Isoxazoline parasiticide formulations and methods for treating blepharitis

Abstract

To provide isoxazoline parasiticide formulations and methods for treating blepharitis.SOLUTION: Disclosed herein are methods for treating or preventing ophthalmic and dermatologic conditions in a patient, including ocular surface conditions such as blepharitis. The methods include topically administering, directly to an ocular surface of one or more eyes of a patient in need of treatment, an effective amount of an isoxazoline parasiticide, a formamidine parasiticide, or another active ingredient formulated into an ophthalmic composition. The ophthalmic composition further comprises a pharmaceutically acceptable vehicle. Compositions are also disclosed.SELECTED DRAWING: Figure 1B

Description

[Technical Field]

[0001] (Priority Claim) This application claims the benefit under 35 U.S.C. § 119 of U.S. Provisional Patent Application No. 62 / 863,822, filed June 19, 2019, and U.S. Provisional Patent Application No. 63 / 029,689, filed May 25, 2020. Each of the foregoing applications is incorporated herein by reference in its entirety. [Background technology]

[0002] Blepharitis, an inflammation of the eyelid, is a common, often chronic condition that can be difficult to treat and affects people of all ages. Blepharitis can occur both anteriorly (the outer surface of the affected eyelid, where the eyelashes attach) and / or posteriorly (the inner surface of the affected eyelid). Blepharitis can be associated with systemic diseases, including rosacea and seborrheic dermatitis, and with other eye diseases, including chalazion, conjunctivitis, keratitis, and dry eye.

[0003] Demodex folliculorum and Demodex brevis are microscopic, elongated mites, the most common parasitic mites. They are resistant to certain environments and reside in the hair follicles and sebaceous glands of humans and other animals, where they reside intradermally. There are 65 Demodex species, which parasitize 11 mammalian orders and belong to the arachnid order, acaridae family, and the family Demodex. Mating occurs at the hair follicle opening, and eggs are laid inside the hair follicle or sebaceous gland. After 3–4 days, six-legged larvae hatch, which mature into adults in approximately 7 days. The Demodex life cycle is approximately 14 days. The Demodex lifespan is several weeks. Dead mites decay inside the hair follicles or sebaceous glands.

[0004] Demodex mites can be found on the face, including the cheeks, nose, chin, forehead, temples, eyelashes, and eyebrows, as well as on the scalp, neck, and ears. Other seborrheic areas, such as the nasolabial folds and periorbital region, and rarely the upper and central chest and back, may also be infested. Demodex mites may also be found within ectopic sebaceous glands on the penis, mons pubis, buttocks, and buccal mucosa. In some cases, mite densities of more than five mites per square centimeter in the pilosebaceous gland unit or five or more mites per hair follicle correlate with Demodex infestation.

[0005] Demodex infestation can be diagnosed clinically by removing the eyelashes (epilation), but densities of greater than one mite per eyelash are generally considered positive. Another characteristic sign that is pathognomonic for Demodex infestation (80% positive correlation) is the presence of collarettes (also known as cylindrical dandruff). This material is the result of mite by-products. This sign can be detected by slit-lamp examination or other magnified examination of the eyelid margin. This can further assist clinicians in diagnosing Demodex blepharitis. Both collarettes (curling rings) and mite density can also be used as clinical inclusion criteria and endpoints in clinical trials.

[0006] Blepharitis is a disease characterized by inflammation of the eyelid margin. Participants with blepharitis often experience itching, burning, or stinging of the eyelid margin, a foreign body sensation in the eye, and redness of the eye and eyelid. In the United States, blepharitis is estimated to affect 19 million people, most commonly those aged 50 and over. Blepharitis is often caused by Demodex mites.

[0007] Demodex mites (Demodex folliculorum or Demodex brevis) are microscopic ectoparasites that live at the base of the eyelashes, meibomian glands, and sebaceous glands and are found only in certain environments. Demodex mites are the only mites known to infect the human eye. A recent meta-analysis of 11 clinical studies showed that Demodex mites are associated with 45% of cases of blepharitis. Demodex density correlates with signs of blepharitis and other ocular complications.

[0008] In Demodex blepharitis, mites reside in the eyelash follicles. There, they feed on sebum, causing epidermal desquamation, resulting in epidermal hyperplasia and hyperkeratinization. Undigested material binds to epithelial cells, keratin, and eggs, leading to the formation of coralettes (also known as cylindrical dandruff). These coralettes are characteristic of Demodex blepharitis. Coralette-bearing lashes have been shown to contain an average of 2-4 mites per lash, compared with only 0.2 mites per lash without coralettes. Demodex infestations can also cause swelling, irritation, and enlargement of the meibomian glands. A localized granulomatous reaction associated with the chitinous exoskeleton and Demodex waste products can mechanically obstruct the meibomian glands. In addition to surface irritation and inflammation, mites can also activate an inflammatory cascade by infecting bacteria harbored on and within the mites. Finally, eyelid irritation caused by Demodex infestation may itself trigger an immune response. It has also been shown to increase the number of CD4+ T cells, macrophages, and Langerhans cells in participants. Summary of the Invention [Problem to be solved by the invention]

[0009] Of the widespread reported species, only two, Demodex folliculorum and Demodex brevis, are known to infest the human body surface. Demodex folliculorum is found, for example, in the eyelash follicles. Demodex brevis, on the other hand, is found, for example, in the meibomian glands adjacent to the eye and in the sebaceous glands of the skin. The meibomian glands are holocrine exocrine glands located within the tarsal plate at the margin of the eyelid. They produce meibum, an oily substance that prevents the evaporation of the tear film. Meibum prevents tears from spilling onto the cheek and traps tears between the oily margin and the eyeball, creating an airtight seal when the eyelid is closed. Approximately 50 glands are present in the upper eyelid, and 25 in the lower eyelid. Bacteria associated with mites may also contribute to pathology. Increased sebum secretion and an increased number of sebaceous glands can provide favorable infestation sites for mites. Even if certain levels of Demodex are asymptomatic, high Demodex proliferation and / or concurrent immune imbalances usually result in skin damage. A growing body of literature links Demodex to anterior and posterior blepharitis. For example, Demodex has been associated with 45% of blepharitis cases. The prevalence of ocular surface disease is estimated to be approximately 30 million patients. Of these, 19 million patients have meibomian gland dysfunction / posterior blepharitis, 9 million patients have Demodex infestation, and 4 million patients have visible signs of Demodex. Diagnosis of blepharitis is important, and there are currently no approved treatments in the United States. Safe and effective therapies for treating blepharitis and other ocular and dermatological conditions are needed. [Means for solving the problem]

[0010] In some embodiments, topical therapeutic agents are disclosed herein, including, but not limited to, topical medications including one or more isoxazoline parasiticides, formamidine parasiticides, phenylpyrazole parasiticides, drugs commonly used to treat Alzheimer's disease (e.g., galantamine and others), and other agents for the treatment of various ophthalmic and dermatological conditions.

[0011] Without being limited by theory, the inventors have discovered formulations and methods for treating Demodex that are unexpectedly effective and long-lasting with a minimal side effect profile. Some embodiments of the formulations are unexpectedly beneficial in that they contain aqueous solubility and specific excipients suitable for eye drops (including, but not limited to, single-dose and multi-dose eye drop formulations), are present within a specific range of drug concentrations for local action without resulting in significant systemic drug concentrations (e.g., below the therapeutic range), and produce rapid, complete, and sustained responses not previously seen in blepharitis.

[0012] Formulations according to some embodiments may include any number of combinations of features in the present disclosure.

[0013] Devices according to some embodiments may include any number of combinations of the features of the present disclosure.

[0014] Methods according to some embodiments may include a combination of any number of the features of the present disclosure.

[0015] In some configurations, disclosed herein are methods for treating blepharitis in a patient. The methods comprise topically administering an effective amount of an isoxazoline parasiticide directly to the ocular surface of one or both eyes of a patient in need of treatment for blepharitis. The isoxazoline parasiticide is formulated into an ophthalmic composition further comprising a pharmaceutically acceptable solvent.

[0016] In some configurations, the ophthalmic composition is sterile and non-irritating to the eye.

[0017] In some configurations, the isoxazoline parasiticide may be the only active ingredient for the ophthalmic composition.

[0018] In some configurations, about 0.01% to about 1% of the isoxazoline parasiticide is administered based on the total weight of the composition.

[0019] In some configurations, about 0.03% by weight of the isoxazoline parasiticide is administered based on the total weight of the composition.

[0020] In some configurations, about 0.10% by weight of the isoxazoline parasiticide is administered based on the total weight of the composition.

[0021] In some configurations, about 0.30% by weight of the isoxazoline parasiticide is administered based on the total weight of the composition.

[0022] In some configurations, the ophthalmic composition comprises eye drops.

[0023] In some configurations, the ophthalmic composition does not include essential oils.

[0024] In some configurations, the isoxazoline parasiticide is selected from the group consisting of fluralaner, sarolaner, lotilaner, afoxolaner, fluxametamide, and isocycloceram.

[0025] In some configurations, the ocular surface includes at least one of the conjunctiva or cornea of ​​one or both eyes of the patient.

[0026] In some configurations, the ophthalmic composition includes a polysorbate or castor oil surfactant.

[0027] In some configurations, the formulation also includes a polymer (e.g., HPMC, CMC) to enhance viscosity, a sugar (e.g., glycerin, sorbitol, mannitol, or others) for physiological osmolality, a buffer (e.g., phosphate, TRIS) to achieve a neutral to slightly basic pH, and a preservative (e.g., LAK or BAK, or sorbate).

[0028] In some configurations, disclosed herein are methods for treating blepharitis in a patient. The methods involve topically administering an effective amount of an isoxazoline parasiticide directly to one or both eyes, eyelids, or one or more eyelashes of a patient in need of blepharitis treatment. The isoxazoline parasiticide is formulated into an ophthalmic composition further comprising a pharmaceutically acceptable solvent. The ophthalmic composition is sterile and non-irritating to the eye, and the isoxazoline parasiticide is the only active ingredient in the ophthalmic composition.

[0029] In some configurations, the patient's eyes are closed when the ophthalmic composition is topically administered so that the composition contacts the orifices of the patient's meibomian glands and the outer lid margin of the patient's eye.

[0030] In some configurations, the method further comprises spreading the composition onto the eyelashes and eyelash follicles.

[0031] In some configurations, the method further comprises spreading the composition onto the eyelashes and eyelash follicles with an applicator.

[0032] In some configurations, about 0.001% to about 1% of an isoxazoline parasiticide is administered.

[0033] In some configurations, about 0.001% to about 1% of an isoxazoline parasiticide is administered.

[0034] In some configurations, the method further comprises topically administering the ophthalmic composition at least once daily for at least about two weeks.

[0035] In some configurations, the method further comprises topically administering the ophthalmic composition at least once daily for about 4 weeks or about 6 weeks, or for at least about 4 weeks or 6 weeks.

[0036] In some configurations, disclosed herein are methods for treating Demodex ocular infestation in a patient. The methods comprise topically administering an effective amount of an isoxazoline parasiticide directly to one or both eyes, eyelids, or eyelashes of one or both eyes of a patient in need of treatment for the infestation. The isoxazoline parasiticide is formulated into an ophthalmic composition further comprising a pharmaceutically acceptable solvent. The ophthalmic composition is sterile and non-irritating to the eye, and the isoxazoline parasiticide is the only active ingredient in the ophthalmic composition.

[0037] In some configurations, the method further includes obtaining a first assessment of the amount of Demodex or Coralette in the patient's anatomy, and topically administering an ophthalmic composition if the amount of Demodex or Coralette is greater than a predetermined value.

[0038] In some configurations, the ophthalmic formulation more quickly stops the movement of the abdominal and caudal portions of Demodex mites in a patient compared to the cephalothorax portion of Demodex mites.

[0039] In some configurations, disclosed herein are methods for treating blepharitis and / or rosacea, comprising topically applying an isoxazoline parasiticide to the vicinity of one or more eyelashes, the topical application being therapeutically effective in reducing movement of the Demodex body relative to the Demodex head, and preferentially absorbing the Demodex body relative to uptake by the Demodex, the method being sufficient to reduce or eliminate Demodex in the vicinity of the eyelashes and ameliorating the symptoms of blepharitis and / or rosacea.

[0040] In some configurations, disclosed herein are topical ophthalmic formulations for treating blepharitis in a patient, the formulations comprising an effective amount of an isoxazoline parasiticide and a pharmaceutically acceptable solvent, the ophthalmic composition being sterile and non-irritating to the eye, and the isoxazoline parasiticide being the only active ingredient in the ophthalmic composition.

[0041] In some configurations, about 0.01% to about 1% of the isoxazoline parasiticide is administered based on the total weight of the composition.

[0042] In some configurations, about 0.03% by weight of the isoxazoline parasiticide is administered based on the total weight of the composition.

[0043] In some configurations, about 0.10% or 0.3% by weight of the isoxazoline parasiticide is administered based on the total weight of the composition.

[0044] In some configurations, the ophthalmic composition comprises eye drops.

[0045] In some configurations, the ophthalmic composition does not include essential oils.

[0046] In some configurations, the isoxazoline parasiticide is selected from the group consisting of fluralaner, sarolaner, lotilaner, afoxolaner, fluxametamide, and isocycloceram.

[0047] In some configurations, a topical formulation for use in treating ocular surface diseases is disclosed herein. The formulation includes an isoxazoline parasiticide, at least one of Pemulen and HPMC, polysorbate 80 or castor oil, glycerin, a buffer, and lauralkonium chloride or benzalkonium chloride. The formulation is therapeutically effective in reducing or eliminating Demodex mites near the eyelashes and improving the symptoms of blepharitis and / or rosacea. In some configurations, the formulation does not include polysorbate and / or phosphate buffer.

[0048] In some configurations, the formulation is used to treat blepharitis.

[0049] In some configurations, the formulation is used to treat anterior blepharitis.

[0050] In some configurations, the formulations are used to treat posterior blepharitis, meibomian gland dysfunction, or dry eye disease.

[0051] In some configurations, the formulations are used to treat ocular rosacea, including corneal inflammation, ulcers, or scarring.

[0052] In some configurations, disclosed herein are methods for treating blepharitis in a patient. The methods involve topically administering an effective amount of a formamidine parasiticide directly to the ocular surface of one or both eyes of a patient in need of blepharitis treatment. The formamidine parasiticide is formulated into an ophthalmic composition further comprising a pharmaceutically acceptable solvent. The ophthalmic composition is sterile and non-irritating to the eye, and the formamidine parasiticide is the only active ingredient in the ophthalmic composition.

[0053] In some configurations, about 0.01% to about 1% by weight of the formamidine parasiticide is administered based on the total weight of the composition.

[0054] In some configurations, about 0.03% by weight of formamidine parasiticide is administered based on the total weight of the composition.

[0055] In some configurations, about 0.10% or about 0.30% by weight of the formamidine parasiticide is administered based on the total weight of the composition.

[0056] In some configurations, the ophthalmic composition comprises eye drops.

[0057] In some configurations, the ophthalmic composition comprises an ointment or cream.

[0058] In some configurations, the ophthalmic composition does not include essential oils.

[0059] In some configurations, the formamidine parasiticide is selected from the group consisting of amitraz, N-(2,4-dimethylphenyl)-N-methyformamidine (DPMF), and 2,4-dimethylanaline.

[0060] In some configurations, the ocular surface includes at least one of the conjunctiva or cornea of ​​one or both eyes of the patient.

[0061] In some configurations, the ophthalmic composition comprises a polysorbate.

[0062] In some configurations, methods for treating blepharitis in a patient are disclosed herein. The methods involve topically administering an effective amount of a formamidine parasiticide directly to one or both eyes, eyelids, or one or more eyelashes of a patient in need of blepharitis treatment. The formamidine parasiticide is formulated into an ophthalmic composition further comprising a pharmaceutically acceptable solvent. The ophthalmic composition is sterile and non-irritating to the eye, and the formamidine parasiticide is the only active ingredient in the ophthalmic composition.

[0063] In some configurations, the patient's eyes are closed when the ophthalmic composition is topically administered so that the composition contacts the orifices of the patient's meibomian glands and the outer lid margin of the patient's eye.

[0064] In some configurations, the method further comprises spreading the composition onto the eyelashes and eyelash follicles.

[0065] In some configurations, the method further comprises spreading the composition onto the eyelashes and eyelash follicles with an applicator.

[0066] In some configurations, about 0.001% to about 1% formamidine parasiticide is administered.

[0067] In some configurations, about 0.001% to about 1% formamidine parasiticide is administered.

[0068] In some configurations, the method further comprises topically administering the ophthalmic composition at least once daily for at least about two weeks.

[0069] In some configurations, the method further comprises topically administering the ophthalmic composition at least once daily for at least about four or six weeks.

[0070] In some configurations, disclosed herein are methods for treating Demodex ocular infestation in a patient. The methods involve topically administering an effective amount of a formamidine parasiticide directly to one or both eyes, eyelids, or eyelashes of one or both eyes of a patient in need of treatment for the infestation. The formamidine parasiticide is formulated into an ophthalmic composition further comprising a pharmaceutically acceptable solvent. The ophthalmic composition is sterile and non-irritating to the eye, and the formamidine parasiticide is the only active ingredient in the ophthalmic composition.

[0071] In some configurations, the method further comprises obtaining a first assessment of the amount of Demodex mites in the patient's anatomy, and topically administering an ophthalmic composition if the amount of Demodex mites or Corallette is greater than a predetermined value.

[0072] In some configurations, the ophthalmic formulation more quickly stops the movement of the abdominal and caudal portions of Demodex mites in a patient compared to the cephalothorax portion of Demodex mites.

[0073] In some configurations, disclosed herein are methods for treating blepharitis and / or rosacea, comprising topically applying a formamidine parasiticide near one or more eyelashes, the topical application being therapeutically effective in reducing movement of the Demodex body relative to the Demodex head, and preferentially absorbing the Demodex body relative to uptake by the Demodex, the method being sufficient to reduce or eliminate Demodex near the eyelashes and ameliorating the symptoms of blepharitis and / or rosacea.

[0074] In some configurations, disclosed herein are topical ophthalmic formulations for treating blepharitis in a patient, the formulations comprising an effective amount of a formamidine parasiticide and a pharmaceutically acceptable solvent, the ophthalmic composition being sterile and non-irritating to the eye, and the formamidine parasiticide being the only active ingredient in the ophthalmic composition.

[0075] In some configurations, about 0.01% to about 1% by weight of the formamidine parasiticide is administered based on the total weight of the composition.

[0076] In some configurations, about 0.03% by weight of formamidine parasiticide is administered based on the total weight of the composition.

[0077] In some configurations, about 0.10% by weight of formamidine parasiticide is administered based on the total weight of the composition.

[0078] In some configurations, the ophthalmic composition comprises eye drops, a cream, or an ointment.

[0079] In some configurations, the ophthalmic composition does not include essential oils.

[0080] In some configurations, the formamidine parasiticide is selected from the group consisting of amitraz, N-(2,4-dimethylphenyl)-N-methyformamidine (DPMF), and 2,4-dimethylanaline.

[0081] In some configurations, methods are disclosed herein for treating symptoms of blepharitis and / or ocular rosacea in one or both eyes. The symptoms are selected from the group consisting of burning eye, stinging eye, dry eye, itchy eyelid margin, sticky eye, irritation, heaviness, tearing, dryness, redness, crusting, foreign body sensation, grittiness, flakes or debris, increased sensitivity to light, blurred vision, and intracorneal ocular rosacea complications. The methods include topically administering an effective amount of a formamidine parasiticide directly to the conjunctiva of one or both eyes and / or to one or both corneas of one or both eyes of an individual in need of such treatment. The formamidine parasiticide is then formulated into an eyewash composition containing a pharmaceutically acceptable solvent. The eyewash composition is sterile, non-irritating to the eye, and compatible with ocular tissue.

[0082] In some configurations, the formamidine parasiticide is administered in an amount of 0.001% to 10% by weight based on the total weight of the composition.

[0083] In some configurations, the formamidine parasiticide is administered in an amount of 0.01% to 5% by weight based on the total weight of the composition.

[0084] In some configurations, 0.03% by weight of formamidine parasiticide is administered based on the total weight of the composition.

[0085] In some configurations, 0.10% by weight of formamidine parasiticide is administered based on the total weight of the composition.

[0086] Disclosed herein, in some configurations, are methods of treating blepharitis and / or rosacea by orally or topically applying a formamidine parasiticide in a dosage sufficient to fill one or more anatomical locations and eliminate Demodex mites, resulting in the cessation of symptoms of blepharitis and / or rosacea.

[0087] In some configurations, the dose of formamidine parasiticide is repeated about 2-4 times with 3-7 days between doses.

[0088] In some configurations, the topically applied formamidine parasiticide is formulated in a carrier lotion, cream, or gel.

[0089] In some configurations, the concentration of the formamidine parasiticide in the topically applied lotion, cream, or gel is about 1 to 5 weight percent.

[0090] In some configurations, the topically applied formamidine parasiticide is applied to the eyelid.

[0091] In some configurations, the topically applied formamidine parasiticide is applied to the affected skin area at least once daily and at most twice daily for a period of about 2 to 4 weeks.

[0092] In some configurations, the topically applied formamidine parasiticide is encapsulated in microliposomes before being formulated into the carrier lotion, cream, or gel.

[0093] Disclosed herein, in some configurations, are compositions for treating blepharitis and / or rosacea, comprising a formamidine parasiticide in an oral or topical pharmaceutical formulation at a dosage sufficient to eliminate Demodex mites at one or more anatomical locations, resulting in the cessation of symptoms of the blepharitis and / or rosacea.

[0094] In some configurations, disclosed herein are methods for treating cylindrical eyelash dandruff associated with blepharitis and / or ocular rosacea in one or both eyes. The methods comprise topically administering an effective amount of a formamidine parasiticide directly to the conjunctiva of one or both eyes and / or the cornea of ​​one or both eyes of an individual in need of such treatment. The formamidine parasiticide is then formulated into an eyewash composition containing a pharmaceutically acceptable solvent. The eyewash composition is sterile, non-irritating to the eye, and compatible with ocular tissue.

[0095] In some configurations, the formamidine parasiticide is administered in an amount of 0.001% to 10% by weight based on the total weight of the composition.

[0096] In some configurations, the formamidine parasiticide is administered in an amount of 0.01% to 5% by weight based on the total weight of the composition.

[0097] In some configurations, 0.03% by weight of formamidine parasiticide is administered based on the total weight of the composition.

[0098] In some configurations, 0.10% by weight of formamidine parasiticide is administered based on the total weight of the composition.

[0099] Disclosed herein, in some configurations, are methods of treating blepharitis and / or rosacea by orally or topically applying a formamidine parasiticide in a dosage sufficient to fill one or more anatomical locations and eliminate Demodex mites, resulting in the cessation of symptoms of blepharitis and / or rosacea.

[0100] In some configurations, the administration of the formamidine parasiticide is repeated about 2-4 times with an interval of 3-7 days between administrations.

[0101] In some configurations, the topically applied formamidine parasiticide is formulated in a carrier lotion, cream, or gel. Gels can be formulated by adding specific gelling agents and modifying the concentration of water in the eye drop formulation.

[0102] In some configurations, the concentration of the formamidine parasiticide in the topically applied lotion, cream, or gel is about 1 to 5 weight percent.

[0103] In some configurations, the topically applied formamidine parasiticide is applied to the eyelid.

[0104] In some configurations, the topically applied formamidine parasiticide is applied to the affected skin area at least once daily and at most twice daily for a period of about 2 to 4 weeks.

[0105] In some configurations, the topically applied formamidine parasiticide is encapsulated in microliposomes before being formulated into the carrier lotion, cream, or gel.

[0106] Disclosed herein, in some configurations, are compositions for treating blepharitis and / or rosacea, comprising a formamidine parasiticide in an oral or topical pharmaceutical formulation at a dosage sufficient to eliminate Demodex mites at one or more anatomical locations, resulting in the cessation of symptoms of the blepharitis and / or rosacea.

[0107] In some configurations, disclosed herein are methods for treating symptoms of blepharitis and / or ocular rosacea in one or both eyes. The symptoms are selected from the group consisting of burning eyes, stinging eyes, dry eyes, increased sensitivity to light, blurred vision, and intracorneal complications of ocular rosacea. The methods comprise topically administering an effective amount of the formamidine parasiticide directly to the conjunctiva of one or both eyes and / or to one or both corneas of one or both eyes of an individual in need of such treatment. The formamidine parasiticide is therefore formulated into an eyewash composition containing a pharmaceutically acceptable solvent. The eyewash composition is sterile, non-irritating to the eye, and compatible with ocular tissue.

[0108] In some configurations, the formamidine parasiticide is administered in an amount of 0.001% to 10% by weight based on the total weight of the composition.

[0109] In some configurations, the formamidine parasiticide is administered in an amount of 0.01% to 5% by weight based on the total weight of the composition.

[0110] In some configurations, 0.03% by weight of formamidine parasiticide is administered based on the total weight of the composition.

[0111] In some configurations, 0.10% by weight of formamidine parasiticide is administered based on the total weight of the composition.

[0112] Disclosed herein, in some configurations, are methods of treating blepharitis and / or rosacea by orally or topically applying a formamidine parasiticide in a dosage sufficient to fill one or more anatomical locations and eliminate Demodex mites, resulting in the cessation of symptoms of blepharitis and / or rosacea.

[0113] In some configurations, the dose of formamidine parasiticide is repeated about 2-4 times with 3-7 days between doses.

[0114] In some configurations, the topically applied formamidine parasiticide is formulated in a carrier lotion, cream, or gel.

[0115] In some configurations, the concentration of the formamidine parasiticide in the topically applied lotion, cream, or gel is about 1 to 5 weight percent.

[0116] In some configurations, the topically applied formamidine parasiticide is applied to the eyelid.

[0117] In some configurations, the topically applied formamidine parasiticide is applied to the affected skin area at least once daily and at most twice daily for a period of about 2 to 4 weeks.

[0118] In some configurations, the topically applied formamidine parasiticide is encapsulated in microliposomes before being formulated into the carrier lotion, cream, or gel.

[0119] Disclosed herein, in some configurations, are compositions for treating blepharitis and / or rosacea, comprising a formamidine parasiticide in an oral or topical pharmaceutical formulation at a dosage sufficient to eliminate Demodex mites at one or more anatomical locations, resulting in the cessation of symptoms of the blepharitis and / or rosacea.

[0120] In some configurations, disclosed herein are methods for treating cylindrical eyelash dandruff associated with blepharitis and / or ocular rosacea in one or both eyes. The methods comprise topically administering an effective amount of a formamidine parasiticide directly to the conjunctiva of one or both eyes and / or the cornea of ​​one or both eyes of an individual in need of such treatment. The formamidine parasiticide is then formulated into an eyewash composition containing a pharmaceutically acceptable solvent. The eyewash composition is sterile, non-irritating to the eye, and compatible with ocular tissue.

[0121] In some configurations, the formamidine parasiticide is administered in an amount of 0.001% to 10% by weight based on the total weight of the composition.

[0122] In some configurations, the formamidine parasiticide is administered in an amount of 0.01% to 5% by weight based on the total weight of the composition.

[0123] In some configurations, 0.03% by weight of formamidine parasiticide is administered based on the total weight of the composition.

[0124] In some configurations, 0.10% by weight of formamidine parasiticide is administered based on the total weight of the composition.

[0125] Disclosed herein, in some configurations, are methods of treating blepharitis and / or rosacea by orally or topically applying a formamidine parasiticide in a dosage sufficient to fill one or more anatomical locations and eliminate Demodex mites, resulting in the cessation of symptoms of blepharitis and / or rosacea.

[0126] In some configurations, the administration of the formamidine parasiticide is repeated about 2-4 times with an interval of 3-7 days between administrations.

[0127] In some configurations, the topically applied formamidine parasiticide is formulated in a carrier lotion, cream, or gel.

[0128] In some configurations, the concentration of the formamidine parasiticide in the topically applied lotion, cream, or gel is about 1 to 5 weight percent.

[0129] In some configurations, the topically applied formamidine parasiticide is applied to the eyelid.

[0130] In some configurations, the topically applied formamidine parasiticide is applied to the affected skin area at least once daily and at most twice daily for a period of about 2 to 4 weeks.

[0131] In some configurations, the topically applied formamidine parasiticide is encapsulated in microliposomes before being formulated into the carrier lotion, cream, or gel.

[0132] Disclosed herein, in some configurations, are compositions for treating blepharitis and / or rosacea, comprising a formamidine parasiticide in an oral or topical pharmaceutical formulation at a dosage sufficient to eliminate Demodex mites at one or more anatomical locations, resulting in the cessation of symptoms of the blepharitis and / or rosacea.

[0133] In some configurations, methods are disclosed herein for treating symptoms of blepharitis and / or ocular rosacea in one or both eyes. The symptoms are selected from the group consisting of burning eyes, stinging eyes, dry eyes, increased sensitivity to light, blurred vision, and intracorneal complications of ocular rosacea. The methods involve topically administering an effective amount of a phenylpyrazole parasiticide directly to the conjunctiva of one or both eyes and / or to one or both corneas of one or both eyes of an individual in need of such treatment. The phenylpyrazole parasiticide is therefore formulated into an eyewash composition containing a pharmaceutically acceptable solvent. The eyewash composition is sterile, non-irritating to the eye, and compatible with ocular tissue.

[0134] In some configurations, 0.001% to 10% by weight of the phenylpyrazole parasiticide is administered based on the total weight of the composition.

[0135] In some configurations, 0.01% to 5% by weight of the phenylpyrazole parasiticide is administered based on the total weight of the composition.

[0136] In some configurations, 0.03% by weight of the phenylpyrazole parasiticide is administered based on the total weight of the composition.

[0137] In some configurations, 0.10% by weight of the phenylpyrazole parasiticide is administered based on the total weight of the composition.

[0138] Disclosed herein, in some configurations, are methods of treating blepharitis and / or rosacea by orally administering or topically applying a phenylpyrazole parasiticide at one or more anatomical locations in a dosage sufficient to fill and eliminate Demodex mites, resulting in the cessation of symptoms of blepharitis and / or rosacea.

[0139] In some configurations, the dose of phenylpyrazole parasiticide is repeated about 2-4 times with 3-7 days between doses.

[0140] In some configurations, the topically applied phenylpyrazole parasiticide is formulated in a carrier lotion, cream, or gel.

[0141] In some configurations, the concentration of the phenylpyrazole parasiticide in the topically applied lotion, cream, or gel is about 1 to 5 weight percent.

[0142] In some configurations, the topically applied phenylpyrazole parasiticide is applied to the eyelid.

[0143] In some configurations, the topically applied phenylpyrazole parasiticide is applied to the affected skin area at least once daily and at most twice daily for a period of about 2 to 4 weeks.

[0144] In some configurations, the topically applied phenylpyrazole parasiticide is encapsulated in microliposomes before being formulated into the carrier lotion, cream, or gel.

[0145] Disclosed herein, in some configurations, are compositions for treating blepharitis and / or rosacea, comprising an oral or topical pharmaceutical formulation comprising a phenylpyrazole parasiticide in a dosage sufficient to eliminate Demodex mites at one or more anatomical locations, resulting in the cessation of symptoms of the blepharitis and / or rosacea.

[0146] In some configurations, disclosed herein are methods for treating blepharitis and / or cylindrical eyelash dandruff associated with ocular rosacea in one or both eyes. The symptoms are selected from the group consisting of burning eyes, stinging eyes, dry eyes, increased sensitivity to light, blurred vision, and intracorneal complications of ocular rosacea. The methods involve topically administering an effective amount of the phenylpyrazole parasiticide directly to the conjunctiva of one or both eyes and / or to one or both corneas of one or both eyes of an individual in need of such treatment. The phenylpyrazole parasiticide is then formulated into an eyewash composition containing a pharmaceutically acceptable solvent. The eyewash composition is sterile, non-irritating to the eye, and compatible with ocular tissue.

[0147] In some configurations, 0.001% to 10% by weight of the phenylpyrazole parasiticide is administered based on the total weight of the composition.

[0148] In some configurations, 0.01% to 5% by weight of the phenylpyrazole parasiticide is administered based on the total weight of the composition.

[0149] In some configurations, 0.03% by weight of the phenylpyrazole parasiticide is administered based on the total weight of the composition.

[0150] In some configurations, 0.10% by weight of the phenylpyrazole parasiticide is administered based on the total weight of the composition.

[0151] Disclosed herein, in some configurations, are methods of treating blepharitis and / or rosacea by orally administering or topically applying a phenylpyrazole parasiticide at one or more anatomical locations in a dosage sufficient to fill and eliminate Demodex mites, resulting in the cessation of symptoms of blepharitis and / or rosacea.

[0152] In some configurations, the dose of phenylpyrazole parasiticide is repeated about 2-4 times with an interval of 3-7 days between doses.

[0153] In some configurations, the topically applied phenylpyrazole parasiticide is formulated in a carrier lotion, cream, or gel.

[0154] In some configurations, the concentration of the phenylpyrazole parasiticide in the topically applied lotion, cream, or gel is about 1 to 5 weight percent.

[0155] In some configurations, the topically applied phenylpyrazole parasiticide is applied to the eyelid.

[0156] In some configurations, the topically applied phenylpyrazole parasiticide is applied to the affected skin area at least once daily and at most twice daily for a period of about 2 to 4 weeks.

[0157] In some configurations, the topically applied phenylpyrazole parasiticide is encapsulated in microliposomes before being formulated into the carrier lotion, cream, or gel.

[0158] Disclosed herein, in some configurations, are compositions for treating blepharitis and / or rosacea, comprising a phenylpyrazole parasiticide in an oral or topical pharmaceutical formulation at a dosage sufficient to eliminate Demodex mites at one or more anatomical locations, resulting in the cessation of symptoms of the blepharitis and / or rosacea.

[0159] In some configurations, methods are disclosed herein for treating symptoms of blepharitis and / or ocular rosacea in one or both eyes. The symptoms are selected from the group consisting of burning eyes, stinging eyes, dry eyes, increased sensitivity to light, blurred vision, and intracorneal ocular rosacea complications. The methods involve topically administering an effective amount of a drug used to treat Alzheimer's disease directly to the conjunctiva of one or both eyes and / or to one or both corneas of one or both eyes of an individual in need of such treatment. The drug (medicine) is therefore formulated into an eye wash composition containing a pharmaceutically acceptable solvent. The eye wash composition is sterile, non-irritating to the eye, and compatible with ocular tissue.

[0160] In some configurations, 0.001% to 10% by weight of a drug used to treat Alzheimer's disease is administered based on the total weight of the composition.

[0161] In some configurations, 0.01% to 5% by weight of a drug used to treat Alzheimer's disease is administered based on the total weight of the composition.

[0162] In some configurations, 0.03% by weight of a drug used to treat Alzheimer's disease is administered relative to the total weight of the composition.

[0163] In some configurations, 0.10% by weight of a drug used to treat Alzheimer's disease is administered based on the total weight of the composition.

[0164] Disclosed herein, in some configurations, are methods for treating blepharitis and / or rosacea by orally or topically applying a medication used to treat Alzheimer's disease at one or more anatomical locations in a dosage sufficient to fill and eliminate Demodex mites, resulting in the cessation of symptoms of blepharitis and / or rosacea.

[0165] In some configurations, the dose of drug used to treat Alzheimer's disease is repeated about 2-4 times with an interval of 3-7 days between doses.

[0166] In some configurations, the topically applied drug used to treat Alzheimer's disease is formulated in a carrier lotion, cream, or gel.

[0167] In some configurations, the concentration of the drug used to treat Alzheimer's disease in the topically applied lotion, cream, or gel is about 1 to 5 weight percent.

[0168] In some configurations, the topically applied medication used to treat Alzheimer's disease is applied to the eyelid.

[0169] In some configurations, the topically applied drug used to treat Alzheimer's disease is applied to the affected skin area at least once daily and at most twice daily for a period of about 2 to 4 weeks.

[0170] In some configurations, the topically applied drug used to treat Alzheimer's disease is encapsulated in microliposomes before being formulated into the carrier lotion, cream, or gel.

[0171] Disclosed herein, in some configurations, are compositions for treating blepharitis and / or rosacea, comprising a drug used to treat Alzheimer's disease, in an oral or topical pharmaceutical formulation, in a dosage sufficient to eliminate Demodex mites at one or more anatomical locations, resulting in the cessation of symptoms of the blepharitis and / or rosacea.

[0172] In some configurations, disclosed herein are methods for treating lice, scabies, and / or bed bugs in a patient. The methods involve topically administering an effective amount of an isoxazoline parasiticide or a formamidine parasiticide directly to the skin surface of a patient in need of such treatment. The parasiticide is formulated into a composition further comprising a pharmaceutically acceptable solvent. The composition may be non-irritating to the skin. The isoxazoline parasiticide may be the sole active ingredient in the composition, or it may be combined with other active ingredients.

[0173] In some configurations, methods for preventing host-borne disease in a patient are disclosed herein. The methods involve topically administering an effective amount of an isoxazoline or formamidine parasiticide directly to the skin surface of a patient in need of treatment for the disease. The parasiticide is formulated into a composition further comprising a pharmaceutically acceptable solvent. The composition may be non-irritating to the skin. The isoxazoline parasiticide may be the sole active ingredient in the composition, or it may be combined with other active ingredients.

[0174] In some configurations, methods for improving eyelash health in a patient are disclosed herein. The methods can include topically administering an effective amount of an isoxazoline parasiticide directly to the ocular surface of one or both eyes of a patient in need of blepharitis treatment. The isoxazoline parasiticide is formulated into an ophthalmic composition further comprising a pharmaceutically acceptable solvent. The ophthalmic composition can be sterile and non-irritating to the eye. The isoxazoline parasiticide can be the sole active ingredient of the composition, or it can be combined with other active ingredients. Improving eyelash health can, for example, increase the number, growth rate, thickness, and / or appearance of a patient's eyelashes.

[0175] In some configurations, the composition is not absorbed systemically, or the composition is not absorbed systemically enough to have a therapeutic effect or any adverse effects systemically.

[0176] In some embodiments, the present disclosure provides a multi-dose topical ophthalmic or dermatological formulation for use in treating ocular surface diseases. The formulation may include any number of isoxazoline parasiticides, a castor oil solubilizer, a polyol, an acid, tromethamine (TRIS), and lauralkonium chloride or benzalkonium chloride. The formulation may be therapeutically effective in reducing or eliminating Demodex mites near the eyelashes, improving the symptoms of blepharitis and / or rosacea.

[0177] In some configurations, the topical formulation is for use in treating blepharitis (e.g., anterior blepharitis or posterior blepharitis). In some configurations, the topical formulation is for use in treating ocular rosacea.

[0178] In some configurations, the isoxazoline parasiticide comprises about 0.01% to about 0.50% w / w of the formulation, for example, about 0.01%, 0.05%, 0.10%, 0.15%, 0.20%, 0.25%, 0.30%, 0.35%, 0.40%, 0.45%, 0.50%, or a range inclusive of any two of the values ​​recited herein.

[0179] In some configurations, the ophthalmic composition does not include essential oils.

[0180] In some configurations, the isoxazoline parasiticide is selected from the group consisting of fluralaner, sarolaner, lotilaner, afoxolaner, fluxametamide, and isocycloceram.

[0181] In some configurations, the castor oil solubilizer is about 3% to about 7% w / w of the formulation, or about 5% w / w of the formulation.

[0182] In some configurations, the polyol is selected from the group consisting of glycerol, xylitol, erythritol, mannitol, and sorbitol.

[0183] In some configurations, the formulation further comprises HPMC or CMC.

[0184] In some configurations, the formulation does not include a phosphate buffer.

[0185] In some configurations, the formulation is polysorbate-free.

[0186] In some configurations, disclosed herein are topical gel formulations for ophthalmic or dermatological use that include an isoxazoline parasiticide and any number of features such as castor oil, HPMC, carbomer, tromethamine (TRIS), polyols, and / or preservatives (e.g., lauralkonium chloride and benzalkonium chloride), or other features disclosed herein.

[0187] Disclosed herein, in some configurations, are single-dose ophthalmic formulations for use in treating ocular surface diseases. The formulations include any number of isoxazoline parasiticides, a castor oil solubilizer, a polyol, and tromethamine (TRIS). The formulations are preservative-free and are therapeutically effective in reducing or eliminating Demodex mites near the eyelashes and improving the symptoms of blepharitis and / or rosacea.

[0188] In some configurations, the formulation can include one or more of a lipid-producing agent, a keratolytic agent, and / or a mucolytic agent. In some embodiments, disclosed herein are multi-dose topical ophthalmic formulations for use in treating ocular surface diseases. The formulations include an isoxazoline parasiticide, a castor oil solubilizer, a viscosity-enhancing agent, a buffer, a sorbate, and / or a chelating agent. In some embodiments, the formulations are therapeutically effective in reducing or eliminating Demodex mites near the eyelashes and improving symptoms of blepharitis and / or rosacea.

[0189] In some embodiments, the sorbate comprises potassium sorbate, the chelating agent comprises EDTA, and the viscosity enhancing agent comprises HPMC. In some embodiments, the pH of the formulation is about 7 to about 7.5. In some embodiments, the pH of the formulation is about 7.2.

[0190] In some configurations, methods for treating blepharitis in a patient are disclosed herein. The methods include topically administering an effective amount of an isoxazoline parasiticide directly to the ocular surface of one or both eyes of a patient in need of blepharitis treatment. The isoxazoline parasiticide is formulated into an ophthalmic composition comprising a sorbate and a pharmaceutically acceptable solvent, and the ophthalmic composition is sterile and non-irritating to the eye. The isoxazoline parasiticide can be the only active ingredient in the ophthalmic composition. In some embodiments, the sorbate is the only preservative in the composition.

[0191] In some configurations, methods for treating blepharitis in a patient are disclosed herein. The methods involve topically administering an effective amount of an isoxazoline parasiticide directly to one or both eyes, eyelids, or one or more eyelashes of a patient in need of blepharitis treatment. The isoxazoline parasiticide is formulated into an ophthalmic composition containing sorbate, castor oil, and a pharmaceutically acceptable solvent. The ophthalmic composition is sterile and non-irritating to the eye. The isoxazoline parasiticide can be the only active ingredient in the ophthalmic composition.

[0192] In some configurations, methods for treating Demodex ocular infestations in a patient are disclosed herein. The methods include topically administering an effective amount of an isoxazoline parasiticide directly to one or both eyes, eyelids, or eyelashes of one or both eyes of a patient in need of blepharitis treatment. The isoxazoline parasiticide is formulated into an ophthalmic composition comprising a sorbate and a pharmaceutically acceptable solvent. The ophthalmic composition is sterile and non-irritating to the eye. The isoxazoline parasiticide can be the only active ingredient in the ophthalmic composition. The volume of the composition delivered can be less than about 100 microliters.

[0193] In some configurations, methods for treating blepharitis and / or rosacea are disclosed herein. The methods include topically applying a composition comprising an isoxazoline parasiticide to the vicinity of one or more eyelashes, the topical application being therapeutically effective in reducing the movement of Demodex mites' bodies relative to the Demodex heads, and in preferentially absorbing the Demodex mites' bodies relative to uptake by the Demodex mites, the method being sufficient to reduce or eliminate Demodex mites near the eyelashes and improving the symptoms of blepharitis and / or rosacea. The composition can further comprise a sorbate and castor oil, the sorbate being the only preservative in the composition.

[0194] In some configurations, disclosed herein are topical ophthalmic formulations for treating blepharitis in a patient. The formulations include a sorbate, castor oil, and an effective amount of an isoxazoline parasiticide and a pharmaceutically acceptable solvent, and the ophthalmic composition is sterile and non-irritating to the eye. The isoxazoline parasiticide may be the only active ingredient in the ophthalmic composition. The sorbate may be the only preservative in the composition.

[0195] In some configurations, topical formulations for use in treating ocular surface diseases are disclosed herein. The formulations include an isoxazoline parasiticide, at least one of Pemulen and HPMC, castor oil, glycerin, a buffer, and potassium sorbate. The formulations may be therapeutically effective in reducing or eliminating Demodex mites near the eyelashes and improving symptoms of blepharitis and / or rosacea.

[0196] In some configurations, disclosed herein are topical ophthalmic formulations for use in treating ocular surface diseases. The formulations include an isoxazoline parasiticide, a castor oil solubilizer, and a polyol. The formulations are therapeutically effective in reducing or eliminating Demodex mites near the eyelashes and improving the symptoms of blepharitis and / or rosacea. [Brief explanation of the drawings]

[0197] [Figure 1A] 1 shows a schematic of application of an ophthalmic formulation to a Demodex-infested eye. [Figure 1B] 1 shows a schematic of application of an ophthalmic formulation to a Demodex-infested eye. [Figure 2] FIG. 1 shows data demonstrating the activity of selected anatomical forms of Demodex following treatment with topical formulations. [Figure 3A] An example of a formulation with amitraz, fluralaner and lotilaner is shown. [Figure 3B] An example of a formulation with amitraz, fluralaner and lotilaner is shown. [Figure 4A] 1A-1C illustrate various embodiments of diagnostic techniques for Demodex that do not necessarily require hair removal, including the Coralette test. [Figure 4B] 1A-1C illustrate various embodiments of diagnostic techniques for Demodex that do not necessarily require hair removal, including the Coralette test. [Figure 4C] 1A-1C illustrate various embodiments of diagnostic techniques for Demodex that do not necessarily require hair removal, including the Coralette test. [Figure 5A]Human study data related to isoxazoline antiparasitic agents are presented. [Figure 5B] Human study data related to isoxazoline antiparasitic agents are presented. [Figure 5C] Human study data related to isoxazoline antiparasitic agents are presented. DETAILED DESCRIPTION OF THE INVENTION

[0198] In some embodiments, topical therapeutic agents are disclosed herein. These topical therapeutic agents include, but are not limited to, topical pharmaceuticals containing one or more isoxazoline parasiticides, formamidine parasiticides, agents used to treat Alzheimer's disease, and other agents disclosed herein for the treatment of various ophthalmic and dermatological conditions. Also disclosed herein are methods for treating blepharitis, ocular rosacea, and Demodex infestations in patients in need of such treatment. In some embodiments, patients in need of such treatment may be treated with an active agent from the isoxazoline parasiticide family of chemicals, including, but not limited to, isoxazoline-substituted benzamide derivatives. Without being limited by theory, isoxazoline parasiticides act as GABA-chloride antagonists and can selectively target the nervous systems of certain organisms, including, but not limited to, Demodex. GABA-mediated chloride influx can cause hyperpolarization of cell membranes, reducing the potential for action potentials and generating inhibitory postsynaptic potentials. This influx also paralyzes and ultimately kills the Demodex mites. Examples of isoxazoline parasiticides include, for example, fluralaner, sarolaner, lotilaner, afoxolaner, isocycloceram, and / or fluxametamide, including any number of their derivatives, analogs, and L- and D-isomers, including, but not limited to, enantiomers, compositions containing racemic mixtures, and enantiomerically pure compositions. In some embodiments, the isoxazoline parasiticide, formamidine parasiticide, or other active ingredient as disclosed herein is the only active ingredient utilized in the formulation and / or method. In some embodiments, the isoxazoline parasiticide is an isoxazoline-substituted benzamide derivative. In some embodiments, the isoxazoline parasiticide has one, two, three or more fluorine groups in its chemical structure, such as three trifluorine groups (eg, R-CF3).In some embodiments, the formulations can include, instead of or in addition to an isoxazoline parasiticide otherwise disclosed herein, a precursor compound of another isoxazoline parasiticide (e.g., an isoxazole carboxylic acid, including isoxazole-4-carboxylic acid), or a breakdown compound thereof (e.g., an isoxazolethiopene carboxylic acid), in an amount / concentration otherwise disclosed herein, such as, for example, from about 0.001% to about 0.1%, or from about 0.005% to 0.01%. In some embodiments, the formulations do not include any precursor or breakdown compounds, including those disclosed herein. In some embodiments, the formulations can include a pyrazole-5-carboxamide containing an arylisoxazoline moiety.

[0199] Isoxazoline parasiticides have traditionally been utilized in veterinary applications, including animal gums and non-ophthalmic topical "drop" solutions; however, to the inventors' knowledge, no formulations have been developed for human use. Non-limiting examples of isoxazoline parasiticides are disclosed, for example, in U.S. Pat. No. 7,662,972 (Mita et al.), U.S. Pat. No. 8,466,115 (Curtis et al.), U.S. Pat. No. 7,964,204 (Lahm et al.), and U.S. Pat. No. 8,383,659 (Nanchen et al.), each of which is incorporated herein by reference in its entirety. In addition, U.S. Patent Application Publication No. 2010 / 0254960, PCT Application Publication No. WO2007 / 070606, PCT Application Publication No. WO2007 / 123855, PCT Application Publication No. WO2010 / 003923, U.S. Patent No. 7,951,828, U.S. Patent No. 7,662,972, U.S. Patent Application Publication No. 2010 / 0137372, U.S. Patent Application Publication No. 2010 / 0179194, U.S. Patent Application Publication No. 2011 / 0086886, U.S. Patent Application Publication No. 2011 / 0059988, U.S. Patent Application Publication No. 2010 / 0179195, PCT Application Publication No. WO 2007 / 075459, and U.S. Patent No. 7,951,828 describe various other parasiticidal isoxazoline compounds. All of the above documents are incorporated herein by reference in their entireties. Additional non-limiting examples of isoxazoline parasiticides are disclosed, for example, in U.S. Patent Application Publication No. 2014 / 0243375 (El Qacemi et al.) and U.S. Patent No. 8,735,362 (Cassayre et al.). These patents are incorporated herein by reference in their entireties.

[0200] Veterinary oral (e.g., non-topical) formulations, such as gums, result in first-pass hepatic metabolism and systemic effects that may be undesirable for targeted topical applications. A significant issue is that the fluorinated and / or chlorinated groups of certain isoxazoline parasiticides increase the insolubility of these molecules in any pharmaceutical-based solution (including oil-based and water-based solutions), with solubilities of less than about 1 mg / kg or concentrations in water of about 1 mg / L or less. Veterinary topical solutions of isoxazoline parasiticides include, for example, dimethylacetamide, glycofurol, diethyltoluamide, and / or acetone. However, these solutions are only offered as "drops" for the back of the neck of animals, such as cats or dogs, and are undesirable (and potentially toxic) for ophthalmic use, including instructions not to administer the solution into or around the eye. For example, on September 20, 2018, the FDA issued an Animal Drug Safety Communication to alert pet owners and veterinarians to the potential for significant neurological events (including muscle tremors, ataxia, and seizures) in dogs and cats treated with systemically absorbed drugs of the isoxazoline class.

[0201] Such "drop-on" solutions are absorbed systemically by animals and do not provide the desired local activity alone. To the inventors' knowledge, topical ophthalmic formulations of isoxazoline or formamidine parasiticides have not previously been developed. For example, there is a need for therapeutic formulations for both human and other animal use that are safe and non-toxic for ophthalmic or dermatological use, and that are sufficiently soluble to be therapeutically effective in treating ocular Demodex mites and related conditions, such as blepharitis.

[0202] In some embodiments, for ophthalmic and dermatological conditions, the formulations and methods are administered in amounts and / or dosage forms that are not systemically bioavailable or substantially not systemically bioavailable, although in some embodiments the formulations and methods are administered in amounts and / or dosage forms that may be systemically bioavailable. In some embodiments, the formulations or methods have no, or substantially no, systemic action or therapeutic effect outside of a localized target area, e.g., in or around the eye. In some embodiments, the formulations or methods are not systemically absorbed or substantially not systemically absorbed.

[0203] In some embodiments, the formulations or methods result in a patient having peak or random blood, plasma, serum or other bodily fluid levels of an isoxazoline parasiticide, a formamidine parasiticide, a phenylpyrazole parasiticide, or other therapeutic agent, including a parasiticide otherwise disclosed herein, that are undetectable or are no more than about 25 ng / mL, 20 ng / mL, 15 ng / mL, or 10 ng / mL. In some embodiments, the formulation or method provides a concentration of the isoxazoline parasiticide of about 5 ng / mL, about 4 ng / mL, about 3 ng / mL, about 2 ng / mL, about 1 ng / mL, about 0.50 ng / mL, about 0.25 ng / mL, about 0.20 ng / mL, about 0.15 ng / mL, about 0.10 ng / mL, about 0.005 ng / mL, about 0.001 ng / mL, about 0.0005 ng / mL, about 0.0001 ng / mL or less, or only about 5 ng / mL, about 4 ng / mL, about 3 ng / mL, or less, such that the isoxazoline parasiticide has no systemic therapeutic and / or adverse effects in the patient. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 112, 113, 114, 115, 116, 117, 118, 119, 200, 210, 220, 230, 240, 250, 261, 272, 280, 290, 301, 310, 321, 330, 340

[0204] It is determined herein that compounds of the isoxazoline family of parasiticides, formamidine parasiticides, agents for treating Alzheimer's disease, and / or other agents otherwise disclosed herein may be suitable for the treatment of ocular conditions of any etiology, particularly ocular conditions caused by Demodex folliculorum, and in particular blepharitis and / or ocular rosacea. Other conditions that may be treated with the formulations and methods disclosed herein include, for example, rosacea, pityriasis vera caused by Demodex folliculorum, rosacea-like demodex folliculorum, and demodicosis gravis, nonspecific facial dermatitis, atopic dermatitis, acne vulgaris, steroid-induced rosacea, androgenetic alopecia, shedding, lupus miliaris disseminatus faciei, folliculitis dissecans, perioral dermatitis, mite-induced blepharoconjunctivitis, papulopustular scalp rash, eosinophilic folliculitis, pustular folliculitis, Grover's disease, and Demodex folliculorum. In some embodiments, formulations and methods, including those disclosed herein, can improve eyelash health and treat shedding, trichorrhexis, and other conditions. Without being limited by theory, Demodex mites and / or other pathogens may cause inflammation and associated damage such as hair loss, poor growth, premature hair loss, and / or damage to hair follicles and related structures. In some embodiments, immunocompromised patients suffering from demodicosis are treated with the systems and methods as disclosed herein. Such conditions can be surprisingly and effectively treated with the formulations and methods as disclosed herein. In some embodiments, the formulations and methods may have anti-inflammatory and / or antimicrobial effects through indirect and / or direct action through eradication of Demodex mites and / or other parasites. In some embodiments, for maintenance therapy and / or for severe exacerbations, low-dose oral treatment with any of the formulations or methods disclosed herein may be utilized instead of or in addition to topical treatment. For example, low-dose oral treatment may be 500 mg, 400 mg, 300 mg, 200 mg, 100 mg, 50 mg, 25 mg, or greater or less than 500 mg, 400 mg, 300 mg, 200 mg, 100 mg, 50 mg, 25 mg, or a range including any two of the foregoing values.Doses may be given, for example, daily, every other day, every third day, twice a week, once a week, every two weeks, every month, every six weeks, every two months, every three months, or at longer intervals, for example.

[0205] In some embodiments, formulations and methods incorporating the features disclosed herein can be used to treat conditions such as lice (pediculosis), including head lice (Pediculosis capitis) and body lice (Pediculosis corporis). The formulations and methods can also be used to treat pubic lice, such as crab louse or pubic louse. Eyelash infestation, referred to as lid lice infestation or eyelash lice infestation, can in some cases cause intense itching of the eyelid margin, watery, red eyes, and keratoconjunctivitis. Demodex mites are typically smaller than pubic lice (0.1-0.4 mm long) and are not usually found outside of eyelash follicles. Without being limited by theory, the formulations and methods disclosed herein can be surprisingly effective at removing or inactivating lice and other organisms at low concentrations.

[0206] In some embodiments, formulations and methods incorporating features disclosed herein can be utilized for the treatment of scabies. Scabies is an itchy skin condition caused by small, burrowing mites called Sarcoptes scabiei. Intense itching occurs in areas punctured by the mites. Traditionally, scabies has been treated with permethrin cream, lindane lotion, crotamiton cream or lotion, or oral ivermectin. There is a need for less toxic, more effective treatments.

[0207] In some embodiments, formulations and methods, including those disclosed herein, can be utilized to treat bedbugs, such as, for example, bed bugs, including bedbugs.

[0208] In some embodiments, formulations and methods, including those disclosed herein, can be used for vector control to treat or prevent mosquito-, tick-, and flea-borne diseases, including, but not limited to, Zika virus, West Nile virus, Lyme disease, chikungunya, dengue fever, malaria, plague, relapsing fever, Rocky Mountain spotted fever, tularemia, and typhus. In some cases, application of the formulation to skin, clothing, and / or other accessories can repel, counteract, inactivate, prevent, or reduce the risk of mosquito, tick, and / or flea bites. In some embodiments, the topical formulation is not metabolized for at least about 10 minutes, about 15 minutes, about 30 minutes, or about 60 minutes, or for at least 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, or more, thereby increasing the effective time for preventing the aforementioned bites and associated diseases.

[0209] Ivermectin is another drug used to treat Demodex mites and is generally more soluble in solution than isoxazoline parasiticides. However, no known formulations are approved for ocular use (e.g., for blepharitis), and more effective treatments are needed. In some embodiments, the formulations and / or methods do not include an avermectin, such as ivermectin, or another macrocyclic lactone derivative, although the formulation may include an avermectin in other embodiments. In some embodiments, the formulations and / or methods do not include pyrethrins, permethrin, or metronidazole, although the formulation may include pyrethrins, permethrin, and / or metronidazole in other embodiments.

[0210] Disclosed herein are various embodiments of systems, methods, and formulations for treating various ocular conditions, including but not limited to blepharitis, and for treating Demodex infestations (e.g., on the eyelids of a subject, such as a human). The embodiments may include any number of features as disclosed herein. Some embodiments are at least partially free of dimethylacetamide, glycofurol, diethyltoluamide, and / or acetone, which may be toxic and irritating to the eye in some cases.

[0211] Also disclosed herein are the use of topical isoxazoline parasiticides, formamidine parasiticides, agents for treating Alzheimer's disease, and / or other agents otherwise disclosed herein to treat blepharitis, and methods of treating Demodex infestation and blepharitis in patients in need thereof.

[0212] Further disclosed are topical isoxazoline parasiticides, formamidine parasiticides, agents for treating Alzheimer's disease, and / or other agents as otherwise disclosed herein for treating rosacea and / or ocular rosacea, and methods for treating Demodex infestation and rosacea and / or ocular rosacea in a patient in need thereof (e.g., from the isoxazoline parasiticide family of chemicals). Formulations and methods for reducing Demodex numbers near a patient's eyes and dandruff in cylindrical eyelashes are also disclosed.

[0213] Also disclosed herein are topical isoxazoline parasiticides, formamidine parasiticides, agents for treating Alzheimer's disease, and / or other agents as otherwise disclosed herein for treating rosacea and / or ocular rosacea, and methods for treating Demodex infestation and rosacea and / or ocular rosacea in a patient in need thereof.

[0214] In some embodiments, the pharmaceutical composition comprises at least one, two, or more compounds selected from the family of isoxazoline parasiticides, including, for example, fluralaner, soloraner, lotilaner, afoxolaner, isocycloceram, and / or fluxametamide. This is particularly useful for treating other indications, including conjunctivitis, blepharitis, ocular rosacea, pterygium, chalazion, hordeolum, eyelash shedding (to improve the density, health, and appearance of eyelashes), or other ocular surface disorders such as meibomian gland dysfunction or dry eye disease. These may also be used to improve vision outcomes before refractive or cataract surgery.

[0215] Some embodiments may include derivatives, analogs, and L- and D-isomers of an isoxazoline parasiticide, a formamidine parasiticide, or other active therapeutic agent as otherwise disclosed herein, including but not limited to enantiomers, compositions comprising racemic mixtures, and enantiomerically pure compositions.

[0216] Surprisingly, in some embodiments, doses of isoxazoline parasiticides, formamidine parasiticides, drugs for treating Alzheimer's disease, and / or other drugs as otherwise disclosed herein can be used at doses lower than those found to be clinically effective for veterinary drugs that act topically via rinsing or washing and by systemic absorption (e.g., concentrations ranging from 1 to 10 nM or 100 pM to 1 nM), or at doses ranging between any two of the foregoing values. These lower effective concentrations than conventional concentrations can be due, but are not limited to, to direct absorption of the drug by the tick body rather than uptake of the drug by the tick. The tick abdomen is thinner (approximately 0.5 μm), and more likely to absorb the drug than the tick cephalothorax (approximately 2 μm). In some embodiments, direct absorption of the drug by the tick body can be a mechanism responsible for total drug uptake by the tick of at least about 50%, about 60%, about 70%, about 80%, about 90%, or more.

[0217] In some embodiments, daily and topical treatments are administered rather than long-acting, large-volume systemic doses (in veterinary medicine, drugs are administered monthly, every 8 weeks, 12 weeks, 16 weeks, or less frequently), although in other embodiments, long-acting systemic or topical administration may be used.

[0218] In some embodiments, administration can be about 1, 2, 3, 4, 5, 6, 7, 8, or more times, or at least about 1, 2, 3, 4, 5, 6, 7, 8, or more times per day, e.g., 1-2 times per day. In some embodiments, treatment can be a single dose or a limited course weekly. In some embodiments, the formulation can be used preferentially in the morning, at night, or only at night to target exposure to mites during mating hours.

[0219] In some embodiments, formulations may be advantageous in part due to the slow clearance rate of molecules such as isoxazoline parasiticides, but the low doses and localized administration allow for frequent repeated administration, which may be advantageous for disrupting the Demodex life cycle without the associated systemic risks and side effects due to their effectiveness in more susceptible juvenile forms.

[0220] In some embodiments, the active molecule may be preferentially hydrophobic, which concentrates the active molecule in areas containing either sebum or meibum oil (e.g., eyelash follicles and / or meibomian glands). The formulation may be preferentially water-based, which can facilitate delivery to and absorption by the hydrophilic Demodex chitin chitosan.

[0221] In some embodiments, the therapeutic agent may be delivered in the form of eye drops, creams, ointments, eye washes, wipes, ointments, or gels, or immediate-release or sustained-release formulations. In some embodiments, the therapeutic agent may be delivered in the form of punctal plugs, canalicular plugs, or emulsions. In some cases, oily, gel-like, or viscous ointments may also impede the movement of Demodex mites across the skin surface during mating.

[0222] In some embodiments, formulations such as isoxazoline parasiticides, formamidine parasiticides, agents for treating Alzheimer's disease, and / or other agents as otherwise disclosed herein may have preferential selectivity for insect receptors / mite receptors / acari receptors on vertebrates / mammalian receptors / human receptors.

[0223] In some embodiments, the active agent is delivered in an oral formulation (e.g., tablet, capsule, solution, etc.), and very low doses may be delivered to avoid significant systemic exposure or non-topical skin exposure (this is in contrast to veterinary teachings), although in some embodiments, the active agent is delivered in a parenteral formulation, such as a topical formulation, e.g., a topical ophthalmic formulation.

[0224] In some embodiments, for example, a dose of 1 microgram to 1 mg / mL or 0.0001% to 1% by weight of an active agent (e.g., an isoxazoline parasiticide, a formamidine parasiticide, an agent for treating Alzheimer's disease, and / or other agent as otherwise disclosed herein), or about 0.01% to 10% by weight, about 0.05% to about 0.5% by weight, or about 0.01% to about 0.01% by weight, about 0.01% to about 0.05% by weight, or about 0.01% to about 0.05% by weight, ... .015% by weight, approximately 0.02% by weight, approximately 0.025% by weight, approximately 0.03% by weight, approximately 0.04% by weight, approximately 0.05% by weight, approximately 0.06% by weight, approximately 0.07% by weight, approximately 0.08% by weight, approximately 0.09% by weight, approximately 0. 10% by weight, approximately 0.15% by weight, approximately 0.20% by weight, approximately 0.25% by weight, approximately 0.30% by weight, approximately 0.35% by weight, approximately 0.40% by weight, approximately 0.45% by weight, approximately 0.50% by weight, approximately 0.55% by weight, approximately 0.60% by weight %, about 0.65%, about 0.70%, about 0.75%, about 0.80%, about 0.85%, about 0.90%, about 0.95%, about 1.00%, or a range including any two of the foregoing values, or 1 ng to 1 microgram / mL or 0.0000001 to 0.0001% by weight of an active agent (e.g., an isoxazoline parasiticide, a formamidine parasiticide, an Alzheimer's disease inhibitor, an antiparasitic agent ... In some embodiments, the active agent is an isoxazoline parasiticide, a formamidine parasiticide, a drug for treating Alzheimer's disease, and / or other drug as otherwise disclosed herein, or 1 mg / mL to 100 mg / mL or 0.1 to 10% by weight of the active agent (e.g., an isoxazoline parasiticide, a formamidine parasiticide, a drug for treating Alzheimer's disease, and / or other drug as otherwise disclosed herein), or a dose range inclusive of any of the foregoing values. In some embodiments, the isoxazoline parasiticide, a formamidine parasiticide, a drug for treating Alzheimer's disease, and / or other drug as otherwise disclosed herein is the only active agent.

[0225] In some embodiments, the ophthalmic formulation may be configured for delivery directly onto the ocular surface, including, but not limited to, the conjunctiva and / or cornea of ​​the eye. In some embodiments, the ophthalmic formulation may be configured for delivery directly or indirectly onto any number of the anterior or posterior eyelids, eyelashes, or eyebrows. In some embodiments, the ophthalmic formulation is not delivered directly to any number of the conjunctiva, cornea, anterior or posterior eyelids, eyelashes, or eyebrows.

[0226] Eye drop formulations may be designed to specifically and simultaneously treat blepharitis and Demodex mites in both the eyelash follicles and / or meibomian glands, without being limited by the use of oil-based additives, emulsions, ointments, or creams, delivery devices such as eyelash brushes, or application sites. In some embodiments, the "drop and coat on eyelashes" (DACTL) technique may be used. The patient is instructed to close one or both eyes during administration. This allows the formulation to contact the orifices of the meibomian glands on one or both eyelid margins, with the goal of accumulating the formulation on the outer lid margins. The patient can then use their fingers or an applicator to spread the formulation accumulated on the outer lid margins onto the eyelashes and / or the eyelash follicles on the lower and / or upper lashes. Without being limited by theory, because Demodex mites reside in both the eyelash follicles and the meibomian glands, it may be advantageous to apply the eye drop formulation directly to one or both of these locations. Because these two combined targets are unique to this disease, therapeutic agents can be delivered to these locations simultaneously. The orifices of the meibomian glands are located on the upper and lower surfaces of the lower and upper eyelids. Therefore, eye drops placed directly on the ocular surface can deliver the formulation directly to the upper and lower meibomian gland orifices. Optionally, the patient can also rub the eyelid margin to further mechanically debride the mites and mites present in the eyelashes and meibomian glands, further enhancing the pharmacological effect.

[0227] In some embodiments, the method for treating blepharitis and / or Demodex infestation does not include or require eyelid scrubs and / or wipes. Some wipe or eyelid scrub regimens, including CLIRADEX (Bio-Tissue, Inc., Miami, FL), which contains tea tree oil, can be highly irritating to the eyes, even when using terpinen-4-ol alone as an active ingredient, temporarily or otherwise. Such methods that do not include eyelid scrubs and / or wipes can advantageously be simpler and more convenient. This may also result in improved patient compliance. However, some embodiments may include a wipe or eyelid scrub regimen.

[0228] In some embodiments, the methods for treating blepharitis and / or Demodex infestations do not include or require the use of abrasive particles, powders, or crystals. There is also no need to otherwise perform microdermabrasion procedures on eye-area tissues, such as the eyelid, eyelash, or hair follicle areas. However, in some embodiments, any of the methods disclosed herein may include one or more of the following treatment modalities:

[0229] In some embodiments, the methods for treating blepharitis and / or meibomian gland (GLAD) dysfunction do not include mechanical treatment of the eyelid (e.g., vibratory), electromagnetic treatment (e.g., RF, microwave, laser, or ultrasound), or heat-based treatments such as the LipiFlow Thermal Pulsation System (Johnson & Johnson Vision, Morrisville, North Carolina), iLux (Tearfilm Innovations, Carlsbad, California), or BlephEx (Scope Ophthalmics, West Sussex, UK) devices. However, in some embodiments, any of the methods disclosed herein may include one or more of the following treatment modalities:

[0230] Methods for treating blepharitis and / or Demodex infestations may include the formulation / treatment (or the like) being specifically delivered by applying eye drops to the eye and then coating the base of the hair follicles on the upper and / or lower eyelids using a finger or an instrument (e.g., an eyelash brush). In some embodiments, desirable features of the formulation may include any number of maximizing the aqueous solubility of the drug (in solution and suspension) to enhance bioavailability, using polymers / thickeners to improve the residence time of the formulation in the eye, and obtaining acceptable vision and comfort.

[0231] The viscosity of the formulation, in some embodiments, can be high enough to coat the formulation over the meibomian gland orifices on the upper and / or lower eyelid margins when the eye is blinked or closed.

[0232] In some cases, the viscosity may be high enough to slowly drain the formulation through the punctum of the eye over at least 5 seconds, or 10 seconds, or 20 seconds, or 30 seconds or more, increasing the contact time of the formulation with the meibomian gland orifices and causing the formulation to overflow (e.g., by flowing and / or by spreading the formulation using fingers and / or instruments) over the eyelid margin to a point where it can be accessed for delivery to the eyelash follicle.

[0233] Without being limited by theory, some patients with meibomian gland dysfunction (MGD) experience changes in the quantity, quality, and / or composition of meibum. Therefore, some patients may have a lipid deficiency in their meibum. Furthermore, with meibomian gland dysfunction, the quality of the expressed lipids changes from a clear fluid in appearance to a viscous fluid containing particulate matter and a dense, opaque, toothpaste-like substance. The meibomian gland orifices may become plugged or show swelling of the skin above the surface of the eyelid, a condition known as protrusion. This may be due to peripheral duct obstruction and the extrusion of increasingly viscous meibum lipids.

[0234] Lipid deficiency and / or increased viscosity of meibum are, in some cases, important pathogenic factors in MGD and can be observed in cases of obstructive MGD. Therefore, in some cases, it may be desirable to reduce the viscosity of a meibum oily composition, which can enhance lipogenesis and lipid secretion from the meibomian glands to overcome lipid deficiency and dissolve any obstruction in the meibomian glands.

[0235] In some embodiments, the formulations and methods can be used to treat or prevent MGD, blepharitis, or other conditions, for example, as otherwise disclosed herein. Such formulations include a therapeutically effective amount of at least one or more of an isoxazoline parasiticide, a formamidine parasiticide, a phenylpyrazole parasiticide, a macrocyclic lactone, an organophosphate, an agent for treating Alzheimer's disease, and / or other active agents, including any disclosed herein, as well as one, two, or more of a lipid-producing agent, a keratolytic agent, and / or a mucolytic agent, for example, as disclosed in U.S. Patent Application Publication Nos. 2019 / 0125766 (Alster et al.) and 2017 / 0087179 (Amselem et al.), which are incorporated herein by reference in their entireties.

[0236] Highly viscous meibum can be expressed in pathological human meibum prepared as smears or mixed with hyperkeratotic cellular material, as confirmed by impression cytology and histopathology and verified by molecular biology and immunohistochemistry. Increased viscosity has also been observed within the glands of obstructed animal models. Therefore, in some cases, it may be desirable to soften and liquefy the obstructing lipids to open the duct and restore normal flow of the drained lipids.

[0237] Thiol-containing drugs, -SeH (e.g., selenol)-containing drugs, and / or disulfide-containing drugs can increase lipid production in the meibomian glands and / or increase lipid secretion from the meibomian glands to the eyelids. In some cases, when combined with one or more agents therapeutically effective against Demodex mites, for example, they are unexpectedly synergistically effective in preventing, treating, and / or ameliorating certain adverse eyelid conditions, such as MGD. Some embodiments may include a combination therapy of one or more thiol-containing drugs, -SeH-containing drugs, and / or disulfide-containing drugs in addition to a therapeutically effective amount of at least one or more isoxazoline parasiticides, formamidine parasiticides, phenylpyrazole parasiticides, macrocyclic lactones, organophosphates, agents for treating Alzheimer's disease, and / or other active agents, including any disclosed herein. The combination therapy may be in a single combined formulation or in separate formulations that are delivered separately.

[0238] Some treatments for MGD include the use of mucolytic and / or keratolytic agents. One goal of mucolytic therapy is to optimize the viscoelasticity of mucus, thereby promoting physiological clearance. Meanwhile, keratolytic therapy aims to soften keratin, a major component of skin. For example, when combined with one or more therapeutically effective agents against Demodex mites, they are unexpectedly synergistically effective in preventing, treating, and / or ameliorating certain adverse eyelid symptoms, such as MGD. Some embodiments may include a combination therapy of one or more mucolytic and / or keratolytic agents in addition to a therapeutically effective amount of at least one or more of an isoxazoline parasiticide, a formamidine parasiticide, a phenylpyrazole parasiticide, a macrocyclic lactone, an organophosphate, an agent for treating Alzheimer's disease, and / or other active agents, including any disclosed herein. The combination therapy may be in a single combined formulation or in separate formulations that are delivered separately.

[0239] In some embodiments, keratolytic agents can include one or more of selenium disulfide, dithranol, benzoyl peroxide, urea, salicylic acid, boric acid, butyric acid, retinoic acid, and alpha-hydroxy acids, although in some embodiments, the treatment does not include any mucolytic and / or keratolytic agents.

[0240] Acetylcysteine, also known as N-acetylcysteine ​​or N-acetyl-L-cysteine ​​(NAC), can also be used as a mucolytic agent. This ability to break disulfide bonds can be beneficial, for example, in thinning abnormally thick mucus in patients with cystic fibrosis and pulmonary fibrosis. For example, a formulation or method can include acetylcysteine ​​in addition to a therapeutically effective amount of at least one or more of an isoxazoline parasiticide, a formamidine parasiticide, a phenylpyrazole parasiticide, a macrocyclic lactone, an organophosphate, an agent for treating Alzheimer's disease, and / or other active agents, including any of those disclosed herein. The combination therapy can be present in a single-dose combined formulation or in separate formulations delivered separately.

[0241] In some embodiments, a method for increasing lipid secretion from the meibomian glands is disclosed. For example, when combined with one or more therapeutically effective agents against Demodex mites, it is unexpectedly synergistically effective in preventing, treating, and / or ameliorating certain adverse eyelid conditions, such as MGD. In some embodiments, a method is disclosed herein that includes topically administering to the eyelid margin of a patient in need thereof a formulation and an ophthalmic composition comprising an ophthalmologically acceptable carrier and a therapeutically effective amount of at least one agent that increases lipid production in or increases lipid secretion from the meibomian glands. The agent has a sulfhydryl group or disulfide in combination with a therapeutically effective amount of at least one or more of an isoxazoline parasiticide, a formamidine parasiticide, a phenylpyrazole parasiticide, a macrocyclic lactone, an organophosphate, an agent for treating Alzheimer's disease, and / or other active agents, including any of those disclosed herein. The combination therapy may be in a single combined formulation or in separate formulations that are delivered separately.

[0242] In some embodiments, disclosed herein are formulations and methods for treating meibomian gland dysfunction (MGD), comprising topically administering to the eyelid margin of a patient in need thereof an ophthalmic composition comprising an ophthalmologically acceptable carrier and a therapeutically effective amount of at least one of the following agents: captopril, zofenopril, tiopronin, penicillamine, glutathione, dithiothreitol, thiorphan, cysteamine, bucillamine, dimercaprol, 1,1-ethanedithiol, dimercaptosuccinic acid, furan-2-ylmethanethiol, omapatrilat, ovothiol A, pantetheine, lentiapril, thiosalicylic acid, tixocortol, mycothiol, coenzyme A, and coenzyme B, or a combination thereof. In some embodiments, the formulation may include a disulfide and a therapeutically effective amount of an isoxazoline parasiticide, a formamidine parasiticide, a phenylpyrazole parasiticide, a macrocyclic lactone, an organophosphate, an agent for treating Alzheimer's disease, and / or other active agents, including any as otherwise disclosed herein, and / or other agents, for example, as otherwise disclosed herein. The combination therapy may be present in a single combined formulation or in separate formulations that are delivered separately.

[0243] In some embodiments, the therapeutic agent comprises a disulfide bond. In certain embodiments, the agent may be one or more of disulfiram, psammaplin A, dixanthogen, pantethine, fursultiamine, octotiamine, sulbutiamine, prosultiamine, thiuram, lipoic acid, lenthionine, ajoene, allicin, gemopatrilat, and sulfangene. Formulations containing one or more of the foregoing agents may be used in combination with therapeutically effective amounts of at least one or more of an isoxazoline parasiticide, a formamidine parasiticide, a phenylpyrazole parasiticide, a macrocyclic lactone, an organophosphate, an agent for treating Alzheimer's disease, and / or other active agents, including any of those disclosed herein. The combination therapy may be present in a single combined formulation or in separate formulations delivered separately.

[0244] In some embodiments, a method for lowering the melting point of lipids secreted by the meibomian glands is disclosed herein. The method comprises topically administering to the eyelid margin of a patient in need thereof an ophthalmic composition comprising an ophthalmologically acceptable carrier and a therapeutically effective amount of at least one agent that increases lipid production in or increases lipid secretion from the meibomian glands. The agent comprises a sulfhydryl group, an -SeH group, or a disulfide, and a therapeutically effective amount of at least one or more of an isoxazoline parasiticide, a formamidine parasiticide, a phenylpyrazole parasiticide, a macrocyclic lactone, an organophosphate, an agent for treating Alzheimer's disease, and / or other active agents, including any of those disclosed herein. The combination therapy may be present in a single-dose combination formulation or in separate formulations delivered separately.

[0245] In some embodiments, a method for reducing the viscosity of lipids secreted by the meibomian glands is disclosed herein. The method includes topically administering to the eyelid margin of a patient in need thereof an ophthalmic composition comprising an ophthalmologically acceptable carrier and a therapeutically effective amount of at least one agent that increases lipid production in or increases lipid secretion from the meibomian glands. The agent comprises a sulfhydryl group, an -SeH group, or a disulfide, and a therapeutically effective amount of at least one or more of an isoxazoline parasiticide, a formamidine parasiticide, a phenylpyrazole parasiticide, a macrocyclic lactone, an organophosphate, an agent for treating Alzheimer's disease, and / or other active agents, including any of those disclosed herein. The combination therapy may be present in a single-dose combination formulation or in separate formulations delivered separately.

[0246] In certain embodiments, the formulation may include one or more drugs containing a thiol or -SeH group, hi certain embodiments, the drug is selected from the group consisting of captopril, zofenopril, tiopronin, penicillamine, L-cysteine, selenocysteine, glutathione, dithiothreitol, thiorphan, cysteamine, bucillamine, dimercaprol, 1,1-ethanedithiol, dimercaptosuccinic acid, furan-2-ylmethanethiol, omapatrilat, ovothiol A, pantetheine, lentiapril, thiosalicylic acid, tixocortol, mycothiol, coenzyme A, and coenzyme B. Any of the aforementioned agents may be delivered in combination with at least one or more therapeutically effective amounts of an isoxazoline parasiticide, a formamidine parasiticide, a phenylpyrazole parasiticide, a macrocyclic lactone, an organophosphate, an agent for treating Alzheimer's disease, and / or other active agents, including any of those disclosed herein. The combination therapy may be present in a single-use combined formulation or in separate formulations delivered separately. In some embodiments, a method for reducing lipid viscosity at the eyelid margin is disclosed herein. The method includes topically administering to the eyelid margin of a patient in need thereof an ophthalmic composition comprising an ophthalmologically acceptable carrier and a therapeutically effective amount of at least one lipid derivative containing a sulfhydryl group or a disulfide. Any of the foregoing agents may be delivered in combination with a therapeutically effective amount of at least one or more of an isoxazoline parasiticide, a formamidine parasiticide, a phenylpyrazole parasiticide, a macrocyclic lactone, an organophosphate, an agent for treating Alzheimer's disease, and / or other active agents, including any disclosed herein. The combination therapy may be present in a single combined formulation or in separate formulations delivered separately.

[0247] One embodiment provides a method for enhancing lipid production and lipid secretion from the meibomian glands in a patient in need thereof by administering a topical composition comprising a lipid derivative. The composition comprises 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2.0%, 2.5%, 5%, or 10% of the lipid derivative, or a range inclusive of any two of the foregoing values. In some embodiments, the composition is formulated as a suspension, emulsion, cream, lotion, gel, or ointment. In some embodiments, the composition is applied as a thin layer to cleanse the skin once daily, every other day, gradually increasing the frequency to up to twice daily as tolerance develops. In some embodiments, the composition is an ointment or paste. In some embodiments, the composition begins as a 0.1% ointment. After 7 days, the concentration may be increased to 0.25%, and then substantially doubled at weekly intervals as needed to a maximum strength of 2%. In some embodiments, a thin layer of ointment is applied to the affected area once daily for 2-4 weeks. In some embodiments, the ointment is left to sit for 10-20 minutes, and the area is rinsed thoroughly. In some embodiments, the concentration of the thiol- or disulfide-containing drug or pharmaceutical agent that enhances lipid production and secretion is gradually increased up to a maximum of 5% or more, and treatment is continued as long as necessary.

[0248] In certain embodiments, the lipid derivative is a derivative of a lipid selected from the group consisting of a fatty acid, a glycerolipid, a glycerophospholipid, a sphingolipid, a sterol lipid, a prenol lipid, a glycolipid, a polyketide, and any combination thereof. Each possibility represents a separate embodiment of the invention. In certain embodiments, the lipid derivative is a derivative of a lipid naturally found in meibum.

[0249] In some embodiments, the lipid derivative is an -SH or disulfide-containing lipid, such as a thiophospholipid, thiocholesterol, 12-mercaptododecanoic acid, or 23-(9-mercaptononyl)-3,6,9,12,15,18,21-heptaoxatricosane.

[0250] Another embodiment provides a method for increasing lipid secretion from the meibomian glands, wherein the lipid is a phospholipid selected from the group consisting of phosphatidylcholine (PC), phosphatidylethanolamine (PE), alkylacylphosphatidylcholine, sphingomyelin, dihydrosphingomyelin, dimethylphosphatidylethanolamine, diphosphatidylglycerol (cardiolipin), ethanolamine plasmalogen, lysoethanolamine plasmalogen, lysophosphatidylcholine, lysophosphatidylethanolamine, lysophosphatidylserine, phosphatidic acid, phosphatidylglycerol, phosphatidylinositol, and phosphatidylserine.

[0251] Another embodiment provides a method for increasing lipid secretion from the meibomian glands, wherein the lipid is a fatty acid amide, the fatty acid amide being selected from the group consisting of oleamide, myristamide, palmitamide, stearamide, erucamide, and ceramide.

[0252] Any of the features disclosed herein may be delivered in combination with a therapeutically effective amount of at least one or more of an isoxazoline parasiticide, a formamidine parasiticide, a phenylpyrazole parasiticide, a macrocyclic lactone, an organophosphate, an agent for treating Alzheimer's disease, and / or other active agent, including any disclosed herein. The combination therapy may be in a single combined formulation or in separate formulations delivered separately.

[0253] Formulation ingredients can be selected to allow the active agent to dissolve in solution, using low concentrations of organic solvent by weight, such as, for example, 50% or less, 20% or less, 10% or less, 5% or less, 2% or less, or 1% or less organic solvent by weight, or more. This can be achieved, at least in part, by using surfactants such as polysorbate-80 or polysorbate 20. In some cases, low concentrations of polysorbate 80 may be preferred (e.g., 0.001 to 0.1% by weight polysorbate 80), since higher concentrations may cause hydrolysis of the isoxazoline parasiticide.

[0254] In some cases, this may be achieved by increasing the solubility of the isoxazoline parasiticide in organic solvents such as propylene glycol.

[0255] Solubility and viscosity may also be simultaneously enhanced by choosing appropriate additives, for example, polyvinyl alcohol, carboxymethyl cellulose, etc. to minimize osmotic pressure.

[0256] The formulation ingredients can be selected to render the active agent (e.g., an isoxazoline parasiticide or other active agent) soluble in solution and stable without hydrolysis for periods of up to 1 year, 1.5 years, 2 years or more to allow for a commercial shelf life, for example, at an optimum pH range, such as neutral to slightly alkaline (e.g., pH 7-10, 7-7.5) or slightly acidic (e.g., pH 5-7 in other embodiments).

[0257] The buffer concentration required to obtain the desired pH can be minimized in some cases, thereby slowing the rate of hydrolysis (e.g., phosphate buffer concentrations of 0.01-0.1 M). This may be achieved by using organic solvents and surfactants in the concentration ranges described above.

[0258] Cationic surfactants can also be advantageous because they form cationic micelles, slowing the rate of hydrolysis.

[0259] The emulsions and emulsifiers may be mixed with water to protect the isoxazoline parasiticide, formamidine parasiticide, drug for treating Alzheimer's disease, and / or other drug, and / or other active agent from the water in the water-in-oil droplets, for example, using a carbodiimide additive to form more complex anhydrous micelles to extend stability.

[0260] To obtain shelf-stable oil-based formulations, a water scavenger such as Stabaxol I® (bis-2,6-diisopropylphenylcarbodiimide) may be added to wash out water as a solvent.

[0261] In some embodiments, the pharmaceutical compositions can comprise at least one compound selected from among the isoxazoline family of parasiticides, formamidine parasiticides, phenylpyrazole parasiticides, macrocyclic lactones, organophosphates, agents for treating Alzheimer's disease, and / or other active agents including any disclosed herein, and / or other agents and / or other active agents that are particularly useful for treating ophthalmic conditions selected from a burning or stinging sensation in the eye, a foreign body sensation in the eye, a dry eye sensation, increased sensitivity to light, blurred vision, telangiectasia of the eyelid margin, meibomitis, chalazion, conjunctival hyperemia, and mammary conjunctivitis.

[0262] The term "treatment" may include treatment in humans and / or other animals.

[0263] Pharmaceutical compositions according to some embodiments of the present invention may be used topically, orally, parenterally, or rectally to treat the eye.

[0264] Topical application is the most common method for administering ophthalmic medications, and can involve instilling eye drops into the eye, or applying solutions, eye washes, suspensions, salves, ointments, gels, sprays, foams, powders, lotions, viscous solutions to the eye, and / or placing solid forms such as impregnated pads, detergents, or wipes on the surface of the eye.

[0265] Some formulations may also be provided in the form of microparticle or nanoparticle suspensions, or in the form of vesicles formed from lipids or polymers, in the form of polymer or polymeric patches, or in the form of hydrogels, allowing for controlled release. Such compositions for topical application may be provided in anhydrous, aqueous, or emulsion form.

[0266] Pharmaceutical compositions for topical application are preferably non-irritating and compatible with ocular tissues. Solutions may be sterile preparations and may be free of all particles. Suspensions may be sterile preparations and may contain solid particles in a solvent suitable for ophthalmic drops. Ointments are semi-solid and may be sterile preparations.

[0267] Orally administered pharmaceutical compositions may be provided in liquid, pasty, or solid form, in powder form, and more particularly in the form of tablets, including sugar-coated tablets, hard gelatin capsules, syrups, suspensions, solutions, powders, granules, emulsions, microparticles or nanoparticles or vesicles formed from lipids or polymers that allow controlled release. Parenterally applied compositions may be provided in the form of solutions or suspensions for infusion or injection. Rectally applied compositions may be provided in the form of suppositories. In some cases, the pharmaceutical composition is a topical ophthalmic composition and is not an oral or rectal composition.

[0268] In some embodiments, the composition comprises 0.001% to 10% by weight of at least one compound selected from the isoxazoline parasiticide family, formamidine parasiticides, agents for treating Alzheimer's disease, and / or other agents as disclosed herein, based on the total weight of the composition. In some embodiments, the composition according to the present invention comprises 0.01% to 5% by weight of at least one compound selected from the isoxazoline parasiticide family, based on the total weight of the composition.

[0269] In some embodiments, the compositions according to the present invention are provided in the form of an eye wash or eye drops. The term "eye wash" refers to a liquid formulation that is particularly suitable for administration to the conjunctiva and cornea of ​​the eye. Eye wash solutions can include, for example, instillation drops having a volume of approximately 25-50 microliters, or about 5 microliters, 10 microliters, 15 microliters, 20 microliters, 25 microliters, 30 microliters, 35 microliters, 40 microliters, 45 microliters, 50 microliters, 55 microliters, 60 microliters, 65 microliters, 70 microliters, or 75 microliters, or a range inclusive of any two of the foregoing values. In some embodiments, the total volume of the formulation delivered in a treatment session (once a day, twice a day, three times a day, or at other time intervals as otherwise disclosed herein) is about or less than 200 microliters, about or less than 150 microliters, about or less than 100 microliters, about or less than 75 microliters, about or less than 50 microliters, about or less than 25 microliters, or more or less. In some embodiments, the composition is provided as a kit, such as eye drops and shampoo. It can be used with sterilizing agents such as tea tree oil and derivatives, which have been shown to have Demodex activity, and hypochlorous acid. Alternatively, the composition optionally does not contain tea tree oil or other oils.

[0270] As noted above, in some embodiments, a composition may meet certain requirements for application to the eye. These requirements include, among other things, sterility, non-irritation, and compatibility with eye tissue. The latter criteria are more difficult to achieve than those for compositions applied to the skin; in particular, compounds such as ethanol or glycols that are formulated in compositions applied to the skin may not be included in compositions intended for use in the eye.

[0271] Topical compositions allow for direct and specific treatment of symptoms of eye and eyelid conditions by local action, and may be more effective because they target only the eye.

[0272] In some embodiments, the formulation may be a solution, suspension, cream, ointment, or other form.

[0273] Liquid compositions formulated for topical ophthalmic use are formulated so that they can be administered topically to the eye. Comfort can be maximized as much as possible, but sometimes formulation considerations (e.g., drug stability) may require less-than-optimal comfort. If comfort cannot be maximized, the liquid may be formulated so that it is acceptable to patients for topical ophthalmic use. In addition, ophthalmologically acceptable liquids may be sealed for single use or contain preservatives to prevent contamination throughout multiple uses.

[0274] For application to the eye, solutions or drugs are often prepared using saline solution as the main solvent.These solvents include, but are not limited to, polyvinyl alcohol, povidone, hydroxypropylmethylcellulose, poloxamer, carboxymethylcellulose, hydroxyethylcellulose, and purified water.Ophthalmic solutions are preferably maintained at a comfortable pH using an appropriate buffer system.The formulation may also contain pharmaceutically acceptable preservatives, stabilizers, and surfactants.

[0275] In some embodiments, topical formulations do not contain skin penetration enhancers, which may increase systemic absorption and may in some cases be counter to the intention of maintaining the formulation locally at or near the site of application. In some embodiments, the formulations contain one or more of laurocapram derivatives, such as laurocapram (Azone®) and 1-alkylazacycloheptan-2-ones, as well as oleic acid and its ester derivatives, such as methyl oleate, ethyl oleate, propyl oleate, isopropyl oleate, butyl oleate, vinyl oleate, and glyceryl monooleate, and sorbitan esters, such as sorbitan monolaurate and sorbitan monooleate, and isopropyl laurate, isopropyl myristate, and the like. The formulations are free of any skin penetration enhancers such as other fatty acid esters such as esters of 2-pyrrolidone, isopropyl palmitate, diisopropyl adipate, propylene glycol monolaurate, and propylene glycol monooleate, and long-chain alkyl esters of 2-pyrrolidone (specifically, the 1-lauryl, 1-hexyl, and 1-(2-ethylhexyl) esters of 2-pyrrolidone) and their skin penetration enhancers such as dodecyl(N,N-dimethylamino)acetate and dodecyl(N,N-dimethylamino)propionate, and 2-n-nonyl-1-3-dioxolane, although some embodiments of the formulations may include one or more skin penetration enhancers.

[0276] In some embodiments, topical formulations can include one or more gelling agents. The gelling agent can be a copolymer, such as Pemulen™ TR1 and / or TR2 polymeric emulsifier (Lubrizol Corp., Wickliffe, Ohio), which is a high-molecular-weight copolymer of acrylic acid and C10-C30 alkyl acrylate crosslinked with allyl pentaerythritol. These gelling agents are light-textured white powders and are primarily used to form stable water-in-oil emulsions. Pemulen polymers contain both hydrophilic and hydrophobic moieties within the molecule. The hydrophobic portion of the polymer adsorbs at the oil-water interface, while the hydrophilic portion swells in water to form a gel network around the oil droplets, providing emulsion stability. Pemulen polymers can form stable water-in-oil emulsions without the need for any additional surfactants. Therefore, they can be advantageous, for example, for developing mild lotions and creams. Pemulen polymers provide high yield values ​​that allow for viscosity building and suspension, and stabilization of soluble material and particulates. In some embodiments, gelling agents may be absent, or may comprise from about 0.001 w / w% to about 1 w / w%, from about 0.01 w / w% to about 0.10 w / w%, or about 0.001 w / w%, about 0.005 w / w%, about 0.01 w / w%, about 0.02 w / w%, about 0.03 w / w%, about 0.04 w / w%, about 0.05 w / w%, about 0.06 w / w%, or about 0.07 w / w% of the formulation. %, about 0.08 w / w%, about 0.09 w / w%, about 0.10 w / w%, about 0.15 w / w%, about 0.20 w / w%, about 0.25 w / w%, about 0.30 w / w%, about 0.35 w / w%, about 0.40 w / w%, about 0.45 w / w%, about 0.50 w / w%, or a range inclusive of any two of the foregoing values.

[0277] In some embodiments, oil-based formulations such as creams, ointments, or emulsions may contain one or more of liquid paraffin, castor oil, or petrolatum, e.g., at about 20% to about 80% w / w, or about 30% to about 70% w / w of the formulation. The formulation may also include a cyclodextrin as a carrier molecule to promote dissolution.

[0278] In some embodiments, topical formulations may include one or more thickening agents, including thickening polysaccharides / emulsions such as hydroxypropyl methylcellulose (HPMC) and sodium CMC, polyvinyl alcohol, polyvinylpyrrolidone, dextran 70, and others. In some embodiments, the thickening agent may be present in about 0% to about 2% w / w, about 0.10% to about 1.00% w / w, about 0.25% to about 1.00% w / w, or a range inclusive of any two of the foregoing values, such as about 0.10%, about 0.20%, about 0.25%, about 0.30%, about 0.35%, about 0.40%, about 0.50%, about 0.60%, about 0.70%, about 0.80%, about 0.90%, about 1.00%, or about 0.1% to about 0.5% w / w of the formulation. In some embodiments, the formulation may have a viscosity of about 50 cP to about 100 cP to increase the residence time of the formulation in the eye. In some embodiments, the formulation may have a viscosity of, for example, 5 cP, or 20 cP, or 40 cP, or 100 cP, or 250 cP, or 400 cP, or 1000 cP or more, or 5 cP or more, or 20 cP or more, or 40 cP or more, or 100 cP or more, or 250 cP or more, or 400 cP or more, or 1000 cP or more, or a range including any two of the foregoing values. In some cases, the formulation is configured to have a residence time in the eye of about 90 seconds to about 10 minutes, or about 60 seconds, about 90 seconds, about 120 seconds, about 180 seconds, about 240 seconds, about 300 seconds, about 6 minutes, about 7 minutes, about 8 minutes, about 9 minutes, about 10 minutes, or at least about 60 seconds, at least about 90 seconds, at least about 120 seconds, at least about 180 seconds, at least about 240 seconds, at least about 300 seconds, at least about 6 minutes, at least about 7 minutes, at least about 8 minutes, at least about 9 minutes, at least about 10 minutes, or a range inclusive of any two of the foregoing values.

[0279] In some embodiments, topical formulations may include one or more solubilizing agents and / or surfactants, including non-ionic surfactants such as polysorbates, such as polysorbate 80, polysorbate 65, polysorbate 60, polysorbate 40, or polysorbate 20. In some embodiments, polysorbate 80 has been unexpectedly found to provide increased solubility of isoxazoline parasiticides compared to other polysorbates. Other surfactants, such as fluorinated surfactants, may be used in place of or in addition to non-ionic surfactants. In some embodiments, the solubilizing agent may be a sorbitan ester solubilizing agent, such as SPAN 20 (sorbitan monolaurate), SPAN 40 (ester of sorbitan and palmitic acid), SPAN 60 (ester of sorbitan and stearic acid), SPAN 80 (ester of sorbitan and oleic acid), SPAN 65 (ester of sorbitan and tristearic acid), and SPAN 85 (ester of sorbitan and trioleic acid). In some embodiments, the solubilizer and / or surfactant is present in an amount of about 0 w / w% to about 5 w / w%, about 0.10 w / w% to about 4 w / w%, about 0.50 w / w% to about 4 w / w%, or about 0.50 w / w%, about 0.75 w / w%, about 1.00 w / w%, about 1.25 w / w%, about 1.50 w / w%, about 1.75 w / w%, about 2.00 w / w%, about 2.25 w / w%, about 2.50 w / w%, about 2.75 w / w%, or about 3.00 w / w% of the formulation. , about 3.25 w / w%, about 3.50 w / w%, about 3.75 w / w%, about 4.00 w / w%, about 4.25 w / w%, about 4.50 w / w%, about 4.75 w / w%, about 5.00 w / w%, about 5.25 w / w%, about 5.50 w / w%, about 5.75 w / w%, about 6.00 w / w%, about 6.25 w / w%, about 6.50 w / w%, about 6.75 w / w%, or about 7.00 w / w%, or a range including any two of the foregoing values.Polysorbate 80 may also be replaced with a castor oil solubilizer, including, but not limited to, polyoxyl 35 castor oil (Cremophor EL), polyoxyl 40 hydrogenated castor oil (Cremophor RH 40), polyoxyl 40 stearate, or Cremophor RH 60 (polyoxyl 60 hydrogenated castor oil), at up to 5%, 6%, or 7%, such as about 1%, about 2%, about 3%, about 4%, or about 5%, or at a range of about 1% to about 5%, about 3% to about 7%, about 5% to about 7%, or a range including any two of the foregoing values, to facilitate higher drug concentrations. Castor oil solubilizers have, in some cases, demonstrated unexpectedly superior solubility of isoxazoline parasiticides, for example, compared to polysorbates.

[0280] In some embodiments, formulations (including but not limited to eye drops, creams, ointments, or other forms as otherwise disclosed herein) may contain both castor oil (e.g., hydrogenated castor oil) and a thickening polysaccharide / emulsion such as HPMC or sodium CMC. In some cases, this combination can advantageously and unexpectedly form a long-lasting film layer.

[0281] In some embodiments, the formulation includes a castor oil solubilizer but does not include a polysorbate solubilizer. Without being limited by theory, in some embodiments, the castor oil solubilizer has been found to unexpectedly provide beneficial solubility for relatively low-solubility molecules, such as isoxazoline parasiticides, including, but not limited to, fluralaner, sarolaner, afoxolaner, isocycloceram, fluxametamide, or lotilaner. This significantly exceeds the solubility provided by polysorbates. However, the castor oil solubilizer micelles, even at relatively high concentrations, such as about 3% to about 7%, or about 4% to about 5%, have been found to sequester and inactivate phosphate-based preservatives, such as, for example, disodium phosphate heptahydrate or monosodium phosphate monohydrate. Therefore, some embodiments do not include a phosphate buffer / preservative. For example, tromethamine (TRIS) in combination with benzalkonium chloride was surprisingly not found to inactivate the preservative, so in some cases this may be advantageous for use with castor oil solubilizers.

[0282] In some embodiments, topical formulations may include one or more tonicity agents, such as, for example, glycerin or other polyols, dextrose, mannitol, potassium chloride, and / or sodium chloride. Among polyols, xylitol (5 carbons), erythritol (4 carbons), and glycerol / glycerin (3 carbons) may be preferred, for example, for ophthalmic use. Six-carbon forms (mannitol, sorbitol, and related deoxygenated compounds) may be useful in combination with smaller molecules. In one embodiment, deoxygenated derivatives (1- and 2-carbons), including but not limited to combinations of polyols with 3-6 carbons, areomers, stereoisomers, and the like, may be utilized as needed. Without being limited by theory, polyols may be advantageous, for example, when used in combination with castor oil solubilizers, which disrupt the micelles of castor oil and prevent inactivation of preservatives such as BAK or LAK, the sterility of which may be important in multi-dose vial formulations. In some embodiments, uncharged or zwitterionic amino acids are useful as compatible organic solute components in the context of the present invention. In some embodiments, a carnitine component (e.g., carnitine itself, its isomers / stereoisomers, salts, derivatives, and the like, and mixtures thereof) may be a compatible solute component useful in the ophthalmic compositions of the present invention. Carnitine is well established as essential for various roles in fatty acid metabolism and therefore plays a critical role in the metabolism of liver and muscle cells. Carnitine can serve as an energy source for many types of cells, including ocular cells. Carnitine components may have unique properties in multiple roles, such as as an osmoprotectant, an antioxidant in fatty acid metabolism, a protein chaperone in promoting wound healing, and in neuroprotection.In some embodiments, the one or more tonicity agents comprise from about 0 w / w% to about 5 w / w%, from about 0.10 w / w% to about 4 w / w%, from about 0.50 w / w% to about 4 w / w%, or about 0.50 w / w%, about 0.75 w / w%, about 1.00 w / w%, about 1.25 w / w%, about 1.50 w / w%, about 1.75 w / w%, about 2.00 w / w% of the formulation. %, about 2.25 w / w%, about 2.50 w / w%, about 2.75 w / w%, about 3.00 w / w%, about 3.25 w / w%, about 3.50 w / w%, about 3.75 w / w%, about 4.00 w / w%, about 4.25 w / w%, about 4.50 w / w%, about 4.75 w / w%, about 5.00 w / w%, or a range including any two of the foregoing values. In some embodiments, the formulation is stored in a single-dose or multi-dose dispenser, including, for example, an ophthalmic multi-dose bottle (e.g., a preservative-free bottle) containing the formulation without any preservative. Some embodiments utilize a preservative-free multi-dose pressurized dispensing container, such as, for example, a bottle including, but not limited to, a bottle containing a check valve dispenser.

[0283] In some embodiments, topical formulations may contain one, two, or more buffers. Buffers may include, for example, acetate buffer, citrate buffer, phosphate buffer, and borate buffer. The pH of such formulations may be adjusted, as needed, using an acid or base. Examples of 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-acetamido)-2-iminodiacetic acid) buffer, and the like. ) 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 solution, CAPSO (3-(cyclohexylamino)-2-hydroxy-1-propanesulfonic acid) buffer solution, CHES (2-(N-cyclohexylamino)ethanesulfonic acid) buffer solution, DIPSO (3-[N,N-bis(2-hydroxyethyl)amino]-2-hydroxy-propanesulfonic acid) buffer solution, HEPPS (N-(2-hydroxyethylpiperazine)-N'-(3-propanesulfonic acid) buffer solution, HEPPSO (N-(2-hydroxyethyl N-(2-hydroxypropanesulfonic acid) buffer solution, MES (2-(N-morpholino)ethanesulfonic acid) buffer solution, triethanolamine buffer solution, imidazole buffer solution, glycine buffer solution, ethanolamine buffer solution, phosphate buffer solution, MOPSO (3-(N-morpholino)-2-hydroxypropanesulfonic acid) buffer solution, PIPES (piperazine-N,N'-bis(2-ethanesulfonic acid) buffer solution, POPSO (piperazine-N,The buffer may be one or more of 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, Tricine (N-tris(hydroxymethyl)methylglycine buffer), 2-amino-2-methyl-1,3-propanediol buffer, and 2-amino-2-methyl-1-propanol buffer, and combinations thereof. In some embodiments, the buffer is Tris and / or disodium hydrogen phosphate (NaHPO) and sodium dihydrogen phosphate heptahydrate (NaHPO7H0). In some embodiments, the buffering agent is about 0% to about 2%, about 0.01% to about 1%, about 0.01% to about 0.75%, or about 0.01%, about 0.02%, about 0.03%, about 0.04%, about 0.05%, about 0.06%, about 0.07%, about 0.08%, about 0.09%, about 0.10%, about 0.11%, about 0.12%, about 0.13%, about 0.14%, about 0.15%, about 0.20% , about 0.25%, about 0.30%, about 0.35%, about 0.40%, about 0.45%, 0.50 w / w%, 0.55 w / w%, 0.60 w / w%, 0.65 w / w%, 0.70 w / w%, 0.75 w / w%, 0.80 w / w%, 0.85 w / w%, 0.90 w / w%, 0.95 w / w%, 1.00 w / w% of the formulation, or a range inclusive of any two of the foregoing values. The buffering agent may be 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 about 7.55, or about 7.30, about 7.35, about 7.40, about 7.45, about 7.50, about 7.55, about 7.60, or a range including any two of the foregoing values.

[0284] In some embodiments, the topical formulation may include one or more preservatives, including, but not limited to, lauralkonium chloride and benzalkonium chloride. Other preservatives may include, for example, PHMB, chlorobutanol, thimerosal, phenylmercuric acetate, acetate, and phenylmercuric nitrate. Still other preservatives may include, for example, sorbates. Sorbates may include, for example, one or more of potassium sorbate, sodium sorbate, and calcium sorbate. Sorbates are different from polysorbates. In some embodiments, the formulation includes a sorbate but does not include a polysorbate. In some embodiments, a sorbate may be the only preservative in the formulation. In some embodiments, the formulation does not include lauralkonium chloride and / or benzalkonium chloride. In some embodiments, the preservative is from about 0.001 w / w% to about 0.5 w / w%, from about 0.001 w / w% to about 0.3 w / w%, from about 0.20 w / w% to about 0.50 w / w%, from about 0.001 w / w% to about 0.1 w / w%, from about 0.001 w / w% to about 0.01 w / w%, or about 0.001 w / w%, about 0.002 w / w%, about 0.003 w / w%, about 0.004 w / w%, about 0.005 w / w%, about 0.006 w / w%. %, about 0.007 w / w%, about 0.008 w / w%, about 0.009 w / w%, about 0.010 w / w%, about 0.05 w / w%, about 0.10 w / w%, about 0.15 w / w%, about 0.20 w / w%, about 0.25 w / w%, about 0.30 w / w%, about 0.35 w / w%, about 0.40 w / w%, about 0.45 w / w%, about 0.50 w / w% of the formulation, or a range including any two of the foregoing values. In some embodiments, the formulation may be preservative-free, e.g., a single dose formulation, e.g., a single-use unit dose ophthalmic formulation.In some embodiments, a single-use unit dose can include a volume of about 20 μL to about 300 μL, such as about 20 μL, about 25 μL, about 30 μL, about 35 μL, about 40 μL, about 45 μL, about 50 μL, about 55 μL, about 60 μL, about 65 μL, about 70 μL, about 75 μL, about 100 μL, about 150 μL, about 200 μL, about 250 μL, about 300 μL, or a range including any two of the foregoing values.

[0285] Pharmaceutical compositions according to some embodiments of the present invention may additionally contain inert additives such as humectants, emollients, agents for enhancing flavor, preservatives, stabilizers, moisture regulators, pH adjusters, buffers, osmolality adjusters, emulsifiers, viscosity enhancers, and antioxidants, or combinations of these additives. Ophthalmically acceptable antioxidants include, but are not limited to, sodium metabisulfite, sodium thiosulfate, acetylcysteine, butylated hydroxyanisole, and butylated hydroxytoluene. Another excipient component that may be included in ophthalmic formulations is a chelating agent. A useful chelating agent is, for example, ethylenediaminetetraacetic acid or its salts or derivatives, such as edetate disodium (EDTA), although other chelating agents may also be used instead of or in combination with this. In some embodiments, EDTA is present at about 0.001% to about 0.10%, about 0.01% to about 0.05%, about 0.001%, about 0.005%, about 0.01%, about 0.02%, about 0.03%, about 0.04%, about 0.05%, or more or less than, or a range inclusive of any two of the foregoing values, of the formulation.

[0286] In some embodiments, the pharmaceutical composition can include tocopherol. In some cases, tocopherol can be effective in preventing the decomposition of isoxazoline in water. In some cases, vitamin E is tocopherol, and in further embodiments, the tocopherol is α-tocopherol or γ-tocopherol, with α-tocopherol being more preferred. In some embodiments, the pharmaceutical composition does not include tocopherol.

[0287] In some embodiments, the pharmaceutical formulation does not contain essential oils such as tea tree oil, α-terpineol, cardien, d-carvone, 1-carvone, γ-terpinene, α-terpinene, 1,8-cineole, α-terpineol, para-cymene, α-pinene, limonene, α-thugen, eucalyptol, (+)-ledene, cuminaldehyde, terpinen-4-ol, sabinene, or myrcene. Tea tree oil and its derivatives can be highly irritating to the eyes, potentially reducing patient compliance. However, some embodiments may include one or more of the aforementioned essential oils.

[0288] In some embodiments, the pharmaceutical formulation may also include neem oil and / or coconut oil. In some embodiments, the pharmaceutical formulation does not include neem oil and / or coconut oil.

[0289] In some embodiments, the pharmaceutical formulation can include povidone-iodine (PVP-I) and / or dimethyl sulfoxide (DMSO). In some embodiments, the pharmaceutical formulation does not include PVP-I and / or DMSO.

[0290] In some embodiments, one or more optional compounds may be added to these compositions such that the advantageous properties inherently associated with some embodiments of the present invention are not adversely affected or are not substantially adversely affected by the possible addition of, for example, tetracycline or omega-3 fatty acids, which may have a favorable effect in blepharitis.

[0291] In some embodiments, an isoxazoline parasiticide is orally administered to a patient suffering from blepharitis, rosacea, or other conditions as otherwise disclosed herein. Because one particular target organism, Demodex folliculorum (and / or Demodex brevis), is an ectoparasite of the family Mites, effective treatment in some cases therapeutically eradicates the entire life cycle of the microscopic insect, including egg, larval, and adult stages. Thus, some embodiments treat patients with blepharitis and / or rosacea with at least two doses, separated by about three to seven days. This interval allows time for Demodex eggs to hatch into immature mites, which are killed before fully developing into egg-producing adults. In some embodiments, one, two, three, four, or more doses, spaced three to seven days apart, may be used. After an isoxazoline parasiticide or other active agent disclosed herein delivers acaricidal activity to organisms such as Demodex folliculorum (and / or Demodex brevis) on the skin, the inflammatory response to such organisms is reduced. However, dead mite debris still induces some flushing and lesion formation until it is removed by the body's cleansing process, a process that can take 6 to 8 weeks in some cases. During this initial phase of treatment, other medications, including but not limited to oral tetracycline and topical metronidazole, antibiotics, and / or anti-inflammatory drugs, such as NSAIDs and / or steroids, may be used to suppress early recurrences and induce an early clinical response. However, in some embodiments, the formulation or method does not include tetracycline or other antibiotics, steroids, and / or metronidazole. After a prolonged symptom-free period, treatment can be repeated if classic signs begin to appear.

[0292] In some embodiments, the formulation or method may include an antiparasitic drug combined with a steroid to synergistically reduce inflammatory symptoms. The steroid may be, for example, one or more of clobetasol, betamethasone, halobetasol, diflorasone, fluocinonide, halcinonide, amicinonide, desoximetasone, triamcinolone, mometasone, fluticasone, hydrocortisone, fluralenolide, desonide, prednisone, prednisolone, dexamethasone, or alclometasone. The steroid may be delivered separately or in the same formulation as the antiparasitic drug. The steroid may have a concentration of about 0.001%, about 0.005%, about 0.01%, about 0.025%, about 0.05%, about 0.1%, about 0.2%, about 0.25%, about 0.5%, about 0.75%, about 1%, about 1.5%, about 2%, about 2.5%, about 3%, or more or less than, or a range including any two of the foregoing values. In some embodiments, the formulation does not contain any steroid.

[0293] In some embodiments, the formulation may include an NSAID to reduce inflammatory symptoms. NSAIDs include, for example, pyrazolone / pyrazolidine NSAIDs, including aminophenazone, ampirone, azapropazone, clofezone, diphenamizole, famprofazone, feprazone, kebuzone, metamizole, mofebutazone, morazon, nifenazone, oxyphenbutazone, phenazone, phenylbutazone, propyphenazone, sulfinpyrazone, and succinpyrazone; aspirin (acetylsalicylic acid), aloxiprine, benorilate, carbasalate calcium, diflunisal, dipyrocetyl, and ethenzamide. Salicylate NSAIDs, including guacetisal, magnesium salicylate, methyl salicylate, salsalate, salicin, salicylamide, salicylic acid (salicylates), and sodium salicylate; aceclofenac, acemetacin, alclofenac, amfenac, bendazac, bromfenac, bumadizone, bufexamac, diclofenac, difenpyramide, etodolac, felbinac, fenclozic acid, fentiazac, indomethacin, indomethacin funnesyl, isoxepac, ketorolac, lonazola NSAIDs of acetic acid derivatives and related substances, including but not limited to oxametacin, prodolic acid, proglumetacin, sulindac, tiopinac, tolmetin, and zomepirac; oxicam NSAIDs, including ampiroxicam, droxicam, isoxicam, lornoxicam, meloxicam, piroxicam, and tenoxicam; alminoprofen, benoxaprofen, carprofen, dexibuprofen, dexketoprofen, fenbufen, fenoprofen, flunoxaprofen, flurbiprofen, isopropyl myristate, propyl myristate, propyl myristate; Propionic acid derivative NSAIDs, including buprofen, ibuproxam, indoprofen, ketoprofen, loxoprofen, micloprofen, naproxen, oxaprozin, pirprofen, suprofen, tarenflurbil, tepoxalin, tiaprofenic acid, and bedaprofen; N-arylanthranilic acid NSAIDs, including azapropazone, clonixin, etofenamate, flufenimic acid, flunixin, meclofenamic acid, mefenamic acid, morniflumate, niflumic acid, tolfenamic acid, and fluthiazine;and / or one or more of the following coxib NSAIDs: apricoxib, celecoxib, cimicoxib, deracoxib, etoricoxib, firocoxib, lumiracoxib, mavacoxib, parecoxib, robenacoxib, rofecoxib, and valdecoxib. The NSAID may be delivered separately or in the same formulation as the antiparasitic drug. In some embodiments, the formulation does not include any NSAIDs.

[0294] In some embodiments, the formulation can include one, two, or more antibiotics, such as, for example, antibacterial agents, such as penicillins, including amoxicillin, ampicillin, bacampicillin, carbenicillin indanyl, mezlocillin, piperacillin, and ticarcillin; penicillins and beta-lactamase inhibitors, including amoxicillin-clavulanic acid, ampicillin-sulbactam, benzylpenicillin, cloxacillin, dicloxacillin, methicillin, oxacillin, penicillin G, penicillin VK, piperacillin plus tazobactam, ticarcillin plus clavulanic acid, and nafcillin; first-generation, second-generation, and Third- or fourth-generation cephalosporins; macrolides and lincosamines, including azithromycin, clarithromycin, clindamycin, dirithromycin, erythromycin, lincomycin, and troleandomycin; cinoxacin, ciprofloxacin, enoxacin, gatifloxacin, grepafloxacin, levofloxacin, lomefloxacin, moxifloxacin, nalidixic acid, norfloxacin, ofloxacin, sparfloxacin, trovafloxacin, and oxolinic acid. Quinolones and fluoroquinolones, including gemifloxacin and perfloxacin; carbapenems, including imipenem, ertapenem, doripenem, and meropenem; conobactams, including aztreonam; aminoglycosides, including amikacin, gentamicin, kanamycin, neomycin, netilmicin, streptomycin, tobramycin, and paromomycin; glycopeptides, including teicoplanin and vancomycin; demeclocycline, doxycycline, methacycline, minocycline, and oxyte Tetracyclines, including tracycline, tetracycline, and chlortetracycline; sulfonamides, including mafenide, silver sulfadiazine, sulfacetamide, sulfadiazine, sulfamethoxazole, sulfasalazine, sulfisoxazole, trimethoprim-sulfamethoxazole, and sulfamethizole; rifampins, including rifabutin, rifampin, and rifapentine; oxazolidnones, including linezolid; streptogramins, including quinopristin and dalfopristin;Other antibiotics include bacitracin, chloramphenicol, colistimethate, fosfomycin, isoniazid, methenamine, metronidazole, mupirocin, nitrofurantoin, nitrofurazone, novobiocin, polymyxin b, spectinomycin, trimethoprim, colistin, cycloserine, capreomycin, ethionamide, pyrazinamide, para-aminocycloaliphatic acids, erythromycin ethylsuccinate + sulfisoxazole, and combinations thereof. In some embodiments, the antibiotic is therapeutically effective for treating streptococci, including Staphylococcus aureus (including MRSA) and Streptococcus pyogenes. In some embodiments, the antibiotic is therapeutically effective for treating bacilli, including Bacillus cereus and Bacillus orellonius. The antibiotic can be delivered separately or in the same formulation as the antiparasitic agent. In some embodiments, the formulation does not include any antibiotics, such as antibacterial agents.

[0295] In some embodiments, the formulation may include a vasoconstrictor, for example, to reduce eye redness. The vasoconstrictor may include, for example, epinephrine, phenylephrine, norepinephrine, or methoxyamine, or a combination thereof. The vasoconstrictor may be delivered separately or in the same formulation as the antiparasitic agent. In some embodiments, the formulation does not include any vasoconstrictor.

[0296] In some alternative embodiments, the isoxazoline parasiticide may be formulated into a cosmetically acceptable topical lotion, cream, or gel that is applied to the skin, eyelids, eyelashes, meibomian glands, or other anatomical locations as described elsewhere herein. In some cases, such treatment routes may require once-daily or twice-daily application over a four-week period to achieve sufficient hair follicle penetration and effective acaricidal activity. A topical formulation capable of achieving such efficacy may, for example, optionally contain about 0.01-5% active agent. Penetration can be enhanced if the active agent is encapsulated within microliposomes. Such topical treatments may need to be repeated more frequently than the preferred oral embodiment, provided that a disease-free interval is achieved with each route of treatment.

[0297] In some embodiments, an isoxazoline parasiticide, a formamidine parasiticide, or other agents, or a combination of other agents as otherwise disclosed, may be incorporated into a gel formulation. The gel formulation may include a gelling agent. The gelling agent may be a carbomer gelling agent or a cellulose gelling agent. One gelling agent may be hydroxyethyl cellulose (Natrosol, Hercules Inc., Wilmington, Delaware). Other suitable gelling agents include carboxyvinyl polymers such as Carbopol® 934, 940, or 941 (Noveon, Inc., Akron, Ohio). The polyacrylic acid gelling agent may be a carbomer gelling agent, such as Carbomer 940, 974P, or TR1. The carbomer gelling agent can be present at, for example, about 0.2-1 wt.%, such as, for example, about 0.25 wt.% or about 0.5 wt.%. In some embodiments, the polyacrylic acid gel composition comprises about 2.5-3.5 wt.% benzyl alcohol. In some embodiments, the composition comprises about 3 wt.% benzyl alcohol. The viscosity of the carbomer composition can be, for example, about 500 cps to about 32,000 cps, about 500 cps to about 15,000 cps, about 10,000 cps to about 15,000 cps, or about 26,000 cps to about 32,000 cps, depending on, for example, the amount of carbomer used in the formulation. The cellulose gelling agent can be, for example, a hydroxyalkyl cellulose gelling agent, such as hydroxycellulose (HEC) or hydroxymethylcellulose (HMC). The cellulose gelling agent may be present at about 1-3 wt%, such as about 1 wt%, about 1.25 wt%, about 1.5 wt%, or about 2 wt%. In some embodiments, the cellulose gel composition comprises about 2-3 wt% benzyl alcohol. In one specific embodiment, the composition comprises about 2.5 wt% benzyl alcohol.

[0298] In some embodiments, an isoxazoline parasiticide, a formamidine parasiticide, or other drug, or combinations of drugs as otherwise disclosed herein, can be incorporated into an ophthalmic insert. The ophthalmic insert can be a sterile, thin-layered, drug-impregnated, solid or semi-solid, rigid device placed in the cul-de-sac or conjunctival sac, the size and shape of which are specifically designed for ophthalmic use. They can include a polymeric support containing one, two, or more therapeutic agents, such as an isoxazoline parasiticide or others as otherwise disclosed herein. The therapeutic agents can be subsequently incorporated into the polymeric support as a dispersion or solution, which can provide several benefits, such as increased ocular exposure and sustained ocular release of the drug. The insert can include a body portion sized for placement within the lacrimal canaliculus of the eyelid. Inserts are classified according to their solubility as insoluble, soluble, biodegradable, or non-erodible inserts. In some embodiments, an isoxazoline parasiticide, a formamidine parasiticide, or other agent, or combination of other agents as otherwise disclosed herein, can be incorporated into a punctal plug, or contact lens, or other device placed within the punctum or canaliculus.

[0299] In some embodiments, pharmaceutical formulations comprising any of those disclosed herein may be configured to advantageously eradicate mites near the eyelashes by preferentially absorbing the pharmaceutical formulation through the mite's exoskeleton (e.g., the abdomen or opisthosoma) rather than through systemic absorption of the pharmaceutical formulation by the mite (e.g., through uptake of skin cells, sebum, and other elements that may contain a certain amount of the active agent). Without being limited by theory, Demodex mites have a hydrophobic chitinous outer surface and a relatively thin exoskeleton (approximately 0.5 μm in the abdominal / opisthosoma region, compared to approximately 2.0 μm in the cephalothorax). This surprisingly allows for more rapid absorption of the formulation through the abdomen, instead of the predominant uptake seen in existing veterinary formulations of isoxazoline parasiticides. Figures 1A-1B schematically illustrate application of a formulation 120 onto an eye 140 having an iris / pupil 142. The eyelids around the eye 140 may contain hair follicles 180 for eyelashes 186, which may contain sebum oil 182. The eyelids may contain meibomian glands 160 with meibum oil 162. As shown in FIGS. 1A-1B, the "prone" orientation of the mite (e.g., Demodex folliculorum 164, Demodex brevis 184) relative to the hair follicles 180 or meibomian glands 160 (with the mite body pointing toward the opening of the hair follicle 180 or meibomian glands 160) may promote preferential abdominal absorption of the formulation 120 through the abdominal / posterior body portion 190. In ex vivo studies, it was surprisingly observed that after delivery of certain pharmaceutical formulations as disclosed herein, the abdominal and caudal portions of Demodex mites cease movement more rapidly than the cephalothorax portion in FIG. 2. This indicates that Demodex mites are particularly susceptible to topical ophthalmic formulations such as those disclosed herein.

[0300] In some embodiments, the compositions and methods disclosed herein can include any number of the following agents, in topical or other form, which can be formulated with parameters including, but not limited to, concentrations, excipients, and any other characteristics, including, but not limited to, other characteristics otherwise disclosed herein, or the absence of other characteristics: These drugs include albendazole, cambandazole, fenbendazole, flubendazole, mebendazole, oxfendazole, parabendazole, thiabendazole, triclabendazole, amitraz, demidraz, clorsulon, closantel, oxyclonazide, rafoxanide, cyphenothrin, flumethrin, permethrin, promazine, delquantel, diamfenetide, dicycyanil, dinotefuran, imidacloprid, nitenpyram, thiamethoxam, abamectin, doramectin, emamectin, epnomectin, ivermectin, moxidectin, selamectin, milbemycin oxime, emodepside, epsamectin, milbemycin oxime ... ciprantel, fipronil, fluazuron, fluhexafon, indoxacarb, levamisole, lufenuron, metaflumizone, methoprene, monepantel, morantel, niclosamide, nitroscanate, nitroxyfen, novaluron, oxantel, praziquantel, pyrantel, pimprol, priproxifen, cisaprom, spinosyns and spinosoids (e.g., Spinosyn A, B, C, D, E, F, G, H, J, K, L, M, N, O, P, Q, R, S, T, U, V, W, Y and / or spinosad), spinetoram, lindane, picrotoxin, dieldrin, alpha-endosulfan and / or triflumezopyrim.In some embodiments, compositions and methods may include meta-diamides (e.g., broflanilide, tetraniliprole, or cyclaniliprole), cyclodiene, and / or phosphodiesterase-4 inhibitors (including PDE4A, PDE4B, PDE4C, and / or PDE4D inhibitors, including but not limited to apremuriast, cilomilast, crisaborole, diazepam, ibudilast, luteolin, mesembrenone, piclamilast, roflumilast, or ropripram), and / or macrocyclic lactones (including avermectin and milbemycin). In some embodiments, formulations and methods may include immunomodulatory agents (e.g., immunostimulants or immunosuppressants). Immunosuppressants may include, for example, steroids and / or nonsteroidal anti-inflammatory drugs. Nonsteroidal anti-inflammatory drugs can include, for example, calcineurin inhibitors (e.g., tacrolimus, sirolimus, or pimecrolimus), cyclosporine, diclofenac, ibuprofen, ketoprofen, indomethacin, piroxicam, etc. In some embodiments, drugs for Alzheimer's disease can be active agents such as galantamine, donepezil and other piperidine analogs, rivastigmine and other carbamate analogs, tacrine, 7-methoxytacrine, other pyridine analogs, huperazine A and other alkaloid analogs, which may also have anti-Demodex activity. For example, galantamine is a selective, rapidly competitive, reversible acetylcholinesterase inhibitor with an anionic substrate and an aromatic cleft, and is an allosteric ligand / activator at nicotinic cholinergic receptors, which increases GABA activity. In some cases, other acetylcholinesterase inhibitors can be similarly utilized. Derivatives, analogs, and L- and D-isomers, including but not limited to compositions containing enantiomers, racemic mixtures, and enantiomerically pure compositions of any of the foregoing in this paragraph may also be utilized. In some embodiments, the formulation does not include any number or all of the agents listed in this paragraph.

[0301] In some embodiments, the dermatological and / or ophthalmological formulations may include a formamidine parasiticide active therapeutic agent instead of, or in addition to, an isoxazoline parasiticide as previously disclosed. The formamidine parasiticide may be, for example, amitraz, which can function as an octopamine receptor modulator. N-(2,4-dimethylphenyl)-N-methylformamidine (DPMF), a metabolite of amitraz, is believed to be the active agent exerting its acaricidal and insecticidal effects by acting as an active therapeutic agent on octopamine receptors, which may be, alone or in addition to, other active therapeutic agents. 2,4-Dimethylanaline is a hydrolysis metabolite of DPMF, which may also be the active therapeutic agent in other embodiments. Derivatives, analogs, and L- and D-isomers, including, but not limited to, compositions containing enantiomers, racemic mixtures, and enantiomerically pure compositions may also be utilized. In some embodiments, the dermatological and / or ophthalmological formulations may include an active therapeutic agent that is a phenylpyrazole parasiticide, instead of or in addition to an isoxazoline parasiticide or a formamidine parasiticide as previously disclosed.The chemical structure of these insecticides is characterized by a central pyrazole ring with a phenyl group bonded to one of the pyrazole nitrogen atoms.Some non-limiting examples of phenylpyrazole parasiticides include, for example, acetoprole, ethiprole, fipronil, flufiprole, pyraclofos, pyrafluprole, pyriprole, pyrrolan, and vaniliprole.

[0302] In some embodiments, the formulation may include an organophosphate with anti-Demodex activity instead of or in addition to an isoxazoline parasiticide, a formamidine parasiticide, a phenylpyrazole parasiticide, an avermectin, or a combination thereof, such as acephate, azamethiphos, azinphos-ethyl, azinphos-methyl, bromophos, bromophos-ethyl, cadsophos, carbophenithione, chlormephos, chlorphoxim, chlorpyrifos, chlorpyrifos-methyl, chlorthiophos, chlorbinophos, chlorumaphos, crotoxyphos, crufomate, cyanofenphos, cyanophos, demefuron-O, demefuron-S, demeton-O, demeton-S, demeton-S-methionine, or a combination thereof. ru, Demeton-S-methylsulfone, Diarifos, Diazinon, Diclofenthion, Dichlorvos, Dicrotophos, Dimefox, Dimethoate, Dioxabenzophos, Dioxathion, Disulfoton, Ditalmiphos, Edifenphos, EPBP, EPN, ESP, Ethion, Ethopropos, Etomphos, Fanfur, Fenamiphos, Fenchlorphos, Fenitrothion, Fensulfothion, Fenthion, Fenophos, Formothion, Fosmethira Heptenophos, Isazophos, Isofenphos, Isothioate, Isoxathion, Iodofenphos, Leptophos, Metrifonate, Malathion, Menasone, Mephosphoran, Methacrifos, Methamidophos, Methidathion, Mevinphos, Monocrotophos, Naled, Omethoate, Oxydemeton-methyl, Parathion, Parathion-methyl, Phentoate, Phorate, Phosalone, Phosmet, Phosphamidon, Phosphamidonamide, Phosphorane, Hoxane Examples of the anti-inflammatory drug include one or more of sim, pirimiphos-ethyl, pirimiphos-methyl, profenofos, propafos, propetamphos, prothiofos, protoate, pyraclofos, pyridaphenthion, quinlfos, shladan, sulfotep, sulprofos, temephos, TEPP, terbufos, tetrachlorvinphos, thiometon, thionazine, triazophos, trichlorfon, vamidothion, prodrugs thereof, and pharmaceutically acceptable salts or esters thereof.In some embodiments, the organophosphate may be dichlorvos or a prodrug thereof, or a pharmaceutically acceptable salt thereof, or an ester thereof. In some embodiments, the organophosphate may be metrifonate or a prodrug thereof, or a pharmaceutically acceptable salt thereof, or an ester thereof. In some embodiments, the formulation or method does not include any organophosphate.

[0303] To further illustrate some embodiments and their advantages, Table 1 below lists, for illustrative purposes only, some non-limiting examples of topical isoxazoline antiparasitic formulations. All ingredients are listed as w / w % or grams per 100 g of formulation, and Figures 3A-3B show examples of formulations containing amitraz and fluralaner. [Table 1]

[0304] One exemplary embodiment of an amitraz solution includes 0.100 w / w% amitraz in 99.9% light liquid paraffin. Another example of an amitraz ointment may include 0.100 w / w% amitraz, 29.9% liquid paraffin, and 70.0% petrolatum.

[0305] To further illustrate some embodiments and their advantages, Table 2 below lists, for illustrative purposes only, some non-limiting specific examples of topical isoxazoline parasiticide formulations. All ingredients are listed as w / w % or grams per 100 g of formulation. [Table 2]

[0306] To further illustrate some embodiments and their benefits, Table 2A below lists, for illustrative purposes only, additional non-limiting examples of topical isoxazoline parasiticide formulations. All ingredients are listed as w / w % or grams per 100 g of formulation. [Table 2A]

[0307] To further illustrate some embodiments and their benefits, Table 2B below lists, for illustrative purposes only, additional non-limiting examples of topical isoxazoline parasiticide formulations. All ingredients are listed as w / w % or grams per 100 g of formulation. [Table 2B]

[0308] To further illustrate some embodiments and their advantages, Table 3 below lists, for illustrative purposes only, some non-limiting specific examples of topical isoxazoline antiparasitic gel formulations. All ingredients are listed as w / w % or grams per 100 g of formulation. [Table 3]

[0309] To further illustrate some embodiments and their advantages, Table 4 below lists, for illustrative purposes only, some non-limiting specific examples of topical isoxazoline antiparasitic gel formulations. All ingredients are listed as w / w % or grams per 100 g of formulation. [Table 4]

[0310] In some embodiments, the topical ophthalmic formulation may include the following instructions for use: The patient may be instructed to first shower or bathe and wash their hands before applying the test drug. A unit dose, such as one drop of the formulation, may be applied directly to each eye once or twice daily, for example, once in the morning and once in the evening. After delivering the eye drops to the conjunctiva and / or cornea of ​​the eye, the patient closes their eye and applies gentle pressure to the upper eyelid to allow the drug to manifest across the upper and lower eyelid margins. The formulation is then allowed to dry without patting the tissue. The formulation can then be stored at room temperature (15-30°C) in a temperature- and humidity-controlled environment, avoiding extreme heat or cold. In some embodiments, the patient is instructed not to apply any other topical ophthalmic medications within a specific time period, for example, one hour before and one hour after administering the test drug.

[0311] In some embodiments, the systems and methods include qualitative and / or quantitative assessment of Demodex mites at a patient's anatomical location, such as on the eyelashes and / or within the glands. In some embodiments, the methods include obtaining a first assessment of Demodex mites load at the patient's anatomy, and initiating topical administration of a dermatological and / or ophthalmic composition if the Demodex mites load is greater than a predetermined value, such as greater than about 1, about 1.5, about 2, about 2.5, about 3, about 4, about 5, or more mites per square centimeter of skin (or mites per eyelash). In some embodiments, the methods may include obtaining a second assessment of Demodex mites load after treatment to quantitatively assess improvement, and continuing, modifying (by increasing or decreasing the dose, frequency, formulation, etc.), or discontinuing treatment based on the second assessment. This can be about 1 day, about 2 days, about 3 days, about 5 days, about 7 days, about 10 days, about 14 days, about 21 days, about 28 days, about 30 days, or less than about 1 day, about 2 days, about 3 days, about 5 days, about 7 days, about 10 days, about 14 days, about 21 days, about 28 days, about 30 days, or at least about 1 day, about 2 days, about 3 days, about 5 days, about 7 days, about 10 days, about 14 days, about 21 days, about 28 days, about 30 days, or more or less, after the first assessment. In some embodiments, treatment results in about a 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 100% eradication of Demodex mites at an anatomical location, or at least about a 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 100% eradication.

[0312] In some embodiments, the formulations or methods provide a surprisingly sustained effect with no recurrence or increase, or substantially no recurrence or increase, in Demodex presence for at least about 1 week, 2 weeks, 3 weeks, 4 weeks, or more, or at least about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 months, or more, after the last administration to the patient.

[0313] The presence of cylindrical dandruff, also known as cylindrical casts, is a clear cuff of scale at the base of the eyelashes that adheres to the base of the eyelashes. Cylindrical dandruff on the eyelashes is generally considered characteristic of Demodex infestation, which can be diagnosed by hair removal, examined using a slit lamp microscope, and then counted automatically or manually. The skin surface biopsy (SSB) technique using cyanoacrylic adhesive is a commonly used method for measuring Demodex density. This allows collection of the superficial portion of the stratum corneum and the contents of the pilosebaceous follicles. Other sampling methods used to evaluate the presence of Demodex under a microscope include adhesive bands, skin scrapings, skin examination, exposed hair follicle contents, comedone extraction, hair removal, and punch biopsy.

[0314] In some embodiments, systems and methods are disclosed for detecting Demodex mites in patients who do not necessarily require hair removal. Because Demodex mites, particularly Demodex brevis, can be difficult to detect and quantify with hair removal, such criteria for diagnosing Demodex mites can be advantageous. Furthermore, many patients dislike hair removal due to discomfort. Furthermore, initiation of treatment can be accelerated according to the desired criteria.

[0315] For example, a device such as a disposable hydrogel contact lens can be used to collect tears from a subject. The device, e.g., lens, can then be sent to a laboratory for detection and, potentially, quantification of Demodex DNA by PCR or other means. The genomes of both Demodex folliculorum and Demodex brevis have been sequenced. A "diagnostic" lens is placed on the eye and removed after a short, predetermined period of time, e.g., about 30 minutes, about 20 minutes, about 15 minutes, about 10 minutes, or about 5 minutes, or less than about 30 minutes, about 20 minutes, about 15 minutes, about 10 minutes, or about 5 minutes. Such lenses can be made from hydrogels that have a relatively high affinity for Demodex biomarkers, including DNA.

[0316] In some embodiments, tear sampling utilizes a device containing a glass capillary tube to collect tears from the tear meniscus of the lower eyelid, as shown in Figure 4A. This method can be particularly useful when small, quantifiable volumes are required. Additionally, evaporation can be easily eliminated by sealing both ends of the tube, if this is beneficial.

[0317] Some embodiments also include non-contact lens skin and tear sampling methods, such as paper-wicking embodiments similar to the "litmus paper" or Schirmer test (shown in FIG. 4B), or eyelash brush collection techniques (shown in FIG. 4C). In some embodiments, chitin, chitosan, or other Demodex-specific biomarkers can be detected and quantified and correlated with mite numbers.

[0318] Demodex DNA can be quantified, for example, as the density of DNA copies encoding a particular Demodex target sequence (e.g., as a non-limiting example, 18S rRNA). In some embodiments, the density (Demodex, human gDNA (×10 -6A threshold for initiating treatment can be when the IL-10 mAb (defined as the number of DNA copies encoding the target region of Demodex per ng of IL-10 mAb) is greater than about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, or more.

[0319] Infestations can be further classified as the causative species of Demodex (e.g., Demodex folliculorum vs. Demodex brevis). Demodex brevis is often present within the meibomian and sebaceous glands. Treatments can be modified, enhanced, or targeted based on the dominant species, for example, by increasing delivery of therapeutic formulations to selected glands.

[0320] Figures 5A-5C show human study data from a randomized clinical trial of an isoxazoline antiparasitic eye drop formulation compared to vehicle in patients suffering from Demodex blepharitis. As shown in Figure 5A, the Coralette scores of patients receiving the isoxazoline antiparasitic formulation were dramatically reduced, with a statistically significant reduction compared to vehicle after 28 days of twice-daily administration. As shown in Figure 5B, the Coralette cure rate, e.g., a score of 10 Coralettes or less, was greater than 80% for the isoxazoline antiparasitic formulation and was statistically significant compared to vehicle after 28 days of twice-daily administration. As shown in Figure 5C, there was a sustained effect after discontinuing use of the isoxazoline antiparasitic formulation after 28 days. This was statistically significant, with no rebound in mite counts per eyelash or Coralette scores at 60 or 90 days. The foregoing data demonstrate unexpectedly rapid, complete, and durable responses for the formulations and methods disclosed herein that have not previously been observed in blepharitis.

[0321] Various other modifications, adaptations, and alternative designs are naturally possible in light of the above teachings. It is therefore to be understood at this point that, within the scope of the appended claims, the invention may be practiced other than as specifically described herein. It is contemplated that various combinations or subcombinations of the specific features and aspects of the above-disclosed embodiments may be made and still belong to one or more inventions. Furthermore, any particular feature, aspect, method, property, characteristic, quality, property, element, etc. associated with one embodiment may be used in all other embodiments defined herein. It is therefore to be understood that various features and aspects of the disclosed embodiments may be combined with or substituted for one another to form varying modes of the disclosed invention. The scope of the invention disclosed herein, therefore, should not be limited by the specific disclosed embodiments described above. Moreover, while the invention is susceptible to various modifications and alternative forms, specific examples of these have been shown in the drawings and are described in detail herein. It will be understood, however, that the invention is not limited to the particular forms or methods disclosed, but rather, the invention is intended to cover all modifications, equivalents, and alternatives falling within the spirit and scope of the various described embodiments and the appended claims. Any methods disclosed herein do not have to be performed in the order recited. Methods disclosed herein include specific actions performed by a practitioner, which may also include any third-party instructions, either express or implied, regarding those actions. For example, an action such as "applying an isoxazoline parasiticide to the eye" includes "instructing to apply an isoxazoline parasiticide to the eye." Ranges disclosed herein also encompass any and all overlapping portions, subranges, and combinations thereof. Words such as "up to," "at least," "greater than," "less than," "between," and the like, are inclusive of the recited numbers. As used herein, numbers preceded by terms such as "approximately," "about," and "substantially" are inclusive of the recited number (e.g., about 10% equals 10%) and also represent an amount that approximates the stated amount that will still perform the desired function and produce the desired result.For example, the terms "approximately," "about," and "substantially" can refer to an amount that is within less than 10%, within less than 5%, within 1%, within less than 0.1%, and within less than 0.01% of the stated amount.

Claims

1. 1. A method for treating blepharitis in a patient, comprising: the method comprising topically administering an effective amount of an isoxazoline parasiticide formulated in an ophthalmic composition directly to the ocular surface of one or both eyes of a patient in need of treatment for blepharitis; The isoxazoline parasiticide further comprises a pharmaceutically acceptable solvent; the ophthalmic composition is sterile and non-irritating to the eye; the isoxazoline parasiticide is the only active ingredient in the ophthalmic composition; The composition comprises a sorbate.

2. 10. The method of claim 1, wherein the sorbate is the only preservative in the composition.

3. 10. The method of claim 1, wherein the composition comprises 0.01% to 0.50% by weight of the sorbate.

4. The method of any one of claims 1 to 3, wherein the sorbate further comprises a chelating agent.

5. 5. The method of claim 1, wherein the chelating agent comprises EDTA or edetate disodium hydrate.

6. The method of any one of claims 1 to 5, wherein the ophthalmic composition comprises eye drops.

7. The method of any one of claims 1 to 6, wherein the ophthalmic composition does not contain essential oils.

8. 8. The method of any one of claims 1 to 7, wherein the isoxazoline parasiticide is selected from the group consisting of fluralaner, sarolaner, lotilaner, afoxolaner, isocycloceram and fluxametamide.

9. 9. The method of any one of claims 1 to 8, wherein the ocular surface comprises at least one of the conjunctiva or cornea of ​​the one or both eyes of the patient.

10. 10. The method of any one of claims 1 to 9, wherein the sorbate comprises potassium sorbate.

11. 11. The method of any one of claims 1 to 10, wherein the ophthalmic composition comprises castor oil but does not comprise polysorbate.

12. 1. A method for treating blepharitis in a patient, comprising:

2. The method of claim 1, further comprising administering an effective amount of an isoxazoline parasiticide formulated in an ophthalmic composition directly to one or both eyes, one or both eyelids, or one or more eyelashes of a patient in need of treatment for blepharitis; The isoxazoline parasiticide further comprises a pharmaceutically acceptable solvent; the ophthalmic composition is sterile and non-irritating to the eye; the isoxazoline parasiticide is the only active ingredient in the ophthalmic composition; the composition comprises a sorbate; The method, wherein the composition further comprises castor oil.

13. 13. The method of claim 12, wherein the patient's eyes are closed when the ophthalmic composition is topically administered such that the composition contacts the orifices of the patient's meibomian glands and the outer lid margin of the patient.

14. 14. The method of claim 13, further comprising spreading the composition onto the eyelashes and their hair follicles.

15. 14. The method of claim 13, further comprising spreading the composition onto the eyelashes and their follicles with an applicator.

16. 16. The method of any one of claims 12 to 15, wherein about 0.001% to about 1% of the isoxazoline parasiticide is administered.

17. 17. The method of any one of claims 12 to 16, comprising topically administering the ophthalmic composition at least once daily for at least about two weeks.

18. 18. The method of any one of claims 12 to 17, comprising topically administering the ophthalmic composition at least once daily for at least about four weeks.

19. 1. A method for treating Demodex ocular infestation in a patient, comprising: topically administering an effective amount of an isoxazoline parasiticide formulated in an ophthalmic composition directly to one or both eyes, one or both eyelids, or one or both eyelashes of a patient in need of treatment; The isoxazoline parasiticide further comprises a pharmaceutically acceptable solvent; the ophthalmic composition is sterile and non-irritating to the eye; the isoxazoline parasiticide is the only active ingredient in the ophthalmic composition; the ophthalmic composition comprises a sorbate; wherein the amount of the composition delivered is less than about 100 microliters.

20. obtaining a first assessment of Demodex burden in the patient's anatomy; topically administering the ophthalmic composition if the amount of Demodex mites is greater than a predetermined value; 20. The method of claim 19, further comprising:

21. obtaining an initial assessment of the amount of dandruff (columnar flakes) in the patient's anatomy; topically administering the ophthalmic composition if the amount of Coralette is greater than a predetermined value; 21. The method of claim 19 or 20, further comprising:

22. 22. The method of any one of claims 19 to 21, wherein the ophthalmic preparation more rapidly stops the movement of the abdominal and caudal portions of Demodex mites in the patient compared to the cephalothorax of Demodex mites.

23. 1. A method of treating blepharitis and / or rosacea, comprising: topically applying a composition comprising an isoxazoline parasiticide to the vicinity of one or more eyelashes; the topical application is therapeutically effective by preferential absorption into the body of the Demodex mite for uptake by the Demodex mite, such that the body movement of the Demodex mite is reduced relative to the head of the Demodex mite; the method is sufficient to reduce or eliminate Demodex mites near the eyelashes and improve symptoms of blepharitis and / or rosacea; The composition further comprises sorbate and castor oil; The method of claim 1, wherein the sorbate is the only preservative in the composition.

24. 1. A topical ophthalmic formulation for treating blepharitis in a patient, comprising: comprising an effective amount of an isoxazoline parasiticide and a pharmaceutically acceptable solvent; the ophthalmic composition is sterile and non-irritating to the eye; the isoxazoline parasiticide is the only active ingredient in the ophthalmic composition; The ophthalmic composition further comprises a sorbate and castor oil; A topical ophthalmic formulation, wherein the sorbate is the only preservative in the composition.

25. 25. The topical ophthalmic formulation of claim 24, wherein the isoxazoline parasiticide is administered in an amount of from about 0.01% to about 1% by weight based on the total weight of the composition.

26. 25. The topical ophthalmic formulation of claim 24, wherein about 0.03% by weight of the isoxazoline parasiticide is administered based on the total weight of the composition.

27. 25. The topical ophthalmic formulation of claim 24, wherein about 0.10% by weight of the isoxazoline parasiticide is administered based on the total weight of the composition.

28. 25. The topical ophthalmic formulation of claim 24, wherein about 0.30% by weight of the isoxazoline parasiticide is administered based on the total weight of the composition.

29. The topical ophthalmic formulation of any one of claims 24 to 28, wherein the ophthalmic composition comprises eye drops.

30. 30. The topical ophthalmic formulation of any one of claims 24 to 29, wherein the ophthalmic composition does not contain essential oils.

31. 31. The topical ophthalmic formulation of any one of claims 24 to 30, wherein the isoxazoline parasiticide is selected from the group consisting of fluralaner, sarolaner, lotilaner, isocycloceram, afoxolaner and fluxametamide.

32. 1. A topical formulation for use in treating an ocular surface disease, comprising: an isoxazoline parasiticide; At least one of Pemulen and HPMC; Castor oil and Glycerin and A buffering agent; potassium sorbate, Including, A topical formulation, wherein the formulation is therapeutically effective in reducing or eliminating Demodex mites in the vicinity of the eyelashes and improving the symptoms of blepharitis and / or rosacea.

33. 33. The topical formulation of claim 32, for use in treating blepharitis.

34. 33. The topical formulation of claim 32, for use in treating anterior blepharitis.

35. 33. The topical formulation of claim 32, for use in treating posterior blepharitis.

36. 36. The topical formulation of any one of claims 32 to 35, for use in the treatment of ocular rosacea.

37. 1. A method for treating blepharitis in a patient, comprising: administering an effective amount of a formamidine parasiticide formulated in an ophthalmic composition directly to the ocular surface of one or more eyes of a patient in need of said treatment for blepharitis, The formamidine parasiticide further comprises a pharmaceutically acceptable solvent; the ophthalmic composition is sterile and non-irritating to the eye; wherein the formamidine parasiticide is the only active ingredient in the ophthalmic composition.

38. 38. The method of claim 37, wherein about 0.01% to about 1% by weight of the formamidine parasiticide is administered based on the total weight of the composition.

39. 38. The method of claim 37, wherein about 0.03% by weight of the formamidine parasiticide is administered based on the total weight of the composition.

40. 38. The method of claim 37, wherein about 0.10% by weight of the formamidine parasiticide is administered based on the total weight of the composition.

41. 41. The method of any one of claims 38 to 40, wherein the ophthalmic composition comprises eye drops.

42. 41. The method of any one of claims 38 to 40, wherein the ophthalmic composition comprises an ointment or cream.

43. The method of any one of claims 38 to 42, wherein the ophthalmic composition does not contain essential oils.

44. 44. The method of any one of claims 38 to 43, wherein the formamidine parasiticide is selected from the group consisting of amitraz, N-(2,4-dimethylphenyl)-N-methylformamidine (DPMF), and 2,4-dimethylanaline.

45. 45. The method of any one of claims 38 to 44, wherein the ocular surface comprises at least one of the conjunctiva or cornea of ​​one or both eyes of the patient.

46. 46. ​​The method of any one of claims 38 to 45, wherein the ophthalmic composition comprises a polysorbate.

47. 1. A method for treating lice, scabies and / or bed bugs in a patient, comprising: topically administering an effective amount of an isoxazoline or formamidine parasiticide formulated in a composition directly to the skin surface of a patient in need of said lice, scabies, and / or bed bug treatment; The parasiticide further comprises a pharmaceutically acceptable solvent; the composition is non-irritating to the skin; The method of claim 1, wherein the isoxazoline parasiticide is the only active ingredient in the composition.

48. 1. A method for preventing host-borne disease in a patient, comprising: topically administering an effective amount of an isoxazoline or formamidine parasiticide formulated in a composition directly to the skin surface of a patient in need of treatment for said condition; The parasiticide further comprises a pharmaceutically acceptable solvent; the composition is non-irritating to the skin; The method of claim 1, wherein the isoxazoline parasiticide is the only active ingredient in the composition.

49. 1. A method for improving eyelash health in a patient, comprising: administering an effective amount of an isoxazoline parasiticide formulated in an ophthalmic composition directly to the ocular surface of one or both eyes of a patient in need of treatment to improve the health of said eyelashes; The isoxazoline parasiticide further comprises a pharmaceutically acceptable solvent; the ophthalmic composition is sterile and non-irritating to the eye; the isoxazoline parasiticide is the only active ingredient in the ophthalmic composition; 10. A method of increasing the number, growth rate, thickness and / or appearance of the patient's eyelashes by improving the health of the eyelashes.

50. 50. The method of claim 49, wherein the composition is not absorbed systemically to produce a therapeutic systemic effect.

51. 1. A multi-dose topical ophthalmic formulation for use in treating an ocular surface disease, comprising: an isoxazoline parasiticide; a castor oil solubilizer; A polyol, Acid and Tromethamine (TRIS), Lauralkonium chloride or benzalkonium chloride, Including, A topical ophthalmic formulation, wherein the formulation is therapeutically effective in reducing or eliminating Demodex mites in the vicinity of the eyelashes and improving the symptoms of blepharitis and / or rosacea.

52. 52. The topical ophthalmic formulation of claim 51, for use in treating blepharitis.

53. 52. The topical ophthalmic formulation of claim 51, for use in treating anterior blepharitis.

54. 52. The topical ophthalmic formulation of claim 51, for use in treating posterior blepharitis.

55. 56. A topical ophthalmic formulation according to any one of claims 51 to 55, for use in the treatment of ocular rosacea.

56. 56. A topical ophthalmic formulation according to any one of claims 51 to 55, wherein the formulation comprises from about 0.01% w / w to about 0.50% w / w of the isoxazoline parasiticide.

57. 56. A topical ophthalmic formulation according to any one of claims 51 to 55, wherein the formulation comprises about 0.10 w / w% of the isoxazoline parasiticide.

58. 56. A topical ophthalmic formulation according to any one of claims 51 to 55, wherein the formulation comprises about 0.30 w / w% of the isoxazoline parasiticide.

59. 59. The topical ophthalmic formulation of any one of claims 51 to 58, wherein the ophthalmic composition does not contain essential oils.

60. 60. The topical ophthalmic formulation of any one of claims 51 to 59, wherein the isoxazoline parasiticide is selected from the group consisting of fluralaner, sarolaner, lotilaner, afoxolaner, isocycloceram, and fluxametamide.

61. 61. The topical ophthalmic formulation of any one of claims 51 to 60, wherein the formulation comprises about 3% w / w to about 7% w / w of a solubilizer for the castor oil.

62. 62. The topical ophthalmic formulation of any one of claims 51 to 61, wherein the formulation comprises about 5% w / w of a solubilizer for the castor oil.

63. 63. The topical ophthalmic formulation of any one of claims 51 to 62, wherein the polyol is selected from the group consisting of glycerol, xylitol, erythritol, mannitol and sorbitol.

64. 64. The topical ophthalmic formulation of any one of claims 51 to 63, wherein the formulation further comprises HPMC or CMC.

65. 65. The topical ophthalmic formulation of any one of claims 51 to 64, wherein the formulation does not contain a phosphate buffer.

66. 66. The topical ophthalmic formulation of any one of claims 51 to 65, wherein the formulation is polysorbate-free.

67. 67. The topical ophthalmic formulation of any one of claims 51 to 66, wherein the formulation provides only a local therapeutic effect without any systemic effect.

68. 1. A single-dose topical ophthalmic formulation for use in treating an ocular surface disease, comprising: an isoxazoline parasiticide; a castor oil solubilizer; A polyol, Tromethamine (TRIS), Including, The formulation is preservative-free; A topical ophthalmic formulation, wherein the formulation is therapeutically effective in reducing or eliminating Demodex mites in the vicinity of the eyelashes and improving the symptoms of blepharitis and / or rosacea.

69. 69. The topical ophthalmic formulation of claim 68, wherein the formulation provides only a local therapeutic effect without providing any systemic effect.

70. 1. A multi-dose topical ophthalmic formulation for use in treating an ocular surface disease, comprising: an isoxazoline parasiticide; a castor oil solubilizer; a viscosity enhancer; and A buffering agent; Sorbate and A chelating agent; Including, A topical ophthalmic formulation, wherein the formulation is therapeutically effective in reducing or eliminating Demodex mites in the vicinity of the eyelashes and improving the symptoms of blepharitis and / or rosacea.

71. 71. The formulation of claim 70, wherein the sorbate comprises potassium sorbate, the chelating agent comprises EDTA or a salt of EDTA, and the viscosity enhancing agent comprises HPMC.

72. 72. The formulation of claim 70 or 71, wherein the pH of the formulation is from about 7 to about 7.

5.

73. 73. The formulation of any one of claims 70 to 72, wherein the pH of the formulation is about 7.

2.

74. 1. A topical ophthalmic formulation for use in treating an ocular surface disease, comprising: an isoxazoline parasiticide; a castor oil solubilizer; A polyol, Including, A topical ophthalmic formulation, wherein the formulation is therapeutically effective in reducing or eliminating Demodex mites in the vicinity of the eyelashes and improving the symptoms of blepharitis and / or rosacea.

75. 75. The topical formulation of claim 74, for use in treating blepharitis.

76. 75. The topical formulation of claim 74, for use in treating anterior blepharitis.

77. 75. The topical formulation of claim 74, for use in treating posterior blepharitis.

78. 78. The topical formulation of any one of claims 74 to 77, for use in the treatment of ocular rosacea.

79. 79. A topical ophthalmic formulation according to any one of claims 74 to 78, wherein the formulation comprises from about 0.01% w / w to about 0.50% w / w of the isoxazoline parasiticide.

80. 79. The topical ophthalmic formulation of any one of claims 74 to 78, wherein the formulation is an eye drop formulation.

81. 79. A topical ophthalmic formulation according to any one of claims 74 to 78, wherein the formulation comprises about 0.30 w / w% of the isoxazoline parasiticide.

82. 82. The topical ophthalmic formulation of any one of claims 74 to 81, wherein the ophthalmic composition is free of essential oils.

83. 83. The topical ophthalmic formulation of any one of claims 74 to 82, wherein the isoxazoline parasiticide is selected from the group consisting of fluralaner, sarolaner, lotilaner, afoxolaner, isocycloceram, and fluxametamide.

84. 84. The topical ophthalmic formulation of any one of claims 74 to 83, wherein the formulation comprises about 3% w / w to about 7% w / w of a solubilizer for the castor oil.

85. 85. The topical ophthalmic formulation of any one of claims 74 to 84, wherein the formulation comprises about 5% w / w of a solubilizer for the castor oil.

86. 86. The topical ophthalmic formulation of any one of claims 74 to 85, wherein the polyol is selected from the group consisting of glycerol, xylitol, erythritol, mannitol and sorbitol.

87. 87. The topical ophthalmic formulation of any one of claims 74 to 86, wherein the formulation further comprises HPMC or CMC.

88. 88. The topical ophthalmic formulation of any one of claims 74 to 87, wherein the formulation is free of phosphate buffer.

89. 89. The topical ophthalmic formulation of any one of claims 74 to 88, wherein the formulation is polysorbate-free.

90. 90. A topical ophthalmic formulation according to any one of claims 74 to 89, characterized in that the formulation provides only a local therapeutic effect without any systemic effect.

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