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EP-4739312-A1 - COMPOSITIONS AND METHODS FOR DELIVERY OF OPHTHALMOLOGICAL ACTIVES

EP4739312A1EP 4739312 A1EP4739312 A1EP 4739312A1EP-4739312-A1

Abstract

The present application provides compositions, methods, and dispensers for topical delivery of ophthalmological active pharmaceutical ingredients (APIs). In one example, a composition is provided comprising an active pharmaceutical ingredient soluble in MCT wherein the API is not atropine or a salt thereof; a medium chain triglyceride (MCT); and a semi-fluorinated alkane compound. In another example, a nano-emulsion is provided comprising about an active pharmaceutical ingredient soluble in MCT; a medium chain triglyceride (MCT); and a semi-fluorinated alkane compound, wherein the nano-emulsion has a droplet particle size D90 of less than about 100 nm. Dispensers containing the compositions are also provided and include glass and polyethylene terephthalate dispensers or containers. Methods of using the compositions are also provided and include a method for treating an ocular condition in a subject comprising administering the compositions or nano-emulsions to an eye of the subject. The present application also provides compositions and methods for treating ophthalmological conditions such as presbyopia and glaucoma. The compositions can comprise a muscarinic cholinergic receptor agonist and a semi-fluorinated alkane compound; or can comprise a muscarinic cholinergic receptor agonist, a semi-fluorinated alkane compound, and an organic cosolvent. The compositions can confer chemical stability of the muscarinic cholinergic receptor agonist.

Inventors

  • DINH, Van
  • FANG, WENKUI KEN
  • NI, JINSONG
  • YANG, RONG

Assignees

  • ADS Therapeutics LLC

Dates

Publication Date
20260513
Application Date
20240802

Claims (20)

  1. 1. A topical ophthalmological composition comprising: about 0.001% to about 5% (w/w) or about 0.0001% to about 20% (w/w) active pharmaceutical ingredient (API), wherein the API has a solubility in medium chain triglyceride (MCT) of at least from about 0.01% to about 10% (w/w), and wherein the API is not atropine or a salt thereof; from about 1% to about 50% (w/w) of an MCT, optionally wherein the MCT is a triglyceride of fatty acids and the fatty acids comprise hexanoic acid, octanoic acid, decanoic acid, dodecanoic acid or combinations of two or more thereof; and from about 50% to about 99% (w/w) of a semi-fluorinated alkane compound, optionally 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); and optionally wherein composition is non-aqueous.
  2. 2. A topical ophthalmological composition comprising: a therapeutically effective amount of a muscarinic cholinergic receptor agonist as an active pharmaceutical ingredient, wherein the muscarinic cholinergic receptor agonist is selected from the group consisting of aceclidine, pilocarpine, bethanechol, cevimeline, methacholine, xanomeline, and aprolidine; and a semifluorinated alkane compound; and optionally further comprising one or more organic cosolvents, optionally wherein the organic cosolvent is selected from the group consisting of medium-chain triglycerides (MCT), medium-chain triglycerides (MCT) having two or three fatty acids each independently having an aliphatic tail of 6-12 carbon atoms, liquid paraffin, vitamin E acetate, D-a-tocopherol, oleic acid, ethyl oleate and combinations thereof.
  3. 3. A topical ophthalmological nano-emulsion comprising: about 0.001% to about 5% (w/w) or about 0.0001% to about 20% (w/w) active pharmaceutical ingredient (API), wherein the API has a solubility in MCT of at least from about 0.01% to about 10% (w/w); from about 1% to about 50% (w/w) of a medium chain triglyceride (MCT); and from about 50% to about 99% (w/w) of a semi-fluorinated alkane compound, wherein the nano-emulsion has a droplet particle size D90 of less than about 100 nm.
  4. 4. The topical ophthalmological composition of claim 1 or 2 or the topical ophthalmological nano-emulsion of claim 3, wherein the API: (a) is not a muscarinic receptor antagonist; or (b) 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, cycloplegics/mydriatics, mast cell stabilizers, miotics, ophthalmic NS AIDs, cyclosporine, riboflavin 5'-phosphate ophthalmic compounds, and VEGF inhibitors and VEGF receptor inhibitors.
  5. 5. The topical ophthalmological composition of claim 1 or 2 or the topical ophthalmological nano-emulsion of claim 3, wherein the API is aceclidine, or a derivative, analogue, pharmaceutically acceptable salt, free base form, racemic mixture, or diastereomer or enantiomer thereof.
  6. 6. The topical ophthalmological composition of claim 1 or 2 or the topical ophthalmological nano-emulsion of claim 2, wherein the API is lotilaner, or a derivative, analogue, racemic mixture, or diastereomer or enantiomer thereof.
  7. 7. The topical ophthalmological composition of claim 1 or 2 or the topical ophthalmological nano-emulsion of claim 3, wherein the API is AR-15512 ((1R,2S,5R)- N-(4-methoxyphenyl)-5-methyl-2-(l-methylethyl) cyclohexanecarboxamide) or a derivative, analogue, racemic mixture, or diastereomer or enantiomer thereof.
  8. 8. The topical ophthalmological nano-emulsion of claim 3, wherein the API is muscarinic receptor agonist, optionally wherein the API is atropine, an atropine mimetic or analog, or a free base or salt form thereof.
  9. 9. Eye drops comprising the topical ophthalmological composition of claim 2.
  10. 10. A method for treating presbyopia in a subject in need thereof, comprising administering the topical ophthalmological composition of claim 2 or the eye drops of claim 9 to an eye of the subject.
  11. 11. A method for treating glaucoma in a subject in need thereof, for improving the ability of a subject to focus on a near object, or for reducing intraocular pressure in an eye of a subject in need thereof, the method comprising administering the topical ophthalmological composition of claim 2 or the eye drops of claim 9 to an eye of the subject.
  12. 12. A method of delivering an API to an eye of a subject comprising administering to an eye of the subject (i) the topical ophthalmological composition of any one of claims 1, 2, and 4-8, (ii) the topical ophthalmological nano-emulsion of any one of claims 3-8, or (iii) a topical ophthalmological composition comprising: about 0.001% to about 5% (w/w) API, wherein the API has a solubility in medium chain triglyceride (MCT) of at least from about 0.01% to about 10% (w/w), and wherein the API is atropine; from about 1% to about 50% (w/w) of an MCT; and from about 50% to about 99% (w/w) of a semi-fluorinated alkane compound; wherein (a) the topical ophthalmological composition of (iii) is administered to the eye of the subject every about 6 to about 8 hours or three times a day, or (b) the topical ophthalmological composition of (iii) is non-aqueous, and wherein the topical ophthalmological composition of (iii) 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 SO- 70% less than a dose of an aqueous topical ophthalmological composition comprising the API for treating, slowing the progression of, or reducing one or more symptoms of the ocular condition; optionally wherein the topical ophthalmological composition of (iii) is nonaqueous; optionally wherein the API is in a free base form; and optionally wherein the method comprises selectively delivering the API to a cornea of the eye of the subject.
  13. 13. A method for treating, slowing the progression of, or reducing one or more symptoms of an ocular condition in a subject comprising administering to an eye of the subject: (i) the topical ophthalmological composition of any one of claims 1, 2, and 4-8, (ii) the topical ophthalmological nano-emulsion of any one of claims 3-8, or (iii) a topical ophthalmological composition comprising: about 0.001% to about 5% (w/w) API, wherein the API has a solubility in medium chain triglyceride (MCT) of at least from about 0.01% to about 10% (w/w), and wherein the API is atropine; from about 1% to about 50% (w/w) of an MCT; and from about 50% to about 99% (w/w) of a semifluorinated alkane compound; optionally wherein (a) the topical ophthalmological composition of (iii) is administered to the eye of the subject every about 6 to about 8 hours or three times a day, or (b) the topical ophthalmological composition of (iii) is non-aqueous, and wherein the topical ophthalmological composition of (iii) 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 topical ophthalmological composition comprising the API for treating, slowing the progression of, or reducing one or more symptoms of the ocular condition; optionally wherein the topical ophthalmological composition is non-aqueous; and optionally wherein the API is in a free base form.
  14. 14. A method of administering to a subject a topical ophthalmological composition for selective transcomeal absorption, the method comprising administering (i) the topical ophthalmological composition of any one of claims 1, 2, and 4-8, or (ii) the topical ophthalmological nano-emulsion of any one of claims 3-8 to an eye of the subject; optionally wherein the topical ophthalmological composition is non-aqueous; and optionally wherein the API is in free base form.
  15. 15. A method for treating or reducing one or more symptoms of blepharitis, ocular rosacea, rosacea, or eyelid margin redness in a subject, or for improving eyelash health in a subject, or for treating or eradicating Demodex mites, lice, scabies, or bed bugs in a subject, or for treating or preventing a vector-borne disease in a subject, comprising administering (i) the topical ophthalmological composition of claim 1 or 2, or (ii) the topical ophthalmological nano-emulsion of claim 3 to an eye of the subject to an eye of the subject, or to skin or hair of the subject, wherein the API is an anti-parasitic.
  16. 16. 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 (i) the topical ophthalmological composition of claim 1 or 2, or (ii) the topical ophthalmological nano-emulsion of claim 3 to an eye of the subject, wherein the API is selected from one or more of lifitegrast, AR-15512 ((lR,2S,5R)-N-(4-methoxyphenyl)-5-methyl-2-(l -methylethyl) cyclohexanecarboxamide), cyclosporine, or derivatives, analogues, pharmaceutically acceptable salts, free base form, racemic mixtures, or diastereomers or enantiomers thereof.
  17. 17. A method for treating, slowing the progression of, or reducing one or more symptoms of glaucoma, ocular hypertension, or high fluid pressure in an eye of a subject, or a method of lowering fluid pressure in an eye of a subject, comprising administering (i) the topical ophthalmological composition of claim 1 or 2, or (ii) the topical ophthalmological nano-emulsion of claim 3 to an eye of the subject, wherein the API is a pressure regulator.
  18. 18. A method for slowing myopia progression in a subject or for relieving vitreous floater symptoms in a subject, comprising administering the nano-emulsion of claim 3 to an eye of the subject, wherein the API is a muscarinic receptor antagonist, optionally wherein the API is selected from atropine, an atropine mimetic or analog, or a free base or salt form thereof.
  19. 19. 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 a composition, wherein the composition (i) is the topical ophthalmological composition of any one of claims 1, 2, and 4-8, or (ii) the topical ophthalmological nano-emulsion of any one of claims 3-8; optionally wherein the topical ophthalmological composition is non-aqueous; and optionally wherein the API is in free base form, or (iii) is a topical ophthalmological composition comprising: about 0.001% to about 5% (w/w) API, wherein the API has a solubility in MCT of at least from about 0.01% to about 10% (w/w), and wherein the API is atropine; from about 1% to about 50% (w/w) of an MCT; and from about 50% to about 99% (w/w) of a semi-fluorinated alkane compound; optionally wherein the topical ophthalmological composition is non-aqueous; and optionally wherein the API is in a free base form.
  20. 20. A method for slowing myopia progression in a subject or for relieving vitreous floater symptoms in a subject, comprising administering to an eye of the subject a topical ophthalmological composition, wherein the topical ophthalmological composition comprises: about 0.001% to about 5% (w/w) active pharmaceutical ingredient (API), wherein the API has a solubility in medium chain triglyceride (MCT) of at least from about 0.01% to about 10% (w/w), and wherein the API is selected from atropine or an atropine mimetic; from about 1% to about 50% (w/w) of an MCT; and from about 50% to about 99% (w/w) of a semi-fluorinated alkane compound; wherein (i) the topical ophthalmological composition is administered to the eye of the subject every about 6 to about 8 hours or three times a day, or (ii) the topical ophthalmological composition is non-aqueous, and wherein the topical ophthalmological 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 topical ophthalmological composition comprising the API for slowing myopia progression in a subject or for relieving vitreous floater symptoms in a subject; optionally wherein the topical ophthalmological composition is non-aqueous; and optionally wherein the API is in a free base form.

Description

COMPOSITIONS AND METHODS FOR DELIVERY OF OPHTHALMOLOGICAL ACTIVES CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Patent Application No. 63/667,874, filed on July 5, 2024, U.S. Provisional Patent Application No. 63/658,306, filed on June 10, 2024, U.S. Provisional Patent Application No. 63/632,214, filed on April 10, 2024, U.S. Provisional Patent Application No. 63/631,841, filed on April 9, 2024, U.S. Provisional Patent Application No. 63/596,913, filed on November 7, 2023, and U.S. Provisional Patent Application No. 63/530,919, filed on August 4, 2023, the contents of each of which are hereby incorporated by reference in their entireties. TECHNICAL FIELD This disclosure relates to compositions for topical delivery of ophthalmological active pharmaceutical ingredients (APIs), and methods for making and using the compositions. This disclosure also relates to pharmaceutical compositions comprising a muscarinic cholinergic receptor agonist and a semi-fluorinated alkane compound. This disclosure also relates to methods of treatment of ophthalmological diseases such as presbyopia using the compositions. BACKGROUND Various attempts have been made to formulate active pharmaceutical ingredients compounds (APIs) for ocular delivery, e.g., for treating and preventing conditions in the eye or improving symptoms thereof. However, 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. In common practice, APIs for ophthalmological are often formulated in aqueous formulations, however, many APIs can degrade in aqueous formulations. Sometimes adjustments to pH can slow the degradation of APIs in aqueous formulations, but such pH adjustments can result in ocular irritation and discomfort for the user. There remains a need for improved compositions for ophthalmological delivery of APIs. Presbyopia is an ophthalmological condition in which adults develop difficulty seeing close objects clearly. The condition develops with age and is most common in adults 45 years or older. It is believed that a decrease in the flexibility of the eye lens over time disrupts the proper focusing of light on the retina, causing blurriness. Current treatments involve eyeglasses or contact lenses, lens implant surgery, or refractive surgery. Some compounds are under investigation for potential pharmaceutical treatment of presbyopia. SUMMARY This disclosure relates to compositions for topical delivery of ophthalmological active pharmaceutical ingredients (APIs), comprising medium chain triglycerides (MCT), a semi-fluorinated alkane (SFA), 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, an ocular condition in a subject. Also provided herein are dispensers or containers comprising the compositions. The compositions can, in some instances, be non-aqueous. Applicant has surprisingly discovered that compositions comprising medium chain triglycerides (MCT) and a semi-fluorinated alkane (SFA) can act as an advantageous delivery system for ophthalmological APIs that are soluble in MCT, resulting in ocularly tolerable formulation with increased stability and long-term shelf life of the API in the formulations, and improved tissue distribution and retention time of the API. Applicant has further surprisingly discovered that compositions comprising MCT, SFA, and an API can be made into nano-emulsions having a droplet size D90 of less than 100 nm, less than 50 nm, less than 20 nm, less than 15 nm, less than 10 nm, and even less than 5 nm. Applicant has further surprisingly discovered that compositions comprising MCT, SFA, and an API can, in some instances, exhibit incompatibility or lesser compatibility with certain materials used for storage and delivery containers or can have improved shelf life and stability of the API when stored or delivered in certain materials as compared to certain other materials. This disclosure is based, at least in part, on a surprising realization that any API soluble in MCT can be effectively delivered to ocular tissues using the compositions described herein, and further that in some embodiments, the compositions can result in improved stability and shelf life for the API. Without being bound by theory, it is believed that the MCT provides increased solubility of the API for delivery in a formulation comprising a SFA. Without being bound by theory, it is further believed the SFA assists in maintaining a non-irritating, and in some embodiments, non-aqueous formulation for delivery of the API. This disclosure is also based on the surprising realization that, in some instances described herein, it is possible to create nanoemulsions of the compositions having droplet size D90 of less than 100 nm, less than 10 nm, an