea comprising an oral or topical pharmaceutical formulation of a formamidine anthelmintic in an amount sufficient to eliminate Demodex mites at one or more anatomical locations, resulting in cessation of manifestations of blepharitis and / or rosacea.

[0087] In some configurations, disclosed herein are methods of treating cylindrical eyelash dandruff associated with blepharitis and / or ocular rosacea in the eye, the methods comprising topically administering directly to the conjunctiva and / or cornea of ​​an eye of an individual in need of such treatment an effective amount of a formamidine repellent formulated in an eyewash composition having a pharmaceutically acceptable vehicle thereof, the eyewash composition being sterile, non-irritating, and compatible with ocular tissue.

[0088] In some configurations, 0.001% to 10% by weight of the formamidine anthelmintic is administered relative to the total weight of the composition.

[0089] In some configurations, 0.01% to 5% of the formamidine anthelmintic is administered relative to the total weight of the composition.

[0090] In some configurations, 0.03% by weight of the formamidine anthelmintic is administered relative to the total weight of the composition.

[0091] In some configurations, 0.10% by weight of the formamidine anthelmintic is administered relative to the total weight of the composition.

[0092] In some configurations, disclosed herein are methods of treating blepharitis and / or rosacea by orally administering or topically applying a formamidine anthelmintic in a dose sufficient to populate and eliminate Demodex mites at one or more anatomical locations, resulting in cessation of manifestations of blepharitis and / or rosacea.

[0093] In some configurations, the dosage of the formamidine anthelmintic is repeated about 2 to 4 times with intervals of 3 to 7 days therebetween.

[0094] In some configurations, the topically applied formamidine anthelmintic is formulated as a carrier lotion, cream, or gel.

[0095] In some configurations, the concentration of the formamidine repellent in the topically applied lotion, cream, or gel is about 1% to 5% by weight.

[0096] In some configurations, the topically-administered formamidine repellent is applied to the eyelid.

[0097] In some configurations, the topically-administered formamidine anthelmintic is applied to the affected area of ​​skin at least once and no more than twice daily for a period of about two to four weeks.

[0098] In some configurations, the topically applied formamidine anthelmintic is encapsulated within microliposomes prior to formulation into the carrier lotion, cream, or gel.

[0099] In some configurations, disclosed herein are compositions for treating blepharitis and / or rosacea comprising an oral or topical pharmaceutical formulation of a formamidine anthelmintic in an amount sufficient to eliminate Demodex mites at one or more anatomical locations, resulting in cessation of manifestations of blepharitis and / or rosacea.

[0100] In some configurations, disclosed herein are methods of treating symptoms of blepharitis and / or ocular rosacea in the eye, the symptoms selected from: burning sensation of the eye, stinging sensation of the eye, dryness of the eye, increased sensitivity to light, blurred vision, and complications of ocular rosacea in the cornea, the method comprising topically administering directly to the conjunctiva and / or cornea of ​​the eye of an individual in need of such treatment an effective amount of a formamidine repellent formulated in an eyewash composition having a pharmaceutically acceptable vehicle thereof, the eyewash composition being sterile, non-irritating, and compatible with ocular tissue.

[0101] In some configurations, 0.001% to 10% by weight of the formamidine anthelmintic is administered relative to the total weight of the composition.

[0102] In some configurations, 0.01% to 5% of the formamidine anthelmintic is administered relative to the total weight of the composition.

[0103] In some configurations, 0.03% by weight of the formamidine anthelmintic is administered relative to the total weight of the composition.

[0104] In some configurations, 0.10% by weight of the formamidine anthelmintic is administered relative to the total weight of the composition.

[0105] In some configurations, disclosed herein are methods of treating blepharitis and / or rosacea by orally administering or topically applying a formamidine anthelmintic in a dose sufficient to populate and eliminate Demodex mites at one or more anatomical locations, resulting in cessation of manifestations of blepharitis and / or rosacea.

[0106] In some configurations, the dosage of the formamidine anthelmintic is repeated about 2 to 4 times with intervals of 3 to 7 days therebetween.

[0107] In some configurations, the topically applied formamidine anthelmintic is formulated as a carrier lotion, cream, or gel.

[0108] In some configurations, the concentration of the formamidine repellent in the topically applied lotion, cream, or gel is about 1% to 5% by weight.

[0109] In some configurations, the topically-administered formamidine repellent is applied to the eyelid.

[0110] In some configurations, the topically-administered formamidine anthelmintic is applied to the affected area of ​​skin at least once and no more than twice daily for a period of about two to four weeks.

[0111] In some configurations, the topically applied formamidine anthelmintic is encapsulated within microliposomes prior to formulation into the carrier lotion, cream, or gel.

[0112] In some configurations, disclosed herein are compositions for treating blepharitis and / or rosacea comprising an oral or topical pharmaceutical formulation of a formamidine anthelmintic in an amount sufficient to eliminate Demodex mites at one or more anatomical locations, resulting in cessation of manifestations of blepharitis and / or rosacea.

[0113] In some configurations, disclosed herein are methods of treating cylindrical eyelash scaling associated with blepharitis and / or ocular rosacea in the eye, the methods comprising topically administering directly to the conjunctiva and / or cornea of ​​the eye of an individual in need of such treatment an effective amount of a formamidine repellent formulated in an eyewash composition having a pharmaceutically acceptable vehicle thereof, the eyewash composition being sterile, non-irritating, and compatible with ocular tissue.

[0114] In some configurations, 0.001% to 10% by weight of the formamidine anthelmintic is administered relative to the total weight of the composition.

[0115] In some configurations, 0.01% to 5% of the formamidine anthelmintic is administered relative to the total weight of the composition.

[0116] In some configurations, 0.03% by weight of the formamidine anthelmintic is administered relative to the total weight of the composition.

[0117] In some configurations, 0.10% by weight of the formamidine anthelmintic is administered relative to the total weight of the composition.

[0118] In some configurations, disclosed herein are methods of treating blepharitis and / or rosacea by orally administering or topically applying a formamidine anthelmintic in a dose sufficient to populate and eliminate Demodex mites at one or more anatomical locations, resulting in cessation of manifestations of blepharitis and / or rosacea.

[0119] In some configurations, the dosage of the formamidine anthelmintic is repeated about 2 to 4 times with intervals of 3 to 7 days therebetween.

[0120] In some configurations, the topically applied formamidine anthelmintic is formulated as a carrier lotion, cream, or gel.

[0121] In some configurations, the concentration of the formamidine repellent in the topically applied lotion, cream, or gel is about 1% to 5% by weight.

[0122] In some configurations, the topically-administered formamidine repellent is applied to the eyelid.

[0123] In some configurations, the topically-administered formamidine anthelmintic is applied to the affected area of ​​skin at least once and no more than twice daily for a period of about two to four weeks.

[0124] In some configurations, the topically applied formamidine anthelmintic is encapsulated within microliposomes prior to formulation into the carrier lotion, cream, or gel.

[0125] In some configurations, disclosed herein are compositions for treating blepharitis and / or rosacea comprising an oral or topical pharmaceutical formulation of a formamidine anthelmintic in an amount sufficient to eliminate Demodex mites at one or more anatomical locations, resulting in cessation of manifestations of blepharitis and / or rosacea.

[0126] In some configurations, disclosed herein are methods of treating symptoms of blepharitis and / or ocular rosacea in the eye, the symptoms selected from: burning sensation of the eye, stinging sensation of the eye, dryness of the eye, increased sensitivity to light, blurred vision, and complications of ocular rosacea in the cornea, the method comprising topically administering directly to the conjunctiva and / or cornea of ​​the eye of an individual in need of such treatment an effective amount of a phenylpyrazole insect repellent formulated in an eyewash composition having a pharmaceutically acceptable vehicle thereof, the eyewash composition being sterile, non-irritating, and compatible with ocular tissue.

[0127] In some configurations, 0.001% to 10% by weight of the phenylpyrazole anthelmintic is administered relative to the total weight of the composition.

[0128] In some configurations, 0.01% to 5% of the phenylpyrazole anthelmintic is administered relative to the total weight of the composition.

[0129] In some configurations, 0.03% by weight of the phenylpyrazole anthelmintic is administered relative to the total weight of the composition.

[0130] In some configurations, 0.10% by weight of the phenylpyrazole anthelmintic is administered relative to the total weight of the composition.

[0131] In some configurations, disclosed herein are methods of treating blepharitis and / or rosacea by orally administering or topically applying a phenylpyrazole anthelmintic in a dose sufficient to populate and eliminate Demodex mites at one or more anatomical locations, resulting in cessation of manifestations of blepharitis and / or rosacea.

[0132] In some configurations, the dose of the phenylpyrazole anthelmintic is repeated about 2 to 4 times with intervals of 3 to 7 days therebetween.

[0133] In some configurations, the topically applied phenylpyrazole anthelmintic is formulated as a carrier lotion, cream, or gel.

[0134] In some configurations, the concentration of the phenylpyrazole insect repellent in the topically applied lotion, cream, or gel is about 1% to 5% by weight.

[0135] In some configurations, the topically-administered phenylpyrazole insect repellent is applied to the eyelid.

[0136] In some configurations, the topically-administered phenylpyrazole anthelmintic is applied to the affected area of ​​skin at least once and no more than twice daily for a period of about two to four weeks.

[0137] In some configurations, the topically applied phenylpyrazole anthelmintic is encapsulated within microliposomes prior to formulation into the carrier lotion, cream, or gel.

[0138] In some configurations, disclosed herein are compositions for treating blepharitis and / or rosacea comprising an oral or topical pharmaceutical formulation of a phenylpyrazole anthelmintic in an amount sufficient to eliminate Demodex mites at one or more anatomical locations, resulting in cessation of manifestations of blepharitis and / or rosacea.

[0139] In some configurations, disclosed herein are methods of treating cylindrical eyelash scaling associated with blepharitis and / or ocular rosacea in the eye, the methods comprising topically administering directly to the conjunctiva and / or cornea of ​​the eye of an individual in need of such treatment an effective amount of a phenylpyrazole insect repellent formulated in an eyewash composition having a pharmaceutically acceptable vehicle thereof, the eyewash composition being sterile, non-irritating, and compatible with ocular tissue.

[0140] In some configurations, 0.001% to 10% by weight of the phenylpyrazole anthelmintic is administered relative to the total weight of the composition.

[0141] In some configurations, 0.01% to 5% of the phenylpyrazole anthelmintic is administered relative to the total weight of the composition.

[0142] In some configurations, 0.03% by weight of the phenylpyrazole anthelmintic is administered relative to the total weight of the composition.

[0143] In some configurations, 0.10% by weight of the phenylpyrazole anthelmintic is administered relative to the total weight of the composition.

[0144] In some configurations, disclosed herein are methods of treating blepharitis and / or rosacea by orally administering or topically applying a phenylpyrazole anthelmintic in a dose sufficient to populate and eliminate Demodex mites at one or more anatomical locations, resulting in cessation of manifestations of blepharitis and / or rosacea.

[0145] In some configurations, the dose of the phenylpyrazole anthelmintic is repeated about 2 to 4 times with intervals of 3 to 7 days therebetween.

[0146] In some configurations, the topically applied phenylpyrazole anthelmintic is formulated as a carrier lotion, cream, or gel.

[0147] In some configurations, the concentration of the phenylpyrazole insect repellent in the topically applied lotion, cream, or gel is about 1% to 5% by weight.

[0148] In some configurations, the topically-administered phenylpyrazole insect repellent is applied to the eyelid.

[0149] In some configurations, the topically-administered phenylpyrazole anthelmintic is applied to the affected area of ​​skin at least once and no more than twice daily for a period of about two to four weeks.

[0150] In some configurations, the topically applied phenylpyrazole anthelmintic is encapsulated within microliposomes prior to formulation into the carrier lotion, cream, or gel.

[0151] In some configurations, disclosed herein are compositions for treating blepharitis and / or rosacea comprising an oral or topical pharmaceutical formulation of a phenylpyrazole anthelmintic in an amount sufficient to eliminate Demodex mites at one or more anatomical locations, resulting in cessation of manifestations of blepharitis and / or rosacea.

[0152] In some configurations, disclosed herein are methods of treating symptoms of blepharitis and / or ocular rosacea in the eye, the symptoms selected from: burning sensation in the eye, stinging sensation in the eye, dryness of the eye, increased sensitivity to light, blurred vision, and complications of ocular rosacea in the cornea, the method comprising topically administering directly to the conjunctiva and / or cornea of ​​the eye of an individual in need of such treatment an effective amount of a drug for treating Alzheimer's disease formulated in an eyewash composition having a pharmaceutically acceptable vehicle thereof, the eyewash composition being sterile, non-irritating, and compatible with ocular tissue.

[0153] In some configurations, 0.001% to 10% by weight of a drug for treating Alzheimer's disease is administered relative to the total weight of the composition.

[0154] In some configurations, 0.01% to 5% of the drug for treating Alzheimer's disease is administered relative to the total weight of the composition.

[0155] In some configurations, 0.03% by weight of a drug for treating Alzheimer's disease is administered relative to the total weight of the composition.

[0156] In some configurations, 0.10% by weight of a drug for treating Alzheimer's disease is administered relative to the total weight of the composition.

[0157] In some configurations, disclosed herein are methods of treating blepharitis and / or rosacea by orally administering or topically applying a drug for treating Alzheimer's disease in a dose sufficient to populate and eliminate Demodex mites at one or more anatomical locations, resulting in cessation of manifestations of blepharitis and / or rosacea.

[0158] In some configurations, the dose of the drug for treating Alzheimer's disease is repeated about 2 to 4 times with intervals of 3 to 7 days in between.

[0159] In some configurations, the topical medicament for treating Alzheimer's disease is formulated as a carrier lotion, cream, or gel.

[0160] In some configurations, 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.

[0161] In some configurations, the topically administered drug for treating Alzheimer's disease is administered to the eyelid.

[0162] In some configurations, the topically administered medicament for treating Alzheimer's disease is applied to the affected area of ​​skin at least once and no more than twice daily for a period of about 2 to 4 weeks.

[0163] In some configurations, the topically administered drug for treating Alzheimer's disease is encapsulated in microliposomes prior to formulation into the carrier lotion, cream or gel.

[0164] In some configurations, disclosed herein are compositions for treating blepharitis and / or rosacea comprising an oral or topical pharmaceutical formulation for treating Alzheimer's disease in an amount sufficient to eliminate Demodex mites at one or more anatomical locations, resulting in cessation of manifestations of blepharitis and / or rosacea. BRIEF DESCRIPTION OF THE DRAWINGS

[0165] Figure 1A -B schematically shows the application of an ophthalmic formulation on an eye infested with Demodex.

[0166] Figure 2 Data showing activity on selected Demodex anatomical structures following treatment with topical formulations are presented.

[0167] Figure 3A-3B An example of a formulation with amitraz and flurellan is shown.

[0168] Figures 4A-4C Embodiments of various Demodex diagnosis techniques that do not necessarily require hair removal are shown. DETAILED DESCRIPTION OF THE INVENTION

[0170] In some embodiments, topical therapeutic agents are disclosed herein, including but not limited to topical agents, which include one or more isoxazoline anthelmintics, formamidine anthelmintics, agents for treating Alzheimer's disease, and other agents for treating various ophthalmic and dermatological conditions as disclosed herein. Methods for treating blepharitis, ocular rosacea, and Demodex infection in patients in need are also disclosed herein. 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 limited by theory, isoxazoline anthelmintics can act as GABA-chloride antagonists to selectively target certain organisms, including but not limited to the nervous system of Demodex. GABA-mediated chloride influx can cause hyperpolarization of cell membranes and produce inhibitory postsynaptic potentials, which reduces the probability of action potentials and causes paralysis and ultimate death of Demodex. Isoxazoline anthelmintics can include, for example, flurana, sarolana, lotirana, afolan and / or fluoxazolamide, including derivatives, analogs and L-isomers and D-isomers of the above, including but not limited to enantiomers, compositions comprising racemic mixtures, and any one or more of optically pure compositions. In some embodiments, the isoxazoline anthelmintics, formamidine anthelmintics or other active ingredients disclosed herein are the only active ingredients utilized in the formulation and / or method. In some embodiments, the isoxazoline anthelmintics are benzamide derivatives substituted with isoxazoline. In some embodiments, the isoxazoline anthelmintics have one, two, three or more fluorine groups in their chemical structure, such as trifluoro groups (e.g., R-CF3).

[0171] Isoxazoline anthelmintics have been routinely used in veterinary applications, including chews and non-ophthalmic topical "pour on" solutions, but no human formulations have been developed to the inventor's knowledge. Non-limiting examples of isoxazoline anthelmintics can be found, for example, in U.S. Pat. No. 7,662,972 to Mita et al., U.S. Pat. No. 8,466,115 to Curtis et al., U.S. Pat. No. 7,964,204 to Lahm et al., and U.S. Pat. No. 8,383,659 to Nanchen et al., each of which is incorporated herein by reference in its entirety. In addition, 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, U.S. Publication No. 2010 / 0179194A2, U.S. Publication No. 2011 / 0086886A2, U.S. Publication No. 2011 / 0059988A1, U.S. Patent No. 2010 / 0179195 A1, PCT Publication No. WO2007 / 075459A2 and U.S. Patent No. 7,951,828 describe various other insecticidal isoxazoline compounds, all of which are incorporated herein by reference in their entirety. Oral veterinary preparations such as chews result in first-pass liver metabolism and systemic effects, which may be undesirable for targeted topical applications in some cases. An important challenge is that the fluorinated and / or chlorinated groups of certain isoxazoline anthelmintics cause these molecules to be highly insoluble in any drug-based solution, including oil-based and water-based solutions, and have a solubility of less than about 1 mg / kg, or 1 mg / mL aqueous concentration, or even lower. Veterinary topical solutions of isoxazoline anthelmintics include, for example, dimethylacetamide, glycofurol, diethyltoluamide and / or acetone. However, such solutions are indicated only as "sprinkle" solutions on the back of the neck of an animal such as a cat or dog, are not suitable for ophthalmic use (and are potentially toxic), and include instructions not to administer the solution in or around the eye. Such "sprinkle" solutions are absorbed systemically by the animal and do not result in only targeted local activity. To the best of the inventor's knowledge, topical ophthalmic formulations of isoxazoline anthelmintics or formamidine anthelmintics have not been developed previously. For example, there is a need for therapeutic formulations that are safe and nontoxic for ocular use and soluble enough to be therapeutically effective in treating ocular Demodex and related conditions such as blepharitis.

[0172] It has now been determined that compounds of the family of isoxazoline anthelmintics, formamidine anthelmintics, agents for treating Alzheimer's disease and / or other agents as disclosed elsewhere herein may be suitable for treating ophthalmic conditions of any origin, particularly ophthalmic conditions due to Demodex folliculorum, and more particularly blepharitis and / or ocular rosacea. Other conditions that can be treated by the formulations and methods as disclosed herein include, for example, rosacea, pityriasis folliculitis, demodicosis rosacea-like and demodicosis gravis, nonspecific facial dermatitis, steroid rosacea, androgenic alopecia, madarosis, lupus miliaris disseminates faciei, anatomic folliculitis, perioral dermatitis, acarica blepharoconjuncitivitis, papulopustular scalp eruptions, eosinophilic folliculitis, pustular folliculitis, Grover's disease, and demodicosis abscess.

[0173] Ivermectin is another drug that has been used to treat Demodex 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 formulations and / or methods do not involve avermectin, such as ivermectin or other macrolide derivatives. However, in other embodiments, the formulation may include avermectin.

[0174] Disclosed herein are various embodiments of systems, methods, and formulations for treating various ocular conditions including, but not limited to, blepharitis and treating Demodex infestation (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, ethylene glycol tetramethylene glycol ether, diethyltoluamide, and / or acetone, at least some of which may be toxic or irritating to the eye in some cases.

[0175] Also disclosed herein are uses of topical isoxazoline anthelmintics, formamidine anthelmintics, agents for treating Alzheimer's disease, and / or other agents as disclosed elsewhere herein for treating blepharitis in a patient in need thereof and methods of treating Demodex infestation and blepharitis in a patient in need thereof.

[0176] Also disclosed are topical isoxazoline anthelmintics, formamidine anthelmintics, agents for treating Alzheimer's disease, and / or other agents as disclosed elsewhere herein (e.g., from the isoxazoline anthelmintic family of chemicals) for use in treating rosacea and / or ocular rosacea in a patient in need thereof and methods of treating Demodex infestation and rosacea and / or ocular rosacea in a patient in need thereof. Also disclosed are formulations and methods for reducing Demodex counts and cylindrical eyelash scaling near the eyes of a patient.

[0177] Also disclosed herein are topical isoxazoline anthelmintics, formamidine anthelmintics, agents for treating Alzheimer's disease, and / or other agents as disclosed elsewhere herein for use in treating rosacea and / or ocular rosacea in a patient in need thereof and methods of treating Demodex infestation and rosacea and / or ocular rosacea in a patient in need thereof.

[0178] According to some embodiments, the pharmaceutical composition may include at least one, two or more compounds selected from the family of isoxazoline anthelmintics, including, for example, flurella, sarolana, lotirana, afollana and / or fluoxetine, which are administered particularly for the treatment of conjunctivitis, blepharitis, ocular rosacea or other indications, including other ocular surface diseases such as meibomian gland dysfunction or dry eye.

[0179] Some embodiments may include derivatives, analogs, and L- and D-isomers of isoxazoline anthelmintics, formamidine anthelmintics, or other active therapeutic agents as disclosed elsewhere herein, including, but not limited to, enantiomers, compositions comprising racemic mixtures, and optically pure compositions.

[0180] In some embodiments, it may be surprising to use a dose of an isoxazoline anthelmintic, a formamidine anthelmintic, an agent for treating Alzheimer's disease, and / or other agent as disclosed elsewhere herein that is lower than the dose that has shown clinical effectiveness in veterinary medicine acting by systemic absorption via topical irrigation or washing (e.g., concentrations in the range of 1-10 nM or 100 pM-1 nM, or a range including any two of the foregoing values). These lower effective concentrations may be, but are not limited to, due to direct absorption of the drug by the mite body rather than ingestion of the drug by the mite, the abdomen of the mite (~2 um) being thinner and more likely to absorb the drug than the cephalothorax of the mite (~0.5 um). In some embodiments, direct absorption of the drug by the mite body may be the mechanism responsible for at least about 50%, 60%, 70%, 80%, 90%, or more of the total uptake of the drug by the mite.

[0181] In some embodiments, daily and local treatments are given, rather than large, long-acting systemic doses (as in veterinary medicine, once a month, every 8 weeks, every 12 weeks, every 16 weeks, or less frequently). However, in other embodiments, long-acting systemic or local doses may be used.

[0182] In some embodiments, administration can be, for example, about or at least about 1, 2, 3, 4, 5, 6, 7, 8 or more times per day, such as 1-2 times per day. In some embodiments, treatment can also be weekly, single dose or limited course of treatment. In some embodiments, the formulation can be preferably used in the morning, at night or only at night to target exposure to mites during mating.

[0183] In some embodiments, formulations may be advantageous due in part to the slow elimination rates of molecules such as isoxazoline anthelmintics, however, small topical doses allow for repeated and frequent dosing, which may be beneficial for disrupting the Demodex life cycle by affecting the more susceptible juvenile forms without the associated systemic risks and side effects.

[0184] In some embodiments, the active molecule may preferably be hydrophobic so that it concentrates in areas with sebum or meibum oil (e.g., eyelash follicles and / or meibomian glands). The formulation may preferably be water-based to facilitate delivery to and absorption by the hydrophilic chitin chitosan on the exterior of the Demodex mite.

[0185] In some embodiments, the therapeutic agent can be delivered in the form of drops, creams, ointments, eye washes, liniments, ointments or gels or immediate release formulations or sustained release formulations. In some embodiments, the therapeutic agent can be delivered in the form of punctal plugs or punctal plugs or emulsions. In some cases, oily, gel-like, viscous ointments can also prevent Demodex from moving across the skin surface during mating.

[0186] In some embodiments, the isoxazoline anthelmintics, formamidine anthelmintics, agents for treating Alzheimer's disease, and / or other agents as disclosed elsewhere herein may have preferential selectivity for insect / mite / acarina receptors relative to vertebrate / mammalian / human receptors.

[0187] In some embodiments, the active agent is delivered in an oral formulation (e.g., tablet, capsule, solution, etc.), and very small doses may be delivered to avoid significant systemic exposure or non-local skin exposure (contrary to veterinary teachings). However, in some embodiments, the active agent is delivered in a non-oral formulation, such as a topical formulation, e.g., a topical ophthalmic formulation.

[0188] In some embodiments, the dosage is, for example, 1 microgram to 1 mg / ml or 0.0001%-1% by weight of an active agent (e.g., an isoxazoline anthelmintic, a formamidine anthelmintic, an agent 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%, 0.70%, 0.80%, 0.90%, 0.110%, 0.120%, 0.130%, 0.140%, 0.150%, 0.160%, 0.170%, 0.180%, 0.190%, 0.210%, 0.220%, 0.230%, 0.240%, 0.250%, 0.260%, 0.270%, 0.280%, 0.290%, 0.300%, 0.310%, 0.320%, 0.330%, 0.340%, 0.350%, 0.360%, 0.370%, 0.380%, 0.390%, 0.401%, 0.410%, 0.420%, 0.430%, 0.440%, 0.4 %, 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 foregoing values, or 1 ng-1 microgram / ml or 0.0000001%-0.0001% by weight of active agent (e.g., isoxazoline anthelmintics, formamidine anthelmintics, agents for treating Alzheimer's disease, and / or other agents as disclosed elsewhere herein), or 1 mg / ml–100 mg / ml or 0.1%-10% by weight of active agent (e.g., isoxazoline anthelmintics, formamidine anthelmintics, agents for treating Alzheimer's disease, and / or other agents as disclosed elsewhere herein), or a range including any one of the foregoing values. In some embodiments, an isoxazoline anthelmintic, a formamidine anthelmintic, an agent treating Alzheimer's disease, or other agent as disclosed elsewhere herein is the only active agent.

[0189] In some embodiments, the ophthalmic preparation can be formulated for direct delivery to the ocular surface, including but not limited to the conjunctiva and / or cornea of ​​the eye. In some embodiments, the ophthalmic preparation can be formulated for direct or indirect delivery to any one or more of the anterior or posterior eyelid, 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 eyelid, eyelashes, or eyebrows.

[0190] Eye drop preparations can be designed to specifically and simultaneously treat blepharitis and Demodex in eyelash follicles and / or meibomian glands, but are not limited to delivery tools such as eyelash brushes or application sites due to oily additives, emulsions, preparations based on ointments or creams. In some embodiments, the "Drop and Coat the Lashes" (DACTL) technique can be used. Patients can be instructed to administer to closed eyes so that the preparation contacts the meibomian gland opening on the eyelid margin and accumulates the preparation outside the eyelid margin. Then, patients can apply the preparation accumulated outside the eyelid margin to the follicles of the eyelashes and / or lower eyelashes and / or upper eyelashes using their fingers or applicators. Not limited by theory, since Demodex is present both in the eyelash follicles and in the meibomian glands, it may be advantageous to apply the eye drop preparation directly to one or both of these locations. Since the combination of these two targets is unique to this disease, the therapeutic agent can be delivered to these locations simultaneously. The meibomian gland openings are located on the upper and lower surfaces of the lower eyelid and upper eyelid, respectively. Thus, eye drops placed directly on the ocular surface allow for direct delivery of the formulation to both the superior and inferior meibomian gland openings.

[0191] Methods of treating blepharitis and / or Demodex infestation may include specific delivery of the formulation / treatment (or the like) by applying drops in the eye and then coating the base of the hair follicles in the upper and / or lower eyelids using a finger or an instrument (e.g., a mascara brush). In some embodiments, desirable features of the formulation may include maximizing drug water solubility to increase bioavailability (in solutions and suspensions), using polymers / viscosity agents to improve residence time of the drug product in the eye, and achieving any one or more of acceptable visual acuity and comfort.

[0192] The viscosity of the formulation may, in some embodiments, be high enough to cause the formulation to coat the meibomian gland openings on the upper and / or lower eyelid margins when the eye is blinked or closed.

[0193] In some cases, the viscosity may be high enough to slow the drainage of the formulation through the tear puncta for at least 5 seconds, or 10 seconds, or 20 seconds, or 30 seconds or longer to enhance the contact time of the formulation with the meibomian gland openings and allow the formulation to overflow the eyelid margin to a location where it can be accessed for delivery to the eyelash follicles (e.g., by runoff and / or by applying the formulation using fingers and / or an instrument).

[0194] The formulation ingredients may be selected to allow the active agent to dissolve into solution, but with a low concentration of organic solvent by weight, e.g., ≤50%, 20%, 10%, 5%, 2% or 1% by weight, or less or more organic solvent. This may be achieved at least in part by using a surfactant such as, for example, polysorbate-80 or polysorbate-20. In some cases, it may be preferred to use low concentrations of polysorbate 80, as higher concentrations may cause hydrolysis of the isoxazoline anthelmintic (e.g., 0.001%-0.1% by weight of polysorbate 80).

[0195] In some cases, this can also be achieved by enhancing the solubility of the isoxazoline repellent with an organic solvent such as propylene glycol.

[0196] The osmotic pressure can also be minimized by selecting appropriate additives to enhance both solubility and viscosity, such as polyvinyl alcohol, carboxymethyl cellulose, etc.

[0197] The formulation ingredients can be selected to enable the active agent (e.g., isoxazoline anthelmintic or other active agent) to dissolve into solution, and can be selected to be stable to hydrolysis for 1, 1.5, 2 years or longer to achieve a commercial shelf life, for example, with an optimal pH range of neutral to slightly alkaline (e.g., in other embodiments, pH 7-10, 7-7.5 or pH 5-7).

[0198] In some cases, the buffer concentration required to achieve the desired pH can be minimized, thereby slowing the rate of hydrolysis (e.g., phosphate buffer concentration 0.01-0.1 M). This can also be achieved using organic solvents and surfactants in the above concentration ranges.

[0199] Cationic surfactants can also be beneficial by retarding the rate of hydrolysis by creating cationic micelles.

[0200] Emulsions and emulsifiers can be mixed with water to prevent the isoxazoline anthelmintics, formamidine 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, with carbodiimide additives to prolong stability by forming more complex anhydrous micelles.

[0201] Water scavengers such as Stabaxol can be added (bis-2,6-diisopropylphenylcarbodiimide) to achieve long-term oil-based formulations to remove solvents in water.

[0202] In some embodiments, the pharmaceutical composition may comprise at least one compound selected from isoxazoline anthelmintics, formamidine anthelmintics, agents for treating Alzheimer's disease, and / or other agents and / or other families of active agents, which are particularly useful for treating ophthalmic symptoms, symptoms selected from the following: burning or stinging sensation or perception of the eye, foreign body sensation or perception in the eye, dry eye sensation or perception, increased sensitivity to light, blurred vision, eyelid telangiectasia, blepharitis, chalazion, conjunctival hyperemia, and papillary conjunctivitis.

[0203] The term "treatment" may include treatment in humans and / or other animals.

[0204] Pharmaceutical compositions according to some embodiments of the invention may be used for topical, oral, parenteral or rectal treatment of the eye.

[0205] Topical administration is the most common method of administering ophthalmic drugs. Topical routes enable the instillation of drops into the eye, or the application of solutions, eyewashes, suspensions, ointments, pastes, gels, sprays, foams, powders, lotions, viscoelastic solutions into the eye, and / or the formulation of solid forms, impregnated pads, compositions or wipes at the ocular surface.

[0206] Some preparations can also be provided in the form of suspensions of microspheres or nanospheres or vesicles formed by lipids or polymers or polymer patches and hydrogels that enable controlled release. These compositions for topical administration can be provided in anhydrous form, aqueous form or emulsion form.

[0207] The pharmaceutical composition for topical application is preferably non-irritating and compatible with eye tissue. The solution can be a sterile preparation and may not contain all particles. The suspension can be a sterile preparation and may include solid particles in a liquid vehicle suitable for eye instillation. The ointment can be a semisolid and sterile preparation.

[0208] Orally, the pharmaceutical composition can be provided in liquid, pasty 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 by lipids or polymers that make controlled release possible. Parenterally, the composition can be provided in the form of a solution or suspension for infusion or for injection. Rectally, the composition can be provided in the form of a suppository. In some cases, the pharmaceutical composition is a topical ophthalmic composition, rather than an oral or rectal composition.

[0209] In some embodiments, the composition may comprise from 0.001% to 10% by weight, relative to the total weight of the composition, of at least one compound selected from the family of isoxazoline anthelmintics, formamidine anthelmintics, agents for treating Alzheimer's disease and / or other agents as disclosed herein. In some embodiments, the composition according to the invention comprises from 0.01% to 5% by weight, relative to the total weight of the composition, of at least one compound selected from the family of isoxazoline anthelmintics.

[0210] In some embodiments, the composition according to the present invention is provided in the form of an eyewash or eye drops. The term "eyewash" means a liquid formulation particularly suitable for administration to the conjunctiva and cornea of ​​the eye. The eyewash may include, for example, drops of instillation in a volume of about 25-50 microliters. In some embodiments, the composition is provided as a kit, such as eye drops and shampoo, and can be used with a sterilizing agent such as tea tree oil and derivatives and hypochlorous acid, which has also been shown to have demodex activity, or in some cases does not include tea tree oil or other oils.

[0211] As indicated above, in some embodiments, the composition may meet specific conditions for administration in the eye. Such conditions include, among others, sterility, non-irritation, and compatibility with eye tissue. The latter criteria are more difficult to obtain than for compositions intended for use on the skin; in particular, compounds such as ethanol or ethylene glycol formulated into compositions intended for application to the skin cannot, in some cases, be included in compositions intended for use on the eye.

[0212] Topical compositions may make it possible to treat the symptoms of disorders in the eye and eyelid directly and specifically by local action; in particular, since only the eye is targeted, a better effect may be expected.

[0213] In some embodiments, the formulation may be in the form of a solution, suspension, cream, ointment, or other form.

[0214] Liquid compositions formulated for topical ophthalmic use are formulated so that they can be topically administered to the eye. Comfort can be maximized as much as possible, although sometimes formulation considerations (e.g., drug stability) may require less than optimal comfort. In situations where comfort cannot be maximized, liquids can be formulated so that the liquid is tolerable for topical ophthalmic use by the patient. In addition, ophthalmologically acceptable liquids can be packaged for single use, or contain preservatives to prevent contamination during multiple uses.

[0215] For ophthalmic applications, physiological saline solutions are usually used as the main vehicle to prepare solutions or medicines. These vehicles include, but are not limited to, polyvinyl alcohol, povidone, hydroxypropyl methylcellulose, poloxamer, carboxymethyl cellulose, hydroxyethyl cellulose and purified water. Ophthalmic solutions can preferably be maintained at a comfortable pH with an appropriate buffer system. The preparation can also contain pharmaceutically acceptable preservatives, stabilizers and surfactants.

[0216] In some embodiments, the topical formulation does not include a skin penetration enhancer, which can increase systemic absorption and in some cases contradict the intent to maintain the formulation topically at or near the site of administration. In some embodiments, the formulation does not include any skin penetration enhancer, such as one or more of the following: With laurocapone derivatives, such as 1-alkylazacycloheptan-2-one, and oleic acid and its ester derivatives, such as methyl, ethyl, propyl, isopropyl, butyl, vinyl and glycerol 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-pyrrolidone, and those skin penetration enhancers, such as (N, N-dimethylamino) dodecyl acetate and (N, N-dimethylamino) dodecyl propionate and 2-n-nonyl-1-3-dioxolane. However, some embodiments of the preparation may include one or more skin penetration enhancers.

[0217] In some embodiments, the topical formulation may include one or more gelling agents. The gelling agent may be a copolymer such as Pemulen TMTR1 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 hydrophilic and hydrophobic portions within the molecule. 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. Thus, for example, they can be useful in the development of low irritation lotions and creams. Pemulen polymers provide viscosity building and high yield values ​​to allow suspension and stabilization of insoluble materials and particles. In some embodiments, the gelling agent may be absent, 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 of the formulation, or a range comprising any two of the foregoing values.

[0218] In some embodiments, oil-based formulations such as creams, ointments or emulsions may, for example, include one or more of mineral oil, castor oil or petrolatum, for example, from about 20% to about 80%, or from about 30% to about 70% w / w of the formulation. The formulation may also include cyclodextrin as a carrier molecule to facilitate dissolution.

[0219] In some embodiments, topical preparations may include one or more thickeners, including polysaccharide thickeners, such as hydroxypropylmethylcellulose (HPMC) and sodium CMC. In some embodiments, the thickener may be present in an amount of 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 of the preparation, or in an amount of about 0.1% to about 0.5% including any two of the aforementioned values. In some embodiments, the preparation may have a viscosity of about 50cp to about 100cp to increase the residence time of the preparation in the eye. In some embodiments, the formulation may include, for example, a viscosity 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 greater, 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 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.

[0220] In some embodiments, topical formulations 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, it has been found that polysorbate 80 unexpectedly increases the solubility of isoxazoline insect repellents relative to other polysorbates. In addition to nonionic surfactants, other surfactants, such as fluorinated surfactants, may also be substituted or used. In some embodiments, the solubilizer and / or surfactant can 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 of the formulation, or a range including any two of the foregoing values. Polysorbate 80 can also be replaced by Cremphor EL (hydrogenated castor oil) 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 the FDA monograph limit to promote higher drug concentrations.

[0221] 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 may advantageously and unexpectedly form a durable film layer.

[0222] In some embodiments, for example, topical formulations may include one or more tonicity agents, such as glycerol, dextrose, mannitol, potassium chloride, and / or sodium chloride. In some embodiments, the tonicity agent may be present in an amount of 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 of the formulation, or a range including any two of the foregoing values.

[0223] In some embodiments, the topical formulation may include one, two or more buffers. The buffer may include, for example, acetate buffer, citrate buffer, phosphate buffer, and borate buffer. Acid or base may be used to adjust the pH of these formulations as needed. The buffer 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-acetylamino)-2-iminodiacetic acid) buffer, AMPSO (3-[(1,1-dimethyl-2-hydroxyethyl)amino]-2-propanesulfonic acid) buffer, BE S (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, HEPPS (N- (2 1-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; TAPS (N-tris[hydroxymethyl) In some embodiments, the buffer is Tris and / or sodium dihydrogen phosphate (Na2HPO4) and sodium dihydrogen phosphate heptahydrate (NaH2PO47H2O).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%, 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%, 0.50%, 0.55%, 0.60%, 0.65%, 0.70%, 0.75%, 0.80%, 0.85%, 0.90%, 0.95%, 1.00% w / w of the formulation, or a range comprising any two of the foregoing values. A therapeutically effective amount of a buffer can be selected so 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 comprising any two of the foregoing values.

[0224] In some embodiments, topical preparations may include one or more preservatives, including but not limited to lauralkonium chloride and benzalkonium chloride. Other preservatives may include, for example, PHMB, chlorobutanol, thimerosal, phenylmercury, acetate and phenylmercury nitrate. In some embodiments, preservatives may be present in topical preparations in an amount of 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 of the preparation, or in an amount of any two aforementioned values.

[0225] The pharmaceutical composition according to some embodiments of the present invention may additionally include inert additives or combinations of these additives, such as: wetting agents, emollients; agents for improving flavor; preservatives; stabilizers; agents for regulating moisture; pH adjusting agents; buffers; agents for regulating osmotic pressure; emulsifiers; agents for increasing viscosity; and antioxidants. Ophthalmologically acceptable antioxidants include, but are not limited to, sodium pyrosulfite, sodium thiosulfate, acetylcysteine, butylated hydroxyanisole, and butylated hydroxytoluene. Other excipient components that may be included in ophthalmic preparations are chelating agents. Available chelating agents are disodium ethylenediaminetetraacetic acid (EDTA), although other chelating agents may also be appropriately used or used in combination therewith.

[0226] 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, the vitamin E is tocopherol; in other embodiments, the tocopherol is alpha-tocopherol or gamma-tocopherol; more preferably, alpha-tocopherol. In some embodiments, the pharmaceutical composition does not include tocopherol.

[0227] In some embodiments, the pharmaceutical formulation 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 aldehyde or myrcene. However, some embodiments may include one or more of the foregoing essential oils.

[0228] In some embodiments, optional one or more compounds may be added to these compositions such that the advantageous properties inherently associated with some embodiments of the invention are not or are not substantially adversely affected by the contemplated additions, such as tetracycline or omega-3 fatty acids, which may have a beneficial effect in blepharitis.

[0229] In some embodiments, the isoxazoline anthelmintic is orally administered to patients suffering from blepharitis, rosacea, or other conditions disclosed elsewhere herein. Because one target organism, Demodex folliculorum (and / or Demodex sebaceum), is an ectoparasite in the family Acaridae, effective treatment in some cases is to therapeutically eradicate the entire life cycle of this microscopic insect, including the egg, larvae, and adult stages. To this end, some embodiments treat blepharitis and / or rosacea patients with at least two timed doses, such that the doses are separated by about 3 to about 7 days. This interval allows time for the Demodex eggs to hatch into immature mites, which are killed before they can mature into egg-laying adults. In some embodiments, 1, 2, 3, 4, or more doses may be used, separated by three to seven days. After the isoxazoline anthelmintics or other active agents disclosed herein have acaricidal activity against the skin follicular Demodex organisms (and / or sebaceous Demodex), the inflammatory response to them begins to decrease, but the residue of dead mites still causes some flushing and lesion formation until the body's clearance process removes them, which in some cases requires 6-8 weeks. During this initial dosing phase, other drugs such as oral tetracycline and topical metronidazole, and / or anti-inflammatory agents such as NSAIDs and / or steroids can be used to suppress early flareups and provide early clinical response. However, in some embodiments, the formulation or method does not involve tetracycline or other antibiotics, steroids and / or metronidazole. After a long symptom-free interval, if the classic signs begin to reappear, the treatment can be repeated.

[0230] In an alternative embodiment, the isoxazoline repellent may be formulated into a cosmetically acceptable topical lotion, cream or gel and applied to the skin, eyelids, eyelashes, meibomian glands, or other anatomical locations as shown elsewhere herein. In some cases, such a therapeutic approach may require one or two applications per day for up to 4 weeks to achieve adequate follicular penetration and effective acaricidal activity. In some cases, a topical formulation that can achieve this effect may contain, for example, about 0.01%-5% active ingredient, and penetration may be enhanced if the active agent is encapsulated in microliposomes. Such topical treatment may need to be repeated more frequently than the preferred oral embodiment, but disease-free intervals should be achieved with each course of treatment.

[0231] In some embodiments, a pharmaceutical formulation, including any disclosed herein, can be formulated to advantageously allow eradication of mites near the eyelashes via preferential absorption of the pharmaceutical formulation through the mite's exoskeleton (e.g., abdomen or opisthsoma) rather than ingestion of the pharmaceutical formulation by the mite (e.g., via ingestion of skin cells, sebum, and other sites that may include an amount of active agent via systemic absorption). Without being limited by theory, Demodex mites have a hydrophobic chitinous outer surface and a relatively thin exoskeleton in the abdomen / opisthoma region (about 0.5 μm, compared to about 2.0 μm for the cephalothorax), which surprisingly allows the formulation to be absorbed more rapidly through the abdomen rather than primarily via ingestion (as in previous veterinary formulations of isoxazoline anthelmintics). Figure 1A -B schematically illustrates application of formulation 120 to eye 140 having iris / pupil 142. Eyelids surrounding eye 140 may include follicles 180 of eyelashes 186, and follicles 180 may include sebum 182. Eyelids may include meibomian glands 160 having meibum 162. Figure 1A -B, the "face down" orientation of the mite (e.g., Demodex folliculorum 164, Demodex sebaceus 184) relative to the hair follicle 180 or meibomian gland 160 (with the mite body pointing toward the opening of the hair follicle 180 or gland 160) can promote preferential abdominal absorption of the formulation 120 through the abdominal / posterior body region 190. In ex vivo studies, it has been surprisingly observed that the abdomen and tail of the Demodex mite stop moving faster than the cephalothorax after delivery of certain drug formulations as disclosed herein (e.g., Figure 2 ), indicating that Demodex mites are particularly sensitive to topical ophthalmic formulations as disclosed herein.

[0232] In some embodiments, the compositions and methods as disclosed herein can be used in a topical or other form, alone or in combination with any one or more of the following agents, which can be formulated to have parameters including any characteristics, including but not limited to concentration, excipients, and other characteristics, or the absence of other characteristics as disclosed elsewhere herein: albendazole, cambendazole, fenbendazole, flubendazole, mebendazole, oxfendazole, parabendazole, thiabendazole, triclabendazole, amitraz, demiditraz, clorsulon, closantel, oxyclonazide, rafonide, cypermethrin, flumethrin, permethrin, promazine, derquantel, difenantide, dicynil, dinotefuran, imidacloprid, nitenpyram, thiamethoxam, avermectin, doramectin , emamectin, epnnomectin, ivermectin, moxidectin, selamectin, milbemycin oxime, emodepside, epsiprantel, fipronil, fluazuron, fluhexafon, indoxacarb, levamisole, lufenuron, metaflumizone, methoprene, monepantel, morantel, niclosamide, nitrosocyanate, nitroiodine, novaluron, octadecyl, praziquantel, pyrantel, pynprole, pyriproxyfen, sisaproml, spinosad, spinosad, lindane, picrotoxin, dieldrin, alpha-endosulfan and / or triflumezopyrim. In some embodiments, the compositions and methods may include metadiamides (e.g., broflanilide), cyclodienes, and / or macrolides (including avermectins and milbemycins). In some embodiments, Alzheimer's disease drugs may be active agents 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 activity. For example, galantamine is a selective, competitive, rapidly reversible acetylcholinesterase inhibitor with anionic substrates and aromatic gorges, as well as an allosteric ligand / activator at nicotinic cholinergic receptors, thereby increasing GABA activity. Other acetylcholinesterase inhibitors may also be used in some cases.Derivatives, analogs, and L-isomers and D-isomers thereof may also be used, including but not limited to enantiomers, compositions comprising racemic mixtures, and optically pure compositions of any of the above in this paragraph. In some embodiments, the formulation does not include any one or more or all of the agents listed in this paragraph.

[0233] In some embodiments, the dermatological and / or ophthalmic preparations may include an active therapeutic agent of a formamidine anthelmintic instead of or in addition to an isoxazoline anthelmintic as disclosed above. The formamidine anthelmintic may be, for example, amitraz, which may be used as an octopamine receptor modulator. N-(2,4-dimethylphenyl)-N-methylformamidine (DPMF), a metabolite of amitraz, is believed to be 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 hydrolysis metabolite of DPMF and may also be an active therapeutic agent in other embodiments. Derivatives, analogs, and L-isomers 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, the dermatological and / or ophthalmic formulations may include an active therapeutic agent of a phenylpyrazole anthelmintic instead of or in addition to an isoxazoline or formamidine anthelmintic as disclosed above. The chemical structure of these insecticides is characterized by a central pyrazole ring having a phenyl group attached to one of the nitrogen atoms of the pyrazole. Some non-limiting examples of phenylpyrazole anthelmintics include, for example, acetoprole, ethiprole, fipronil, butenefipronil, pyraclofos, pyriprole, pyrolan, and vaniliprole.

[0234] To further illustrate some embodiments and their advantages, several non-limiting specific examples of topical isoxazoline anthelmintic formulations are listed in Table 1 below for illustrative purposes only. All ingredients are listed as % w / w or grams per 100 grams of formulation, and Figure 3A-3B An example of a formulation with amitraz and flurellan is shown.

[0235] An exemplary embodiment of an amitraz solution includes 0.100% w / w amitraz in 99.9% light mineral oil. Another example of an amitraz cream may include 0.100% w / w amitraz and 29.9% mineral oil and 70.0% petrolatum.

[0236] Table 1

[0237] Element Solution 1 Solution 2 Suspension 1 Flurellana 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 Lauratinium chloride 0.0050 0.0050 0.0050 water qsad 100% qsad 100% qsad 100%

[0238] In some embodiments, topical ophthalmic preparations may include the following instructions for use. Before applying the study drug, the patient may be instructed to shower or bathe first, and wash their hands before applying the study drug. Unit doses, such as single drops of preparations, may be applied directly to each eye once or twice a day, for example, once in the morning and once in the evening. After the drops are delivered to the conjunctiva and / or cornea of ​​the eye, the patient may close their eyes and apply slight pressure to the upper eyelid to squeeze the drug through their upper and lower eyelid margins. The preparation may then be allowed to dry without dabbing with a tissue. The preparation may then be stored at room temperature in a climate-controlled environment (15-30° C.), avoiding extreme heat or extreme cold. In some embodiments, the patient is instructed not to apply any other topical ophthalmic medications within a specific period, for example, 1 hour before and 1 hour after the study drug is administered.

[0239] In some embodiments, the systems and methods include qualitative and / or quantitative assessment of Demodex mites in the patient's anatomical locations, such as on the eyelashes and / or in the glands. In some embodiments, the method may include receiving a first assessment of the amount of Demodex mites on the patient's anatomical structure, and starting topical administration of the 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 an increase or decrease in dosage, frequency, formulation, etc.) or interrupting treatment based on the second assessment, which may be about, no more than about, 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 less days after the first assessment. In some embodiments, the treatment results in about or at least about a 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% reduction in the elimination of Demodex mites at the anatomical location.

[0240] The presence of cylindrical scales, also known as cylindrical casts, is a scale that forms a transparent sheath at the base of the eyelashes that fits over the root of the eyelashes. The cylindrical scales on the eyelashes are generally considered to be unique to Demodex infection and can be diagnosed by depilation and observation under a slit lamp microscope, followed by automatic or manual counting. The skin surface biopsy (SSB) technique with cyanoacrylic acid adhesion is a common method for measuring Demodex density. It allows the collection of the surface portion of the stratum corneum and the contents of the hair follicles of the sebaceous glands. Other sampling methods for evaluating the presence of Demodex by microscopy include adhesive tape, skin scraping, skin impressions, expressed follicular contents, comedone extraction, hair depilation, and punch biopsy.

[0241] In some embodiments, systems and methods for detecting Demodex in a subject are disclosed that do not necessarily require hair removal. Such measurements for diagnosing Demodex may be advantageous because detection and quantification of Demodex, particularly sebaceous Demodex, via hair removal is challenging. Furthermore, many patients object to hair removal due to discomfort. Furthermore, initiation of treatment may be earlier and based on objective criteria.

[0242] For example, a device such as a disposable hydrogel contact lens can be used to collect tears from a subject. The device, such as a contact lens, can then be sent to a laboratory for detection and potentially quantification of Demodex DNA by PCR or other methods. The genomes of Demodex folliculorum and Demodex sebaceous 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, for example, 30, 20, 15, 10, or 5 minutes. Such a contact lens can be made of a hydrogel that has a relatively high affinity for Demodex biomarkers, including DNA.

[0243] In some embodiments, such as Figure 4A As shown, tear sampling can utilize a device including a capillary glass tube to collect tears from the tear meniscus of the lower eyelid. This method may be particularly useful when small volumes are required for quantitation. In addition, evaporation can be eliminated simply by sealing both ends of the tube if it is advantageous to do so.

[0244] Some embodiments also include non-contact lens skin and tear sampling methods, such as "litmus paper" or wicking paper embodiments similar to the Schirmer test ( Figure 4B shown), or eyelash brush collection technology ( Figure 4C In some embodiments, chitin, chitosan or other Demodex-specific biomarkers can be detected and quantified to correlate with mite populations.

[0245] Demodex DNA can be quantified, for example, as the density of DNA copies encoding a particular Demodex target sequence (e.g., 18S rRNA, as a non-limiting example). In some embodiments, the density of Demodex (defined as the number of DNA copies encoding the target region of Demodex per ng human gDNA (x10 -6 )) can be a threshold for initiating treatment.

[0246] Infections can be further categorized based on the causative species of Demodex (e.g., Folliculorum Demodex vs. Sebaceous Demodex). Sebaceous Demodex is primarily located in the meibomian and sebaceous glands. Treatments can be improved, enhanced, or targeted based on the dominant species, such as, for example, increasing the delivery of therapeutic agents to selected glands.

[0247] According to the above teachings, various other modifications, adjustments and alternative designs are certainly possible. Therefore, it should be understood at this time that within the scope of the appended claims, the present invention can be implemented in a manner different from that specifically described herein. It is conceivable that various combinations or sub-combinations of the specific features and aspects of the above disclosed embodiments can be performed, and these combinations or sub-combinations still fall within one or more scopes of the present invention. In addition, the disclosure of any specific features, aspects, methods, characteristics, features, qualities, attributes, elements, etc. of the embodiments herein can be used in all other embodiments shown in this article. Therefore, it should be understood that the various features and aspects of the disclosed embodiments can be combined or replaced with each other to form a variation mode of the disclosed invention. Therefore, the scope of the present invention disclosed herein is not intended to be limited by the above-mentioned particularly disclosed embodiments. In addition, although the present invention is susceptible to various modifications and alternative forms, its specific examples have been shown in the drawings and described in detail herein. However, it should be understood that the present invention is not limited to the disclosed specific forms or methods, but on the contrary, the present invention covers all modifications, equivalents and replacements falling within the spirit and scope of the various embodiments described and the appended claims. Any method disclosed herein does not need to be performed in the order described. The methods disclosed herein include certain actions taken by the practitioner; however, they may also include any third-party instructions for those actions, whether explicitly or implicitly. For example, an action such as "applying an isoxazoline insect repellent to the eye" includes "instructing that an isoxazoline insect repellent be applied to the eye". The ranges disclosed herein also include any and all overlaps, sub-ranges, and combinations of the above. Language such as "up to", "at least", "greater than", "less than", "between", etc. includes the listed numbers. As used herein, the numbers before terms such as "approximately", "about", and "substantially" include the numbers (e.g., about 10% = 10%), and also represent an amount close to the amount, which still performs the desired function or achieves the desired result. For example, the terms "approximately", "about", and "substantially" may refer to an amount within less than 10%, less than 5%, less than 1%, less than 0.1%, and less than 0.01% of the amount.

[0248] This application also relates to the following implementation schemes:

[0249] Embodiment 1. A method of treating blepharitis in a patient, comprising:

[0250] administering topically directly to the ocular surface of one or more eyes of a patient in need of treatment an effective amount of an isoxazoline anthelmintic formulated as an ophthalmic composition further comprising a pharmaceutically acceptable vehicle,

[0251] wherein the ophthalmic composition is sterile and non-irritating to the eyes,

[0252] wherein the isoxazoline insect repellent is the sole active ingredient of the ophthalmic composition.

[0253] Embodiment 2. The method of embodiment 1, wherein about 0.01% to about 1% of the isoxazoline anthelmintic is administered relative to the total weight of the composition.

[0254] Embodiment 3. The method of embodiment 1, wherein about 0.03% by weight of the isoxazoline anthelmintic relative to the total weight of the composition is administered.

[0255] Embodiment 4. The method of embodiment 1, wherein about 0.10% by weight of the isoxazoline anthelmintic relative to the total weight of the composition is administered.

[0256] Embodiment 5. The method of embodiment 1, wherein the ophthalmic composition comprises eye drops.

[0257] Embodiment 6. The method of embodiment 1, wherein the ophthalmic composition does not include any essential oils.

[0258] Embodiment 7. The method of embodiment 1, wherein the isoxazoline anthelmintic is selected from the group consisting of fluralaner, sarolaner, lotilaner, afoxolaner, and fluxametamide.

[0259] Embodiment 8. A method as described in Embodiment 1, wherein the ocular surface comprises at least one of the conjunctiva or cornea of ​​one or more eyes of the patient.

[0260] Embodiment 9. The method of embodiment 1, wherein the ophthalmic composition comprises polysorbate.

[0261] Embodiment 10. A method of treating blepharitis in a patient, comprising:

[0262] administering topically directly to one or more of the eyes, eyelids or eyelashes of a patient in need of treatment an effective amount of an isoxazoline anthelmintic formulated as an ophthalmic composition further comprising a pharmaceutically acceptable vehicle, wherein the ophthalmic composition is sterile and non-irritating to the eye,

[0263] wherein the isoxazoline insect repellent is the sole active ingredient of the ophthalmic composition.

[0264] Embodiment 11. The method of embodiment 10, wherein the patient's eye is closed following topical administration of the ophthalmic composition such that the composition is in contact with the patient's meibomian gland openings and the exterior of the patient's eyelid margin.

[0265] Embodiment 12. The method of embodiment 11 further comprising applying the composition to eyelashes and eyelash follicles.

[0266] Embodiment 13. The method of embodiment 11 further comprises applying the composition to the eyelashes and eyelash follicles with an applicator.

[0267] Embodiment 14. The method of embodiment 10, wherein about 0.001% to about 1% of the isoxazoline anthelmintic is administered.

[0268] Embodiment 15. The method of embodiment 10, wherein about 0.001% to about 1% of the isoxazoline anthelmintic is administered.

[0269] Embodiment 16. The method of embodiment 10, comprising topically administering the ophthalmic composition at least once a day for at least about 2 weeks.

[0270] Embodiment 17. The method of embodiment 10, comprising topically administering the ophthalmic composition at least once a day for at least about 4 weeks.

[0271] Embodiment 18. A method of treating an ocular Demodex infestation in a patient, comprising:

[0272] administering topically directly to one or more of the eyes, eyelids or eyelashes of one or more eyes of a patient in need of treatment an effective amount of an isoxazoline anthelmintic formulated as an ophthalmic composition further comprising a pharmaceutically acceptable vehicle,

[0273] wherein the ophthalmic composition is sterile and non-irritating to the eyes,

[0274] wherein the isoxazoline insect repellent is the sole active ingredient of the ophthalmic composition.

[0275] Embodiment 19. The method of embodiment 18, further comprising receiving a first assessment of the amount of Demodex mites on the patient's anatomical structure, and topically administering the ophthalmic composition when the amount of Demodex mites is greater than a predetermined value.

[0276] Embodiment 20. The method of embodiment 18, wherein the ophthalmic formulation causes the abdomen and tail of a Demodex mite on a patient to cease movement more rapidly relative to the cephalothorax of the Demodex mite.

[0277] Embodiment 21. A method of treating blepharitis and / or rosacea, comprising:

[0278] Topical application of an isoxazoline repellent proximate one or more eyelashes is therapeutically effective to be preferentially absorbed by the body of the Demodex mite relative to ingestion by the Demodex mite, sufficient to cause a reduction in 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 mite proximate the eyelashes, resulting in improved manifestations of blepharitis and / or rosacea.

[0279] Embodiment 22. A topical ophthalmic formulation for treating blepharitis in a patient, comprising:

[0280] an effective amount of an isoxazoline anthelmintic and a pharmaceutically acceptable vehicle,

[0281] wherein the ophthalmic composition is sterile and non-irritating to the eyes,

[0282] wherein the isoxazoline insect repellent is the sole active ingredient of the ophthalmic composition.

[0283] Embodiment 23. The topical ophthalmic formulation of embodiment 22, wherein about 0.01% to about 1% of the isoxazoline anthelmintic is administered relative to the total weight of the composition.

[0284] Embodiment 24. The topical ophthalmic formulation of embodiment 22, wherein about 0.03% by weight of the isoxazoline anthelmintic is administered relative to the total weight of the composition.

[0285] Embodiment 25. The topical ophthalmic formulation of embodiment 22, wherein about 0.10% by weight of the isoxazoline anthelmintic is administered relative to the total weight of the composition.

[0286] Embodiment 26. The topical ophthalmic formulation of embodiment 22, wherein the ophthalmic composition comprises eye drops.

[0287] Embodiment 27. The topical ophthalmic formulation of embodiment 22, wherein the ophthalmic composition does not include any essential oils.

[0288] Embodiment 28. The topical ophthalmic formulation of embodiment 22, wherein the isoxazoline anthelmintic is selected from the group consisting of flurellan, sarolanab, lotiranab, afoxolanab, and fluoxazolidinone.

[0289] Embodiment 29. A topical formulation for treating an ocular surface disease, comprising:

[0290] Isoxazoline insect repellents;

[0291] At least one of Pemulen and HPMC;

[0292] Polysorbate 80;

[0293] glycerin;

[0294] Buffering agents; and

[0295] Loralinium chloride,

[0296] The formulation is therapeutically effective in reducing or eliminating Demodex mites adjacent to the eyelashes, resulting in improvements in manifestations of blepharitis and / or rosacea.

[0297] Embodiment 30. The topical formulation of embodiment 29 for use in treating blepharitis.

[0298] Embodiment 31. The topical formulation of embodiment 29 for use in treating anterior blepharitis.

[0299] Embodiment 32. The topical formulation of embodiment 29 for use in treating posterior blepharitis.

[0300] Embodiment 33. The topical formulation of embodiment 29 for use in treating ocular rosacea.

[0301] Embodiment 34. A method of treating blepharitis in a patient, comprising:

[0302] administering topically directly to the ocular surface of one or more eyes of a patient in need of treatment an effective amount of a formamidine anthelmintic formulated as an ophthalmic composition further comprising a pharmaceutically acceptable vehicle,

[0303] wherein the ophthalmic composition is sterile and non-irritating to the eyes,

[0304] wherein the formamidine anthelmintic is the sole active ingredient of the ophthalmic composition.

[0305] Embodiment 35. The method of embodiment 34, wherein the formamidine anthelmintic is administered at about 0.01% to about 1% by weight relative to the total weight of the composition.

[0306] Embodiment 36. The method of embodiment 34, wherein about 0.03% by weight of the formamidine anthelmintic relative to the total weight of the composition is administered.

[0307] Embodiment 37. The method of embodiment 34, wherein about 0.10% by weight of the formamidine anthelmintic relative to the total weight of the composition is administered.

[0308] Embodiment 38. The method of embodiment 34, wherein the ophthalmic composition comprises eye drops.

[0309] Embodiment 39. The method of embodiment 34, wherein the ophthalmic composition comprises an ointment or a cream.

[0310] Embodiment 40. The method of embodiment 34, wherein the ophthalmic composition does not include any essential oils.

[0311] Embodiment 41. The method of embodiment 34, wherein the formamidine anthelmintic is selected from the group consisting of amitraz, N-(2,4-dimethylphenyl)-N-methylformamidine (DPMF) and 2,4-dimethylanaline.

[0312] Embodiment 42. A method as described in Embodiment 34, wherein the ocular surface comprises at least one of the conjunctiva or cornea of ​​one or more eyes of the patient.

[0313] Embodiment 43. The method of embodiment 34, wherein the ophthalmic composition comprises polysorbate.

[0314] Embodiment 44. A method of treating blepharitis in a patient, comprising:

[0315] administering topically directly to one or more of the eyes, eyelids or eyelashes of a patient in need of treatment an effective amount of a formamidine anthelmintic formulated as an ophthalmic composition further comprising a pharmaceutically acceptable vehicle, wherein the ophthalmic composition is sterile and non-irritating to the eye,

[0316] wherein the formamidine anthelmintic is the sole active ingredient of the ophthalmic composition.

[0317] Embodiment 45. The method of embodiment 44, wherein the patient's eye is closed following topical administration of the ophthalmic composition such that the composition is in contact with the patient's meibomian gland openings and the exterior of the patient's eyelid margin.

[0318] Embodiment 46. The method of embodiment 44 further comprises applying the composition to eyelashes and eyelash follicles.

[0319] Embodiment 47. The method of embodiment 44 further comprises applying the composition to the eyelashes and eyelash follicles with an applicator.

[0320] Embodiment 48. The method of embodiment 44, wherein about 0.001% to about 1% of the formamidine anthelmintic is administered.

[0321] Embodiment 49. The method of embodiment 44, wherein about 0.001% to about 1% of the formamidine anthelmintic is administered.

[0322] Embodiment 50. The method of embodiment 44, comprising topically administering the ophthalmic composition at least once a day for at least about 2 weeks.

[0323] Embodiment 51. The method of embodiment 44, comprising topically administering the ophthalmic composition at least once a day for at least about 4 weeks.

[0324] Embodiment 52. A method of treating an ocular Demodex infestation in a patient, comprising:

[0325] administering topically directly to one or more of the eyes, eyelids or eyelashes of one or more eyes of a patient in need of treatment an effective amount of a formamidine anthelmintic formulated to further comprise a pharmaceutically acceptable vehicle,

[0326] wherein the ophthalmic composition is sterile and non-irritating to the eyes,

[0327] wherein the formamidine anthelmintic is the sole active ingredient of the ophthalmic composition.

[0328] Embodiment 53. The method of embodiment 52, further comprising receiving a first assessment of the amount of Demodex mites on the patient's anatomical structure, and topically administering the ophthalmic composition when the amount of Demodex mites is greater than a predetermined value.

[0329] Embodiment 54. The method of embodiment 52, wherein the ophthalmic formulation causes the abdomen and tail of the Demodex mite in the patient to cease movement more rapidly relative to the cephalothorax of the Demodex mite.

[0330] Embodiment 55. A method of treating blepharitis and / or rosacea, comprising:

[0331] Topical application of a formamidine repellent proximate one or more eyelashes is therapeutically effective to be preferentially absorbed by the body of the Demodex mite relative to ingestion by the Demodex mite, sufficient to cause a reduction in 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 mite proximate the eyelashes, resulting in an improvement in the manifestations of blepharitis and / or rosacea.

[0332] Embodiment 56. A topical ophthalmic formulation for treating blepharitis in a patient, comprising:

[0333] an effective amount of a formamidine anthelmintic and a pharmaceutically acceptable vehicle,

[0334] wherein the ophthalmic composition is sterile and non-irritating to the eyes,

[0335] wherein the formamidine anthelmintic is the sole active ingredient of the ophthalmic composition.

[0336] Embodiment 57. The topical ophthalmic formulation of embodiment 56, wherein the formamidine anthelmintic is administered at about 0.01% to about 1% relative to the total weight of the composition.

[0337] Embodiment 58. The topical ophthalmic formulation of embodiment 56, wherein about 0.03% by weight of the formamidine anthelmintic is administered relative to the total weight of the composition.

[0338] Embodiment 59. The topical ophthalmic formulation of embodiment 56, wherein about 0.10% by weight of the formamidine anthelmintic is administered relative to the total weight of the composition.

[0339] Embodiment 60. The topical ophthalmic formulation of embodiment 56, wherein the ophthalmic composition comprises eye drops, cream or ointment.

[0340] Embodiment 61. The topical ophthalmic formulation of embodiment 56, wherein the ophthalmic composition does not include any essential oils.

[0341] Embodiment 62. The topical ophthalmic formulation of embodiment 56, wherein the formamidine anthelmintic is selected from the group consisting of amitraz, N-(2,4-dimethylphenyl)-N-methylformamidine (DPMF), and 2,4-dimethylaniline.

Claims

1. A method of treating blepharitis in a patient, comprising: administering topically directly to the ocular surface of one or more eyes of a patient in need of treatment an effective amount of an isoxazoline anthelmintic formulated as an ophthalmic composition further comprising a pharmaceutically acceptable vehicle, wherein the ophthalmic composition is sterile and non-irritating to the eyes, wherein the isoxazoline insect repellent is the sole active ingredient of the ophthalmic composition.

2. A method of treating blepharitis in a patient, comprising: administering topically directly to one or more of the eyes, eyelids or eyelashes of a patient in need of treatment an effective amount of an isoxazoline anthelmintic formulated as an ophthalmic composition further comprising a pharmaceutically acceptable vehicle, wherein the ophthalmic composition is sterile and non-irritating to the eye, wherein the isoxazoline insect repellent is the sole active ingredient of the ophthalmic composition.

3. A method of treating an ocular Demodex infection in a patient, comprising: administering topically directly to one or more of the eyes, eyelids or eyelashes of one or more eyes of a patient in need of treatment an effective amount of an isoxazoline anthelmintic formulated as an ophthalmic composition further comprising a pharmaceutically acceptable vehicle, wherein the ophthalmic composition is sterile and non-irritating to the eyes, wherein the isoxazoline insect repellent is the sole active ingredient of the ophthalmic composition.

4. Methods for treating blepharitis and / or rosacea, comprising: Topical application of an isoxazoline repellent proximate one or more eyelashes is therapeutically effective to be preferentially absorbed by the body of the Demodex mite relative to ingestion by the Demodex mite, sufficient to cause a reduction in 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 mite proximate the eyelashes, resulting in improved manifestations of blepharitis and / or rosacea.

5. A topical ophthalmic formulation for treating blepharitis in a patient, comprising: an effective amount of an isoxazoline anthelmintic and a pharmaceutically acceptable vehicle, wherein the ophthalmic composition is sterile and non-irritating to the eyes, wherein the isoxazoline insect repellent is the sole active ingredient of the ophthalmic composition.

6. A topical preparation for treating ocular surface diseases, comprising: Isoxazoline insect repellents; At least one of Pemulen and HPMC; Polysorbate 80; glycerin; Buffering agents; and Loralinium chloride, The formulation is therapeutically effective in reducing or eliminating Demodex mites adjacent to the eyelashes, resulting in improvements in manifestations of blepharitis and / or rosacea.

7. A method of treating blepharitis in a patient, comprising: administering topically directly to the ocular surface of one or more eyes of a patient in need of treatment an effective amount of a formamidine anthelmintic formulated as an ophthalmic composition further comprising a pharmaceutically acceptable vehicle, wherein the ophthalmic composition is sterile and non-irritating to the eyes, wherein the formamidine anthelmintic is the sole active ingredient of the ophthalmic composition.

8. A method of treating blepharitis in a patient, comprising: administering topically directly to one or more of the eyes, eyelids or eyelashes of a patient in need of treatment an effective amount of a formamidine anthelmintic formulated as an ophthalmic composition further comprising a pharmaceutically acceptable vehicle, wherein the ophthalmic composition is sterile and non-irritating to the eye, wherein the formamidine anthelmintic is the sole active ingredient of the ophthalmic composition.

9. A method of treating an ocular Demodex infection in a patient, comprising: administering topically directly to one or more of the eyes, eyelids or eyelashes of one or more eyes of a patient in need of treatment an effective amount of a formamidine anthelmintic formulated to further comprise a pharmaceutically acceptable vehicle, wherein the ophthalmic composition is sterile and non-irritating to eyes, wherein the formamidine anthelmintic is the only active ingredient of the ophthalmic composition.

10. A topical ophthalmic formulation for treating blepharitis in a patient, comprising: an effective amount of a formamidine anthelmintic and a pharmaceutically acceptable vehicle, wherein the ophthalmic composition is sterile and non-irritating to the eyes, wherein the formamidine anthelmintic is the sole active ingredient of the ophthalmic composition.

Images