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WO2025131038A1 - Compositions et procédés d'administration d'agents actifs pharmaceutiques - Google Patents

Compositions et procédés d'administration d'agents actifs pharmaceutiques Download PDF

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Publication number
WO2025131038A1
WO2025131038A1 PCT/CN2024/140886 CN2024140886W WO2025131038A1 WO 2025131038 A1 WO2025131038 A1 WO 2025131038A1 CN 2024140886 W CN2024140886 W CN 2024140886W WO 2025131038 A1 WO2025131038 A1 WO 2025131038A1
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WO
WIPO (PCT)
Prior art keywords
methyl
api
composition
amino
subject
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
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PCT/CN2024/140886
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English (en)
Inventor
Wenkui Ken Fang
Van DINH
Jinsong Ni
Rong Yang
Tao Zhang
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Cloudbreak Bio Pharmaceutical Science And Technology Guangzhou Co Ltd
ADS Therapeutics LLC
Original Assignee
Cloudbreak Bio Pharmaceutical Science And Technology Guangzhou Co Ltd
ADS Therapeutics LLC
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Publication date
Application filed by Cloudbreak Bio Pharmaceutical Science And Technology Guangzhou Co Ltd, ADS Therapeutics LLC filed Critical Cloudbreak Bio Pharmaceutical Science And Technology Guangzhou Co Ltd
Publication of WO2025131038A1 publication Critical patent/WO2025131038A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • 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
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions

Definitions

  • compositions for delivery of active pharmaceutical ingredients relates to compositions for delivery of active pharmaceutical ingredients (APIs) , and methods for making and using the compositions.
  • APIs active pharmaceutical ingredients
  • APIs active pharmaceutical ingredients compounds
  • Formulation of active pharmaceutical ingredients compounds is an important step in delivering useful medicinal compounds to humans and animals in need and in making the compounds biologically available within the body, e.g., for treating and preventing various conditions or improving symptoms thereof.
  • challenges with delivery formulations can limit the usability of the APIs, their activity and shelf life, and can in some instances result in systemic side effects.
  • APIs are often formulated in aqueous formulations, however, many APIs can be insoluble in or degrade in aqueous formulations. Additionally, delivery needs, such as tissue type and preferences of the patient, among others, may make aqueous formulations less practical in some situations.
  • This disclosure relates to excipient systems and to compositions for delivery of active pharmaceutical ingredients (APIs) .
  • APIs active pharmaceutical ingredients
  • an excipient system comprising semi-fluorinated alkanes (SFA) in combination with semi-fluorinated alkyl alcohols (SFAOH) can act as an ideal composition for formulating APIs, including difficult to formulate APIs.
  • SFA semi-fluorinated alkanes
  • SFAOH semi-fluorinated alkyl alcohols
  • SFAOH semi-fluorinated alkyl alcohols
  • the excipient system described herein and compositions described herein can provide improved delivery of an API to the cornea, e.g., by transcorneal absorption.
  • the compositions described herein are selectively transcorneally absorbed (e.g., compared with periorbital absorption) .
  • the improved delivery of the API to the cornea can allow for lower doses to be administered to a subject, and/or more frequent lower doses.
  • the improved delivery of the API to the cornea reduces one or more adverse side effects of an API and can be used to treat ocular conditions in subjects highly sensitive to the API.
  • compositions comprising: an active pharmaceutical ingredient (API) ; a semi-fluorinated alkyl alcohol compound; and a semi-fluorinated alkane compound.
  • API active pharmaceutical ingredient
  • an excipient system for delivering an API to a subject comprising: a semi-fluorinated alkyl alcohol compound; and a semi-fluorinated alkane compound.
  • compositions described herein can result in improved solubility of both water soluble and water insoluble APIs.
  • This disclosure provides an excipient system for APIs comprising a semi-fluorinated alkane (SFA) , a semi-fluorinated alkyl alcohol (SFAOH) , and also provides compositions comprising a semi-fluorinated alkane (SFA) , a semi-fluorinated alkyl alcohol (SFAOH) , and an active pharmaceutical ingredient (API) , and methods for making and using the compositions.
  • the compositions described herein can provide improved delivery formulations for APIs.
  • the delivery can be topical delivery.
  • the delivery can be to ocular tissues, skin, mucosal membrane, oral tissue, esophageal tissue, or lung tissue.
  • composition comprising: an active pharmaceutical ingredient (API) ; a semi-fluorinated alkyl alcohol compound; and a semi-fluorinated alkane compound.
  • API active pharmaceutical ingredient
  • compositions can optionally have the following features.
  • the composition can be non-aqueous.
  • the semi-fluorinated alkane compound can be selected from the group consisting of perfluorobutylheptane (F4H5) , perfluorobutylhexane (F4H6) , perfluorohexylbutane (F6H4) , perfluorohexylhexane (F6H6) , perfluorohexyloctane (F6H8) , and perfluorohexyl decane (F6H10) .
  • the semi-fluorinated alkyl alcohol compound can be a compound of Formula (II) :
  • R 6 is a linear or branched alkyl having 1 to 8 carbon atoms; x is from 1 to 10; and y is from 1 to 4.
  • the semi-fluorinated alkyl alcohol compound can be present in a concentration of from about 0.1%to about 99% (w/w) , from about 0.1%to about 80% (w/w) , from about 0.1%to about 50% (w/w) , from about 0.1%to about 30% (w/w) , from about 0.1%to about 20% (w/w) , from about 0.1%to about 15% (w/w) , from about 0.1%to about 10% (w/w) , from about 0.1%to about 5% (w/w) , about 20% (w/w) , about 15% (w/w) , about 10% (w/w) , about 5% (w/w) , about 3% (w/w) , or about 1% (w/w) .
  • the semi-fluorinated alkane compound can be present in a concentration of from about 1%to about 99.9% (w/w) , from about 20%to about 99.9% (w/w) , from about 50%to about 99.9% (w/w) , from about 70%to about 99.9% (w/w) , from about 80%to about 99.9% (w/w) , from about 85%to about 99.9% (w/w) , from about 90%to about 99.9% (w/w) , from about 95%to about 99.9% (w/w) , about 80% (w/w) , about 85% (w/w) , about 90% (w/w) , about 95% (w/w) , about 97% (w/w) , or about 99% (w/w) .
  • the API can be present in a concentration of from about 0.001%to about 20%, from about 0.01%to 15% (w/w) , from about 0.01%to 10% (w/w) , from about 0.01%to 5% (w/w) , from about 0.1%to 5% (w/w) , or from about 0.1%to 4% (w/w) .
  • the API can be in a free base or salt form.
  • the semi-fluorinated alkyl alcohol compound can be selected from pentafluoropentanol, trifluorobutanol, trifluoropropanol, heptafluorobutanol, nonafluoropentanol, pefluorohexanol, perfluoroheptanol, perfluorooctanol, perfluorononanol, (perfluorohxyl) propanol, and pentafluoroactanol, or combinations of two or more thereof.
  • the semi-fluorinated alkyl alcohol compound can be selected from F (CF2) 6 (CH2) 2 OH, F (CF2) 4 (CH2) 2 OH, F (CF2) 6 CH2OH, F (CF2) 4 CH2OH, and F (CF2) 3 CH2OH, or combinations of two or more thereof.
  • the semi-fluorinated alkane can be perfluorohexyloctane (F6H8) .
  • the semi-fluorinated alkane can be perfluorobutylheptane (F4H5) .
  • the API in the composition can be chemically stable for at least 6 months, at least 1 year, at least 18 months, at least 2 years or longer.
  • the API can be selected from alpha agonists, antibiotics, corticosteroids, antinicotinic agents, antiglaucoma agents, antihistamines, antivirals, cycloplegics/mydriatics, mast cell stabilizers, miotics, ophthalmic NSAIDs, cyclosporine, riboflavin 5'-phosphate ophthalmic compounds, and VEGF inhibitors and VEGF receptor inhibitors.
  • compositions can optionally have the following features.
  • the API can be selected from the group consisting of aceclidine, pilocarpine, bethanechol, cevimeline, methacholine, xanomeline, and aprolidine.
  • the API can be riboflavin or a riboflavin derivative, optionally the API can be selected from riboflavin, riboflavin tetraacetate, riboflavin tetrapropionate, riboflavin tetrabutyrate, riboflavin tetrapalmitate, or combinations thereof.
  • the API can be a multikinase inhibitor, optionally wherein the multikinase inhibitor is selected from afatinib, amuvatinib, axitinib, cabozantinib, canertinib, cediranib, ceritinib, crenolanib, crizotinib, dabrafenib, dacomitinib, dasatinib, erlotinib, foretinib, gefitinib, golvatinib, ibrutinib, icotinib, idelalisib, imatinib, lapatinib, lenvatinib, neratinib, nilotinib, nintedanib, palbociclib, pazopanib, ponatinib, quizartinib, regorafenib, ruxolitinib, sorafenib, sunitini
  • the API can be a co-drug selected from the group consisting of (2R, 3S) -3- (2- ( (4-bromo-lH-benzo [d] imidazol-5-yl) amino) -4, 5-dihydro-lH-imidazole-lcarbonyl) -2- ( (l-methyl-lH-imidazol-5-yl) methyl) pentyl acetate; (2R, 3S) -3- (2- ( (4-bromo-lHbenzo [d] imidazol-5-yl) amino) -4, 5-dihydro-lH-imidazole-l-carbonyl) -2- ( (l-methyl-1Himidazol-5-yl) methyl) pentyl propionate; (2R, 3S) -3- (2- ( (4-bromo-lH-benzo [d] imidazol-5-yl) amino) -4, 5-dihydro-lH-imidazole-l-carbony
  • compositions can optionally comprise: from about 0.001%to about 20%of the (w/w) active pharmaceutical ingredient (API) ; from about 0.1%to about 20% (w/w) of the semi-fluorinated alkyl alcohol compound; and from about 80%to about 99.9% (w/w) of the semi-fluorinated alkane compound.
  • API active pharmaceutical ingredient
  • compositions can optionally consist of or consist essentially of: the (w/w) active pharmaceutical ingredient (API) ; the semi-fluorinated alkyl alcohol compound; and the semi-fluorinated alkane compound.
  • API active pharmaceutical ingredient
  • the API is in a free base form.
  • the API can be lifitegrast or a derivative, analogue, pharmaceutically acceptable salt, free base form, racemic mixture, or diastereomer or enantiomer thereof.
  • the compositions can optionally have the following features.
  • the semi-fluorinated alkyl alcohol compound can be present in an amount of from about 5%to about 50% (w/w) , optionally selected from about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, and about 50% (w/w) ; and the semi-fluorinated alkane compound can be present in an amount of from about 50%to about 95% (w/w) , optionally selected from about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, and about 95% (w/w) .
  • the semi-fluorinated alkane compound can be selected from perfluorobutylheptane (F4H5) and perfluorohexyloctane (F6H8) .
  • the semi-fluorinated alkyl alcohol compound can be selected from F 3 H 1 OH, F 4 H 1 OH, F 4 H 2 OH, F 6 H 1 OH, and F 6 H 2 OH.
  • the lifitegrast or a derivative, analogue, pharmaceutically acceptable salt, free base form, racemic mixture, or diastereomer or enantiomer thereof can be present in the composition in an amount of from about 1 to about 100 mg/ml, optionally from about 4 to about 50 mg/ml, optionally from about 4 to about 20 mg/ml.
  • the lifitegrast or a derivative, analogue, pharmaceutically acceptable salt, free base form, racemic mixture, or diastereomer or enantiomer thereof can be present in the composition in an amount of from about 0.5%to about 20 % (w/w) , optionally from about 1%to about 10% (w/w) , optionally about 5% (w/w) .
  • the API can be selected from the group consisting of aceclidine, pilocarpine, bethanechol, cevimeline, methacholine, xanomeline, and aprolidine, and optionally the API can be aceclidine or a derivative, analogue, pharmaceutically acceptable salt, free base form, racemic mixture, or diastereomer or enantiomer thereof.
  • the compositions can optionally have the following features.
  • the semi-fluorinated alkyl alcohol compound can be present in an amount of from about 1%to about 20% (w/w) , optionally selected from about 5%, about 10%, about 15%, or and about 20% (w/w) ; and the semi-fluorinated alkane compound can be present in an amount of from about 80%to about 99% (w/w) , optionally selected from about 80%, about 85%, about 90%and about 95% (w/w) .
  • the semi-fluorinated alkane compound can be selected from perfluorobutylheptane (F4H5) and perfluorohexyloctane (F6H8) .
  • the semi-fluorinated alkyl alcohol compound is selected from F 3 H 1 OH, F 4 H 1 OH, F 4 H 2 OH, F 6 H 1 OH, and F 6 H 2 OH.
  • the API can be present in the composition in an amount of from about 1 to about 30 mg/ml, optionally from about 5 to about 20 mg/ml, optionally from about 10 to about 15 mg/ml.
  • the API can be present in the composition in an amount of from about 0.1%to about 10 % (w/w) , optionally from about 1%to about 3% (w/w) , optionally about 1.75% (w/w) .
  • the API can be atropine, an atropine mimetic or analog, or a free base or salt form thereof.
  • the compositions can optionally have the following features.
  • the semi-fluorinated alkyl alcohol compound can be present in an amount of from about from about 0.1%to about 10% (w/w) , optionally about 5% (w/w) ; and the semi-fluorinated alkane compound can be present in an amount of from about 90%to about 99% (w/w) , optionally selected from about 95%, about 96%, about 97%, about 98%, about 99%, about 99.5%, and about 99.9% (w/w) .
  • the semi-fluorinated alkane compound can be selected from perfluorobutylheptane (F4H5) and perfluorohexyloctane (F6H8) .
  • the semi-fluorinated alkyl alcohol compound can be selected from F 3 H 1 OH, F 4 H 1 OH, F 4 H 2 OH, F 6 H 1 OH, and F 6 H 2 OH.
  • the API can be present in the composition in an amount of from about 0.005 to about 1 mg/ml, optionally from about 0.01 to about 0.75 mg/ml, optionally from about 0.01 to about 0.1 mg/ml, optionally from about 0.05 to about 0.75 mg/ml, optionally from about 0.01 to about 0.03 mg/ml, optionally from about 0.1 to about 0.5 mg/ml.
  • the API can be present in the composition in an amount of from about from about 0.0005%to about 2 % (w/w) , optionally from about 0.001%to about 0.005%, 0.001%to about 0.01%, optionally from about 0.005%to about 0.5%, optionally from about 0.005%to about 0.1% (w/w) , optionally from about 0.008%to about 0.02%, optionally about 0.01% (w/w) .
  • provided herein are methods for delivering an API to a subject comprising dissolving the API in a composition comprising: a semi-fluorinated alkyl alcohol compound; and a semi-fluorinated alkane compound, to form an API composition, and administering the API composition to the subject.
  • the methods can optionally have the following features.
  • the method can comprise dissolving the API in the semi-fluorinated alkyl alcohol compound to form a first composition; and mixing the first composition with the semi-fluorinated alkane compound, to form the API composition.
  • the API can be selected from alpha agonists, antibiotics, corticosteroids, anticholinergic agents, antiglaucoma agents, antihistamines, antivirals, cycloplegics/mydriatics, mast cell stabilizers, miotics, ophthalmic NSAIDs, cyclosporine, riboflavin 5'-phosphate ophthalmic compounds, and VEGF inhibitors and VEGF receptor inhibitors.
  • Administering the API composition to the subject comprises administering the API composition to skin or mucosal membrane of a subject, to an eye of the subject, or to a lung of the subject.
  • a method for delivering an API to a target tissue of a subject comprising administering any one of the compositions described herein to said target tissue of the subject.
  • the API can be selected from alpha agonists, antibiotics, corticosteroids, anticholinergic agents, antiglaucoma agents, antihistamines, antivirals, cycloplegics/mydriatics, mast cell stabilizers, miotics, ophthalmic NSAIDs, cyclosporine, riboflavin 5'-phosphate ophthalmic compounds, and VEGF inhibitors and VEGF receptor inhibitors.
  • a method for treating, slowing the progression of, or reducing one or more symptoms of a condition in a subject, or inducing one or more symptoms of miosis in a subject comprising administering a composition described herein to the subject.
  • a method for treating, slowing the progression of, or reducing one or more symptoms of an ocular condition in a subject, or inducing one or more symptoms of miosis in a subject comprising administering a composition described herein to an eye of the subject.
  • the ocular condition can be selected from neurotrophic keratitis, glaucoma, elevated intraocular pressure, ocular hypertension, presbyopia, myopia, ocular rosacea, dry eye disease, meibomian gland dysfunction, blepharitis, allergic conjunctivitis, atopic keratoconjunctivitis, vernal keratoconjunctivitis, pterygium, pinguecula, corneal transplant rejection, graft versus host disease, ocular allergy, uveitis, anterior uveitis, Behcet's disease, Sjogren's syndrome, Stevens-Johnson syndrome, ocular cicatricial pemphigoid, chronic ocular surface inflammation caused by viral infection, herpes simplex keratitis, atopic conjunctivitis, Lyell’s syndrome, neovascularization induced by viral, bacterial, fungal
  • a method for slowing myopia progression in a subject or for relieving vitreous floater symptoms in a subject comprising administering a composition described herein to an eye of the subject, wherein the API is a muscarinic receptor antagonist.
  • the API can optionally be selected from atropine, an atropine mimetic or analog, or a free base or salt form thereof.
  • a method for treating, slowing the progression of, or reducing one or more symptoms of presbyopia or glaucoma in a subject, or for inducing miosis in a subject comprising administering a composition described herein to an eye of the subject, wherein the API comprises a muscarinic cholinergic receptor agonist.
  • the API can be selected from the group consisting of aceclidine, Acetazolamide, Acetylcholine, Ketorolac, ketotifen, acyclovir, cyclopentolate, polymyxin B, bacitracin, levobunolol, naphazoline, lidocaine, tobramycin, alcaftadine, proparacaine, nedocromil, lodoxamide, loteprednol, phenylephrine, apraclonidine, azithromycin, azelastine, brinzolamide, benoxinate, fluorescein, bepotastine, besifloxacin, betaxolol, timolol, bimatoprost, sulfacetamide, prednisolone, bromfenac, carbachol, carteolol, cetirizine, chloroprocaine, ciprofloxacin
  • the API can be riboflavin or a riboflavin derivative, optionally the API can be selected from riboflavin, riboflavin tetraacetate, riboflavin tetrapropionate, riboflavin tetrabutyrate, riboflavin tetrapalmitate, or combinations thereof.
  • the API can be a multikinase inhibitor, optionally wherein the multikinase inhibitor is selected from afatinib, amuvatinib, axitinib, cabozantinib, canertinib, cediranib, ceritinib, crenolanib, crizotinib, dabrafenib, dacomitinib, dasatinib, erlotinib, foretinib, gefitinib, golvatinib, ibrutinib, icotinib, idelalisib, imatinib, lapatinib, lenvatinib, neratinib, nilotinib, nintedanib, palbociclib, pazopanib, ponatinib, quizartinib, regorafenib, ruxolitinib, sorafenib, sunitini
  • the API can be a co-drug selected from the group consisting of (2R, 3S) -3- (2- ( (4-bromo-lH-benzo [d] imidazol-5-yl) amino) -4, 5-dihydro-lH-imidazole-lcarbonyl) -2- ( (l-methyl-lH-imidazol-5-yl) methyl) pentyl acetate; (2R, 3S) -3- (2- ( (4-bromo-lHbenzo [d] imidazol-5-yl) amino) -4, 5-dihydro-lH-imidazole-l-carbonyl) -2- ( (l-methyl-1Himidazol-5-yl) methyl) pentyl propionate; (2R, 3S) -3- (2- ( (4-bromo-lH-benzo [d] imidazol-5-yl) amino) -4, 5-dihydro-lH-imidazole-l-carbony
  • a method for crosslinking collagen in a tissue of a subject comprising:
  • R1, R2, and R3 are each independently selected from hydrogen or -C (O) R 5 ;
  • R4 is selected from hydrogen, -C (O) R 5 , a phosphate, or a salt thereof;
  • R5 is a linear or branched or cyclic alkyl having 1 to 26 carbon atoms
  • a method for crosslinking a structural protein comprising:
  • R1, R2, and R3 are each independently selected from hydrogen or -C (O) R 5 ;
  • R4 is selected from hydrogen, -C (O) R 5 , a phosphate, or a salt thereof;
  • R5 is a linear or branched or cyclic alkyl having 1 to 26 carbon atoms
  • the API can optionally be selected from riboflavin, riboflavin tetraacetate, riboflavin tetrapropionate, riboflavin tetrabutyrate, riboflavin tetrapalmitate, or combinations thereof.
  • an excipient system for delivering an API to a subject comprising: a semi-fluorinated alkyl alcohol compound; and a semi-fluorinated alkane compound.
  • a method for making a composition described herein comprising dissolving the API in a composition comprising: a semi-fluorinated alkyl alcohol compound; and a semi-fluorinated alkane compound.
  • the method can optionally have the following features.
  • the method can comprise dissolving the API in the semi-fluorinated alkyl alcohol compound to form a first composition; and mixing the first composition with the semi-fluorinated alkane compound.
  • a dispenser comprising: a container portion comprising an interior wall defining an interior volume and adapted to contact and store a liquid within at least a portion of the interior volume; and a composition or excipient system described herein contained within the interior volume.
  • the interior wall can comprise less than about 10%of one or more of low density polyethylene (LDPE) or polypropylene (PP) .
  • the interior wall does not comprise low density polyethylene (LDPE) or polypropylene (PP) .
  • the interior wall can comprise glass or polyethylene terephthalate.
  • the interior wall can consist essentially of glass or polyethylene terephthalate (PET) .
  • a concentration of the API can remain more than 90%of an initial API concentration after storage in the dispenser for a period of at least 6 months, or a concentration of the API can remain more than 90%of an initial API concentration after storage in the dispenser for a period of at least 12 months or a concentration of the API can remain more than 90%of an initial API concentration after storage in the dispenser for at least a period of 24 months.
  • the dispenser can further comprise: a dispensing portion adapted to dispense one or more drops of a liquid out of the container portion; and wherein the container portion and the dispensing portion each, independently, consist essentially of glass or polyethylene terephthalate (PET) .
  • PET polyethylene terephthalate
  • the dispenser can further comprise: a dispensing portion adapted to dispense one or more drops of a liquid out of the container portion; and wherein the volume of the one or more drops each independently is from about 5 ⁇ l to about 40 ⁇ l.
  • the disclosure provides a method of administering to a subject a topical ophthalmological composition for selective transcorneal absorption, the method comprising administering to an eye of the subject a composition described herein; optionally wherein the composition is non-aqueous; and optionally wherein the API is in free base form.
  • the API is selectively absorbed transcorneally in the eye as compared to periorbitally.
  • the composition is non-aqueous; optionally wherein the composition is an emulsion.
  • the API is in a free base form.
  • the composition is non-aqueous, and the composition is administered at a dose 5-10%, 5-15%, 5-20%, 5-25%, 5-30%, 10-30%, 10-40%, 10-50%, 10-60%, 10-70%, 20-30%, 20-40%, 20-50%, 20-60%, 20-70%, 30-40%, 30-50%, 30-60%, 30-70%, 40-50%, 40-60%, 40-70%, or 50-70%less than a dose of an aqueous composition comprising the API used for the same purpose (e.g., if the administering is for treating an ocular condition, the dose is compared to the dose of an aqueous composition comprising the API used for treating the ocular condition) .
  • the composition is administered to the subject: (i) every about 6 to about 8 hours or three times a day, (ii) once a day, or (iii) twice a day.
  • the disclosure provides a method of treating an ocular condition in a subject, the method comprising: (a) (i) selecting a subject in need of transcorneal absorption of an API; or (ii) selecting a subject having an ocular condition, wherein the ocular condition is in need of transcorneal absorption of an API; and (b) administering to an eye of the subject a composition described herein; optionally wherein the composition is non-aqueous; and optionally wherein the API is in free base form.
  • the API is selectively absorbed transcorneally in the eye as compared to periorbitally.
  • the composition is non-aqueous; optionally wherein the composition is an emulsion.
  • the API is in a free base form.
  • the composition is non-aqueous, and wherein the composition is administered at a dose 5-10%, 5-15%, 5-20%, 5-25%, 5-30%, 10-30%, 10-40%, 10-50%, 10-60%, 10-70%, 20-30%, 20-40%, 20-50%, 20-60%, 20-70%, 30-40%, 30-50%, 30-60%, 30-70%, 40-50%, 40-60%, 40-70%, or 50-70%less than a dose of an aqueous composition comprising the API for the ocular condition.
  • the composition is administered to the subject: (i) every about 6 to about 8 hours or three times a day, (ii) once a day, or (iii) twice a day.
  • the disclosure provides a method of selectively delivering an API to a cornea of an eye of a subject, the method comprising administering to the eye of the subject a composition described herein; optionally wherein the composition is non-aqueous; and optionally wherein the API is in free base form.
  • the API is absorbed transcorneally in the eye.
  • the API is selectively absorbed transcorneally in the eye as compared to periorbitally.
  • the composition is non-aqueous; optionally wherein the composition is an emulsion.
  • the API is in a free base form.
  • the composition is non-aqueous, and wherein the composition is administered at a dose 5-10%, 5-15%, 5-20%, 5-25%, 5-30%, 10-30%, 10-40%, 10-50%, 10-60%, 10-70%, 20-30%, 20-40%, 20-50%, 20-60%, 20-70%, 30-40%, 30-50%, 30-60%, 30-70%, 40-50%, 40-60%, 40-70%, or 50-70%less than a dose of an aqueous composition comprising the API used for the same purpose (e.g., if the administering is for treating an ocular condition, the dose is compared to the dose of an aqueous composition comprising the API used for treating the ocular condition) .
  • the composition is administered to the subject: (i) every about 6 to about 8 hours or three times a day, (ii) once a day, or (iii) twice a day.
  • the disclosure provides a method of formulating a topical ophthalmological composition for transcorneal absorption, the method comprising combining an active pharmaceutical ingredient (API) , a semi-fluorinated alkyl alcohol compound, and a semi-fluorinated alkane compound.
  • API active pharmaceutical ingredient
  • compositions and methods provided herein can provide several advantages.
  • the compositions provided herein can provide increased solubility of the API.
  • the compositions provided herein can provide increased solubility of the API in non-aqueous formulations, for example increased solubility of the API in a SFA. This is especially beneficial in instances where the API cannot achieve desired solubility in SFA alone.
  • the unique dual properties of the perfluorinated moiety and the hydroxyl moiety of the SFAOHs can act as a solubilizer or carrier to solubilize and/or emulsify all APIs, including even difficult to solubilize, in a SFA, thus leading to a robust composition for carrying and delivery of an API.
  • the compositions can provide better stability of the API as compared to, e.g., aqueous or other standard formulations of the API.
  • This provides several additional advantages, including, in some instances, the possibility to use certain APIs that were previously difficult to formulate for use, or the prevention of formation of API-based impurities, or improved shelf life and storage time as compared to other standard formulations or aqueous formulations of the API.
  • compositions described herein can be made into nanoemulsions having droplet sizes below 500 nm, 100 nm, 50 nm, 15 nm, 10 nm, and even 5 nm, or microemulsion, or an emulsion solution.
  • droplet sizes can lead to improved longer term stability of the API in the formulation as compared to aqueous formulations, as well as increased availability of the API, improved tissue penetration and distribution of the API, and improved residence time in ocular tissues.
  • the dispenser provided herein can provide increased compatibility with the compositions described herein, e.g. compositions comprising SFAOH and SFA.
  • the increased compatibility of the dispensers can lead to better stability of the compositions and of the API in the compositions, longer shelf life for the compositions, and improved delivery of the prescribed or desired amount of API to a patient’s or subject’s eye or ocular tissue.
  • the SFAOH can provide a dual role of both solubilizing the API, and acting on its own in a manner like a surfactant for stabilizing a micro-or nano-emulsion, emulsion solution, or suspension, thus potentially eliminating the need for an added surfactant and thereby eliminating potential toxic complications from such surfactants. In some instances, this can lead to stability of the compositions and stability of the API in the compositions without added surfactants. In some instances, additional surfactant may be added for desired stability, but the presence of SFAOH can, in some instances, allow for decreased amounts of surfactant to achieve desired stability.
  • the compatibility of SFAOH with SFA can allow for useful compositions (e.g., with desired solubility of API in SFA) without undesirable effects to the compositions or the API.
  • compositions e.g., topical ophthalmological compositions
  • the compositions described herein can provide improved delivery of the API to the cornea, e.g., by transcorneal absorption, e.g., as compared to an aqueous composition comprising the API or an aqueous composition comprising a salt of the API.
  • the compositions described herein are selectively transcorneally absorbed (e.g., compared with periorbital absorption) .
  • the improved delivery of the API to the cornea can allow for lower doses to be administered to a subject, and/or more frequent lower doses.
  • the improved delivery of the API to the cornea reduces one or more adverse side effects of an API and can be used to treat ocular conditions in subjects highly sensitive to the API.
  • the disclosure provides a method of administering to a subject a composition (e.g., a topical ophthalmological composition) for selective transcorneal absorption, the method comprising administering to an eye of the subject a composition described herein; optionally wherein the composition is non-aqueous; and optionally wherein the API is in free base form.
  • a composition e.g., a topical ophthalmological composition
  • the method comprising administering to an eye of the subject a composition described herein; optionally wherein the composition is non-aqueous; and optionally wherein the API is in free base form.
  • the disclosure provides a method of treating an ocular condition in a subject, the method comprising: (a) (i) selecting a subject in need of transcorneal absorption of an API; or (ii) selecting a subject having an ocular condition, wherein the ocular condition is in need of transcorneal absorption of an API; and (b) administering to an eye of the subject the composition of any one of claims 1-16; optionally wherein the composition is non-aqueous; and optionally wherein the API is in free base form.
  • Subjects in need of transcorneal absorption of an API include subjects having high sensitivity to an API, subjects in need of a lower dose of an API, subjects having one or more adverse effects of an aqueous API (e.g., an adverse effect attributed to the API and not attributed to another component or feature of the composition comprising the API, e.g., pH or a preservative) , subjects in need of treatment with an API having a target receptor in one or more of the cornea, the aqueous humor, or the iris, and subjects in need of treatment with an API that is associated with one or more adverse events in one or more of conjunctival, scleral, and ciliary body.
  • an aqueous API e.g., an adverse effect attributed to the API and not attributed to another component or feature of the composition comprising the API, e.g., pH or a preservative
  • the disclosure provides a method of selectively delivering an API to a cornea of an eye of a subject, the method comprising administering to the eye of the subject a composition described herein; optionally wherein the composition is non-aqueous; and optionally wherein the API is in free base form.
  • the API is absorbed transcorneally in the eye. In some instances, the API is selectively absorbed transcorneally in the eye as compared to periorbitally.
  • the composition is non-aqueous. In some instances, the composition is an emulsion.
  • the composition is non-aqueous, and the composition is administered at a dose 5-10%, 5-15%, 5-20%, 5-25%, 5-30%, 10-30%, 10-40%, 10-50%, 10-60%, 10-70%, 20-30%, 20-40%, 20-50%, 20-60%, 20-70%, 30-40%, 30-50%, 30-60%, 30-70%, 40-50%, 40-60%, 40-70%, or 50-70%less than a dose of an aqueous composition comprising the API or a salt thereof for the same purpose.
  • the composition is administered at a dose 30%less than a dose of an aqueous composition comprising the API or a salt thereof for treating the ocular condition.
  • the composition is administered to the subject: (i) every about 6 to about 8 hours or three times a day, (ii) once a day, or (iii) twice a day.
  • the API is in a free base form.
  • FIG. 1a is a graph showing solubility (mg/mL) of pilocarpine in the indicated solvents (x-axis) .
  • FIG. 1b is a graph showing solubility (mg/mL) of pilocarpine in the indicated solvents (x-axis) .
  • FIG. 2 is a graph showing solubility (mg/mL) of atropine in the indicated solvents (x-axis) .
  • FIG. 3 is a graph showing solubility (mg/mL) of Compound A in the indicated solvents (x-axis) .
  • FIG. 4 is a graph showing solubility (mg/mL) of riboflavin tetraacetate (RTA) in the indicated solvents (x-axis) .
  • FIG. 5 is a graph showing solubility (mg/mL) of riboflavin tetrabutyrate (RTB) in the indicated solvents (x-axis) .
  • FIG. 6 is a graph showing solubility (mg/mL) of nintedanib in the indicated solvents (x-axis) .
  • FIG. 7 is a graph showing solubility (mg/mL) of axitinib in the indicated solvents (x-axis) .
  • FIG. 8a is a graph showing effect on pupil diameter (mm) of the indicated solutions at the indicated timepoints after instillation.
  • FIG. 8b is a graph showing changes in pupil diameter (mm) of the indicated solutions at the indicated timepoints after instillation.
  • FIG. 8c is a graph showing effect on pupil diameter (mm) of the indicated solutions at the indicated timepoints after instillation.
  • FIG. 8d is a graph showing changes in pupil diameter (mm) of the indicated solutions at the indicated timepoints after instillation.
  • FIG. 9 is an exploded, schematic cross-sectional view of an exemplary embodiment of a dispenser as described herein.
  • FIG. 10 is a graph depicting aceclidine concentration in ocular tissues at different times after topical ocular dosing of aceclidine-10%F6H1OH-90%F6H8 to both eyes in rabbits.
  • compositions for delivery of active pharmaceutical ingredients comprising medium chain a semi-fluorinated alkane (SFA) , a semi-fluorinated alkyl alcohol (SFAOH) , and an active pharmaceutical ingredient (API) , and methods for making and using the compositions, such as methods for treating or slowing the progression of, or reducing one or more symptoms of a condition in a subject, or inducing one or more symptoms of miosis in a subject.
  • dispensers or containers comprising the compositions.
  • the term “about” means “approximately” (e.g., plus or minus approximately 10%of the indicated value) .
  • contacting refers to the bringing together of indicated moieties in an in vitro system or an in vivo system.
  • “contacting” the eye tissue with a compound of the invention includes the administration of a compound of the present invention to an individual or patient, such as a human, having the eye tissue in need of treatment, as well as, for example, introducing a compound of the invention into a sample containing a cellular or purified preparation containing the ocular tissue.
  • a human subject may be of any age, for example, from 0 to 100 years old.
  • “pediatric subject” and “child” are used interchangeably and refer to subjects from 0 to 18 years old, for example, 1, 2, 5, 10, 12, or 14 years old.
  • the phrase “effective amount” or “therapeutically effective amount” refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal, individual or human that is being sought by a researcher, veterinarian, medical doctor or other clinician.
  • treating refers to 1) inhibiting the disease; for example, inhibiting a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., arresting further development of the pathology and/or symptomatology) , or 2) ameliorating the disease; for example, ameliorating a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing the pathology and/or symptomatology) .
  • alkyl refers to saturated, monovalent hydrocarbon moieties having linear or branched moieties or combinations thereof and containing the specified (e.g., 1 to 26) carbon atoms.
  • cycloalkyl refers to a monovalent or divalent group of, e.g., 3 to 8 carbon atoms, derived from a saturated cyclic hydrocarbon. Cycloalkyl groups can be monocyclic or polycyclic.
  • compositions comprising an active pharmaceutical ingredient (API) , a semi-fluorinated alkyl alcohol compound, and a semi-fluorinated alkane compound.
  • API active pharmaceutical ingredient
  • the composition is non-aqueous. In some instances of the compositions described herein, the composition is an oil-in-oil emulsion. In some instances of the compositions described herein, the composition is an emulsion solution.
  • compositions described herein can include an active pharmaceutical ingredient (API) compound.
  • APIs active pharmaceutical ingredient
  • solvates include for example hydrates, alcoholates (e.g., ethanol solvate) , and the like.
  • APIs can exist in different polymorphic forms. Such forms are intended to be included within the scope of the present disclosure.
  • Exemplary, non-limiting APIs useful in the compositions described herein can include alpha agonists, antibiotics, corticosteroids, anticholinergic agents (e.g., antimuscarinics and antinicotinics) , antiglaucoma agents (e.g., alpha agonists, beta-blockers, carbonic anhydrase inhibitors, miotics, prostaglandin agonists, and the like) , antihistamines, antivirals, cycloplegics/mydriatics, mast cell stabilizers, miotics (e.g., cholinesterase inhibitors, direct-acting miotics, and the like) , ophthalmic non-steroidal anti-inflammatory drugs (NSAIDs) , cyclosporine, riboflavin 5'-phosphate ophthalmic compounds, and vascular endothelial growth factor (VEGF) and VEGF receptor inhibitors.
  • NSAIDs ophthalmic non-steroidal anti-inflammatory
  • antibiotics can include Moxifloxacin, Levofloxacin, Ofloxacin, Besifloxacin, Gatifloxacin, Azithromycin, Tobramycin, Erythromycin, Bacitracin, Neomycin-Polymyxin B-Gramicidin, Neomycin-Polymyxin B-Bacitracin, Bacitracin-Polymyxin B, and Sulfacetamide.
  • Exemplary, nonlimiting anti-parasitics can include formamidine parasiticides or isooxazoline parasiticides, such as but not limited to fluralaner, sarolaner, lotilaner, afoxolaner, and/or fluxametamide.
  • Exemplary, nonlimiting steroids and NSAIDs can include Fluorometholone, Loteprednol, Rimexolone, Prednisolone, and Difluprednate.
  • Exemplary, nonlimiting antimicrobials can include Natamycin, Ganciclovir, Trifluiridine, and Cysteamine.
  • Exemplary, nonlimiting pressure regulators can include Brimonidine, Apraclonidine Iopidine, Dorzolamide, Brinzolamide, Azopt, Timolol, Timoptic/Istalol/Betimol, Betaxolol, Betoptic, Levobunolol, Betagan, Metipranolol, Optipranolol, Latanoprost, Xalatan Green, Bimatoprost, Lumigan, Tafluprost, Zioptan, Latanoprostene, Vyzulta Turquoise, Pilocarpine, Carbachol, Isopto Carbachol, Netarsudil, and Rhopressa.
  • Exemplary, nonlimiting dilation and cycloplegia agents include Atropine, Isopto Atropine, Atropisol, Scopolamine, Isopto Hyoscine Red, Cyclopentolate, Cyclogyl, AK Pentolate, Tropicamide, Mydriacyl, Tropicacyl, and Phenylephrine.
  • muscarinic receptor antagonists include atropine, hyoscyamine, scopolamine, diphenhydramine, dimenhydrinate, dicycloverine, tolterodine, oxybutynin, ipratropium, pirenzepine, telenzepine, tripitramine, gallamine, methoctramine, darifenacin, tiotropium, chlorpromazine, and haloperidol, a free base form, or a pharmaceutically acceptable salt thereof.
  • the API can be a muscarinic receptor antagonist.
  • exemplary non-limiting muscarinic receptor antagonists can include atropine, hyoscyamine, scopolamine, diphenhydramine, dimenhydrinate, dicycloverine, tolterodine, oxybutynin, ipratropium, pirenzepine, telenzepine, tripitramine, gallamine, methoctramine, darifenacin, tiotropium, chlorpromazine, and haloperidol, a free base form, or a pharmaceutically acceptable salt thereof.
  • the API is in a free base form.
  • the API is in a free acid form.
  • compositions comprising a therapeutically effective amount of anti-parasitic compound as an active pharmaceutical ingredient; a semi-fluorinated alkyl alcohol; and a semi-fluorinated alkane compound.
  • the compositions can, in some instances, be topical ophthalmological compositions.
  • Anti-parasitic compounds can, in some instances, aid in eradication or reduction of parasite infestations of the eyes, ocular tissue, skin, eyelashes, or other body hair. In some instances, this can temporarily or permanently treat or reduce or relieve symptoms of certain diseases or conditions, such as ocular, skin, vector-borne, or other diseases cause by parasites. In some instances, anti-parasitic compounds can temporarily or permanently treat or reduce or relieve symptoms of certain ocular diseases or conditions, such as blepharitis, meibomian gland disfunction, or rosacea caused by parasites such as Demodex mites.
  • anti-parasitic compounds can temporarily or permanently treat or reduce or relieve symptoms of eyelid margin redness caused by Demodex mites, or improve eyelash health in a subject. In some instances, anti-parasitic compounds can temporarily or permanently eradicate, reduce the population of, treat or reduce or relieve symptoms of lice, scabies, or bed bugs and associated skin, hair, scalp, or follicular conditions. In some instances, the anti-parasitic compound can be an isooxazoline parasiticide or a formamidine parasiticide.
  • the anti-parasitic compound can be an isooxazoline parasiticide selected from fluralaner, sarolaner, lotilaner, afoxolaner, and/or fluxametamide, including derivatives, analogues, and L-and D-isomers thereof, including but not limited to enantiomers, compositions comprising racemic mixtures, and enantiomerically pure compositions.
  • the anti-parasitic compound can be in free base form.
  • the anti-parasitic compound can be present in an amount of from about 0.1%to about 5% (w/w) , from about 0.1%to about 2.5% (w/w) , from about 0.1%to about 2% (w/w) , from about 0.1%to about 1.5% (w/w) , from about 0.1%to about 1% (w/w) , from about 0.1%to about 0.5% (w/w) , from about 0.1%to about 0.45% (w/w) , from about 0.1%to about 0.4% (w/w) , from about 0.1%to about 0.35% (w/w) , from about 0.1%to about 0.3% (w/w) , from about 0.1%to about 0.25% (w/w) , from about 0.1%to about 0.2% (w/w) , from about 0.15%to about 0.5% (w/w) , from about 0.15%to about 0.45% (w/w) , from about 0.15%to about 0.4% (w/w) , from about 0.15%to about 0.5%
  • the anti-parasitic compound can be lotilaner or TP-03.
  • the lotilaner or TP-03 can be in a form including derivatives, analogues, and L-and D-isomers thereof, including but not limited to enantiomers, compositions comprising racemic mixtures, and enantiomerically pure compositions.
  • the lotilaner or TP-03 can be in free base form.
  • the lotilaner or TP-03 can be present in an amount of from about 0.1%to about 5% (w/w) , from about 0.1%to about 2.5% (w/w) , from about 0.1%to about 2% (w/w) , from about 0.1%to about 1.5% (w/w) , from about 0.1%to about 1% (w/w) , from about 0.1%to about 0.5% (w/w) , from about 0.1%to about 0.45% (w/w) , from about 0.1%to about 0.4% (w/w) , from about 0.1%to about 0.35% (w/w) , from about 0.1%to about 0.3% (w/w) , from about 0.1%to about 0.25% (w/w) , from about 0.1%to about 0.2% (w/w) , from about 0.15%to about 0.5% (w/w) , from about 0.15%to about 0.45% (w/w) , from about 0.15%to about 0.4% (w/w) , from about 0.1%) 0.1
  • the corticosteroid can be loteprednol or etiprednol, or a derivative, analogue, pharmaceutically acceptable salt, free base form, racemic mixture, or diastereomer or enantiomer thereof.
  • Loteprednol and etiprednol can be useful in the treatment of various inflammatory eye conditions and in reduction of inflammation after eye surgery, seasonal allergic conjunctivitis, uveitis, and chronic forms of keratitis (e.g., adenoviral, Thygeson's keratitis, vernal keratoconjunctivitis, pingueculitis, giant papillary conjunctivitis, episcleritis) .
  • Non-limiting exemplary conditions that can benefit from application of loteprednol or etiprednol include dry eye disease or keratoconjunctivitis sicca, abnormal corneal neovascularization, Sjogren's syndrome, conjunctivitis, inflammation caused by surgery, injury, or other conditions, eye swelling, redness, itching, or pain, uveitis, scleritis and episcleritis, corneal transplant and corneal allograft rejection (including all forms of endothelial keratoplasty (EK) such as, e.g., Descemet Stripping Endothelial Keratoplasty (DSEK) , Descemet Stripping (Automated) EK (DS AEK) or ultrathin (UT) -DSAEK) , bacterial keratitis, Herpes simplex keratitis, allergic eye diseases, graft vs host disease, cicatrising conjunctival disorders, and anterior uveitis.
  • Loteprednol and etiprednol can also be useful in the treatment of abnormal corneal neovascularization, including neovascularizations that are, are related to, or are caused by a condition selected from alkali burns or injury induced neovascularization, corneal graft rejection in high-risk corneal transplant patients, neovascular glaucoma, contact lens induced redness neovascularization, ocular rosacea, ocular pemphigoid, limbal stem cell deficiency, Sjogren's syndrome, atopic conjunctivitis, graft versus host disease, Lyell's syndrome and Steven Johnson syndrome, ulceration, and redness induced by viral, bacterial, fungal, or parasitic infection.
  • neovascularizations that are, are related to, or are caused by a condition selected from alkali burns or injury induced neovascularization, corneal graft rejection in high-risk corneal transplant patients, n
  • the loteprednol or etiprednol or a derivative, analogue, pharmaceutically acceptable salt, free base form, racemic mixture, or diastereomer or enantiomer thereof can be present in an amount of from about 0.01%to about 10% (w/w) , from about 0.01%to about 9% (w/w) , from about 0.01%to about 8% (w/w) , from about 0.01%to about 7% (w/w) , from about 0.01%to about 6% (w/w) , from about 0.01%to about 5% (w/w) , from about 0.02%to about 10% (w/w) , from about 0.03%to about 10% (w/w) , from about 0.04%to about 10% (w/w) , from about 0.05%to about 10% (w/w) , from about 0.06%to about 10% (w/w) , from about 0.07%to about 10% (w/w) , from about 0.08%to about
  • compositions comprising a therapeutically effective amount of lifitegrast or a derivative, analogue, pharmaceutically acceptable salt, free base form, racemic mixture, or diastereomer or enantiomer thereof as an active pharmaceutical ingredient; a semi-fluorinated alkyl alcohol; and a semifluorinated alkane compound.
  • the compositions can, in some instances, be topical ophthalmological compositions.
  • Lifitegrast is an N-acyl-L-alpha-amino acid obtained by formal condensation of the carboxy group of N- [2- (1-benzofuran-6-carbonyl) ] -5, 7-dichloro-1, 2, 3, 4-tetrahydroisoquinoline-6-carboxylic acid with the amino group of 3- (methanesulfonyl) -L-phenylalanine.
  • Lifitegrast can reduce inflammation by inhibiting inflammatory cell binding through inhibition of an integrin, lymphocyte function-associated antigen 1 (LFA-1) , from binding to intercellular adhesion molecule 1 (ICAM-1) .
  • LFA-1 lymphocyte function-associated antigen 1
  • IAM-1 intercellular adhesion molecule 1
  • Lifitegrast, or a derivative, analogue, pharmaceutically acceptable salt, free base form, racemic mixture, or diastereomer or enantiomer thereof can, in some instances, aid in treatment of dry eye syndrome, or keratoconjunctivitis sicca.
  • lifitegrast or a derivative, analogue, pharmaceutically acceptable salt, free base form, racemic mixture, or diastereomer or enantiomer thereof can slow the progression of, treat, or reduce or relieve symptoms of certain ocular diseases or conditions, such as dry eye syndrome or keratoconjunctivitis sicca, dry eye disease, inflammatory dry eye, redness, or meibomian gland disfunction.
  • the lifitegrast or a derivative, analogue, pharmaceutically acceptable salt, free base form, racemic mixture, or diastereomer or enantiomer thereof can be present in an amount of from about 0.1%to about 10% (w/w) , from about 0.1%to about 9% (w/w) , from about 0.1%to about 8% (w/w) , from about 0.1%to about 7% (w/w) , from about 0.1%to about 6% (w/w) , from about 0.1%to about 5% (w/w) , from about 0.2%to about 10% (w/w) , from about 0.3%to about 10% (w/w) , from about 0.4%to about 10% (w/w) , from about 0.5%to about 10% (w/w) , from about 0.6%to about 10% (w/w) , from about 0.7%to about 10% (w/w) , from about 0.8%to about 10% (w/w) , from about 0.9%to about 10% (w/w)
  • the cyclosporine or a derivative, analogue, pharmaceutically acceptable salt, free base form, racemic mixture, or diastereomer or enantiomer thereof can be present in an amount of from about 0.0001%to about 5% (w/w) , from about 0.1%to about 2.5% (w/w) , from about 0.1%to about 2% (w/w) , from about 0.1%to about 1.5% (w/w) , from about 0.1%to about 1% (w/w) , from about 0.001%to about 0.01% (w/w) , from about 0.001%to about 0.009% (w/w) , from about 0.001%to about 0.008% (w/w) , from about 0.001%to about 0.007% (w/w) , from about 0.001%to about 0.006% (w/w) , from about 0.001%to about 0.005% (w/w) , from about 0.001%to about 0.004% (w/w) , from about 0.001%to about 5% (w
  • compositions comprising a therapeutically effective amount of a pressure regulator, such as Brimonidine, Apraclonidine Iopidine, Dorzolamide, Brinzolamide, Azopt, Timolol, Timoptic/Istalol/Betimol, Betaxolol, Betoptic, Levobunolol, Betagan, Metipranolol, Optipranolol, Latanoprost, Xalatan Green, Bimatoprost, Lumigan, Tafluprost, Zioptan, Latanoprostene, Vyzulta Turquoise, Pilocarpine, Carbachol, Isopto Carbachol, Netarsudil, and Rhopressa, or a derivative, analogue, pharmaceutically acceptable salt, free base form, racemic mixture, or diastereomer or enantiomer thereof as an active pharmaceutical ingredient; a semi-fluorinated alkyl alcohol; and a semi-fluor
  • a pressure regulator such
  • Pressure regulators can, in some instances, aid in treatment of glaucoma.
  • pressure regulators can slow the progression of, treat, or reduce or relieve symptoms of certain ocular diseases or conditions, such as glaucoma, ocular hypertension, or high fluid pressure in an eye of a subject.
  • pressure regulators can lower fluid pressure in an eye of a subject.
  • the pressure regulator such as Brimonidine or a derivative, analogue, pharmaceutically acceptable salt, free base form, racemic mixture, or diastereomer or enantiomer thereof, can be present in an amount of from about 0.0001%to about 5% (w/w) , from about 0.1%to about 2.5% (w/w) , from about 0.1%to about 2% (w/w) , from about 0.1%to about 1.5% (w/w) , from about 0.002%to about 0.3% (w/w) , from about 0.0025%to about 0.25% (w/w) , from about 0.1%to about 1% (w/w) , from about 0.001%to about 0.01% (w/w) , from about 0.001%to about 0.009% (w/w) , from about 0.001%to about 0.008% (w/w) , from about 0.001%to about 0.007% (w/w) , from about 0.001%to about 0.006% (w/w) , from about 0.00 0.001%to
  • compositions comprising a therapeutically effective amount of a muscarinic cholinergic receptor agonist as an active pharmaceutical ingredient; a semi-fluorinated alkyl alcohol; and a semi-fluorinated alkane compound.
  • the compositions can, in some instances, be topical ophthalmological compositions.
  • Muscarinic cholinergic receptor agonists can, in some instances, cause pupil contraction to alter the focusing depth of field of an eye. In some instances, this can temporarily relieve symptoms of certain eye diseases or conditions such as presbyopia.
  • the agonists can lower intraocular pressure (IOP) . This mechanism can, in some instances, be used to treat glaucoma.
  • the muscarinic cholinergic receptor agonist can be selected from the group consisting of aceclidine, pilocarpine, bethanechol, cevimeline, methacholine, xanomeline, and aprolidine, or combinations thereof.
  • the muscarinic cholinergic receptor agonist can be in salt form. In some instances, the muscarinic cholinergic receptor agonist can be in free base form.
  • the muscarinic cholinergic receptor agonist can be present in an amount of from about 0.1%to about 5% (w/w) , from about 0.1%to about 2.5% (w/w) , from about 0.1%to about 2% (w/w) , from about 0.1%to about 1.5% (w/w) , from about 0.1%to about 1% (w/w) , from about 0.1%to about 0.5% (w/w) , from about 0.1%to about 1.7% (w/w) , from about 0.1%to about 1.3% (w/w) , from about 0.1%to about 0.7% (w/w) , from about 0.1%to about 2% (w/w) , from about 0.3%to about 2% (w/w) , from about 0.5%to about 2% (w/w) , from about 0.7%to about 2% (w/w) , from about 1%to about 2% (w/w) , from about 1.3%to about 2% (w/w) , from about 0.5%to about 2% (
  • the muscarinic cholinergic receptor agonist can be aceclidine.
  • the aceclidine can be in salt form, such as, for example aceclidine sulfate.
  • the aceclidine can be in salt form, such as, for example aceclidine hydrochloride.
  • the aceclidine can be in free base form.
  • the aceclidine can be present in an amount of from about 0.01%to about 10% (w/w) , from about 0.01%to about 9% (w/w) , from about 0.01%to about 8% (w/w) , from about 0.01%to about 7% (w/w) , from about 0.01%to about 6% (w/w) , from about 0.01%to about 5% (w/w) , from about 0.01%to about 4% (w/w) , from about 0.01%to about 3% (w/w) , from about 0.01%to about 2% (w/w) , from about 0.01%to about 1% (w/w) , from about 0.01%to about 0.9% (w/w) , from about 0.01%to about 0.8% (w/w) , from about 0.01%to about 0.7% (w/w) , from about 0.01%to about 0.6% (w/w) , from about 0.01%to about 0.5% (w/w)
  • exemplary compounds of Formula (I) can include riboflavin, riboflavin-5-phosphate, riboflavin tetraacetate: (2R, 3S, 4S) -5- (7, 8-dimethyl-2, 4-dioxo-3, 4-dihydrobenzo [g] pteridin-10 (2H) -yl) pentane-1, 2, 3, 4-tetrayl tetraacetate, riboflavin tetrapropionate: (2R, 3S, 4S) -5- (7, 8-dimethyl-2, 4-dioxo-3, 4-dihydrobenzo [g] pteridin-10 (2H) -yl) pentane-1, 2, 3, 4-tetrayl tetrapropionate, riboflavin tetrabutyrate: (2R, 3S, 4S) -5- (7, 8-dimethyl-2, 4-dioxo-3, 4-dihydrobenzo [
  • the API can be a multikinase inhibitor selected from afatinib, amuvatinib, axitinib, cabozantinib, canertinib, cediranib, ceritinib, crenolanib, crizotinib, dabrafenib, dacomitinib, dasatinib, erlotinib, foretinib, gefitinib, golvatinib, ibrutinib, icotinib, idelalisib, imatinib, lapatinib, lenvatinib, neratinib, nilotinib, nintedanib, palbociclib, pazopanib, ponatinib, quizartinib, regorafenib, ruxolitinib, sorafenib, sunitinib, tandutinib
  • the multikinase inhibitor can be selected from axitinib, nintedanib, and pazopanib. In some instances, the multikinase inhibitor can be axitinib, and optionally can be present in the compositions described herein in an amount of from about 0.0001%to about 5% (w/w) , from about 0.0005%to about 2% (w/w) , or from about 0.001%to about 1% (w/w) .
  • the multikinase inhibitor can be nintedanib, and optionally can be present in the compositions described herein in an amount of from about 0.0001%to about 5% (w/w) , from about 0.0005%to about 2% (w/w) , from about 0.001%to about 1% (w/w) , or from about 0.01%to about 1% (w/w) .
  • the multikinase inhibitor can be pazopanib, and optionally can be present in the compositions described herein in an amount of from about 0.0001%to about 5% (w/w) , from about 0.0005%to about 2% (w/w) , or from about 0.001%to about 1% (w/w) .
  • the API can be present in the compositions described herein in an amount of about 0.02% (w/w) . In some instances, the API can be present in the compositions described herein in an amount of about 0.04% (w/w) . In some instances, the API can be present in the compositions described herein in an amount of about 0.05% (w/w) . In some instances, the API can be present in the compositions described herein in an amount of about 1% (w/w) .
  • the API in the composition is chemically stable for at least 6 months, at least 1 year, at least 18 months, or at least 2 years.
  • Suitable examples of semifluorinated alkane compounds include perfluorobutylheptane (F4H5) , perfluorobutylhexane (F4H6) , perfluorohexylbutane (F6H4) , perfluorohexylhexane (F6H6) , perfluorohexyloctane (F6H8) , and perfluorohexyl decane (F6H10) .
  • the SFA is perfluorohexyloctane (F6H8) .
  • F6H8 The structure of F6H8 is shown below:
  • the SFA can be present in the compositions in an amount of from about 1%to about 99.9% (w/w) , from about 1%to about 30% (w/w) , from about 1%to about 25% (w/w) , from about 1%to about 20% (w/w) , from about 5%to about 20% (w/w) , from about 5%to about 15% (w/w) , from about 10%to about 99.9% (w/w) , from about 20%to about 99.9% (w/w) , from about 30%to about 99.9% (w/w) , from about 40%to about 99.9% (w/w) , from about 50%to about 99.9% (w/w) , from about 60%to about 99.9% (w/w) , from about 65%to about 99.9% (w/w) , from about 70%to about 99.9% (w/w) , from about 75%to about 99.9% (w/w) , from about 80%to about 99.9% (w/w)
  • compositions described herein can include a semi-fluorinated alkyl alcohol compound (SFAOH) .
  • SFAOH semi-fluorinated alkyl alcohol compound
  • Applicant has surprisingly found that the addition of SFAOH to SFA can result in high solubility of APIs in the composition, e.g., in SFAs.
  • a semi-fluorinated alkyl alcohol (SFAOH) has two moieties, an alcohol segment and a perfluorinated segment, bound covalently.
  • the hydroxyl functionality of the SFAOH makes the SFAOH a good solvent for organic compounds due to the solubilizing power of hydroxyl group forming hydrogen bonding and to polar interactions with APIs being dissolved and it is further believed the perfluorinated segment allows good solubility, miscibility, and/or emulsifying capability in the SFA of the compositions.
  • the inclusion of the SFAOH in the compositions described herein can create a suitable delivery system for all APIs, including both water soluble and water insoluble APIs.
  • compositions described herein can thus provide suitable delivery compositions for water insoluble APIs for which there were, prior to the present invention disclosed herein, very limited ways to formulate, or APIs that have low solubility in aqueous formulations. Due to the unique properties of the SFAOH, the compositions described herein can also provide beneficial suitable delivery compositions for water soluble APIs, especially those that can otherwise suffer from stability or degradation issues in aqueous formulations.
  • Nonlimiting examples of APIs that have limited or no solubility in aqueous formulations that can be suitably formulated in compositions described herein include, APIs such as steroids, tyrosine kinase inhibitor class compounds, and compounds containing one or more aromatic heterocyclic functionalities.
  • the semi-fluorinated alkyl alcohol can be a partially fluorinated alkyl alcohol compound having a formula F (CF 2 ) x R 1 (OH) y .
  • R 1 can be a linear or branched alkyl having 1 to 8 carbon atoms.
  • x is an integer from 1 to 10
  • y is an integer from 1 to 4.
  • x can be 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
  • y can be 1, 2, 3, or 4, 5.
  • Exemplary, non-limiting semifluorinated alkyl alcohols include 4, 4, 5, 5, 5-pentafluoro-1-pentanol; 4, 4, 4-trifluoro-1-butanol; 3, 3, 3-trifluoro-1-proponal; 2, 2, 3, 3, 4, 4, 4-heptafluoro-1-butanol; 2, 2, 3, 3, 4, 4, 5, 5, 5-nonafluoro-1-pentanol; 1H, 1H-perfluorohexan-1-ol; 1H, 1H-perfluoro-1-heptanol; 1H, 1H-perfluoro-1-octanol; 1H, 1H-perfluoro-1-nonanol; 3- (perfluorohexyl) propanol-1; and 7, 7, 8, 8, 8-pentafluorooctan-1-ol.
  • dispensers comprising the compositions described herein.
  • an example dispenser 10 contains a liquid 14 of the compositions described herein.
  • the compositions described herein can, in some instances, be less stable in low density polyethylene (LDPE) and in poplypropylene (PP) than in other materials such as glass or polyethylene terephthalate (PET) .
  • LDPE low density polyethylene
  • PP poplypropylene
  • PET polyethylene terephthalate
  • LDPE and PET material absorb one or more components of the compositions described herein, thereby reducing the content of the active pharmaceutical ingredient (API) over time.
  • API active pharmaceutical ingredient
  • the interior wall 22 of the dispenser 10 comprises less than about 10%, less than about 5%, or less than about 1%of one or more of low density polyethylene (LDPE) or polypropylene (PP) . In some instances, the interior wall 22 does not comprise low density polyethylene (LDPE) or polypropylene (PP) . In some instances, the interior wall 22 comprises glass or polyethylene terephthalate. In some instances, the interior wall 22 consists essentially of glass or polyethylene terephthalate (PET) .
  • the concentration of the API in the compositions of the liquid 14 remains more than 90%of the initial API concentration after storage in the dispenser 10 for a period of 6 months. In some instances, the concentration of the API in the compositions of the liquid 14 remains more than 90%of the initial API concentration after storage in the dispenser 10 for a period of 12 months.
  • Exemplary, nonlimiting ocular diseases that can be treated with the compositions, dispensers, and methods described herein include chemical burns or a disease selected from keratoconus, thin corneas, keratitis, infectious keratitis including bacterial or fungal keratitis, corneal ulcer, bullous keratopathy and other forms of corneal edema, keratolysis, an autoimmune disease, a cicatricizing disease such as Ocular Cicatricial Pemphigoid, Stevens Johnson Syndrome, Lupus Erythematosus, Rheumatoid Arthritis, corneal ectasia including cornea ectasia appearing after laser-assisted in situ keratomileusis (LASIK) and photorefractive keratectomy (PRK) , post-refractive ectasia, corneal degeneration, brittle cornea syndrome, Ehlers-Danlos Syndrome Type VI, corneal neovascularization, corneal melting including Corneal Melting
  • the disease or condition can be a front of eye disease or condition.
  • exemplary, nonlimiting front of eye diseases or conditions that can be treated with the compositions, dispensers, and methods described herein include neurotrophic keratitis, glaucoma, elevated intraocular pressure, ocular hypertension, presbyopia, myopia, ocular rosacea, dry eye disease, meibomian gland dysfunction, blepharitis, allergic conjunctivitis, atopic keratoconjunctivitis, vernal keratoconjunctivitis, pterygium, pinguecula, corneal transplant rejection, graft versus host disease, ocular allergy, uveitis, anterior uveitis, Behcet's disease, Sjogren's syndrome, Stevens-Johnson syndrome, ocular cicatricial pemphigoid, chronic ocular surface inflammation caused by viral infection, herpes simplex keratitis, atopic conjunctivitis
  • the disease or condition can be a back of eye disease or condition.
  • the methods can include a method for treating, slowing the progression of, or reducing one or more symptoms of an ocular condition in a subject, or inducing one or more symptoms of miosis in a subject, comprising administering the compositions described herein to the eye of a subject.
  • the methods can include a method of delivering an API to an eye of a subject comprising administering the compositions or topical ophthalmological compositions described herein.
  • Administering can in some instances include contacting the eye with the composition.
  • the methods can include a method for slowing myopia progression in a subject or for relieving vitreous floater symptoms in a subject, comprising administering the topical ophthalmological compositions described herein to the subject, wherein the API is a muscarinic receptor antagonist, such as, for example, atropine, an atropine mimetic or analog, or a free base or salt form thereof.
  • the API is a muscarinic receptor antagonist, such as, for example, atropine, an atropine mimetic or analog, or a free base or salt form thereof.
  • compositions described herein can contain APIs, such as, e.g., a co-drug as described herein, or, e.g., a muscarinic cholinergic receptor agonists such as, for example, aceclidine, pilocarpine, or combinations thereof, that can treat ocular diseases or conditions such as presbyopia, refractive errors of the eye, Sjogren's syndrome, glaucoma, conjunctivitis, lacrimal gland disease, or esotropia.
  • methods for treating ocular diseases or conditions using the compositions and methods described herein can be presbyopia.
  • the ocular diseases or conditions can be refractive errors of the eye, Sjogren's syndrome, glaucoma, conjunctivitis, lacrimal gland disease, or esotropia.
  • methods are providing for administering, to the eye of a subject, an effective amount of a muscarinic cholinergic receptor agonist as API using the compositions described herein.
  • the compositions described herein can be in the form of an eye drop.
  • the methods can further comprise applying the eye drop to an eye of the subject.
  • a subject treated in accordance with a method described herein is in need of transcorneal absorption of an API. In some instances, a subject treated in accordance with a method described herein has failed to respond to treatment with an aqueous composition comprising the API or a salt thereof. In some instances, a subject treated in accordance with a method described herein has had an adverse side effect from the API or a salt thereof after receiving an aqueous composition comprising the API or a salt thereof. In some instances, a subject treated in accordance with a method described herein is highly sensitive to an aqueous composition comprising the API or a salt thereof.
  • compositions described herein can contain APIs, such as, e.g., riboflavin or a riboflavin derivative, that can facilitate photo-crosslinking of structural proteins such as collagen.
  • APIs such as, e.g., riboflavin or a riboflavin derivative
  • the structural protein can be in a tissue or in or on a body of a subject such as a mammal, e.g., a human.
  • Structural proteins that can be photo-crosslinked using compositions or methods described herein, such as those in which the API is riboflavin or a riboflavin derivative can include any structural proteins that are photo-crosslinkable in the presence of a reactive oxygen facilitator.
  • Exemplary structural proteins include, without limitation, collagens and collagen derivatives, keratins and keratin derivatives, elastins and elastin derivatives, and the like.
  • collagen includes, without limitation, collagen fibers or fibrils.
  • keratin includes, without limitation, keratin fibers or fibrils.
  • the methods can comprise contacting the structural proteins or a biological tissue comprising the structural proteins with an effective amount of one or more compounds of Formula (I) , or with an effective amount of a composition comprising one or more compounds of Formula (I) ; and irradiating the structural proteins or the tissue comprising the structural proteins.
  • methods are provided for crosslinking collagen in a tissue of a subject.
  • the methods can comprise administering to the tissue of the subject an effective amount of a composition described herein, wherein the API is one or more compounds of Formula (I) ; and irradiating the tissue.
  • the irradiation can include irradiating with UV light (e.g., UVA light) , or with blue light.
  • contacting the structural proteins or a biological tissue comprising the structural proteins can include, without limitation, topically applying the compositions to the proteins or tissues, immersing the proteins or tissues in the compositions, spraying the proteins or tissues with the compositions, injecting the compositions into the tissue or into a matrix comprising the structural proteins, and the like.
  • contacting the structural proteins or a biological tissue comprising the structural proteins can include administering an effective amount of a composition described herein comprising as API one or more compounds of Formula (I) to a tissue in the body of a subject.
  • exemplary bodily tissues or biological tissues can include, without limitation, collagenous tissues, keratinous tissues, corneal tissue, epithelial tissues, epidermal tissues, pericardial tissues, skin, hair, or nails.
  • the tissues can be in or on the body of a subject.
  • the tissues can be ex vivo or in vitro.
  • the tissues can be bovine or porcine tissues.
  • methods are providing for administering, to the eye and/or corneal tissue of a subject, a composition described herein comprising an effective amount of a compound of Formula (I) as API; and irradiating at least a portion of the eye and/or corneal tissue with, e.g., UV light or blue light.
  • the compositions comprising Formula (I) as API can be in the form of an eye drop.
  • the methods can further comprise applying the eye drop to an eye of the subject.
  • the methods can further comprise de-epithelializing at least a portion of the cornea.
  • the crosslinking method can be performed without de-epithelializing any portion of the cornea.
  • biomaterials include, without limitation, natural or synthetic variants of heart valves, corneal transplants, arterial prostheses, arterial grafts, wound healing matrices or grafts, skin grafts, vascular grafts, trandermal drug delivery devices or patches, and the like.
  • these biomaterials can also be subject to photo-crosslinking using the compositions described herein comprising one or more compounds of Formula (I) as API, and corresponding methods described herein within or on the body of a subject, for example, during or after delivery of the biomaterials to the subject such as through surgery or other delivery methods.
  • the API is selectively delivered to the cornea of the subject.
  • the subject has failed to respond to treatment with an aqueous composition comprising the API of the composition. Failure to respond to treatment includes disease progression and failure to achieve clinically significant symptom reduction (s) after treatment.
  • the subject has had an adverse side effect from the API after receiving an aqueous composition comprising the API or a salt thereof.
  • An adverse side effect from the API includes adverse side effects attributed to the API (or the salt thereof) and not to other components or features of a composition comprising the API (e.g., a preservative or pH) .
  • the subject is highly sensitive to an aqueous composition comprising the API or a salt thereof.
  • the API can be present in an effective amount (e.g., a therapeutically effective amount) .
  • Effective doses may vary, depending on the diseases treated, the severity of the disease, the route of administration, the sex, age and general health condition of the subject, excipient usage, the possibility of co-usage with other therapeutic treatments such as use of other agents and the judgment of the treating physician.
  • the compositions described herein may be used to treat a disease in an eye of the patient, such as myopia
  • the treating physician may adjust the dosage and dosage regimen based on the current progression of the disease in the patient, the patient’s age, or other related factors.
  • the API is administered at a dose 5-10%, 5-15%, 5-20%, 5-25%, 5-30%, 10-30%, 10-40%, 10-50%, 10-60%, 10-70%, 20-30%, 20-40%, 20-50%, 20-60%, 20-70%, 30-40%, 30-50%, 30-60%, 30-70%, 40-50%, 40-60%, 40-70%, or 50-70%less than a dose of the API when administered as an aqueous topical ophthalmological composition for the same method of use.
  • the decrease in dose is not due to differences in weight between free base form and acid form of an API.
  • the API dosages can be administered on a daily basis (e.g., as a single dose or as two or more divided doses, e.g., once daily, two times daily, three times daily, or four times daily) or non-daily basis (e.g., every other day, every two days, every three days, once weekly, twice weekly, once every two weeks, once a month) .
  • the API dosages can be administered once every about 6 to about 8 hours.
  • the API dosages can be administered three times a day.
  • the API dosages can be administered once a day.
  • Mobile phase A 0.05% (v/v) TFA in water (Add 0.5 mL trifluoroacetic acid into 1 L of pure water, and ultrasound)
  • Mobile phase B 0.05% (v/v) acetonitrile in water (Add 0.5 mL trifluoroacetic acid into 1 L of acetonitrile, and ultrasound)
  • Pilocarpine was added to F3H1OH or F4H1OH at varying concentrations and shaken.
  • the Pilocarpine/semifluorinated alkyl alcohol mixture was then added to F4H5 or F6H8 at varying dilutions. Concentration of solubilized pilocarpine in the solutions was determined by chromatography as described above.
  • Results are shown in Table 1 below and in Figures 1a and 1b.
  • the SFAOH-SFA excipient system described herein shows increased solubility of the Pilocarpine as compared against various compositions containing MCT and SFA.
  • Mobile phase A Weigh 14 g of potassium dihydrogen phosphate and 12.5 g of sodium dodecyl sulfate, add 2000 mL of water and 1200 mL of acetonitrile to dissolve, and then adjust the pH to 3.0 with phosphoric acid.
  • Compound A was added to various semi-fluorinated alkyl alcohols (represented as F X H Y OH) and mixed.
  • F6H8 was added to the Compound A/SFAOH mixture and mixed.
  • Compound A was added to various semi-fluorinated alkyl alcohols (represented as F X H Y OH) and mixed.
  • F6H8 was added to the Compound A/SFAOH mixture and mixed.
  • oven temperature 70°C
  • RTB was added to F4H1OH and vortexed to mix. After complete dissolution, more RTB was added until it could not be completely dissolved. F4H5 was added to the RTB/SFAOH mixture and shaken to mix.
  • RTB and MCT were mixed, sonicated, and shaken.
  • Mobile phase B 0.1% (v/v) acetonitrile in water (Add 1.0 mL trifluoroacetic acid into 1 L of acetonitrile, and ultrasound)
  • Axitinib was added into mixtures of F6H8 or F4H5 and F3H1OH or F4H1OH or F6H1OH or F6H2OH and vortexed/shaken to dissolve.
  • F6H8 or F4H5 was then added slowly into the Axitinib/SFAOH mixture and vortexed.
  • the obtained mixture was filtered through 0.22 ⁇ m filter and the filtrated solution was analyzed by HPLC.
  • Axitinib was added into F3H1OH or F4H1OH or F6H1OH or F6H2OH and vortexed to dissolve.
  • F6H8 or F4H5 was then added slowly into the Axitinib/SFAOH mixture and vortexed.
  • the obtained mixture was filtered through 0.22 ⁇ m filter and the filtrated solution was analzyed by HPLC.
  • 20%F4H1OH-F6H8 group this sample was placed at 25°C for 24h, then filtered and analyzed by HPLC.
  • the filtered sample was filled into PET bottles, which were placed at 8 °C, 25 °C, and 40 °C. The samples were taken out at 7 Days, 14 Days, and 1 Month, then filtered and analyzed by HPLC.
  • Test Article 0.125%aceclidine in 3%F6H1OH-F6H8, 0.25%aceclidine in 3%F6H1OH-F6H8, 0.5%aceclidine in 3%F6H1OH-F6H8, 1%aceclidine in 3%F6H1OH-F6H8, 0.5%aceclidine in 10%F6H2OH-F6H8, 1%aceclidine in 10%F6H2OH-F6H8, 1%aceclidine in 5%F4H2OH-F6H8
  • Ten (10) female Dutch belted rabbits were assigned to five groups, which includes 2 animals/group.
  • animals were administered by topical instillation to both eyes, with 1%aceclidine in 10%F6H2OH-F6H8, 0.5%aceclidine in 10%F6H2OH-F6H8, 1%aceclidine in 5%F4H2OH-F6H8, 1%aceclidine in 3%F6H1OH-F6H8, and 1.25%Pilocarpine HCl (as control) , respectively, once on Day 1.
  • Pupil size of all animals was measured binocularly on 3 separate days at pretest. The pupil size of both eyes of all animals were measured at pre-dose (30 minutes before dosing) , 0.5 h, 1 h, 2 h, 3 h, 4 h, 6 h, and 8 h after dosing.
  • the baseline pupil diameter was 7.48, 7.86, 7.58, 7.54, 8.07, 7.76, 7.49 and 7.42 mm at 1%aceclidine in 10%F6H2OH-F6H8, 0.5%aceclidine in 10%F6H2OH-F6H8, 1%aceclidine in 5%F4H2OH-F6H8, 1%aceclidine in 3%F6H1OH-F6H8, 0.125%aceclidine in 3%F6H1OH-F6H8, 0.25%aceclidine in 3%F6H1OH-F6H8, 0.5%aceclidine in 3%F6H1OH-F6H8 and 1.25%Pilocarpine HCl, respectively.
  • Lifitegrast was added into F3H1OH, F4H1OH, F6H1OH, or F6H2OH and kept stirring at RT for 24h to dissolve.
  • F6H8 or F4H5 was then added slowly into the Lifitegrast /SFAOH mixture and vortexed. The obtained mixture was filtered through 0.22 ⁇ m filter and the filtrated solution was analyzed by HPLC.
  • Cyclosporine was added into MCT or F6H1OH and vortexed to dissolve.
  • F6H8 was added to the Cyclosporine /SFAOH mixture and vortexed.
  • the obtained mixture was filtered through 0.22 ⁇ m filter and the filtrated solution was injected to HPLC to detect its assay result.
  • SFAOH semi-fluorinated alkyl alcohols
  • Table 18A Stability of Loteprednol and Etiprednol in Exemplary Compositions -Concentration at Day 0 and 1 Month
  • API active pharmaceutical ingredient
  • composition of embodiment 1, wherein the composition is non-aqueous.
  • composition of any one of embodiments 1-2, wherein the semi-fluorinated alkane compound is selected from the group consisting of perfluorobutylheptane (F4H5) , perfluorobutylhexane (F4H6) , perfluorohexylbutane (F6H4) , perfluorohexylhexane (F6H6) , perfluorohexyloctane (F6H8) , and perfluorohexyl decane (F6H10) .
  • composition of any one of embodiments 1-3, wherein the semi-fluorinated alkyl alcohol compound is a compound of Formula (II) :
  • R 6 is a linear or branched alkyl having 1 to 8 carbon atoms
  • x is from 1 to 10;
  • y is from 1 to 4.
  • composition of any one of embodiments 1-7, wherein the API is in a free base or salt form is in a free base or salt form.
  • composition of any one of embodiments 1-8, wherein the semi-fluorinated alkyl alcohol compound is selected from pentafluoropentanol, trifluorobutanol, trifluoropropanol, heptafluorobutanol, nonafluoropentanol, pefluorohexanol, perfluoroheptanol, perfluorooctanol, perfluorononanol, (perfluorohxyl) propanol, and pentafluoroactanol, or combinations of two or more thereof.
  • composition of any one of embodiments 1-9, wherein the semi-fluorinated alkyl alcohol compound is selected from F (CF2) 6 (CH2) 2 OH, F (CF2) 4 (CH2) 2 OH, F (CF2) 6 CH2OH, F (CF2) 4 CH2OH, and F (CF2) 3 CH2OH, or combinations of two or more thereof.
  • composition of any one of embodiments 1-10, wherein the semi-fluorinated alkane is perfluorohexyloctane (F6H8) .
  • composition of any one of embodiments 1-12, wherein the API in the composition is chemically stable for at least 6 months, at least 1 year, at least 18 months, at least 2 years or longer.
  • the API is selected from alpha agonists, antibiotics, corticosteroids, antinicotinic agents, antiglaucoma agents, antihistamines, antivirals, anti-parasitics, pressure regulators, topical transient receptor potential melastatin 8 (TRPM8) agonists, inhibitors of inflammatory cell binding, cycloplegi
  • a method for delivering an API to a subject comprising dissolving the API in a composition comprising:
  • a method for treating, slowing the progression of, or reducing one or more symptoms of an ocular condition in a subject, or inducing one or more symptoms of miosis in a subject comprising administering the composition of any one of embodiments 1-16 to an eye of the subject.
  • a dispensing portion adapted to dispense one or more drops of a liquid out of the container portion
  • volume of the one or more drops each independently is from about 5 ⁇ l to about 40 ⁇ l.
  • a method for treating, slowing the progression of, or reducing one or more symptoms of dry eye disease, meibomian gland disfunction, or inflammatory dry eye in a subject comprising administering the composition of any one of embodiments 1-16 to an eye of the subject, wherein the API is selected from one or more of lifitegrast, AR-15512 ( (1R, 2S, 5R) -N- (4-methoxyphenyl) -5-methyl-2- (1-methylethyl) cyclohexanecarboxamide) , cyclosporine, or derivatives, analogues, pharmaceutically acceptable salts, free base form, racemic mixtures, or diastereomers or enantiomers thereof.
  • the API is selected from one or more of lifitegrast, AR-15512 ( (1R, 2S, 5R) -N- (4-methoxyphenyl) -5-methyl-2- (1-methylethyl) cyclohexanecarboxamide) , cycl
  • AR-15512 (1R, 2S, 5R) -N- (4-methoxyphenyl) -5-methyl-2- (1-methylethyl) cyclohexanecarboxamide
  • composition is non-aqueous; optionally wherein the composition is an emulsion.
  • the semi-fluorinated alkyl alcohol compound is present in an amount of from about 5%to about 50% (w/w) , optionally selected from about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, and about 50% (w/w) ; and
  • the semi-fluorinated alkane compound is present in an amount of from about 50%to about 95% (w/w) , optionally selected from about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, and about 95% (w/w) .
  • composition or method of embodiment 33 wherein:
  • the semi-fluorinated alkyl alcohol compound is present in an amount of from about 1%to about 20% (w/w) , optionally selected from about 5%, about 10%, about 15%, or and about 20% (w/w) ;
  • the semi-fluorinated alkane compound is present in an amount of from about 80%to about 99% (w/w) , optionally selected from about 80%, about 85%, about 90%and about 95% (w/w) .
  • composition or method of embodiment 74, wherein the API is aceclidine or a derivative, analogue, pharmaceutically acceptable salt, free base form, racemic mixture, or diastereomer or enantiomer thereof.
  • the semi-fluorinated alkyl alcohol compound is present in an amount of from about from about 0.1%to about 10% (w/w) , optionally about 5% (w/w) ;
  • the semi-fluorinated alkane compound is present in an amount of from about 90%to about 99% (w/w) , optionally selected from about 95%, about 96%, about 97%, about 98%, about 99%, about 99.5%, and about 99.9% (w/w) .
  • the API is a corticosteroid selected from loteprednol and etiprednol, or a derivative, analogue, pharmaceutically acceptable salt, free base form, racemic mixture, or diastereomer or enantiomer thereof.
  • a method for treating, slowing the progression of, or reducing one or more symptoms of an ocular inflammatory condition in a subject comprising administering the composition of any one of embodiments 1-16 to an eye of the subject, wherein the API is a corticosteroid selected from loteprednol and etiprednol, or a derivative, analogue, pharmaceutically acceptable salt, free base form, racemic mixture, or diastereomer or enantiomer thereof.
  • the API is a corticosteroid selected from loteprednol and etiprednol, or a derivative, analogue, pharmaceutically acceptable salt, free base form, racemic mixture, or diastereomer or enantiomer thereof.
  • a method for treating, slowing the progression of, or reducing one or more symptoms of abnormal corneal neovascularization in a subject comprising administering the composition of any one of embodiments 1-16 to an eye of the subject, wherein the API is a corticosteroid selected from loteprednol and etiprednol, or a derivative, analogue, pharmaceutically acceptable salt, free base form, racemic mixture, or diastereomer or enantiomer thereof.
  • the API is a corticosteroid selected from loteprednol and etiprednol, or a derivative, analogue, pharmaceutically acceptable salt, free base form, racemic mixture, or diastereomer or enantiomer thereof.
  • the abnormal corneal neovascularization is, is caused by, or is related to a condition selected from alkali burns or injury induced neovascularization, corneal graft rejection in high-risk corneal transplant patients, neovascular glaucoma, contact lens induced redness neovascularization, ocular rosacea, ocular pemphigoid, limbal stem cell deficiency, Sjogren's syndrome, atopic conjunctivitis, graft versus host disease, Lyell's syndrome and Steven Johnson syndrome, ulceration, and redness induced by viral, bacterial, fungal, or parasitic infection.
  • a method for treating, slowing the progression of, or reducing one or more symptoms of an ocular condition in a subject comprising administering the composition of any one of embodiments 1-16 to an eye of the subject, wherein the API is a corticosteroid selected from loteprednol and etiprednol, or a derivative, analogue, pharmaceutically acceptable salt, free base form, racemic mixture, or diastereomer or enantiomer thereof,
  • the ocular condition is selected from Sjogren's syndrome, conjunctivitis, inflammation caused by surgery, injury, or other conditions, eye swelling, redness, itching, or pain, uveitis, scleritis and episcleritis, corneal transplant and corneal allograft rejection, bacterial keratitis, Herpes simplex keratitis, allergic eye diseases, graft vs host disease, cicatrising conjunctival disorders, and anterior uveitis.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
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  • Pharmacology & Pharmacy (AREA)
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  • Chemical Kinetics & Catalysis (AREA)
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  • Dermatology (AREA)
  • Ophthalmology & Optometry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente demande concerne des compositions, des systèmes d'excipient, des procédés et des distributeurs pour l'administration d'ingrédients pharmaceutiques actifs (IPA). Dans un exemple, l'invention concerne une composition comprenant un ingrédient pharmaceutique actif; un alcool alkylique semi-fluoré; et un composé alcane semi-fluoré. Dans un autre exemple, l'invention concerne un système d'excipient comprenant un alcool alkylique semi-fluoré et un composé alcane semi-fluoré. L'invention concerne également des distributeurs contenant les compositions et comprennent des distributeurs ou des récipients en verre et en polyéthylène téréphtalate. L'invention concerne également des procédés d'utilisation des compositions et comprennent un procédé de traitement d'un état chez un sujet comprenant l'administration des compositions au sujet.
PCT/CN2024/140886 2023-12-21 2024-12-20 Compositions et procédés d'administration d'agents actifs pharmaceutiques Pending WO2025131038A1 (fr)

Applications Claiming Priority (10)

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CN2023140581 2023-12-21
CNPCT/CN2023/140581 2023-12-21
CN2024086996 2024-04-10
CNPCT/CN2024/086996 2024-04-10
CN2024087532 2024-04-12
CNPCT/CN2024/087532 2024-04-12
CN2024087730 2024-04-15
CNPCT/CN2024/087730 2024-04-15
CN2024098395 2024-06-11
CNPCT/CN2024/098395 2024-06-11

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Citations (5)

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WO2022169788A1 (fr) * 2021-02-03 2022-08-11 Ads Therapeutics Llc Compositions ophtalmologiques topiques
US20220296584A1 (en) * 2017-04-24 2022-09-22 BraneQuest, Inc. Membrane Active Molecules
WO2022221071A1 (fr) 2021-04-16 2022-10-20 Ads Therapeutics Llc Co-médicaments agonistes alpha2 adrénergiques conjugués avec des médicaments agonistes muscariniques
US20230372311A1 (en) * 2020-07-21 2023-11-23 The Regents Of The University Of California Compositions and methods of treating age-related retinal dysfunction

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Publication number Priority date Publication date Assignee Title
US20100150971A1 (en) * 2008-12-16 2010-06-17 Jeffery Richard Seidling Personal care composition containing a volatile and a terpene alcohol
US20220296584A1 (en) * 2017-04-24 2022-09-22 BraneQuest, Inc. Membrane Active Molecules
US20230372311A1 (en) * 2020-07-21 2023-11-23 The Regents Of The University Of California Compositions and methods of treating age-related retinal dysfunction
WO2022169788A1 (fr) * 2021-02-03 2022-08-11 Ads Therapeutics Llc Compositions ophtalmologiques topiques
WO2022221071A1 (fr) 2021-04-16 2022-10-20 Ads Therapeutics Llc Co-médicaments agonistes alpha2 adrénergiques conjugués avec des médicaments agonistes muscariniques

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HOLM ET AL.: "A novel excipient, 1-perfluorohexyloctane shows limited utility for the oral delivery of poorly water-soluble drugs", EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES, vol. 42, no. 4, March 2011 (2011-03-01), pages 416 - 422, XP002720478, DOI: 10.1016/j.ejps.2011.01.007
TSAGOGIORGAS ET AL.: "Semifluorinated Alkanes as New Drug Carriers-An Overview of Potential Medical and Clinical Applications", PHARMACEUTICS, vol. 15, no. 4, April 2023 (2023-04-01), pages 1211, XP093164488, DOI: 10.3390/pharmaceutics15041211

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