WO2019126541A1 - Traitement d'affections ophtalmologiques à l'aide d'inhibiteurs de l'acétylcholinestérase - Google Patents

Traitement d'affections ophtalmologiques à l'aide d'inhibiteurs de l'acétylcholinestérase Download PDF

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Publication number
WO2019126541A1
WO2019126541A1 PCT/US2018/066867 US2018066867W WO2019126541A1 WO 2019126541 A1 WO2019126541 A1 WO 2019126541A1 US 2018066867 W US2018066867 W US 2018066867W WO 2019126541 A1 WO2019126541 A1 WO 2019126541A1
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Prior art keywords
acetylcholinesterase inhibitor
demodex
mites
skin
individual
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PCT/US2018/066867
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English (en)
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Frank Anthony SPALLITTA
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Attillaps Holdings
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Priority to US16/954,798 priority Critical patent/US11446241B2/en
Publication of WO2019126541A1 publication Critical patent/WO2019126541A1/fr
Priority to US17/891,061 priority patent/US20230181459A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/32—Burseraceae (Frankincense family)
    • A61K36/324—Boswellia, e.g. frankincense
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
    • A61K31/37—Coumarins, e.g. psoralen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/473—Quinolines; Isoquinolines ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4748—Quinolines; Isoquinolines forming part of bridged ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/661—Phosphorus acids or esters thereof not having P—C bonds, e.g. fosfosal, dichlorvos, malathion or mevinphos
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/662—Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/683—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/37—Celastraceae (Staff-tree or Bittersweet family), e.g. tripterygium or spindletree
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration

Definitions

  • acetylcholinesterase inhibitors and/or carbamates such as ethyl carbamates to inactivate certain organisms associated with the ophthalmological affliction.
  • carbamates such as ethyl carbamates to inactivate certain organisms associated with the ophthalmological affliction.
  • the methods reduce clinical signs of the ophthalmological afflictions which are primarily due to allergic and inflammatory responses of the body to the demodex organisms and bacteria that are associated or carried by the demodex organism.
  • Eyelid involvement may be manifested by mild conjunctival irritation or inflammation of the meibomian (oil) glands on the eyelid margin. Chronic eyelid irritation can result in loss of eyelashes. Meibomian gland dysfunction caused by the irritation and inflammation can lead to chronic dry eye disease and/or blepharitis.
  • demodex folliculorum has yet to reach consensus and no commercially viable pharmacological solutions are available for treating demodex brevis and demodex folliculorum in the eyelid.
  • Reaction to the presence or metabolic activity of demodex mites in eyelash follicles has been discussed as a cause of blepharitis but previous studies where topical miticides other than
  • acetylcholinesterase inhibitors have been used have shown inconsistent and marginal results. Demodex seems to play a role in meibomian gland dysfunction which can eventually cascade into chronic dry eye disease.
  • meibum causes a cascading effect that leads to chronic dry eye disease.
  • Low tear volume causes a hyperosmolar environment that induces an inflamed state of the ocular surface.
  • This inflammatory response induces apoptosis of the surface cells which in turn prevents proper distribution of the tear film on the ocular surface so that any given tear volume is rendered less effective. This initiates a vicious positive feedback loop cycle where more inflammation can ensue causing more surface cell damage, etc.
  • the neural control loop which controls reflex tear activation, is disrupted because the sensory neurons in the surface of the eye are damaged. As a result, fewer tears are secreted and a second vicious cycle develops that results in further progression of the disease because fewer tears cause nerve cell loss, which results in even fewer tears, etc.
  • Treatment options include: artificial tear substitutes, ointments, gels, warm compresses, environmental modification, topical cyclosporine, omega-3 fatty acid supplements, punctal plugs and moisture chamber goggles. Patients with severe disease may further be treated with punctal cautery, systemic cholinergic agonists, systemic anti-inflammatory agents, mucolytic agents, autologous serum tears, PROSE scleral contact lenses and tarsorrhaphy. Despite these treatment options, dry eye disease continues to be considered one of the most poorly treated diseases in ophthalmology. Accordingly, it would be desirable to have a more effective treatment for dry eye.
  • Cyclosporine can increase tear production that has been reduced by inflammation in the eye(s).
  • RESTASIS® eye drops are used to treat chronic dry eye that may be caused by inflammation.
  • Ocular rosacea is characterized by ocular manifestations such as dry eye, tearing and burning, swollen eyelids, recurrent styes and potential vision loss from corneal damage.
  • keratoconjunctivitis hyperemia, dry eye, and blepharitis. Accordingly, provided herein are various treatments that specifically target this demodex-induced mechanism.
  • treatment methods for demodex-induced inflammatory eye conditions including that alleviate, abrogate, or otherwise reduce or stop any one or more clinical symptoms associated with demodex-induced inflammatory eye conditions by administering or applying specific acetylcholinesterase inhibitors.
  • Embodiments of the invention described herein involve treating
  • ophthalmological afflictions by the topical, intraocular or oral use of one or more than one specified acetylcholinesterase inhibitors.
  • this treatment achieves a more complete remission of clinical signs and symptoms of the ophthalmological afflictions than any previously described method.
  • Embodiments of the invention are useful for treating ophthalmological afflictions related to demodex-induced inflammatory eye conditions, including meibomian gland dysfunction, conjunctivitis, keratoconjunctivitis, hyperemia (excess blood supply to the eye), blepharitis and dry eye disease.
  • An exemplary method embodiment comprises a step of orally- administering or topically-applying to an individual having the ophthalmological affliction, including demodex-induced inflammatory eye conditions, an
  • acetylcholinesterase inhibitor in a dosage sufficient to inactivate demodex brevis and/or demodex folliculorum mites from hair follicles, skin, eyes, eyelids, eyelashes, or meibomian glands of the individual, resulting in amelioration or cessation of the manifestations of allergic and/or inflammatory responses to the mites that cause symptoms and signs of the ophthalmological affliction in the individual.
  • the acetylcholinesterase inhibitor is not an organophosphate, including acetylcholinesterase inhibitors and organophosphates described in WO
  • the acetylcholinesterase inhibitor is topically applied.
  • the topically-applied acetylcholinesterase inhibitor is formulated in a saline solution, carrier lotion, cream, soap, wash, shampoo, gel, impregnated wipe, swab or via a spoolie brush.
  • the administration is around the eye and regions adjacent thereto, but not directly into the eye.
  • a concentration of the acetylcholinesterase inhibitor in the topically-applied lotion, cream, soap, wash, shampoo, saline solution or gel is about 0.001 to 1 percent by weight or about 0.01 to 1 percent by weight.
  • a concentration of the acetylcholinesterase inhibitor in the topically- applied saline solution, lotion, cream, soap, wash, shampoo or gel is a lowest concentration effective for killing the demodex mites.
  • a dosage of acetylcholinesterase inhibitor in the topically-applied lotion, cream, soap, wash, shampoo, saline solution or gel is less than about 1 50 mg/kg of body mass or between about 0.01 mg per kg of body mass and 50 mg/kg of body mass.
  • a dosage of acetylcholinesterase inhibitor in the topically- applied saline solution, lotion, cream, soap, wash, shampoo or gel is a lowest dose effective for killing the demodex mites.
  • acetylcholinesterase inhibitor is encapsulated inside microliposomes before being formulated into the carrier saline solution, lotion, cream, soap, wash, shampoo or gel.
  • methods of the invention include those where the topically- applied acetylcholinesterase inhibitor is applied to said hair follicles, skin, eyes, eyelids, eyelashes, or meibomian glands areas affected by the ophthalmological affliction. In certain embodiments, however, the topically-applied
  • acetylcholinesterase inhibitor is further applied to areas not affected by the ophthalmological affliction.
  • the topically-applied acetylcholinesterase inhibitor is applied to the hair follicles, skin, eyes, eyelids, eyelashes, or meibomian glands areas of the body where demodex brevis and/or demodex folliculorum mites exist.
  • the topically-applied acetylcholinesterase inhibitor is applied to all areas.
  • methods of the invention further comprise a step of applying the acetylcholinesterase inhibitor to the individual's clothing, linens or both clothing and linens.
  • Such application is useful, for example, for preventing the individual's clothing or linens from being a source of demodex mites to reintroduce onto the individual's skin.
  • methods of the invention optionally further comprise a step of orally- administering or topically-applying the acetylcholinesterase inhibitor to others having contact with the individual in a dosage sufficient to fill and eliminate demodex brevis and/or demodex folliculorum mites from hair follicles and/or skin of the others.
  • the others comprise household members, children, spouses, partners, family members or domestic pets.
  • the topically- applied acetylcholinesterase inhibitor is applied to the hair follicles, skin, eyes, eyelids, eyelashes, or meibomian glands of the individual.
  • the topically-applied acetylcholinesterase inhibitor penetrates an outer layer of the skin of the individual, thereby exposing the demodex brevis and/or demodex folliculorum mites present below the outer layer of the skin in the eyelid to the acetylcholinesterase inhibitor.
  • the topically- applied acetylcholinesterase inhibitor penetrates to a subdermal region of the eyelid of the individual, thereby exposing the demodex brevis and/or demodex folliculorum mites present in and around the meibomian glands to the acetylcholinesterase inhibitor.
  • Certain formulations of the topical acetylcholinesterase inhibitor useful with the methods of the invention optionally comprise one or more compositions that increase a permeability of the skin, such as dimethyl sulfoxide (DMSO).
  • DMSO dimethyl sulfoxide
  • the topically-applied acetylcholinesterase inhibitor is applied to affected skin areas at least once and not more than twice daily for a period of about two to twelve weeks.
  • the topically-applied acetylcholinesterase inhibitor is applied to the affected areas and/or to non-affected areas during a first application period, thereby killing and eliminating adult demodex brevis and/or demodex folliculorum mites from the hair follicles, skin, eyes, eyelids, eyelashes, or meibomian glands.
  • the topically-applied acetylcholinesterase inhibitor is further applied to the affected areas and/or to non- affected areas during a second application period, thereby filling and eliminating from the hair follicles, skin, eyes, eyelids, eyelashes, or meibomian glands of the individual demodex brevis and/or demodex folliculorum mites that have matured from a larval form and/or an egg form present on and/or in the skin during the first application period.
  • the topically-applied acetylcholinesterase inhibitor is further applied to the affected areas and/or to non-affected areas during a third application period, thereby filling and eliminating from the hair follicles, skin, eyes, eyelids, eyelashes, or meibomian glands of the individual demodex brevis and/or demodex folliculorum mites that have matured from a larval form and/or an egg form present on and/or in the skin and/or the hair follicles during the first application period and/or the second application period.
  • the first application period and the second application period are separated by at least five but no more than ten days.
  • the first application period and the second application period are separated by at least seven days.
  • the first application period and the second application period are separated by a time sufficient to allow the larva form to mature into an adult form and/or to allow the egg form to mature into the adult form.
  • the second application period and the third application period are separated by at least five but no more than ten days.
  • the second application period and the third application period are separated by at least seven days.
  • the second application period and the third application period are separated by a time sufficient to allow the larva form to mature into an adult form and/or to allow the egg form to mature into the adult form.
  • the acetylcholinesterase inhibitor is orally- administered or topically-applied in a continued intermittent regime sufficient for prophylactic control of demodex mite population in the hair follicles, skin, eyes, eyelids, eyelashes, or meibomian glands of the individual.
  • the acetylcholinesterase inhibitor is orally- administered.
  • the orally-administered acetylcholinesterase inhibitor is administered as an oral dose of the
  • acetylcholinesterase inhibitor of about 1 50 mg per kg of body mass or less or between about 0.01 mg per kg of body mass and 50 mg per kg of body mass.
  • the orally- administered acetylcholinesterase inhibitor is administered as an oral dose of the acetylcholinesterase inhibitor of a lowest dose effective for killing the demodex mites.
  • the orally- administered acetylcholinesterase inhibitor is formulated as a prodrug or
  • the orally-administered acetylcholinesterase inhibitor is administered as a daily dose of 10 mg per kg of body mass.
  • the orally- administered acetylcholinesterase inhibitor is administered as a daily dose of 7.5 mg per kg of body mass.
  • the orally-administered acetylcholinesterase inhibitor is administered as a three times per day dose of 5 mg per kg of body mass.
  • the orally-administered acetylcholinesterase inhibitor is repeated about two to four times with spacing of three to seven days between them. In embodiments where the administration is confined to a local region around the eye, lower doses may be used.
  • the elimination of the demodex brevis and/or demodex folliculorum mites from hair follicles, skin, eyes, eyelids, eyelashes, or meibomian glands of the individual results in a reduction in population of one or more bacteria in the eyes, eyelids, eyelashes of the individual.
  • the allergic and/or inflammatory responses to the mites result from a presence of one or more bacteria associated with the mites in the hair follicles, skin, eyes, eyelids, eyelashes, or meibomian glands of the individual.
  • the one or more bacteria comprise one or more bacteria from the genus staphylococcus or from the genus bacillus.
  • the one or more bacteria comprise bacillus oleronius bacteria.
  • the one or more bacteria comprise staphylococcus epidermidis bacteria.
  • the one or more bacteria are present in a digestive system of the demodex brevis and/or demodex folliculorum mites.
  • Another exemplary method for treating an ophthalmological affliction comprises a step of topically-applying to an individual having the ophthalmological affliction an active ingredient in a dosage sufficient to fill and eliminate demodex brevis and/or demodex folliculorum mites from hair follicles, skin, eyes, eyelids, eyelashes, or meibomian glands of the individual, resulting in cessation of the manifestations of allergic and/or inflammatory responses to the mites that cause symptoms and signs of the ophthalmological affliction in the individual, wherein the topically-applied active ingredient is applied to hair follicles, skin, eyes, eyelids, eyelashes, or meibomian glands areas affected by the ophthalmological affliction and to skin areas not affected by the ophthalmological affliction.
  • the topically-applied active ingredient is applied to all facial skin of the individual, thereby filling and eliminating the demodex brevis and/or demodex folliculorum mites from all facial skin of the individual.
  • methods of the invention are useful, for example, for treating ocular conditions including meibomian gland dysfunction, blepharitis and dry eye disease.
  • the ophthalmological condition is caused by, exacerbated by or otherwise comorbid with an infestation of the skin and/or hair follicles by demodex mites.
  • the acetylcholinesterase inhibitor is a reversible inhibitor.
  • Compounds that are reversible competitive or noncompetitive inhibitors of cholinesterase include those having therapeutic uses, including: Carbamates, Physostigmin, Neostigmine, Pyridostigmine, Ambenonium, Demecarium,
  • the acetylcholinesterase inhibitor is a quasi-reversible inhibitor.
  • Compounds which function as quasi-irreversible inhibitors of cholinesterase tend to have use as pesticides. These include organophosphates and carbamates. Examples of organophosphates include: Echothiophate, Diisopropyl
  • carbamates include: Aldicarb; Bendiocarb; Bufencarb; Carbaryl; Carbendazim; Carbetamide; Carbofuran ;
  • Carbosulfan Chlorbufam; Chloropropham; Ethiofencarb; Formetanate; Methiocarb; Methomyl ; Oxamyl ; Phenmedipham; Pinmicarb; Pirimicarb; Propamocarb;
  • the acetylcholinesterase inhibitor corresponds to a compound currently used in medicine, including those having an established safety profile in humans. Examples include: Aricept; Aricept ODT; Cognex; donepezil;
  • neostigmine neostigmine; parathion ; malathion; dyflos; physostigmine; endrophonium;
  • the application may be a topical administration to an eye region of the individual.
  • the eye region corresponds to an area of between at least 1 cm and 10 cm around an outermost perimeter defined by the eye, eyelid, eyebrow and eyelashes.
  • the inhibitor is confined to a region around the eye, thereby effectively treating the Meibomian glands, and mite- containing regions adjacent thereto that would otherwise tend to result in a relatively quick mite recovery/migration, while avoiding direct application to the eye.
  • Also provided herein is a method of treating an individual having a demodex-induced ophthalmological affliction of Meibomian gland dysfunction, the method comprising the steps of: applying to the individual in need thereof an acetylcholinesterase inhibitor in a dosage sufficient to inactivate demodex brevis mites and/or demodex folliculorum mites from hair follicles, eyelids, eyelashes and Meibomian glands in and around an eye region; wherein a sufficient amount of demodex brevis mites and/or demodex folliculorum mites are inactivated to ameliorate or cease manifestations of allergic and/or inflammatory responses to the mites that cause symptoms or signs of Meibomian gland dysfunction.
  • inactivation may refer to at least 50%, at least 70%, at least 90%, or at least 95% of the relevant mite population that is killed, unable to mature, and/or unable to effectively reproduce.
  • the allergic and/or inflammatory responses to demodex may be manifested as Meibomian gland dysfunction, conjunctivitis, keratoconjunctivitis, hyperemia dry eye or blepharitis, wherein administration of an acetylcholinesterase inhibitor to inactivate demodex brevis and/or demodex folliculorum mites in an eye region reduces or eliminates allergic and/or inflammatory responses to the mites that cause symptoms and signs of the ophthalmological affliction in the individual.
  • the application may be a topical administration to an eye region of the individual.
  • The“eye region” may be quantifiably defined as corresponding to an area of between at least 1 cm and 10 cm around an outermost perimeter defined by the eye, eyelid, eyebrow and eyelashes, and any subranges thereof.
  • composition or compound used with the methods of the invention is isolated or purified.
  • an isolated or purified compound is at least partially isolated or purified as would be understood in the art.
  • the composition or compound of the invention has a chemical purity of 95%, optionally for some applications 99%, optionally for some applications 99.9%, optionally for some applications 99.99%, and optionally for some applications 99.999% pure.
  • lonizable groups include groups from which a proton can be removed (e.g., -COOH) or added (e.g., amines) and groups which can be quaternized (e.g., amines). All possible ionic forms of such molecules and salts thereof are intended to be included individually in the disclosure herein.
  • salts of the compounds herein one of ordinary skill in the art can select from among a wide variety of available counterions that are appropriate for preparation of salts of this invention for a given application. In specific applications, the selection of a given anion or cation for preparation of a salt can result in increased or decreased solubility of that salt.
  • carbamic acid NH 2 COOH
  • NR 2 R 3 COOR 1 an organic compound derived from carbamic acid
  • each of the groups R1-R3 are independently selected to correspond to any of the R groups of the chemicals listed herein. In an aspect, any of R1-R3 are hydrogen.
  • carbamates for use with the methods described herein include, but are not limited to, neostigmine, rivastigmine, meprobamate,
  • carisoprodol, felbamate, tybamate Preferred carabamates are those that have been demonstrated to have miticidal or insecticidal capabilities and that can be provided to a mite on or in hair follicles, skin, eyes, eyelids, eyelashes, or meibomian glands at a level sufficient to inactivate or kill the mite without permanently adversely affecting the host patient.
  • the carbamate may be a naturally occurring compound, such as a purified and isolated naturally occurring compound. Alternatively, the carbamate may be a synthetically produced carbamate, as known in the art. Any of the compounds provided herein may be provided in the form of a derivative, prodrug, or a
  • the carbamate is selected from the group consisting of:
  • R2 and R3 are optionally independently selected as hydrogen.
  • the compounds used in the methods of this invention can contain one or more chiral centers. Accordingly, this invention is intended to include racemic mixtures, diasteromers, enantiomers, tautomers and mixtures enriched in one or more stereoisomer.
  • this invention is intended to include racemic mixtures, diasteromers, enantiomers, tautomers and mixtures enriched in one or more stereoisomer.
  • Pharmaceutically acceptable salts comprise pharmaceutically-acceptable anions and/or cations.
  • pharmaceutically acceptable salt can refer to acid addition salts or base addition salts of the compounds in the present disclosure.
  • a pharmaceutically acceptable salt is any salt which retains at least a portion of the activity of the parent compound and does not impart significant deleterious or undesirable effect on a subject to whom it is administered and in the context in which it is administered.
  • Pharmaceutically acceptable salts include metal complexes and salts of both inorganic and organic acids.
  • Pharmaceutically acceptable salts include metal salts such as aluminum, calcium, iron, magnesium, manganese and complex salts.
  • Pharmaceutically acceptable salts include, but are not limited to, acid salts such as acetic, aspartic, alkylsulfonic, arylsulfonic, axetil, benzenesulfonic, benzoic, bicarbonic, bisulfuric, bitartaric, butyric, calcium edetate, camsylic, carbonic, chlorobenzoic, -32- cilexetil, citric, edetic, edisylic, estolic, esyl, esylic, formic, fumaric, gluceptic, gluconic, glutamic, glycolic, glycolylarsanilic, hexamic, hexylresorcjnoic, hydrabamic, hydrobromic, hydrochloric, hydroiodic, hydroxynaphthoic, isethionic, lactic, lactobionic, maleic, malic, malonic, mandelic, methanesulfonic,
  • salts may be derived from amino acids, including but not limited to cysteine.
  • Other pharmaceutically acceptable salts may be found, for example, in Stahl et al., Handbook of Pharmaceutical Salts: Properties, Selection, and Use, Wiley-VCH; Verlag Helvetica Chimica Acta, Zurich, 2002. (ISBN 3-906390-26-8).
  • Pharmaceutically- acceptable cations include among others, alkali metal cations (e.g., Li + , Na + , K + ), alkaline earth metal cations (e.g., Ca 2+ , Mg 2+ ), non-toxic heavy metal cations and ammonium (NH 4 + ) and substituted ammonium (N(R') 4 +, where R' is hydrogen, alkyl, or substituted alkyl, i.e., including, methyl, ethyl, or hydroxyethyl, specifically, trimethyl ammonium, triethyl ammonium, and triethanol ammonium cations).
  • alkali metal cations e.g., Li + , Na + , K +
  • alkaline earth metal cations e.g., Ca 2+ , Mg 2+
  • NH 4 + non-toxic heavy metal cations and ammonium
  • N(R') 4 + substituted ammonium
  • R' is hydrogen, alky
  • Pharmaceutically- acceptable anions include among other halides (e.g., Cl", Br"), sulfate, acetates (e.g., acetate, trifluoroacetate), ascorbates, aspartates, benzoates, citrates, and lactate.
  • the method may comprise the steps of: applying to the individual in need thereof an acetylcholinesterase inhibitor in a dosage sufficient to inactivate demodex brevis mites and/or demodex folliculorum mites from an eye region of the individual, wherein the eye region includes one or more of hair follicles, eyelids, eyelashes and Meibomian glands in and around an eye region, including such that a sufficient amount of demodex brevis mites and/or demodex folliculorum mites are inactivated to ameliorate or cease manifestations of allergic and/or inflammatory responses to the demodex mites that cause the inflammatory eye condition.
  • This sufficient amount depending on the sensitivity of the individual, may correspond to an at least 50%, 70%, 90% or 95% elimination, including in and around the eye region and/or a whole body decrease.
  • the inflammatory eye condition may correspond to one or more of:
  • Meibomian gland dysfunction dry eye, blepharitis, conjunctivitis, keratoconjunctivitis, or hyperemia.
  • the application may be a topical administration to the eye region of the individual, preferably avoiding application directly to the eye surface.
  • the eye region may correspond to an area of between at least 1 cm and 10 cm around an outermost perimeter defined by the eye, eyelid, eyebrow and eyelashes.
  • FIG. 1 summarizes a topical administration method to an eye region of an individual in need of treatment.
  • FIG. 2 is an illustration of Demodex folliculorum and Demodex brevis mites, including relative sizes and locations in the skin, hair follicles and glands.
  • FIG. 3 illustrates Demodex mites in the eye region, including eye lash and meibomian glands.
  • FIG. 4 is a table summary of Demodex survival time for various reasons.
  • Inactivate is used broadly herein to refer to the functional ability to decrease the impact of demodex brevis and/or demodex folliculorum mites.
  • the inactivation may be by death of the mite.
  • the inactivation may refer to the inability of the mite to reproduce, so that the mite die off occurs as the mites age and die without reproduction. So long as the treatment leads to an adverse effect on the demodex brevis and/or demodex folliculorum mites that corresponds to improved clinical outcome, such as symptom improvement, the treatment is considered herein to inactivate demodex brevis and/or demodex folliculorum mites.
  • “Efficiently transported” refers to the ability of the treatment agent to act against mites that are located beneath the skin surface, such as into an epidermal or subdermal region so that the mites are timely inactivated.
  • “Substantially all” refers to, unless defined in the contrary, at least 90%, at least 95% or at least 99% of the relevant population, so in the context of demodex mites, it refers to inactivation (e.g., killed or eliminated or otherwise unable to propagate) and/or application to hair (number) or skin (surface area).
  • “Demodex” refers to D. folliculorum and D. brevis mites, including Demodex mites in humans that may contribute to a demodex-induced inflammatory eye condition in humans.
  • D. folliculorum and d. brevis mites may play a role in ophthalmological conditions.
  • An increased demodex population has been observed in patients with ophthalmological afflictions.
  • demodex mites live harmlessly in the hair follicles, skin, eyelids, eyelashes, or meibomian glands as a result of either down-regulating host immunity or simply dodging host immune defenses.
  • There is continual debate within the ophthalmology community as to whether or not they are the causative agents of such ophthalmological diseases as meibomian gland dysfunction, dry eye disease and blepharitis (inflammation of the eyelids).
  • D. folliculorum exhibiting a predilection for the hair follicles and D. brevis for the sebaceous ducts and meibomian glands at the rim of the eyelids (the sebaceous ducts transfer the waxy sebum that lubricates the skin and hair from the sebum glands; the meibonmian glands are a special type of such gland)
  • D. folliculorum are a communal bunch, tending to congregate in the follicle area of the hair or eyelashes with their posterior ends protruding from the follicular pores.
  • D. brevis tend to be more solitary and will occupy the sebaceous glands singly [6] Both species are tiny, less than 0.4 mm, with elongated, clear bodies and four pairs of stout legs. D. brevis is usually a tad shorter, ⁇ 0.1 mm, than D. folliculorum. They both have ridged scales along their cephalothorax and sharp, piercing teeth [6]
  • an acetylcholinesterase inhibitor is administered topically to a patient with an active ophthalmological condition in which the underlying cause is a demodex mite.
  • an effective treatment must be capable of eradicating the entire lifecycle of such a microscopic insect, including egg, larval, and adult stages. For this reason, this embodiment treats such patients with several doses. Such spacing allows time for demodex eggs to hatch into immature mites that are killed before they can mature into egg- producing adults.
  • acetylcholinesterase inhibitor administration conventional ophthalmological medications such as artificial tear substitutes, ointments, gels, warm compresses, environmental modification, topical cyclosporine, omega-3 fatty acid supplements, punctal plugs and moisture chamber goggles can be utilized in combination treatment with acetylcholinesterase inhibitor compounds.
  • Patients with severe disease may further be treated with punctal cautery, systemic cholinergic agonists, systemic anti-inflammatory agents, mucolytic agents, autologous serum tears, PROSE scleral contact lenses and tarsorrhaphy can optionally be employed to suppress early flareups and to give early clinical response. No such medications are needed to treat manifestations of the ophthalmological condition after six to twelve weeks have elapsed. After prolonged intervals of freedom from symptoms, should classic signs begin to reappear, treatment can be repeated.
  • the ophthalmological medications such as artificial tear substitutes, ointments, gels, warm compresses, environmental modification, topical cyclo
  • acetylcholinesterase inhibitor is formulated into a cosmetically-acceptable topical saline solution, lotion, cream, shampoo, or gel and applied especially to hair follicles, skin, eyes, eyelids, eyelashes, surrounding the eyes and any area possibly inhabited by demodex brevis and demodex folliculorum. Because of the well-known barrier effect the skin presents to the penetration of topical medications, such a route of treatment with acetylcholinesterase inhibitor is anticipated to require once or twice daily applications for as long as twelve to six weeks to achieve sufficient follicle penetration and effective miticidal activity. A topical formulation that could achieve this effect would contain about 5% or less of the acetylcholinesterase inhibitor.
  • acetylcholinesterase inhibitor that can be used while still receiving the miticidal effect and successfully treating the ocular condition is ideal for limiting any possible side effects of the chemical. Further, full facial treatment is optionally useful for preventing reintroduction of the mites onto facial skin and glands.
  • a method of treating an individual 10 having a demodex-induced ophthalmological affliction of Meibomian gland dysfunction comprising the steps of: applying to the individual in need thereof an acetylcholinesterase inhibitor (indicated by arrow 20) in a dosage sufficient to inactivate demodex brevis mites and/or demodex folliculorum mites from hair follicles 100, eyelids 110, eyebrows 120, eyelashes 130 and Meibomian glands 140 in and around an eye region.
  • an acetylcholinesterase inhibitor indicated by arrow 20
  • the allergic and/or inflammatory responses may be manifested by dry eye or blepharitis, and the symptoms related thereto.
  • the application may be by a topical administration of acetylcholinesterase inhibitor 20 to an eye region 205 of the individual 10.
  • the eye region may be quantifiably defined, such as corresponding to an area of the eye region 205, including a distance 210, such as between at least 1 cm and 10 cm around an outermost perimeter 200 defined by the eye, eyelid, eyebrow and eyelashes.
  • the eye region 205 is illustrated as rectangular in shape, but the invention provided herein is compatible with any shape and region size, although it is preferable to control mite population in the area around the glands 140 so as to avoid relatively fast natural mite migration back to the glands 140 (or region adjacent thereto) with corresponding manifestation of unwanted clinical system. Accordingly, the methods provided herein, upon completion, may be characterized as ameliorating or cessation of symptoms and signs of the
  • ophthalmolgical affliction of at least 30 days - 6 months, and any range therein.
  • FIGs 2-3 illustrate the demodex brevis and folliculorum mites in the skin area generally and the eye region, respectively, demonstrating the need to ensure treatment applications are able to achieve sub-dermal penetration.
  • Urethane ethyl carbamate
  • carbamates are used in human pharmacotherapy, for example, the cholinesterase inhibitors neostigmine and rivastigmine, whose chemical structure is based on the natural alkaloid physostigmine.
  • Other examples are meprobamate and its derivatives like carisoprodol, felbamate, and tybamate, a class of anxiolytic and muscle relaxant drugs widely used in the 60s before the rise of benzodiazepines, and still used nowadays in some cases.
  • cholinesterase inhibitors neostigmine and rivastigmine may be efficacious if they have similar miticidal capabilities compared to many other carbamate compounds.
  • Rivastigmine is an oral medication used to treat patients with Alzheimer's disease. Rivastigmine is in a class of drugs called cholinesterase inhibitors that also includes tacrine (Cognex), donepezil (Aricept), and galantamine (Razadyne - formerly known as Reminyl). Cholinesterase inhibitors inhibit (block) the action of acetylcholinesterase, the enzyme responsible for the destruction of acetylcholine. Acetylcholine is one of several neurotransmitters in the brain, chemicals that nerve cells use to communicate with one another. Reduced levels of acetylcholine in the brain are believed to be responsible for some of the symptoms of Alzheimer's disease.
  • FIG. 4 tabulates demodex survival time, expressed in terms of LT50 (time at which 50% of demodex mites are killed) and/or average minutes to death for various inhibitors.

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Abstract

Certains modes de réalisation de l'invention consistent à traiter des affections ophtalmologiques par l'utilisation topique ou orale d'inhibiteurs de l'acétylcholinestérase. En réduisant ou en éliminant efficacement la population d'acariens demodex dans les zones affectées et les zones dans lesquelles peuvent se trouver des acariens demodex, ce traitement permet d'obtenir une rémission des signes cliniques et des symptômes des affections ophtalmologiques qui est plus complète que celle obtenue par une quelconque autre méthode précédemment décrite. Les modes de réalisation de l'invention sont utiles pour traiter des affections oculaires provoquées par des affections oculaires inflammatoires induites par demodex, comprenant un dysfonctionnement des glandes de Meibomius, une conjonctivite, une kératoconjonctivite, une hyperémie, une blépharite et un syndrome de l'œil sec.
PCT/US2018/066867 2013-07-29 2018-12-20 Traitement d'affections ophtalmologiques à l'aide d'inhibiteurs de l'acétylcholinestérase WO2019126541A1 (fr)

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US10835517B2 (en) 2017-12-15 2020-11-17 Tarsus Pharmaceuticals, Inc. Methods for treating ocular demodex using isoxazoline parasiticide formulations
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