Isoxazoline-based antiparasitic agents and methods for treating blepharitis

Abstract

The present application relates to a method for treating or preventing ocular and skin conditions in a patient, including ocular surface conditions such as blepharitis. The method comprises topically administering an effective amount of an isoxazoline parasiticide, a formamidine parasiticide, or other active ingredient formulated in an ophthalmic composition directly to the ocular surface of one or both eyes of a patient in need of treatment, such as blepharitis. The ophthalmic composition further comprises a pharmaceutically acceptable solvent. The present application also relates to the composition.

Description

Technical Field

[0001] (Priority Claim) This application claims the benefit of 35 U.S.C. 119(e), and claims priority based on U.S. Provisional Application No. 62 / 599,213 filed on December 15, 2017, U.S. Provisional Application No. 62 / 615,855 filed on January 10, 2018, U.S. Provisional Application No. 62 / 626,612 filed on February 5, 2018, U.S. Provisional Application No. 62 / 689,787 filed on June 25, 2018, and U.S. Provisional Application No. 62 / 746,498 filed on October 16, 2018. The entire disclosures of all of them are incorporated herein by reference.

[0002] Blepharitis or eyelid inflammation is a common, difficult-to-treat, chronic condition that affects all age groups. Blepharitis can occur in both the anterior eyelid (the outer eyelid where the eyelashes are located) and / or the posterior eyelid (the inner eyelid). Blepharitis may be associated with systemic diseases including rosacea and seborrheic dermatitis, and may be related to other eye diseases including chalazia, conjunctivitis, keratitis, and dry eye.

Background Art

[0003] Demodex folliculorum and Demodex brevis are microscopic, obligate, elongate mites and are the most common and persistent endoparasites living in the hair follicles and sebaceous glands of humans and animals. There are a total of 65 species in the genus Demodex, which parasitize 11 orders of mammals and belong to the family Demodicidae, order Trombidiformes, class Arachnida. Mating occurs at the follicular opening and eggs are laid within the hair follicle or sebaceous gland. Six-legged larvae hatch after 3 - 4 days and become adults in about 7 days. The life cycle of the Demodex mite is about 14 days. The lifespan of Demodex is several weeks. Dead mites decompose inside the hair follicles and sebaceous glands.

[0004] Demodex mites infest the face, including the cheeks, nose, chin, forehead, temples, eyelashes, eyebrows, scalp, neck, and ears. They can also infest other seborrheic areas such as the nasolabial folds and periorbital regions, as well as less commonly, the upper and inner regions of the chest and back. Demodex mites can also infest ectopic sebaceous glands of the penis, mons pubis, buttocks, and buccal mucosa. In some cases, Demodex infestation is associated with a mite density of 5 or more mites per square centimeter per fur sebaceous gland unit or 5 or more mites per follicle. [Overview of the Initiative] [Problems that the invention aims to solve]

[0005] Of the widely reported species, only two species, Demodex mite and Demodex nematodes, are known to parasitize the human body surface. Demodex mite is found, for example, in the hair follicles of eyelashes. Demodex nematodes, on the other hand, is found, for example, in the meibomian glands (tarsal glands) around the eyes and in locations close to the sebaceous glands of the skin. Meibomian glands are total exocrine glands located on the edge of the eyelid inside the tarsal plate and are responsible for supplying meibum, an oily substance that prevents the evaporation of the tear film. Meibum prevents tears from spilling onto the cheeks, trapping tears between the oily edge and the eyeball, and keeping the inside of the closed eyelid airtight. There are approximately 50 meibomian glands in the upper eyelid and approximately 25 in the lower eyelid. Symbiotic bacteria of mites also contribute pathologically. Increased sebum secretion and an increase in the number of sebaceous glands provide a favorable habitat for mites. While some levels of Demodex mites are asymptomatic, high densities of Demodex mites and / or simultaneous immune imbalances typically lead to skin damage. Increasing literature suggests the involvement of Demodex mites in anterior and posterior blepharitis. For example, Demodex mites are reported to be involved in 45% of blepharitis cases. The prevalence of ocular surface diseases is estimated at approximately 30 million cases, of which 19 million are meibomian gland dysfunction / posterior blepharitis, 9 million are Demodex infestations, and 4 million clearly show signs of Demodex infestation. Blepharitis is an important diagnosis, and there are currently no approved treatments in the United States. Therefore, there is a need for safe and effective treatments for ocular and skin diseases, including blepharitis. [Means for solving the problem]

[0006] As an example, this specification discloses topical therapeutic agents. Topical therapeutic agents include, but are not limited to, topical pharmaceutical agents comprising one or more isoxazoline anthelmintics, formamidine anthelmintics, phenylpyrazole anthelmintics, agents commonly used to treat Alzheimer's disease (e.g., galantamine), and other agents for the treatment of various eye and skin conditions.

[0007] In one embodiment, this specification discloses a method for treating blepharitis in a patient. The method comprises the step of topically administering an effective amount of an isoxazoline antiparasitic agent formulated in an ophthalmic composition directly to the ocular surface of one or both eyes of a patient requiring treatment for blepharitis. The ophthalmic composition comprises a pharmaceutically acceptable solvent.

[0008] In some embodiments, the ophthalmic composition is sterile and non-irritating to the eye.

[0009] In one embodiment, isoxazoline-based antiparasitic agents are the sole active ingredient in an ophthalmic composition.

[0010] In one embodiment, about 0.01 of the total weight of the composition weight % ~ approx. 1 weight Administer % isoxazoline-based antiparasitic agents.

[0011] In one embodiment, an isoxazoline-based antiparasitic agent is administered at a concentration of approximately 0.03% by weight relative to the total weight of the composition.

[0012] In one embodiment, an isoxazoline-based antiparasitic agent is administered at a concentration of approximately 0.10% by weight relative to the total weight of the composition.

[0013] In one embodiment, the ophthalmic composition includes eye drops.

[0014] In some embodiments, the ophthalmic composition does not contain essential oils.

[0015] In one embodiment, the isoxazoline antiparasitic agent is selected from the group consisting of fluralaner, sarolaner, lotilaner, afoxolaner, and fluxametamide.

[0016] In one embodiment, the ocular surface includes at least one of the conjunctiva or cornea of ​​one or both of the patient's eyes.

[0017] In one embodiment, the ophthalmic composition contains polysorbate.

[0018] This specification discloses, in one embodiment, a method for treating blepharitis in a patient. The method comprises the step of topically administering an effective amount of an isoxazoline anthelmintic formulated in an ophthalmic composition directly to one or both eyes, eyelids, or one or more eyelashes of a patient requiring treatment for blepharitis. The ophthalmic composition further comprises a pharmaceutically acceptable solvent. The ophthalmic composition is sterile and non-irritating to the eye. The isoxazoline anthelmintic is the sole active ingredient of the ophthalmic composition.

[0019] In one embodiment, when the ophthalmic composition is administered topically, the patient's eye is closed so that the composition comes into contact with the opening of the patient's meibomian glands and the outer edge of the patient's eyelid margin.

[0020] In one embodiment, the method further includes the step of applying the composition to the eyelashes and eyelash follicles.

[0021] In one embodiment, the method further includes the step of applying the composition to the eyelashes and eyelash follicles with an applicator.

[0022] In one aspect, approximately 0.001 weight % ~ approx. 1 weight Administer % isoxazoline-based antiparasitic agents.

[0024] In one embodiment, the method includes the step of administering the ophthalmic composition topically at least once a day for at least two weeks.

[0025] In one embodiment, the method includes the step of administering the ophthalmic composition topically at least once a day for at least about four weeks.

[0026] This specification discloses, as one aspect, a method for treating Demodex ocular parasitosis in a patient. The method includes topically administering an effective amount of an isoxazoline-based antiparasitic agent formulated in an ophthalmic composition directly to one or both eyes, one or both eyelids, or eyelashes of a patient who requires treatment for Demodex ocular parasitosis. The ophthalmic composition further includes a pharmaceutically acceptable solvent. The ophthalmic composition is sterile and non-irritating to the eye. The isoxazoline-based antiparasitic agent is the only active ingredient in the ophthalmic composition.

[0027] In one aspect, the method further includes receiving a first evaluation of the amount of Demodex mites in the patient's anatomical structure, and topically administering the ophthalmic composition when the amount of Demodex mites is greater than a predetermined value.

[0028] In one aspect, the ophthalmic composition more rapidly stops the movement of the abdomen and tail of Demodex mites compared to the movement of the cephalothorax of Demodex mites parasitizing the patient.

[0029] This specification discloses, as one aspect, a method for treating blepharitis and / or rosacea. The method includes topically applying an isoxazoline-based antiparasitic agent in the vicinity of one or more eyelashes. The step of topical application is therapeutically effective to preferentially absorb into the body of Demodex mites for ingestion by Demodex mites sufficient to reduce the movement of the body of Demodex mites relative to the head of Demodex mites. The method is sufficient to reduce or eliminate Demodex mites in the vicinity of the eyelashes, thereby improving the symptoms of blepharitis and / or rosacea.

[0030] This specification discloses, as one aspect, a topical ophthalmic formulation for treating blepharitis in a patient. The topical ophthalmic formulation includes an effective amount of an isoxazoline-based antiparasitic agent and a pharmaceutically acceptable solvent. The ophthalmic composition is sterile and non-irritating to the eye. The isoxazoline-based antiparasitic agent is the only active ingredient in the ophthalmic composition.

[0031] [[ID=第十九]] In one embodiment, about 0.01 of the total weight of the composition weight % ~ approx. 1 weight A certain percentage of the isoxazoline-based antiparasitic agent is administered.

[0032] In one embodiment, the isoxazoline antiparasitic agent is administered at a concentration of approximately 0.03% by weight relative to the total weight of the composition.

[0033] In one embodiment, the isoxazoline antiparasitic agent is administered at a concentration of about 0.10% by weight relative to the total weight of the composition.

[0034] In one embodiment, the ophthalmic composition includes eye drops.

[0035] In some embodiments, the ophthalmic composition does not contain essential oils.

[0036] In one embodiment, the isoxazoline antiparasitic agent is selected from the group consisting of fluralaner, sarolaner, rotilaner, afoxolaner, and fluxamethamide.

[0037] This specification relates, in one embodiment, to a topical formulation for use in the treatment of ocular surface diseases. The topical formulation comprises an isoxazoline antiparasitic agent, at least one of pemlen and HPMC, polysorbate 80, glycerin, a buffer, and lauralkonium chloride. The topical formulation is therapeutically effective for reducing or eliminating Demodex mites near the eyelashes, thereby improving the symptoms of blepharitis and / or rosacea.

[0038] In one embodiment, the preparation is used to treat blepharitis.

[0039] In one embodiment, the preparation is used to treat anterior blepharitis.

[0040] In one embodiment, the preparation is used to treat posterior blepharitis.

[0041] In one embodiment, the preparation is used to treat ocular rosacea.

[0042] This specification discloses, in one embodiment, a method for treating blepharitis in a patient. The method comprises the step of topically administering an effective amount of a formamidine-based anthelmintic, formulated in an ophthalmic composition, directly to the ocular surface of one or both eyes of a patient requiring treatment for blepharitis. The ophthalmic composition further comprises a pharmaceutically acceptable solvent. The ophthalmic composition is sterile and non-irritating to the eye. The formamidine-based anthelmintic is the sole active ingredient of the ophthalmic composition.

[0043] In one embodiment, about 0.01 of the total weight of the composition weight % ~ approx. 1 weight Administer % of a formamidine-based antiparasitic agent.

[0044] In one embodiment, the formamidine-based antiparasitic agent is administered in an amount of about 0.03% by weight relative to the total weight of the composition.

[0045] In one embodiment, the formamidine-based antiparasitic agent is administered in an amount of about 0.10% by weight relative to the total weight of the composition.

[0046] In one embodiment, the ophthalmic composition includes eye drops.

[0047] In one embodiment, the ophthalmic composition includes an ointment or cream.

[0048] In some embodiments, the ophthalmic composition does not contain essential oils.

[0049] In one embodiment, the formamidine-based antiparasitic agent is amitraz, N-(2,4-dimethylphenyl)-N-methylformamidine (DPMF), and 2,4-dimethylphenyl Ni It is selected from the group consisting of phosphorus.

[0050] In one embodiment, the ocular surface includes at least one of the conjunctiva or cornea of ​​one or both of the patient's eyes.

[0051] In one embodiment, the ophthalmic composition contains polysorbate.

[0052] This specification discloses, in one embodiment, a method for treating blepharitis in a patient. The method comprises the step of topically administering an effective amount of a formamidine-based anthelmintic, formulated in an ophthalmic composition, directly to one or both eyes, eyelids, or one or more eyelashes of a patient requiring treatment for blepharitis. The ophthalmic composition further comprises a pharmaceutically acceptable solvent. The ophthalmic composition is sterile and non-irritating to the eye. The formamidine-based anthelmintic is the sole active ingredient of the ophthalmic composition.

[0053] In one embodiment, when the ophthalmic composition is administered topically, the patient's eye is closed so that the composition comes into contact with the opening of the patient's meibomian glands and the outer edge of the patient's eyelid margin.

[0054] In one embodiment, the method further includes the step of applying the composition to the eyelashes and the hair follicles of the eyelashes.

[0055] In one embodiment, the method further includes the step of applying the composition to the eyelashes and eyelash follicles with an applicator.

[0056] In one aspect, approximately 0.001 weight % ~ approx. 1 weight Administer % of a formamidine-based antiparasitic agent.

[0058] In one embodiment, the method further includes the step of administering the ophthalmic composition topically at least once a day for at least about two weeks.

[0059] In one embodiment, the method includes the step of administering the ophthalmic composition topically at least once a day for at least about four weeks.

[0060] This specification discloses, in one embodiment, a method for treating Demodex ocular infestation in a patient. The method comprises the step of topically administering an effective amount of a formamidine-based anthelmintic, formulated in an ophthalmic composition, directly to one or both eyes, or to the eyelids or eyelashes of one or both eyes, of a patient requiring treatment for Demodex ophthalmic infestation. The ophthalmic composition further comprises a pharmaceutically acceptable solvent. The ophthalmic composition is sterile and non-irritating to the eye. The formamidine-based anthelmintic is the sole active ingredient of the ophthalmic composition.

[0061] In one embodiment, the method further includes the steps of: firstly evaluating the amount of Demodex mites in the anatomical structure of a patient; and, if the amount of Demodex mites is greater than a predetermined value, administering an ophthalmic composition topically.

[0062] In one embodiment, the ophthalmic composition more quickly stops the movement of the abdomen and tail of a Demodex mite parasitizing a patient compared to the cephalothorax of the Demodex mite.

[0063] This specification discloses, in one embodiment, a method for treating blepharitis and / or rosacea. The method comprises the step of topically applying a formamidine-based antiparasitic agent near one or more eyelashes. The topical application step is therapeutically effective in that it is preferentially absorbed by the body of the Demodex mite with respect to ingestion by the Demodex mite that is sufficient to reduce the movement of the body of the Demodex mite relative to the head of the Demodex mite. The method is sufficient to reduce or eliminate Demodex mites near the eyelashes, thereby improving the symptoms of blepharitis and / or rosacea.

[0064] This specification discloses, in one embodiment, a topical ophthalmic formulation for the treatment of blepharitis in a patient. The topical ophthalmic formulation comprises an effective amount of a formamidine anthelmintic and a pharmaceutically acceptable solvent. The ophthalmic composition is sterile and non-irritating to the eye. The formamidine anthelmintic is the sole active ingredient of the ophthalmic composition.

[0065] In one embodiment, about 0.01 of the total weight of the composition weight % ~ approx. 1 weight A % formamidine-based antiparasitic agent is administered.

[0066] In one embodiment, a formamidine-based antiparasitic agent is administered at a concentration of approximately 0.03% by weight relative to the total weight of the composition.

[0067] In one embodiment, a formamidine-based antiparasitic agent is administered at a concentration of approximately 0.10% by weight relative to the total weight of the composition.

[0068] In one embodiment, the ophthalmic composition includes eye drops, a cream, or an ointment.

[0069] In some embodiments, the ophthalmic composition does not contain essential oils.

[0070] In one embodiment, the formamidine-based antiparasitic agent is amitraz, N-(2,4-dimethylphenyl)-N-methylformamidine (DPMF), and 2,4-dimethylphenyl Ni It is selected from the group consisting of phosphorus.

[0071] This specification discloses, in one embodiment, a method for treating symptoms of blepharitis and / or ocular rosacea. The symptoms are selected from the group consisting of a burning sensation in the eye, a tingling sensation in the eye, dryness of the eye, increased sensitivity to light, blurred vision, and complications of ocular rosacea in the cornea. The method comprises the step of topically administering an effective amount of a formamidine-based antiparasitic agent formulated in an eyewash composition directly to the conjunctiva and / or cornea of ​​the eye of an individual requiring such treatment. The eyewash composition further comprises a pharmaceutically acceptable solvent. The eyewash composition is sterile, non-irritating, and compatible with ocular tissue.

[0072] In one embodiment, a formamidine-based antiparasitic agent is administered at a concentration of 0.001 to 10% by weight relative to the total weight of the composition.

[0073] In one embodiment, 0.01 of the total weight of the composition weight %~5 weight Administer % of a formamidine-based antiparasitic agent.

[0074] In one embodiment, a formamidine-based antiparasitic agent is administered at a concentration of 0.03% by weight relative to the total weight of the composition.

[0075] In one embodiment, a formamidine-based antiparasitic agent is administered at a concentration of 0.10% by weight relative to the total weight of the composition.

[0076] This specification discloses, in one embodiment, a method for treating blepharitis and / or rosacea. The method involves orally or topically administering a formamidine-based antiparasitic agent in a dose sufficient to immerse and remove Demodex mites at one or more anatomical locations, thereby cessating the development of blepharitis and / or rosacea.

[0077] In one configuration, the administration of formamidine-based antiparasitic agents is repeated approximately 2 to 4 times at intervals of 3 to 7 days.

[0078] In one embodiment, a topically applied formamidine-based antiparasitic agent is formulated in a carrier lotion, cream, or gel.

[0079] In one embodiment, the concentration of the formamidine-based antiparasitic agent in a topically applied lotion, cream, or gel is approximately 1-5% by weight.

[0080] In one embodiment, a locally applied formamidine-based antiparasitic agent is applied to the eyelids.

[0081] In one embodiment, a locally applied formamidine-based antiparasitic agent is applied to the affected skin area at least once a day, not more than twice, for a period of approximately 2 to 4 weeks.

[0082] In one embodiment, a topically applied formamidine-based antiparasitic agent is encapsulated in microliposomes before being incorporated into a carrier lotion, cream, or gel.

[0083] This specification discloses, in one embodiment, a composition for treating blepharitis and / or rosacea. The composition comprises an oral or topical formamidine-based antiparasitic agent in a dose sufficient to eliminate Demodex mites at one or more anatomical locations, thereby cessating the development of blepharitis and / or rosacea.

[0084] This specification discloses, in one embodiment, a method for treating cylindrical eyelash dandruff associated with blepharitis and / or ocular rosacea. The method comprises the step of topically administering an effective amount of a formamidine-based antiparasitic agent, formulated in an eyewash composition, directly to the conjunctiva and / or cornea of ​​the eye of an individual requiring such treatment. The eyewash composition contains a pharmaceutically acceptable solvent. The eyewash composition is sterile, non-irritating, and compatible with ocular tissue.

[0085] In one embodiment, a formamidine-based antiparasitic agent is administered at a concentration of 0.001 to 10% by weight relative to the total weight of the composition.

[0086] In one embodiment, 0.01 of the total weight of the composition weight %~5 weight Administer % of a formamidine-based antiparasitic agent.

[0087] In one embodiment, a formamidine-based antiparasitic agent is administered at a concentration of 0.03% by weight relative to the total weight of the composition.

[0088] In one embodiment, a formamidine-based antiparasitic agent is administered at a concentration of 0.10% by weight relative to the total weight of the composition.

[0089] This specification discloses, in one embodiment, a method for treating blepharitis and / or rosacea. The method involves orally or topically administering a formamidine-based antiparasitic agent in a dose sufficient to immerse and remove Demodex mites at one or more anatomical locations, thereby cessating the development of blepharitis and / or rosacea.

[0090] In one configuration, the administration of formamidine-based antiparasitic agents is repeated approximately 2 to 4 times at intervals of 3 to 7 days.

[0091] In one embodiment, a topically applied formamidine-based antiparasitic agent is formulated in a carrier lotion, cream, or gel.

[0092] In one embodiment, the concentration of the formamidine-based antiparasitic agent in a topically applied lotion, cream, or gel is approximately 1-5% by weight.

[0093] In one embodiment, a locally applied formamidine-based antiparasitic agent is applied to the eyelids.

[0094] In one embodiment, a locally applied formamidine-based antiparasitic agent is applied to the affected skin area at least once a day, not more than twice, for a period of approximately 2 to 4 weeks.

[0095] In one embodiment, a topically applied formamidine-based antiparasitic agent is encapsulated in microliposomes before being incorporated into a carrier lotion, cream, or gel.

[0096] This specification discloses, in one embodiment, a composition for treating blepharitis and / or rosacea. The composition comprises an oral or topical formamidine-based antiparasitic agent in a dose sufficient to eliminate Demodex mites at one or more anatomical locations, thereby cessating the development of blepharitis and / or rosacea.

[0097] This specification discloses, in one embodiment, a method for treating symptoms of blepharitis and / or ocular rosacea. The symptoms are selected from the group consisting of a burning sensation in the eye, a tingling sensation in the eye, dryness of the eye, increased sensitivity to light, blurred vision, and complications of ocular rosacea in the cornea. The method comprises the step of topically administering an effective amount of a formamidine-based antiparasitic agent formulated in an eyewash composition directly to the conjunctiva and / or cornea of ​​the eye of an individual requiring such treatment. The eyewash composition contains a pharmaceutically acceptable solvent. The eyewash composition is sterile, non-irritating, and compatible with ocular tissue.

[0098] In one embodiment, a formamidine-based antiparasitic agent is administered at a concentration of 0.001 to 10% by weight relative to the total weight of the composition.

[0099] In one embodiment, 0.01 of the total weight of the composition weight %~5 weight Administer % of a formamidine-based antiparasitic agent.

[0100] In one embodiment, a formamidine-based antiparasitic agent is administered at a concentration of 0.03% by weight relative to the total weight of the composition.

[0101] In one embodiment, a formamidine-based antiparasitic agent is administered at a concentration of 0.10% by weight relative to the total weight of the composition.

[0102] This specification discloses, in one embodiment, a method for treating blepharitis and / or rosacea. The method involves orally or topically administering a formamidine-based antiparasitic agent in a dose sufficient to immerse and remove Demodex mites at one or more anatomical locations, thereby cessating the development of blepharitis and / or rosacea.

[0103] In one configuration, the administration of formamidine-based antiparasitic agents is repeated approximately 2 to 4 times at intervals of 3 to 7 days.

[0104] In one embodiment, a topically applied formamidine-based antiparasitic agent is formulated in a carrier lotion, cream, or gel.

[0105] In one embodiment, the concentration of the formamidine-based antiparasitic agent in a topically applied lotion, cream, or gel is approximately 1-5% by weight.

[0106] In one embodiment, a locally applied formamidine-based antiparasitic agent is applied to the eyelids.

[0107] In one embodiment, a locally applied formamidine-based antiparasitic agent is applied to the affected skin area at least once a day, not more than twice, for a period of approximately 2 to 4 weeks.

[0108] In one embodiment, a topically applied formamidine-based antiparasitic agent is encapsulated in microliposomes before being incorporated into a carrier lotion, cream, or gel.

[0109] This specification discloses, in one embodiment, a composition for treating blepharitis and / or rosacea. The composition comprises an oral or topical formamidine-based antiparasitic agent in a dose sufficient to eliminate Demodex mites at one or more anatomical locations, thereby cessating the development of blepharitis and / or rosacea.

[0110] This specification discloses, in one embodiment, a method for treating cylindrical eyelash dandruff associated with blepharitis and / or ocular rosacea. The method comprises the step of topically administering an effective amount of a formamidine-based antiparasitic agent, formulated in an eyewash composition, directly to the conjunctiva and / or cornea of ​​the eye of an individual requiring such treatment. The eyewash composition contains a pharmaceutically acceptable solvent. The eyewash composition is sterile, non-irritating, and compatible with ocular tissue.

[0111] In one embodiment, a formamidine-based antiparasitic agent is administered at a concentration of 0.001 to 10% by weight relative to the total weight of the composition.

[0112] In one embodiment, 0.01 of the total weight of the composition weight %~5 weight Administer % of a formamidine-based antiparasitic agent.

[0113] In one embodiment, a formamidine-based antiparasitic agent is administered at a concentration of 0.03% by weight relative to the total weight of the composition.

[0114] In one embodiment, a formamidine-based antiparasitic agent is administered at a concentration of 0.10% by weight relative to the total weight of the composition.

[0115] This specification discloses, in one embodiment, a method for treating blepharitis and / or rosacea. The method involves orally or topically administering a formamidine-based antiparasitic agent in a dose sufficient to immerse and remove Demodex mites at one or more anatomical locations, thereby cessating the development of blepharitis and / or rosacea.

[0116] In one configuration, the administration of formamidine-based antiparasitic agents is repeated approximately 2 to 4 times at intervals of 3 to 7 days.

[0117] In one embodiment, a topically applied formamidine-based antiparasitic agent is formulated in a carrier lotion, cream, or gel.

[0118] In one embodiment, the concentration of the formamidine-based antiparasitic agent in a topically applied lotion, cream, or gel is approximately 1-5% by weight.

[0119] In one embodiment, a locally applied formamidine-based antiparasitic agent is applied to the eyelids.

[0120] In one embodiment, a locally applied formamidine-based antiparasitic agent is applied to the affected skin area at least once a day, not more than twice, for a period of approximately 2 to 4 weeks.

[0121] In one embodiment, a topically applied formamidine-based antiparasitic agent is encapsulated in microliposomes before being incorporated into a carrier lotion, cream, or gel.

[0122] This specification discloses, in one embodiment, a composition for treating blepharitis and / or rosacea. The composition comprises an oral or topical formamidine-based antiparasitic agent in a dose sufficient to eliminate Demodex mites at one or more anatomical locations, thereby cessating the development of blepharitis and / or rosacea.

[0123] This specification discloses, in one embodiment, a method for treating symptoms of blepharitis and / or ocular rosacea. The symptoms are selected from the group consisting of a burning sensation in the eye, a tingling sensation in the eye, dryness of the eye, increased sensitivity to light, blurred vision, and complications of ocular rosacea in the cornea. The method comprises the step of topically administering an effective amount of a phenylpyrazole antiparasitic agent formulated in an eyewash composition directly to the conjunctiva and / or cornea of ​​the eye of an individual requiring such treatment. The eyewash composition contains a pharmaceutically acceptable solvent. The eyewash composition is sterile, non-irritating, and compatible with ocular tissue.

[0124] In one embodiment, a phenylpyrazole antiparasitic agent is administered in an amount of 0.001 to 10% by weight relative to the total weight of the composition.

[0125] In one embodiment, 0.01 of the total weight of the composition weight %~5 weight Administer % of a phenylpyrazole antiparasitic agent.

[0126] In one embodiment, a phenylpyrazole antiparasitic agent is administered at a concentration of 0.03% by weight relative to the total weight of the composition.

[0127] In one embodiment, a phenylpyrazole antiparasitic agent is administered at a concentration of 0.10% by weight relative to the total weight of the composition.

[0128] This specification discloses, in one embodiment, a method for treating blepharitis and / or rosacea. The method involves orally or topically administering a phenylpyrazole anthelmintic in a dose sufficient to immerse and remove Demodex mites at one or more anatomical locations, thereby cessating the development of blepharitis and / or rosacea.

[0129] In one embodiment, the administration of phenylpyrazole antiparasitic agents is repeated approximately 2 to 4 times at intervals of 3 to 7 days.

[0130] In one embodiment, the topically applied phenylpyrazole antiparasitic agent is formulated in a carrier lotion, cream, or gel.

[0131] In one embodiment, the concentration of the phenylpyrazole antiparasitic agent in a topically applied lotion, cream, or gel is approximately 1-5% by weight.

[0132] In one embodiment, a locally applied phenylpyrazole antiparasitic agent is applied to the eyelids.

[0133] In one embodiment, a topically applied phenylpyrazole antiparasitic agent is applied to the affected skin area at least once a day, not more than twice, for a period of approximately 2 to 4 weeks.

[0134] In one embodiment, a topically applied phenylpyrazole antiparasitic agent is encapsulated in microliposomes before being incorporated into a carrier lotion, cream, or gel.

[0135] This specification discloses, in one embodiment, a composition for treating blepharitis and / or rosacea. The composition comprises an oral or topical feilpyrazole antiparasitic agent in a dose sufficient to eliminate Demodex mites at one or more anatomical locations, thereby cessating the development of blepharitis and / or rosacea.

[0136] This specification discloses, in one embodiment, a method for treating cylindrical eyelash flakes associated with blepharitis and / or ocular rosacea. The method comprises the step of topically administering an effective amount of a phenylpyrazole anthelmintic formulated in an eyewash composition directly to the conjunctiva and / or cornea of ​​the eye of an individual requiring such treatment. The eyewash composition contains a pharmaceutically acceptable solvent. The eyewash composition is sterile, non-irritating, and compatible with ocular tissue.

[0137] In one embodiment, a phenylpyrazole antiparasitic agent is administered in an amount of 0.001 to 10% by weight relative to the total weight of the composition.

[0138] In one embodiment, 0.01 of the total weight of the composition weight %~5 weight Administer % of a phenylpyrazole antiparasitic agent.

[0139] In one embodiment, a phenylpyrazole antiparasitic agent is administered at a concentration of 0.03% by weight relative to the total weight of the composition.

[0140] In one embodiment, a phenylpyrazole antiparasitic agent is administered at a concentration of 0.10% by weight relative to the total weight of the composition.

[0141] This specification discloses, in one embodiment, a method for treating blepharitis and / or rosacea. The method involves orally or topically administering a phenylpyrazole anthelmintic in a dose sufficient to immerse and remove Demodex mites at one or more anatomical locations, thereby cessating the development of blepharitis and / or rosacea.

[0142] In one embodiment, the administration of phenylpyrazole antiparasitic agents is repeated approximately 2 to 4 times at intervals of 3 to 7 days.

[0143] In one embodiment, the topically applied phenylpyrazole antiparasitic agent is formulated in a carrier lotion, cream, or gel.

[0144] In one embodiment, the concentration of the phenylpyrazole antiparasitic agent in a topically applied lotion, cream, or gel is approximately 1-5% by weight.

[0145] In one embodiment, a locally applied phenylpyrazole antiparasitic agent is applied to the eyelids.

[0146] In one embodiment, a topically applied phenylpyrazole antiparasitic agent is applied to the affected skin area at least once a day, not more than twice, for a period of approximately 2 to 4 weeks.

[0147] In one embodiment, a topically applied phenylpyrazole antiparasitic agent is encapsulated in microliposomes before being incorporated into a carrier lotion, cream, or gel.

[0148] This specification discloses, in one embodiment, a composition for treating blepharitis and / or rosacea. The composition comprises an oral or topical phenylpyrazole antiparasitic agent in a dose sufficient to eliminate Demodex mites at one or more anatomical locations, thereby cessating the development of blepharitis and / or rosacea.

[0149] This specification discloses, in one embodiment, a method for treating symptoms of blepharitis and / or ocular rosacea. The symptoms are selected from the group consisting of a burning sensation in the eye, a tingling sensation in the eye, dryness of the eye, increased sensitivity to light, blurred vision, and complications of ocular rosacea in the cornea. The method comprises the step of topically administering an effective amount of an agent used to treat Alzheimer's disease, formulated in an eyewash composition, directly to the conjunctiva and / or cornea of ​​the eye of an individual requiring such treatment. The eyewash composition contains a pharmaceutically acceptable solvent. The eyewash composition is sterile, non-irritating, and compatible with ocular tissue.

[0150] In one embodiment, an Alzheimer's disease treatment agent is administered in an amount of 0.001 to 10% by weight relative to the total weight of the composition.

[0151] In one embodiment, 0.01 with respect to the total weight of the composition weight %~5 weight Administer % of the medication used to treat Alzheimer's disease.

[0152] In one embodiment, an Alzheimer's disease treatment agent is administered at a concentration of 0.03% by weight relative to the total weight of the composition.

[0153] In one embodiment, an Alzheimer's disease treatment agent is administered at a concentration of 0.10% by weight relative to the total weight of the composition.

[0154] This specification discloses, in one embodiment, a method for treating blepharitis and / or rosacea. The method involves orally or topically administering an Alzheimer's disease treatment agent in a dose sufficient to immerse and remove Demodex mites at one or more anatomical locations, thereby cessating the development of blepharitis and / or rosacea.

[0155] In one configuration, the administration of medications for treating Alzheimer's disease is repeated approximately 2 to 4 times at intervals of 3 to 7 days.

[0156] In one embodiment, a topically applied drug for the treatment of Alzheimer's disease is formulated in a carrier lotion, cream, or gel.

[0157] In one embodiment, the concentration of the Alzheimer's disease treatment agent in a topically applied lotion, cream, or gel is approximately 1-5% by weight.

[0158] In one embodiment, a topically applied drug for the treatment of Alzheimer's disease is applied to the eyelids.

[0159] In one embodiment, a topically applied drug for treating Alzheimer's disease is applied to the affected skin area at least once a day, but not more than twice a day, for a period of approximately 2 to 4 weeks.

[0160] In one embodiment, a topically applied drug for the treatment of Alzheimer's disease is encapsulated in microliposomes before being incorporated into a carrier lotion, cream, or gel.

[0161] This specification discloses, in one embodiment, a composition for treating blepharitis and / or rosacea. The composition comprises an oral or topical pharmaceutical preparation used to treat Alzheimer's disease in a dose sufficient to eliminate Demodex mites at one or more anatomical locations, thereby cessating the development of blepharitis and / or rosacea. [Brief explanation of the drawing]

[0162] [Figure 1A] Figure 1A is a schematic diagram illustrating the application of an ophthalmic formulation to an eye infected with Demodex. [Figure 1B] Figure 1B is a schematic diagram illustrating the application of an ophthalmic formulation to an eye infected with Demodex. [Figure 2] Figure 2 is a graph selectively showing data on the anatomical activity of Demodex mites after treatment with topical formulations. [Figure 3A] Figure 3A shows an example of a formulation containing amitraz. [Figure 3B] Figure 3B shows an example of a formulation containing fluralaner. [Figure 4A] Figure 4A shows an example of a diagnostic technique for Demodex that does not require hair removal. [Figure 4B] Figure 4B shows an example of a diagnostic technique for Demodex that does not require hair removal. [Figure 4C] Figure 4C shows an example of a diagnostic technique for Demodex that does not require hair removal. [Modes for carrying out the invention]

[0163] In one embodiment, this specification discloses topical therapeutic agents, including topical pharmaceuticals. These topical pharmaceuticals include, but are not limited to, one or more isoxazoline anthelmintics, formamidine anthelmintics, agents used in the treatment of Alzheimer's disease, and other agents for the treatment of various ocular and skin conditions disclosed herein. This specification also discloses methods for treating blepharitis, ocular rosacea, and Demodex infestation in patients requiring treatment. In one embodiment, patients requiring treatment are treated with an activator of an isoxazoline anthelmintic, which is a chemical substance containing (but not limited to) an isoxazoline-substituted benzamide derivative. While not limited by theory, isoxazoline anthelmintics act as GABA-chloride antagonists to selectively target the nervous systems of certain organisms, including, but not limited to, Demodex. The influx of chlorides via GABA causes hyperpolarization of the cell membrane, generating inhibitory postsynaptic potentials, which in turn reduce the probability of action potentials, leading to paralysis and eventual death of Demodex mites. Isoxazoline anthelmintics include, for example, any number of fluralaner, sarolaner, rotylaner, afoxolaner and / or fluxamethamides, including derivatives, analogs, L-isomers and D-isomers, and include compositions containing enantiomers, racemic mixtures and enantiomerically pure compositions. In one example, the isoxazoline anthelmintic, formamidine anthelmintic, or other active ingredients disclosed herein is the sole active ingredient used in the formulation and / or method. In one example, the isoxazoline anthelmintic is an isoxazoline-substituted benzamide derivative. In one example, the isoxazoline-based antiparasitic agent has one, two, three or more fluorine groups, such as a trifluoro group, in its chemical structure (e.g., R-CF3).

[0164] Isoxazoline antiparasitic agents have conventionally been used in veterinary applications, including chewing agents and non-ophthalmic topical solvents, but to the best of the inventors' knowledge, no formulations for human use have been developed. Isoxazoline antiparasitic agents are disclosed, to an unspecified extent, in U.S. Patent No. 7,662,972 by Mita et al., U.S. Patent No. 8,466,115 by Curtis et al., U.S. Patent No. 7,964,204 by Lahm et al., and U.S. Patent No. 8,383,659 by Nanchen et al., all of which are incorporated herein by reference. Furthermore, U.S. Patent Publication No. 2010 / 0254960, International Publication No. 2007 / 070606, International Publication No. 2007 / 123855, International Publication No. 2010 / 003923, U.S. Patent No. 7,951,828, U.S. Patent No. 7,662,972, U.S. Patent Publication No. 2010 / 0137372, U.S. Patent Publication No. 2010 / 0179194, U.S. Patent Publication No. 2011 / 0086886, U.S. Patent Publication No. 2011 / 0059988, U.S. Patent Publication No. 2010 / 0179195, International Publication No. 2007 / 075459, and U.S. Patent No. 7,951,828 disclose various other antiparasitic isoxazoline compounds, all of which are incorporated herein by reference. Oral formulations for animals, such as chewing medications, undergo first-pass hepatic metabolism and have systemic effects. This can be undesirable for intended topical application. A significant challenge is that fluorination and / or chlorination groups in certain isoxazoline anthelmintics make these molecules highly insoluble in pharmaceutical-based solutions, including oil and water-based solutions, with solubility less than approximately 1 mg / kg or aqueous solution concentrations of 1 mg / mL or less. Veterinary topical solutions of isoxazoline anthelmintics include, for example, dimethylacetamide, glycoflor, diethyltoluamide, and / or acetone. However, such solutions are labeled as "pour-on" solutions to be applied to the back of the neck of animals such as cats and dogs, and are not suitable for use in the eyes (which may be toxic), and instructions indicate that they should not be administered intraocularly or around the eyes.Such "poor-on" type solutions are absorbed throughout the animal's body and do not produce the desired local activity. To the best of the inventor's knowledge, no topical ophthalmic formulations of isoxazoline or formamidine-based antiparasitic agents have been developed to date. A therapeutic formulation is needed that is safe and non-toxic for ophthalmic use and sufficiently soluble to be therapeutically effective in treating symptoms such as ophthalmic demodex infection and blepharitis.

[0165] A group of compounds including isoxazoline anthelmintics, formamidine anthelmintics, agents for the treatment of Alzheimer's disease and / or other agents described elsewhere in this specification have been found to be suitable for the treatment of ocular pathologies of all origins, particularly ocular pathologies caused by demodectic mange, and especially blepharitis and / or ocular rosacea. Other conditions treatable with the formulations and methods disclosed herein include, for example, rosacea, pityriasis folliculorum, rosacea-like demodicosis and severe demodicosis, nonspecific facial dermatitis, steroid rosacea, androgenic alopecia, eyelash and eyebrow loss, facial disseminated miliary lupus, dissociative folliculitis, perioral dermatitis, mite-like blepharoconjunctivitis, papulopustular scalp eruptions, eosinophilic folliculitis, pustular folliculitis, Grover's disease, and Demodex abscess.

[0166] Ivermectin is another drug that has been used to treat Demodex flu and is generally more soluble in solution than isoxazoline antiparasitic agents. However, there are no formulations approved for use in the eye (e.g., blepharitis), and therefore, an effective treatment is needed. In one example, the formulation and / or method does not contain ivermectin or other macrocyclic lactone derivatives such as ivermectin. However, in other examples, the formulation may contain ivermectin.

[0167] This specification discloses examples of systems, methods, and formulations for the treatment of various eye conditions, including (but not limited to) blepharitis, and for the treatment of Demodex parasites (e.g., on the eyelids of subjects such as humans). Various examples may include any number of features described herein. One example does not contain dimethylacetamide, glycoflor, diethyltoluamide, and / or acetone, and at least a portion thereof may be toxic or irritating to the eye.

[0168] Furthermore, this specification discloses the use of topical isoxazoline anthelmintics, formamidine anthelmintics, agents for treating Alzheimer's disease, and / or other agents described elsewhere in this specification, for the treatment of blepharitis in patients and for methods of treating Demodex infestation and blepharitis.

[0169] Furthermore, this specification discloses topical isoxazoline anthelmintics, formamidine anthelmintics, agents for treating rosacea and / or ocular rosacea and methods for treating Demodex mites and rosacea and / or ocular rosacea in patients (e.g., by the isoxazoline anthelmintics group, which are chemical substances), agents for treating Alzheimer's disease and / or other agents described elsewhere in this specification. Formulations and methods for reducing the number of Demodex mites and cylindrical eyelash flakes near a patient's eyes are also disclosed.

[0170] Furthermore, this specification discloses topical isoxazoline anthelmintics, formamidine anthelmintics, agents for treating rosacea and / or ocular rosacea, and methods for treating Demodex infestation and rosacea and / or ocular rosacea in patients, agents for treating Alzheimer's disease, and / or other agents described elsewhere in this specification.

[0171] According to one embodiment, the pharmaceutical composition comprises, for example, at least one, two, or more compounds selected from the isoxazoline anthelmintics group, including fluralaner, sarolaner, rotilaner, afoxolaner, and / or fluxamethamide, and is administered in particular for the treatment of other conditions including conjunctivitis, blepharitis, ocular rosacea, or other ocular surface diseases such as meibomian gland dysfunction or dry eye disease.

[0172] One example includes, but is not limited to, compositions comprising enantiomers, racemic mixtures, and enantiomerically pure compositions, all comprising derivatives, analogues, and L-isomers and D-isomers of isoxazoline anthelmintics, formamidine anthelmintics, or other active therapeutic agents described elsewhere in this specification.

[0173] In one example, isoxazoline anthelmintics, formamidine anthelmintics, agents for treating Alzheimer's disease, and / or other agents described elsewhere in this specification may, surprisingly, be used in doses lower than those shown to be clinically effective in veterinary medicine (e.g., concentrations in the range of 1–10 nM or 100 pM–1 nM) or in a range including any two of the aforementioned values, acting via systemic absorption through topical rinsing or washing. These lower effective concentrations are due to direct absorption of the agent by the tick's body rather than ingestion by the tick. The tick's abdomen is thinner (~approximately 0.5 μm) and absorbs the agent more readily than the tick's cephalothorax (approximately 2 μm). In one example, direct absorption of the agent by the tick's body accounts for at least approximately 50%, 60%, 70%, 80%, 90%, or more of the total drug ingestion by the tick.

[0174] In one embodiment, a daily and local administration is performed, rather than a long-acting, large-dose systemic administration (as is commonly done veterinarily, once a month, every 8 weeks, every 12 weeks, every 16 weeks, or less). However, in other embodiments, a long-acting systemic administration or a local administration may be used.

[0175] In one embodiment, administration is, for example, about once, twice, three, four, five, six, seven, eight or more times per day, for example, once or twice per day. In one embodiment, treatment may be once a week, a single dose, or a limited number of therapeutic units. In one embodiment, the formulation is preferentially used only in the morning, evening, or nighttime for targeted exposure of mites during mating time.

[0176] In one embodiment, the formulation is advantageous, in part, due to the slow elimination rate of molecules such as isoxazoline antiparasitic agents. However, low-dose, localized administration allows for repeated and frequent administration without associated systemic risks and side effects. This is advantageous because it disrupts the life cycle of Demodex through its effect on the more vulnerable juvenile form.

[0177] In one embodiment, the active molecule may be selectively hydrophobic and therefore concentrate in regions containing sebum or meibomian oil (e.g., eyelash follicles and / or meibomian glands). To facilitate delivery of hydrophilic chitin chitosan to the exoskeleton of Demodex mites and absorption by the exoskeleton, the formulation may be selectively water-based.

[0178] In one embodiment, the therapeutic agent may be a drop, cream, ointment, eye wash, wipe, plaster or gel, or an immediate-release or sustained-release formulation. In one embodiment, the therapeutic agent may be applied in the form of a punctal plug or canaliculi plug or emulsion. For example, an oily gel-like viscous ointment may hinder the movement of Demodex mites across the skin surface during mating.

[0179] In one example, isoxazoline anthelmintics, formamidine anthelmintics, agents for treating Alzheimer's disease, and / or other agents described elsewhere in this specification have preferential selectivity for insect / mite / dust mite receptors over vertebrate / mammalian / human receptors.

[0180] In one embodiment, the activator is applied in an oral formulation (e.g., tablets, capsules, solutions, etc.), and a very small amount of the activator may be applied to avoid systemic or non-topical skin exposure (in contrast to veterinary teachings). However, in one embodiment, the activator may also be applied as a parenteral formulation, such as a topical formulation or topical eye drop formulation.

[0181] In one example, for example, 1 microgram to 1 mg / ml or 0.000 wt 1% to 1 wt% of the activator (e.g., isoxazoline parasitic agents, formamidine parasitic agents, agents for treating Alzheimer's disease and / or other agents described elsewhere in this specification), about 0.01 wt% to 10 wt%, about 0.05 wt% to about 0.5 wt%, or about 0.01%, 0.015%, 0.02%, 0.025%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.10%, 0.15%, 0.20%, 0.25%, 0.30%, 0.35%, 0.40%, 0.45%, 0.50%, 0.55%, 0.60%, 0.65%, 0.70 The range includes %, 0.75%, 0.80%, 0.85%, 0.90%, 0.95%, 1.00%, or at least two of the above values, or 1 ng to 1 microgram / ml or 0.0000001 to 0.0001 wt% of an activator (e.g., isoxazoline repellents, formamidine repellents, agents for treating Alzheimer's disease and / or other agents described elsewhere in this specification), or 1 mg / ml to 100 mg / ml or 0.1 to 10 wt% of an activator (e.g., isoxazoline repellents, formamidine repellents, agents for treating Alzheimer's disease and / or other agents described elsewhere in this specification), or a range including the above values. In one embodiment, isoxazoline antiparasitic agents, formamidine antiparasitic agents, agents for treating Alzheimer's disease, or other agents described elsewhere in this specification are the sole active agents.

[0182] In one embodiment, the ophthalmic formulation is configured to be applied directly to the ocular surface, including (but not limited to) the conjunctiva and / or cornea of ​​the eye. In another embodiment, the ophthalmic formulation is configured to be applied directly or indirectly to either the anterior or posterior eye, the eyelashes, or the eyebrows. In yet another embodiment, the ophthalmic formulation is not applied directly to any of the conjunctiva, cornea, anterior or posterior eye, eyelashes, or eyebrows.

[0183] Eye drops may be formulated to simultaneously treat blepharitis and demodex in both the eyelash follicles and / or meibomian glands, without being limited by oily additives, emulsions, ointments or cream-based formulations, or by application tools or application sites such as eyelash brushes. In one embodiment, a “Drop and Coat the Lashes” (DACTL) technique is used. The patient is instructed to close their eyes at administration. This allows the formulation to come into contact with the openings of the meibomian glands at the eyelid margin, and the formulation accumulates on the outside of the eyelid margin. The patient may then spread the formulation accumulated on the outside of the eyelid margin to the eyelashes and / or eyelash follicles of the upper and / or lower eyelids using their fingers or an applicator. Although not limited by theory, since Demodex mites are present in both the eyelash follicles and meibomian glands, it may be beneficial to apply the eye drops directly to one or both of these. The combination of the two targets mentioned above is specific to this disease, and therefore, the therapeutic agent is applied to these locations simultaneously. The openings of the meibomian glands are located on the upper surface of the lower eyelid and the lower surface of the upper eyelid. Therefore, by directly instilling the eye drops onto the ocular surface, the formulation can be directly applied to the upper and lower openings of the meibomian glands.

[0184] Methods for treating blepharitis and / or Demodex infestation include formulations / treatments (or procedures) applied by instilling eye drops and then covering the base of the hair follicles of the upper and / or lower eyelids using a finger or instrument (e.g., an eyelash brush). In one embodiment, desirable features of the formulation include any maximum water solubility of the drug to improve bioavailability (in solutions and suspensions), improve the residence time of the formulation in the eye using polymers / viscosities, and achieve acceptable visual acuity and comfort.

[0185] In one embodiment, the formulation has sufficiently high viscosity to cover the meibomian gland openings at the upper and / or lower eyelid margins when the eyes are closed and / or blinked.

[0186] For example, the viscosity is sufficiently high to delay the drainage of the formulation through the lacrimal lake of the eye by at least 5, 10, 20, 30 seconds or more, thereby increasing the contact time of the formulation with the meibomian gland openings and allowing the formulation to flow across the eyelid margin to the site of application to the eyelash follicles (e.g., by runoff and / or by diffusion of the formulation using fingers and / or instruments).

[0187] The formulation components are selected to allow the dissolution of the activator in the solution, but to contain a low concentration of organic solvent by weight, e.g., 50% or less, 20% by weight, 10% by weight, 5% by weight, 2% by weight, 1% by weight, or less or more. This is at least partially achieved by using a surfactant such as polysorbate 80 or polysorbate 20. In one example, low concentrations of polysorbate 80 are preferred because hydrolysis of isoxazoline antiparasitic agents may occur at high concentrations (e.g., 0.001-0.1% by weight of polysorbate 80).

[0188] In another example, the solubility of isoxazoline antiparasitic agents can be enhanced via organic solvents such as propylene glycol.

[0189] Furthermore, by appropriately selecting additives, both solubility and viscosity can be improved simultaneously, thereby minimizing osmotic pressure using, for example, polyvinyl alcohol or carboxymethylcellulose.

[0190] The formulation components are selected to allow the dissolution of an activator (e.g., isoxazoline antiparasitic agents or other activators) in solution and exhibit stability against hydrolysis reactions for 1 year, 1.5 years, 2 years or more, enabling a commercially viable lifespan in an optimal pH range of neutral to slightly alkaline (e.g., pH 7-10, pH 7-7.5, or pH 5-7 as in other examples).

[0191] In one example, the concentration of buffering agent required to achieve the desired pH can be minimized, and therefore the hydrolysis rate can be slowed (e.g., phosphate buffer concentration of 0.01-0.1 M). This can be achieved with organic solvents and surfactants within the above concentration range.

[0192] Cationic surfactants are beneficial because they can slow down the hydrolysis rate through the formation of cationic micelles.

[0193] For example, an emulsion and emulsifier may be mixed with water to shield isoxazoline antiparasitic agents, formamidine antiparasitic agents, drugs for treating Alzheimer's disease, and / or other drugs and / or other activators from water in the oil droplets in water, using a carbodiimide additive that extends stability by forming more complex water-free micelles.

[0194] By adding a water-retaining agent (scavenger) such as Stavaxol I® (bis-2,6-diisopropylphenylcarbodiimide), it is possible to achieve an oil-based formulation that washes away the water solvent over a long period of time.

[0195] The pharmaceutical composition in one embodiment comprises at least one compound selected from the isoxazoline anthelmintics group, the formamidine anthelmintics group, drugs for treating Alzheimer's disease, and / or other drugs and / or other activators, and is particularly useful for symptoms selected from ocular symptoms, burning sensation of the eyes, stinging pain of the eyes, foreign body sensation in the eyes, dryness of the eyes, increased sensitivity to light, blurred vision, telangiectasia of the eyelid margins, meibomian gland inflammation, chalazion, conjunctival hyperemia, and papillary conjunctivitis.

[0196] The term "treatment" includes the treatment of humans and / or other animals.

[0197] A pharmaceutical composition according to one embodiment of the present invention is useful for topical, oral, parenteral, or rectal treatment of the eye.

[0198] Topical application is the most common method of administering ophthalmic medications. Topical administration methods allow for the instillation or solution of eye drops, eye washes, suspensions, ointments, plasters, gels, sprays, foams, powders, lotions, viscoelastic solutions and / or the application of solids to the surface of the eye, impregnation pads, and the application or wiping of synthetic detergents to the eye.

[0199] Furthermore, some formulations are provided in the form of suspensions of microspheres or nanospheres, or vesicles or polymer patches formed from lipids or polymers, and hydrogels that allow for controlled excretion. For topical application, these compositions may be provided in anhydrous, aqueous, or emulsion form.

[0200] Pharmaceutical compositions for topical application are preferably non-irritating and compatible with ocular tissue. Solutions may be sterile preparations and may not contain all particles. Suspensions may be sterile preparations and may contain solid particles in a liquid medium suitable for ophthalmic use. Ointments are semi-solid sterile preparations.

[0201] Pharmaceutical compositions are provided orally in the form of liquids, pastes, or solids, powders, and more specifically, in the form of tablets, sugar-coated tablets, hard gelatin capsules, syrups, suspensions, solutions, powders, granules, emulsions, microspheres or nanospheres or vesicles, formed from lipids or polymers that allow for controlled excretion. Parenterally, compositions are provided in the form of solutions or suspensions for infusion or injection. Rectally, compositions are provided in the form of suppositories. In other embodiments, the pharmaceutical composition is a topical ophthalmic composition and not an oral or rectal composition.

[0202] In one embodiment, the composition contains 0.001% to 10% by weight of at least one compound selected from the isoxazoline anthelmintics group, the formamidine anthelmintics group, agents for treating Alzheimer's disease and / or other agents described herein, based on the total weight of the composition. In another embodiment, the composition according to the present invention contains 0.01% to 5% by weight of at least one compound selected from the isoxazoline anthelmintics group, based on the total weight of the composition.

[0203] In one embodiment, the composition according to the present invention is provided in the form of an eye wash or eye drops. The term “eye wash” means a liquid formulation particularly suitable for administration to the conjunctiva and cornea of ​​the eye. The eye wash contains, for example, about 25 to 50 microliters of droplets. In one embodiment, the composition is supplied as a kit, for example, eye drops and shampoo, and may be used together with tea tree oil and derivatives and a disinfectant such as hypochlorous acid, which has also been shown to have Demodex activity, or optionally does not contain tea tree oil or other oils.

[0204] As described above, in one embodiment, the composition satisfies specific conditions for application to the eye. Such conditions include, in particular, sterility, non-irritation, and compatibility with eye tissue. The latter criterion is more difficult to meet than that of compositions applied to the skin. This is because, in particular, compounds such as ethanol or glycol, which are incorporated into compositions applied to the skin, may not be included in compositions for ophthalmic use.

[0205] Topical compositions enable the direct and specific treatment of pathological symptoms in the eyes and eyelids through local action. This is particularly beneficial because it targets only the eyes, thus offering potentially better efficacy.

[0206] In one embodiment, the formulation is in the form of a solution, suspension, cream, ointment, or other form.

[0207] Liquid compositions prescribed for topical use in the eye are formulated to be administered topically to the eye. While comfort can be maximized as much as possible, optimal comfort may not be achievable due to formulation considerations (e.g., drug stability). If maximum comfort cannot be achieved, the liquid composition is formulated to be tolerable for patient use as eye drops. Furthermore, ophthalmally acceptable liquids may be packaged for single use or may contain preservatives to prevent contamination for multiple uses.

[0208] For ophthalmic use, solutions or medications are often prepared using physiological saline as the primary medium. These mediums include, but are not limited to, polyvinyl alcohol, povidone, hydroxypropyl methylcellulose, poloxamer, carboxymethylcellulose, hydroxyethylcellulose, and purified water. It is desirable to maintain the ophthalmic solution at a suitable pH using an appropriate buffering system. The formulation may also contain pharmaceutically acceptable preservatives, stabilizers, and surfactants.

[0209] In one embodiment, the topical formulation does not contain a skin penetration enhancer. This skin penetration enhancer may increase systemic absorption, which may be contrary to the intention of locally maintaining the formulation at or near the application site. In one embodiment, the formulation contains a skin penetration enhancer, for example, one or more laurocapram (Azon®) and laurocapram derivatives, for example, 1-alkylazacycloheptan-2-one, and oleic acid and its ester derivatives, for example, methyl, ethyl, propyl, isopropyl, butyl, vinyl, glyceryl monooleate, and sorbitan esters, for example, sorbitan monolaurate and sorbitan monooleate, and other fatty acid esters, for example, isopropyl laurate, myristic The formulation does not contain isopropyl phosphate, isopropyl palmitate, diisopropyl adipate, propylene glycol monolaurate, propylene glycol monooleate, or long-chain alkyl esters of 2-pyrrolidone, particularly 1-(2-ethylhexyl) esters of 1-lauryl, 1-hexyl, and 2-pyrrolidine, nor skin penetration enhancers thereof, such as dodecyl (N,N-dimethylamino) acetate, dodecyl (N,N-dimethylamino) propionate, and 2-n-nonyl-1-3-dioxolane. However, in other embodiments, the formulation may contain one or more skin penetration enhancers.

[0210] In one embodiment, the topical formulation comprises one or more gelling agents. The gelling agents can be high molecular weight copolymers, such as pemlen TR1 and / or TR2 polymer emulsifiers (Lubrizol, Inc., Wickliffe, Ohio), acrylic acid copolymers, and C10-C30 alkyl acrylates crosslinked with allyl pentaerythritol. These are cottony white powders and are primarily used to form stable oil-in-water emulsions. Pemlen polymers contain both hydrophilic and hydrophobic parts within their molecules. The hydrophobic part of the polymer adsorbs at the oil-water interface, while the hydrophilic part swells in water to form a gel network around oil droplets, providing emulsion stability. Pemlen polymers can form stable oil-in-water emulsions without the need for additional surfactants. Therefore, they are advantageous, for example, in developing hypoallergenic lotions and creams. Pemlen polymers provide viscosity and high yield values ​​to enable the suspension and stabilization of insoluble substances and particles. In one embodiment, the gelling agent is either absent, present in amounts of approximately 0.001% to approximately 1%, approximately 0.01% to approximately 0.10% of the formulation, or within a range of approximately 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 within a range including any two of the above values.

[0211] In one embodiment, an oil-based formulation such as a cream, ointment, or emulsion contains one or more mineral oils, castor oil, or petrolatum in amounts such as about 20% to about 80%, or about 30% to about 70% w / w of the formulation. The formulation may also contain cyclodextrin as a carrier molecule to facilitate dissolution.

[0212] In one example, the topical formulation contains one or more thickeners, the thickeners including polysaccharide thickeners such as hydroxypropyl methylcellulose (HPMC) and sodium CMC. In one example, the thickener may be present in a range including any two of the following values: about 0% to about 2%, about 0.10% to about 1.00%, about 0.25% to about 1.00%, or about 0.10%, 0.20%, 0.25%, 0.30%, 0.35%, 0.40%, 0.50%, 0.60%, 0.70%, 0.80%, 0.90%, 1.00% w / w or between about 0.1% and about 0.5%. In one example, the formulation may have a viscosity of about 50 cP to about 100 cP to increase the residence time of the formulation in the eye. In one embodiment, the formulation has a viscosity of, for example, 5 cP, 20 cP, 40 cP, 100 cP, 250 cP, 400 cP, or 1000 cP or higher, or a range including any two of the aforementioned values. In one example, the formulation is configured to have an intraocular residence time of about 90 seconds to about 10 minutes, or at least about 60 seconds, 90 seconds, 120 seconds, 180 seconds, 240 seconds, 300 seconds, 6 minutes, 7 minutes, 8 minutes, 9 minutes, or 10 minutes, or a range including any two of the aforementioned values.

[0213] In one embodiment, the topical formulation comprises one or more solubilizers and / or surfactants, including polysorbates, such as nonionic surfactants including polysorbate 80, polysorbate 65, polysorbate 60, polysorbate 40, or polysorbate 20. In one embodiment, polysorbate 80 has been found to unexpectedly provide a greater increase in the solubility of isoxazoline antiparasitic agents than other polysorbates. Other surfactants, such as fluorinated surfactants, may be used in place of or in addition to the nonionic surfactants. In one embodiment, the solubilizer and / or surfactant are present in a range including about 0% to about 5%, about 0.10% to about 4%, about 0.50% to about 4%, or about 0.50%, 0.75%, 1.00%, 1.25%, 1.50%, 1.75%, 2.00%, 2.25%, 2.50%, 2.75%, 3.00%, 3.25%, 3.50%, 3.75%, 4.00%, 4.25%, 4.50%, 4.75%, 5.00% w / w, or any two of the above values. Furthermore, polysorbate 80 may be substituted with cremofol EL (hydrogenated castor oil) up to 5% of the FDA limit, for example, in the range of approximately 1%, 2%, 3%, 4%, 5%, or in the range of approximately 1% to 5%, or in any two of the aforementioned values, in order to promote higher drug concentrations.

[0214] In one embodiment, the formulation (including, but not limited to, eye drops, creams, ointments, or other forms described elsewhere in this specification) comprises both castor oil (e.g., hydrogenated castor oil) and a polysaccharide thickener such as HPMC or sodium CMC. In one example, this combination can form a long-lasting film layer advantageously and unexpectedly.

[0215] In one example, the topical formulation contains one or more isotonic agents such as glycerin, dextrose, mannitol, potassium chloride, and / or sodium chloride. In one example, the isotonic agent is present in a range 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, or any two of the above values.

[0216] In one embodiment, the topical formulation comprises one, two, or more buffering agents. The buffering agents include, for example, acetate buffer, citrate buffer, phosphate buffer, and borate buffer. The pH of these formulations may be adjusted using an acid or base as needed. Buffers include 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-acetamide)-2-iminodiacetic acid) buffer, AMPSO (3-[(1,1-dimethyl-2-hydroxyethyl)amino]-2-propanesulfonic acid) buffer, BES (N,N-bis(2-hydroxyethyl)-2-aminoethanesulfonic acid) buffer, bicine (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 -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 Zin-N,N′-bis(2-hydroxypropanesulfonic acid) buffer, TAPS (N-tris[hydroxymethyl]methyl-3-aminopropanesulfonic acid) buffer, TAPSO (3-[N-tris(hydroxymethyl)methylamino]-2-hydroxy-propanesulfonic acid) buffer, TES (N-tris(hydroxymethyl)methyl-2-aminoethanesulfonic acid) buffer, Trisine (N-tris(hydroxymethyl)methylglycine buffer, 2-amino-2-methyl-1,3-propanediol buffer, and 2-amino-2-methyl-1-propano This refers to one or more buffering agents, or combinations thereof. In one example, the buffering agents are Tris and / or disodium hydrogen phosphate (Na2HPO4) and sodium dihydrogen phosphate heptahydrate (NaH2PO47H2O). In one example, the buffering agent is present in amounts of approximately 0% to approximately 2%, approximately 0.01% to approximately 1%, approximately 0.01% to approximately 0.75% or approximately 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% of the formulation.The buffer exists in a range including 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 or any two of the above values. The buffer is selected in a therapeutically effective amount such that the pH of the pharmaceutical composition is, 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 any two of the above values.

[0217] In one example, the topical formulation contains one or more preservatives, including (but not limited to) lauralkonium chloride and benzalkonium chloride. Other preservatives include, for example, PHMB, chlorobutanol, thimerosal, phenylmercury, acetic acid, and phenylmercury nitrate. In one example, the preservative is present in the topical formulation 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, or any two of the aforementioned values.

[0218] A pharmaceutical composition according to one embodiment of the present invention further comprises inert additives, or combinations thereof, such as humectants, emollients; flavor enhancers; preservatives; stabilizers; humidity regulators; pH adjusters; buffers; osmotic pressure regulators; emulsifiers; thickeners; and antioxidants. Ophthalmologically acceptable antioxidants include, but are not limited to, sodium disulfite, sodium thiosulfate, acetylcysteine, butylated hydroxyanisole, and butylated hydroxytoluene. Other excipients that may be included in ophthalmic formulations are chelating agents. A useful chelating agent is disodium edetate (EDTA), but other chelating agents may be used as appropriate or in combination.

[0219] In one example, the pharmaceutical composition contains tocopherol. In one example, tocopherol is effective in preventing the degradation of isoxazoline in water. In one example, vitamin E is tocopherol; in further examples, tocopherol is alpha- or gamma-tocopherol; more preferably alpha-tocopherol. In one example, the pharmaceutical composition does not contain tocopherol.

[0220] In one embodiment, the pharmaceutical formulation contains tea tree oil, alpha-terpineol (α-terpineol), cadinene, d-carvone, 1-carvone, gamma-terpinene, alpha-terpinene, and 1,8-cineol. , Pa It does not contain essential oils such as larcymene, alpha-pinene, limonene, alpha-thugen, eucalyptol, (+)-ledene, cumin aldehyde, or myrcene. However, other embodiments may contain one or more of the above essential oils.

[0221] In one embodiment, any one or more compounds may be added to the composition such that the advantageous properties essentially related to some embodiments of the present invention may have a favorable effect on blepharitis, and are not adversely affected or substantially affected by hypothetical additives, such as tetracycline or omega-3 fatty acids.

[0222] In one embodiment, an isoxazoline antiparasitic agent is administered orally to a patient having blepharitis, rosacea, or other conditions as described elsewhere in this specification. One target organism, Demodex mites (and / or Demodex spp.), is an ectoparasite of the family Acrididae, and therefore, in some cases, an effective treatment is to therapeutically eradicate the entire life cycle of such microscopic insects, including the egg, larval, and adult stages. For this reason, in one embodiment, a patient with blepharitis and / or rosacea is treated with at least two doses administered at intervals of approximately 3 to 7 days. This interval allows the Demodex eggs to hatch into immature mites and kill the mites before they can grow into adult mites capable of laying eggs. In one embodiment, one, two, three, four or more doses may be administered at intervals of 3 to 7 days. After the isoxazoline anthelmintics or other activators disclosed herein perform acaricidal activity against Demodex mites (and / or Demodex spp.), the inflammatory response to the mites begins to decrease, but residual dead mites cause some degree of flushing and lesion formation until they are removed by the body's cleansing process. This process may take 6 to 8 weeks. During the initial stages of this administration, other agents such as oral tetracyclines and topical metronidazole, as well as / or anti-inflammatory agents such as NSAIDs and / or steroids, may be used to suppress early relapses and induce an early clinical response. However, in other embodiments, the formulation or method does not include tetracyclines or other antibiotics, steroids and / or metronidazole. If symptoms begin to recur after a long period of symptom-free periods, treatment may be repeated.

[0223] In other embodiments, isoxazoline antiparasitic agents may be formulated as cosmetically acceptable topical lotions, creams, or gels and applied to the skin, eyelids, eyelashes, meibomian glands, or other anatomical sites as described elsewhere herein. In one example, such therapeutic administration requires application once or twice daily for four weeks to achieve sufficient penetration into the follicles and effective acaricidal activity. A topical formulation achieving this effect may contain, for example, about 0.01–5% of the active ingredient, and penetration can be enhanced by encapsulating the active ingredient in microliposomes. Such topical treatments need to be repeated more frequently than preferred oral administrations, but each treatment can be followed by an interval that does not cause disease.

[0224] In one embodiment, a pharmaceutical formulation including the formulation disclosed herein is configured to favorably enable the eradication of mites in proximity to the eyelashes by preferential absorption of the pharmaceutical formulation through the mite's exoskeleton (e.g., the abdomen or posterior body) rather than by ingestion by mites (e.g., ingestion by skin cells, sebum, and other elements that may contain a certain amount of the active agent via systemic absorption). Although not theoretically limited, Demodex mites have a hydrophobic chitin outer surface and a relatively thin exoskeleton in the abdominal / posterior body region (approximately 0.5 μm compared to approximately 2.0 μm in the cephalothorax), which surprisingly allows for more rapid absorption of the formulation via the abdomen rather than primarily via ingestion, as in previous veterinary formulations of isoxazoline antiparasitic agents. Figures 1A-B schematically show the application of formulation 120 to an eye 140 having an iris / pupil 142. The eyelids surrounding the eye 140 contain hair follicles 180 of eyelashes 186, and the hair follicles 180 contain sebum oil 182. The eyelids contain meibomian glands 160 containing meibomian oil 162. As shown in Figures 1A-B, the "face down" orientation of the mite (e.g., Demodex mite 164, Demodex taeniorhynchus 184) to the hair follicles 180 or meibomian glands 160 (the mite's body points to the opening of the hair follicles 180 or meibomian glands 160) promotes preferential abdominal absorption of the formulation 120 via the abdominal / posterior body region 190. As shown in Figure 2, in vitro studies have surprisingly observed that, after application of the specific pharmaceutical formulations described herein, the movement of the abdomen and tail of Demodex mites ceases faster than the movement of the cephalothorax. This indicates that Demodex mites are particularly sensitive to topical ophthalmic formulations.

[0225] In one example, the compositions and methods described herein involve the use, either alone or in combination, topically or in other forms, of any number of the following substances, which are compounded into a formulation having parameters including (but not limited to) concentration, excipients, and any other features described elsewhere herein, or not including any other features: albendazole, cambendazole, fenbendazole, fluvaidazole, mebendazole, oxfendazole, parabendazole, thiabendazole, triclabendazole, amitraz, demiditraz, chlorthrone, closantel, oxyclonazide, lafoxanide, cyphenothrin, flumethrin, permethrin, promazine, derquantel, diamphenetide, dicyanil dinotefuran, i Midacloprid, nitenpyram, thiamethoxam, abamectin, doramectin, emamectin, epnomectin, ivermectin, moxidectin, selamectin, milbemycin oxime, emodepside, epsiplantel, fipronil, fluazurone, fluhexaphon, indoxacarb, levamisol, lufenuron, metaflumizone, methoprene, monepantel, morantel, niclosamide, nitroscanate, nitroxynil, novarone, oxantel, praziquantel, pyrantel, pynprole, pyriproxyfen, sisaproml, spinosad, spinetoram, lindane, picrotoxin, dieldrin, alpha-endosulfan and / or triflumezopyrim. In one embodiment, the composition and method include a metadiamide (e.g., broflanilide), a cyclodiene and / or a macrocyclic lactone (including avermectin and milbemycin). In one embodiment, the agent for Alzheimer's disease is an activator such as galantamine, donepezil and other piperidine analogs, rivastigmine and other carbamate analogs, tacrine, 7-methoxytacrine and other pyridine analogs, huperzine A and other alkaloid analogs, which also possess anti-Demodex activity.For example, galantamine is a selective, competitive, and rapidly reversible acetylcholinesterase inhibitor having an anionic substrate and an aromatic gorge, and an allosteric ligand / activator at nicotinic cholinergic receptors, thus increasing GABA activity. In other examples, other acetylcholinesterase inhibitors are used similarly. Derivatives, analogues, and their L- and D-isomers can also be used, including compositions containing enantiomers, racemic mixtures, and any enantiomerically pure compositions described in this paragraph (not limited to these). In other examples, the formulation does not contain any number or all of the agents listed in this paragraph.

[0226] In one embodiment, the skin and / or ophthalmic formulation includes, in place of or in addition to, the isoxazoline antiparasitic agent described above, an active formamidine antiparasitic agent. The formamidine antiparasitic agent is, for example, amitraz, which functions as an octopamine receptor modulator. N-(2,4-dimethylphenyl)-N-methylformamidine (DPMF), a metabolite of amitraz, is considered to be an active agent that exerts acaricidal and insecticidal effects by acting as an agonist on octopamine receptors, and can be another active agent, either alone or in addition. NiPhosphorus is a hydrolytic metabolite of DPMF and can be an active therapeutic agent in other embodiments. Derivatives, analogues, and their L- and D-isomers can also be used, including (but not limited to) compositions containing enantiomers, racemic mixtures, and enantiomerically pure compositions. In one embodiment, a skin and / or ophthalmic formulation comprises an active therapeutic agent of a phenylpyrazole anthelmintic instead of, or in addition to, the isoxazoline or formamidine anthelmintic agents described above. The chemical structure of these anthelmintic agents is characterized by a central pyrazole ring in which a phenyl group is bonded to one of the nitrogen atoms of the pyrazole. Some non-limiting examples of phenylpyrazole anthelmintic agents include, for example, acetoprole, ethiprole, fipronil, flufiprole, pyraclofos, pyraflprole, pyriprole, pyrorane, and vaniliprole.

[0227] To illustrate the examples and their advantages, Table 1 below lists several non-limiting specific examples of topical isoxazoline antiparasitic agent formulations for illustrative purposes. All components are shown in %w / w or grams / 100 grams of the formulation. Figures 3A-3B show examples of formulations containing amitraz and fluralaner.

[0228] One example of an amitraz solution contains 0.100% / w of amitraz in 99.9% light mineral oil. Another example of an amitraz ointment contains 0.100% w / w of amitraz, 29.9% mineral oil, and 70.0% petrolatum. [Table 1]

[0229] In one embodiment, the topical ophthalmic formulation includes the following instructions for use: The patient is instructed to shower, bathe, or wash their hands before applying the investigational drug. A single dose of the formulation, such as eye drops, is administered directly to each eye once or twice daily, for example, once in the morning and once at night. After applying the eye drops to the conjunctiva and / or cornea of ​​the eye, the patient closes their eye and gently applies pressure to the upper eyelid to allow the drug to spread to the upper and lower eyelid margins. They then allow it to dry without patting with tissue paper. The formulation is then stored at room temperature (15-30°C) in a temperature-controlled environment, avoiding extremely hot or cold places. In one embodiment, the patient is instructed not to apply any other eye drops for a specified period, for example, one hour before and one hour after administration of the investigational drug.

[0230] In one embodiment, the system and method include a qualitative and / or quantitative assessment of Demodex mites at anatomical locations in the patient, such as on the eyelashes and / or within the glands. In one embodiment, the method includes the steps of: undergoing a first assessment of the amount of Demodex mites in the patient's anatomical structures; and, if the amount of Demodex mites is greater than a predetermined value, for example, if there are about 1, 1.5, 2, 2.5, 3, 4, 5 or more mites per square centimeter of skin (or per eyelash), administering a skin and / or ocular composition topically. In one embodiment, the method includes the steps of: undergoing a second assessment of the amount of Demodex mites following treatment to quantitatively evaluate improvement; and, based on the second assessment, continuing, modifying (by increasing or decreasing the dose, frequency, formulation, etc.) or discontinuing treatment. The second evaluation takes place at least approximately 1, 2, 3, 5, 7, 10, 14, 21, 28, or 30 days after the first evaluation, or less than or equal to that. In one example, the treatment can result in a reduction of at least approximately 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% of Demodex in anatomical locations.

[0231] The presence of cylindrical flakes (also known as cylinders) is a type of scale that forms a transparent cuff connecting the base of the eyelashes at the eyelash root. Cylindrical flakes on the eyelashes are generally considered characteristic of Demodex infestation and are diagnosed by alopecia, examined under a slit-lamp microscope, and then counted automatically or manually. Surface skin biopsy (SSB) using cyanoacrylic adhesive is a commonly used method to measure Demodex density. This allows for the collection of contents from the superficial layers of the stratum corneum and sebaceous follicles. Other sampling methods used to assess the presence of Demodex by microscopy include adhesive bands, skin scraping, skin impressions, expressed follicle contents, comedone extraction, alopecia, and punch biopsy.

[0232] In one embodiment, a system and method for detecting Demodex mites in a subject, which does not necessarily require hair removal, is disclosed. Such Demodex detection is beneficial because hair removal makes it difficult to detect and quantify Demodex mites, particularly Demodex lichen. Furthermore, many patients experience discomfort from hair removal. In addition, treatment can be initiated more quickly based on objective criteria.

[0233] For example, tear fluid may be collected from a subject using a device such as a disposable hydrogel contact lens. This device, for example, the lens, is then sent to a laboratory for detection and potential quantification of Demodex DNA by PCR or other means. The genome sequences of Demodex mites and Demodex taeniorhynchus are determined. The “diagnostic” lens is placed in the eye and removed after a short fixation period of, for example, about 30 minutes, 20 minutes, 15 minutes, 10 minutes, 5 minutes, or less. Such lenses are formed from a hydrogel that has a relatively high affinity for Demodex biomarkers containing DNA.

[0234] In one embodiment, as shown in Figure 4A, tear sampling is performed using an apparatus that includes a capillary glass tube for collecting tear fluid from the tear meniscus of the lower eyelid. This method is particularly useful when a quantitatively small amount of tear fluid is required. Furthermore, evaporation can be avoided by simply sealing both ends of the tube as needed.

[0235] Other examples include contact lens-free tear and skin sampling methods, such as those involving "litmus paper" or wicking paper similar to the Schirmer test (shown in Figure 4B), or eyelash sampling techniques (shown in Figure 4C). In one example, chitin, chitosan, or other Demodex-specific biomarkers are detected and quantified to correlate with the number of mites.

[0236] Demodex DNA is quantified, for example, as the density of DNA copies encoding a specific Demodex target sequence (e.g., 18S rRNA as one non-limiting example). In one example, Demodex (Demodex human gDNA (x10) -6 The density (defined as the number of DNA copies encoding the target region of the demodex per ng) can be considered a threshold for initiating treatment if it is approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or higher.

[0237] Parasitism can be further classified by the causative species of Demodex (e.g., Demodex mites, Demodex taeniae, etc.). Demodex taeniae are mainly found in the meibomian glands and sebaceous glands. Treatment is modified, enhanced, or targeted based on the dominant species, for example, by increasing the application of therapeutic formulations to selected glands.

[0238] In light of the above teachings, various other modifications and adaptations may be made, and alternative designs may be adopted. Therefore, it should be understood that the present invention can be implemented within the scope of the claims in ways other than those specifically described herein. Specific features and aspects of the aforementioned embodiments may be combined, and such combinations are also included in the present invention. Furthermore, the disclosure herein of specific features, aspects, methods, characteristics, qualities, attributes, elements, etc., related to one embodiment may apply to all other embodiments described herein. Therefore, it should be understood that various features and aspects of the disclosed embodiments may be combined or substituted for each other to form various forms of the disclosed invention. Thus, the scope of the invention disclosed herein is not limited to the specific embodiments described herein. Furthermore, the present invention allows for various modifications and alternative forms, specific examples of which are shown in the drawings and described in detail herein. However, it should be understood that the present invention is not limited to the specific forms or methods disclosed, and that the present invention encompasses all variations, equivalents, and alternatives that fall within the scope and spirit of the various embodiments and claims described herein. The methods disclosed herein do not necessarily have to be implemented in the order described. The methods disclosed herein include specific procedures (treatments) performed by practitioners, but also include, explicitly or implicitly, instructions to third parties regarding those procedures. For example, a procedure such as "applying an isoxazoline antiparasitic agent to the eyes" includes "instructing to apply an isoxazoline antiparasitic agent to the eyes." Furthermore, the scopes described herein encompass any and all of the overlaps, partial scopes, and combinations thereof. The terms "maximum," "at least," "greater than," "less than," and "between" include the listed numerical values. The numerical values ​​following terms such as "about" and "substantially" used herein include the listed numbers (e.g., about 10% = 10%) and also represent values ​​close to a given value that still performs the desired function or achieves the desired result. For example, the terms "about" and "substantially" represent values ​​that are within the ranges of less than 10%, less than 5%, less than 1%, less than 0.1%, and less than 0.01% of the stated value.

Claims

1. An isoxazoline-based antiparasitic ophthalmic composition for treating Demodex ocular parasite infestation in human patients, The isoxazoline-based antiparasitic agent in the aforementioned ophthalmic composition of antiparasitic agents consists of rotilana. The isoxazoline-based antiparasitic ophthalmic composition is in the form of eye drops. The isoxazoline-based ophthalmic antiparasitic composition contains a pharmaceutically acceptable solvent. The isoxazoline-based ophthalmic antiparasitic composition is characterized by being administered topically to one or both of the patient's eyes, eyelids, or eyelashes.

2. The isoxazoline-based ophthalmic anthelmintic composition according to claim 1, characterized in that it contains about 0.01% to about 1% by weight of the isoxazoline-based anthelmintic agent based on the total weight of the isoxazoline-based anthelmintic composition for ophthalmic use.

3. The isoxazoline-based anthelmintic ophthalmic composition according to claim 1 or 2, characterized in that it contains the isoxazoline-based anthelmintic in an amount of about 0.15% to about 0.40% by weight of the isoxazoline-based anthelmintic in an amount of about 0.15% to about 0.40% by weight of the total weight of the isoxazoline-based anthelmintic ophthalmic composition.

4. The isoxazoline-based anthelmintic ophthalmic composition according to any one of claims 1 to 3, characterized in that it contains the isoxazoline-based anthelmintic in an amount of about 0.25% by weight of the isoxazoline-based anthelmintic in an amount total weight of the isoxazoline-based anthelmintic in an ophthalmic composition according to any one of claims 1 to 3.

5. The isoxazoline-based ophthalmic antiparasitic composition is characterized in that it does not contain essential oils, as described in any one of claims 1 to 4.

6. The isoxazoline-based ophthalmic antiparasitic composition described above is characterized in that it does not contain tea tree oil.

7. The isoxazoline-based antiparasitic ophthalmic composition according to any one of claims 1 to 6, characterized in that the aforementioned Demodex ocular parasitis includes Demodex blepharitis.

8. The isoxazoline-based antiparasitic ophthalmic composition according to any one of claims 1 to 7, characterized in that the aforementioned Demodex ophthalmic parasitis includes pre-blepharitis.

9. The isoxazoline-based antiparasitic ophthalmic composition according to any one of claims 1 to 8, characterized in that the aforementioned Demodex ophthalmic parasitis includes post-blepharitis.

10. The isoxazoline-based antiparasitic ophthalmic composition according to any one of claims 1 to 9, characterized in that the aforementioned Demodex ocular parasitism includes diseases of the meibomian glands.

11. The isoxazoline-based antiparasitic ophthalmic composition according to any one of claims 1 to 10, characterized in that the aforementioned Demodex ocular parasite includes ocular rosacea.

12. The isoxazoline-based antiparasitic ophthalmic composition according to any one of claims 1 to 11, characterized in that the aforementioned Demodex ocular parasitism includes shedding.

13. The isoxazoline-based antiparasitic ophthalmic composition according to any one of claims 1 to 12, characterized in that the aforementioned Demodex ocular parasitism includes dry eye disease.

14. The isoxazoline-based anthelmintic agent is the sole active ingredient of the isoxazoline-based anthelmintic agent ophthalmic composition according to any one of claims 1 to 13.

15. The isoxazoline-based ophthalmic antiparasitic composition is characterized in that it is administered topically at least once a day for at least two weeks, as described in any one of claims 1 to 14.

16. The isoxazoline-based ophthalmic antiparasitic composition is characterized in that it is administered topically at least once a day for at least four weeks, as described in any one of claims 1 to 15.

17. The isoxazoline-based ophthalmic antiparasitic composition is characterized in that it is administered topically at least once a day for at least six weeks, as described in any one of claims 1 to 16.

18. The isoxazoline-based ophthalmic antiparasitic composition is characterized in that it is administered topically at least twice a day for at least six weeks, as described in any one of claims 1 to 17.

19. The isoxazoline-based ophthalmic antiparasitic composition is characterized in that it is administered topically at least twice a day for at least eight weeks, as described in any one of claims 1 to 18.

20. The isoxazoline-based ophthalmic antiparasitic agent composition according to any one of claims 1 to 19, characterized in that the total dose per administration of the isoxazoline-based antiparasitic agent ophthalmic composition administered locally is 25 to 50 microliters.

21. The isoxazoline-based ophthalmic antiparasitic composition is characterized by containing castor oil, as described in any one of claims 1 to 20.

22. The isoxazoline-based antiparasitic ophthalmic composition according to claim 21, characterized in that the castor oil includes hydrogenated castor oil.

23. The isoxazoline-based ophthalmic antiparasitic composition is characterized in that it contains about 1% to about 5% by weight of hydrogenated castor oil based on the total weight of the isoxazoline-based ophthalmic antiparasitic composition.

24. The isoxazoline-based ophthalmic antiparasitic composition is characterized in that it contains about 5% by weight of hydrogenated castor oil relative to the total weight of the isoxazoline-based ophthalmic antiparasitic composition, as described in 23.

25. An isoxazoline-based antiparasitic ophthalmic composition for use in the treatment of ocular demodectic mange infections in human patients, The isoxazoline-based antiparasitic agent in the aforementioned ophthalmic composition of antiparasitic agents consists of rotilana. The isoxazoline-based antiparasitic ophthalmic composition is in the form of eye drops. The isoxazoline-based ophthalmic antiparasitic composition contains a pharmaceutically acceptable solvent. The isoxazoline-based ophthalmic antiparasitic composition is characterized in that it is sterile.

26. The isoxazoline-based ophthalmic anthelmintic composition according to claim 25, characterized in that it contains about 0.01% to about 1% by weight of the isoxazoline-based anthelmintic composition based on the total weight of the isoxazoline-based anthelmintic composition.

27. The isoxazoline-based ophthalmic anthelmintic composition according to claim 25 or 26, characterized in that it contains the isoxazoline-based anthelmintic in an amount of about 0.15% to about 0.40% by weight of the isoxazoline-based anthelmintic in an amount of about 0.15% to about 0.40% by weight of the total weight of the isoxazoline-based anthelmintic in an ophthalmic composition.

28. The isoxazoline-based anthelmintic ophthalmic composition according to any one of 25 to 27, characterized in that it contains the isoxazoline-based anthelmintic in an amount of about 0.25% by weight of the isoxazoline-based anthelmintic in an amount of the isoxazoline-based anthelmintic in an amount of the total weight of the isoxazoline-based anthelmintic in an ophthalmic composition according to any one of 25 to 27.

29. The isoxazoline-based ophthalmic antiparasitic composition is characterized by containing castor oil, as described in any one of 25 to 28.

30. The isoxazoline-based antiparasitic ophthalmic composition according to claim 29, characterized in that the castor oil includes hydrogenated castor oil.

31. The isoxazoline-based ophthalmic antiparasitic composition is characterized in that it contains about 1% to about 5% by weight of hydrogenated castor oil based on the total weight of the isoxazoline-based ophthalmic antiparasitic composition, as described in 30.

32. The isoxazoline-based ophthalmic antiparasitic composition is characterized in that it contains about 5% by weight of hydrogenated castor oil relative to the total weight of the isoxazoline-based ophthalmic antiparasitic composition, as described in claim 30.

33. An isoxazoline-based antiparasitic ophthalmic composition according to any one of 25 to 32, further comprising a thickening agent.

34. The isoxazoline-based antiparasitic ophthalmic composition according to claim 33, characterized in that the thickening agent comprises hydroxypropyl methylcellulose.

35. An isoxazoline-based antiparasitic ophthalmic composition according to any one of 25 to 34, further comprising a chelating agent.

36. The isoxazoline-based antiparasitic ophthalmic composition according to claim 35, characterized in that the chelating agent contains disodium edetate.

37. An isoxazoline-based antiparasitic ophthalmic composition according to any one of 25 to 36, further comprising an isotonic agent.

38. The isoxazoline-based antiparasitic ophthalmic composition according to claim 37, characterized in that the isotonic agent contains glycerin.

39. The isoxazoline-based ophthalmic antiparasitic composition is characterized in that it has a pH of 7 to 7.5, as described in any one of claims 25 to 38.

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