Methods and compositions for the delivery of prostaglandin f2a analogs

Abstract

A solid pharmaceutical composition for oral administration includes a therapeutically effective amount of bimatoprost or a pharmaceutically acceptable salt, stereoisomer, solvate, co-crystal, polymorph, or free acid form thereof, and a pharmaceutically acceptable excipient that stabilizes the pharmaceutical composition and provides oral release of the bimatoprost or the pharmaceutically acceptable salt, stereoisomer, solvate, co-crystal, polymorph, or free acid form thereof.

Description

PCT / US25 / 47729 24 September 2025 (24.09.2025)Atty. Dkt. No.: 130856-0114METHODS AND COMPOSITIONS FOR THE DELIVERY OFPROSTAGLANDIN F2a ANALOGSCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of and priority to U.S. Provisional Patent Application No. 63 / 698,772, filed September 25, 2024, which is incorporated herein by reference in its entirety.TECHNOLOGY

[0002] The present application is generally directed to compositions of prostaglandin F2a analogs for oral administration. In particular, compositions of bimatoprost are provided for oral administration.BACKGROUND

[0003] A migraine is a primary headache disorder, typically moderate to severe in intensity, generally with associated disability. A migraine is usually unilateral, pulsating or throbbing in nature, and may be preceded by an aura. Migraine attacks are frequently associated with both neurological and gastrointestinal symptoms such as nausea, vomiting, diarrhea, sensitivity to light (photophobia), sound (phonophobia), and smells (osmophobia), sleep disruption, and depression. When untreated, a migraine headache attack may last anywhere from 4 to 72 hours. Post-traumatic headaches are considered a secondary headache disorder but the most common presentation is a migraine phenotype. This is classified as post-traumatic headaches of migraine type. All other migraine criteria remain the same except the onset is attributed to a physically traumatic injury.

[0004] A migraine attack can be divided into two major subtypes: a migraine attack without aura and a migraine attack with aura. Migraine without aura (MO) is a clinical syndrome characterized by headache attacks lasting between 4-72 hours. Typical characteristics of the headache are unilateral location, pulsating quality (throbbing), moderate or severe intensity, aggravation by physical activity (which causes a mechanical strain on meningeal blood vessels) and association with nausea, vomiting, photophobia and / or phonophobia. About 70% of subjects suffering from a migraine have migraine without aura. In migraine with aura (MA), attacks are accompanied by reversible focalPCT / US25 / 47729 24 September 2025 (24.09.2025)Atty. Dkt. No.: 130856-0114 neurological symptoms (mostly visual, but also sensory or motor symptoms). Aura develops over 5-20 minutes and lasts for less than 60 minutes. Headache with the features of MO usually follows the aura. About 30% of subjects suffering from a migraine have migraine with aura.

[0005] Other, less common, types of migraine attacks exist and include migraine with prolonged aura (aura symptoms last longer than 60 minutes); migraine aura without headache; migraine with acute onset aura; basilar migraine which can be associated with vertigo, gait perturbances and / or loss of consciousness; ophthalmoplegic migraine associated with ocular paralysis, diplopia and / or ptosis; retinal migraine; and familial hemiplegic migraine associated with hemiparesis or hemiplegia.

[0006] Pharmacological interventions for the management of migraine have traditionally been categorized into two general strategies: prevention of pain and / or associated symptomology and treatment to relieve / stop the pain and associated symptomology. It is commonly held that prostaglandin activity is associated with migraine and that blocking the activity of prostaglandins is an effective treatment for migraine attacks.SUMMARY

[0007] Treatment with prostaglandins was unexpectedly discovered to reduce the frequency, severity, and duration of migraine attacks. Bimatoprost, a prostaglandin analogue used as an ophthalmic solution for the treatment of glaucoma, proved effective at preventing and / or treating migraine attacks when administered as an aqueous formulation onto the nails (cuticles) of the hand (WO 2015 / 106068, incorporated by reference herein and for all purposes). It may also be administered to the eye. At present, aqueous formulations of bimatoprost are commercially available (e.g., Lumigan® and Latisse®) in solution form and are administered topically. No liquid or solid dosage form has been developed for oral and / or oral mucosal administration. These ophthalmic formulations are stable without any added antioxidants, contain buffering agents and only the common antimicrobial agent, benzalkonium chloride, as a preservative. A sustained-release formulation (e.g., Durysta®) of bimatoprost is available by prescription and is in the form of a solid biodegradable intracameral implant. Bimatoprost in the sustained-release formulation is also stable without any added antioxidants.PCT / US25 / 47729 24 September 2025 (24.09.2025)Atty. Dkt. No.: 130856-0114

[0008] The present inventors found that initial laboratory scale solid formulations also appeared suitably stable for commercial use (Example 1). Therefore, it was unexpected and quite surprising when the present inventors subsequently found that engineering scale preparation of the same solid formulations yielded unacceptably high impurity levels in the finished tablets and which appeared to result from oxidative degradation (Example 2) heretofore not seen in any bimatoprost formulation. Additionally, in the pharmacokinetic studies, the present inventors unexpectedly found that the sublingually or oral mucosally administered solid bimatoprost tablet formulation had statistically similar exposures and bioavailability compared to a sublingually or oral mucosally administered bimatoprost liquid formulation.

[0009] According to an aspect of the present technology, a solid pharmaceutical composition for oral administration is provided, the solid pharmaceutical composition comprising a therapeutically effective amount of bimatoprost, or a pharmaceutically acceptable salt, stereoisomer, solvate, co-crystal, polymorph, or free acid form thereof, and pharmaceutically acceptable excipients that stabilize the pharmaceutical composition and provide oral release of bimatoprost, or the pharmaceutically acceptable salt, stereoisomer, solvate, co-crystal, polymorph, or free acid form thereof.

[0010] According to one aspect of the present technology, the solid pharmaceutical composition for oral administration includes: a therapeutically effective amount of bimatoprost, or a pharmaceutically acceptable salt, stereoisomer, solvate, co-crystal, polymorph, or free acid form thereof; an effective amount of an antioxidant to provide a stable solid pharmaceutical composition; and one or more pharmaceutically acceptable excipients that provide oral release of bimatoprost, or the pharmaceutically acceptable salt, stereoisomer, solvate, co-crystal, polymorph, or free acid form thereof.

[0011] In some embodiments, the solid pharmaceutical composition comprises 0.01-8 mg bimatoprost, or the pharmaceutically acceptable salt, stereoisomer, solvate, co-crystal, polymorph, or free acid form thereof. In some embodiments, the solid pharmaceutical composition comprises 0.01-4 mg bimatoprost, or the pharmaceutically acceptable salt, stereoisomer, solvate, co-crystal, polymorph, or free acid form thereof. In some embodiments, the solid pharmaceutical composition includes 0.01-1 mg bimatoprost, or the pharmaceutically acceptable salt, stereoisomer, solvate, co-crystal, polymorph, or free acidPCT / US25 / 47729 24 September 2025 (24.09.2025)Atty. Dkt. No.: 130856-0114 form thereof. In yet another embodiment, the solid pharmaceutical composition includes 0.02-0.7 mg bimatoprost, or the pharmaceutically acceptable salt, stereoisomer, solvate, cocrystal, polymorph, or free acid form thereof.

[0012] In some embodiments, the pharmaceutically acceptable excipients further include a filler and / or a disintegrant. In certain embodiments, the pharmaceutically acceptable excipients further include a binder and / or a lubricant. In some embodiments, the filler includes an insoluble filler and a soluble filler. In some embodiments, the pharmaceutically acceptable excipients include one or more of microcrystalline cellulose, mannitol, propylene glycol, croscarmellose sodium, and magnesium stearate.

[0013] In some embodiments, the antioxidant is selected from the group consisting of butylated hydroxytoluene, citric acid, butylated hydroxy anisole, vitamin E TPGS, HPpCD, and combinations of any two or more thereof. In some embodiments, the antioxidant is selected from the group consisting of butylated hydroxytoluene, citric acid, butylated hydroxyanisole, and combinations of any two or more thereof. In yet another embodiment, the antioxidant includes butylated hydroxytoluene.

[0014] In some embodiments, the solid pharmaceutical composition is formulated for oral administration. In some embodiments, the solid pharmaceutical composition provides oral mucosal release of bimatoprost. In some embodiments, the solid pharmaceutical composition is formulated for sublingual release. In some embodiments, the solid pharmaceutical composition is formulated for buccal release. In some embodiments, the solid pharmaceutical composition is formulated for immediate release.

[0015] In some embodiments, the solid pharmaceutical composition is stable for at least 3 months, at least 6 months, at least 12 months, at least 18 months, or at least 24 months.

[0016] In an aspect, a solid pharmaceutical composition for oral administration is provided. The solid pharmaceutical composition for oral administration includes: about 0.01 mg to about 8 mg bimatoprost, or a pharmaceutically acceptable salt, stereoisomer, solvate, co-crystal, polymorph, or free acid form thereof; about 40 to about 60 weight percent of an insoluble filler; about 30 to about 50 weight percent of a soluble filler; 0 to about 10 weight percent cosolvent; about 0.001 to about 1 weight percent of an antioxidant; about 1 to about 5 weight percent of a disintegrant; and 0 to about 1 weight percent of aPCT / US25 / 47729 24 September 2025 (24.09.2025)Atty. Dkt. No.: 130856-0114 lubricant. In some embodiments, the solid pharmaceutical composition includes: microcrystalline cellulose; mannitol; propylene glycol; butylated hydroxytoluene; croscarmellose sodium; and magnesium stearate.

[0017] In some embodiments, the solid pharmaceutical composition releases at least 70% to 90% of bimatoprost, or the pharmaceutically acceptable salt, stereoisomer, solvate, cocrystal, polymorph, or free acid form thereof, within 2 minutes when measured in 500 mL of 0.05 M phosphate buffer with a pH of 6.8 using a USP II dissolution apparatus at a temperature of 37.0°C ± 0.5°C and a rotation speed of 75 RPM. In some embodiments, the solid pharmaceutical composition releases at least 80% to 100% of bimatoprost, or the pharmaceutically acceptable salt, stereoisomer, solvate, co-crystal, polymorph, or free acid form thereof, within 15 minutes when measured in 500 mL of 0.05 M phosphate buffer with a pH of 6.8 using a USP II dissolution apparatus at a temperature of 37.0°C ± 0.5°C and a rotation speed of 75 RPM.

[0018] In some embodiments, the solid pharmaceutical composition includes: about 45 to about 55 weight percent of the insoluble filler; about 35 to about 45 weight percent of the soluble filler; about 1 to about 5 weight percent cosolvent; about 0.001 to about 1 weight percent of the antioxidant; about 2 to about 4 weight percent of the disintegrant; and about 0.1 to about 0.8 weight percent of the lubricant.

[0019] In some embodiments, the solid pharmaceutical composition includes: about 50 weight percent microcrystalline cellulose; about 40 weight percent mannitol; about 4 weight percent propylene glycol; about 0.1 weight percent butylated hydroxytoluene; about 3 weight percent croscarmellose sodium; and about 0.5 weight percent magnesium stearate.

[0020] In some embodiments, one or more ingredients also function as a binder. In some embodiments, the insoluble filler, the soluble filler or both also function as a binder.

[0021] In some embodiments, the solid pharmaceutical composition includes about 0.03 mg bimatoprost, or the pharmaceutically acceptable salt, stereoisomer, solvate, co-crystal, polymorph, or free acid form thereof. In some embodiments, the solid pharmaceutical composition includes about 0.1 mg bimatoprost, or the pharmaceutically acceptable salt, stereoisomer, solvate, co-crystal, polymorph, or free acid form thereof. In another embodiment, the solid pharmaceutical composition includes about 0.3 mg bimatoprost, orPCT / US25 / 47729 24 September 2025 (24.09.2025)Atty. Dkt. No.: 130856-0114 the pharmaceutically acceptable salt, stereoisomer, solvate, co-crystal, polymorph, or free acid form thereof. In yet another embodiment, the solid pharmaceutical composition includes about 0.5 mg bimatoprost, or the pharmaceutically acceptable salt, stereoisomer, solvate, co-crystal, polymorph, or free acid form thereof. In another embodiment, the solid pharmaceutical composition includes about 0.6 mg bimatoprost, or the pharmaceutically acceptable salt, stereoisomer, solvate, co-crystal, polymorph, or free acid form thereof. In another embodiment, the solid pharmaceutical composition includes about 1.2 mg bimatoprost, or the pharmaceutically acceptable salt, stereoisomer, solvate, co-crystal, polymorph, or free acid form thereof. In yet another embodiment, the solid pharmaceutical composition includes about 2 mg bimatoprost, or the pharmaceutically acceptable salt, stereoisomer, solvate, co-crystal, polymorph, or free acid form thereof. In another embodiment, the solid pharmaceutical composition includes about 3 mg bimatoprost, or the pharmaceutically acceptable salt, stereoisomer, solvate, co-crystal, polymorph, or free acid form thereof. In another embodiment, the solid pharmaceutical composition includes about 4 mg bimatoprost, or the pharmaceutically acceptable salt, stereoisomer, solvate, co-crystal, polymorph, or free acid form thereof. In another embodiment, the solid pharmaceutical composition includes about 8 mg bimatoprost, or the pharmaceutically acceptable salt, stereoisomer, solvate, co-crystal, polymorph, or free acid form thereof.

[0022] In some embodiments, the solid pharmaceutical composition is substantially free of hydroxypropyl cellulose, including less than 1 weight percent hydroxypropyl cellulose. In some embodiments, the solid pharmaceutical composition is free of hydroxypropyl cellulose. In some embodiments, the solid pharmaceutical composition is a solid tablet. In some embodiments, the total weight of the tablet is from about 50 mg to about 500 mg. In some embodiments, the total weight of the tablet is about 100 mg.

[0023] In an aspect, a method of treatment for a migraine is provided. The method includes administering a therapeutically effective amount of bimatoprost, or the pharmaceutically acceptable salt, stereoisomer, solvate, co-crystal, polymorph, or free acid form thereof, in the form of any solid pharmaceutical composition described herein to a subject suffering from or at risk of a migraine.PCT / US25 / 47729 24 September 2025 (24.09.2025)Atty. Dkt. No.: 130856-0114

[0024] In some embodiments, the solid pharmaceutical composition is administered once daily. In some embodiments, the solid pharmaceutical composition is administered twice daily.BRIEF DESCRIPTION OF THE DRAWINGS

[0025] FIG. 1 shows the Single Ascending Dose (SAD) Pharmacokinetic (PK) data for the 0.3 mg bimatoprost sublingual tablet.

[0026] FIG. 2 shows the SAD PK data for the 0.6 mg bimatoprost sublingual tablet.

[0027] FIG. 3 A shows the SAD PK data for the 2mg bimatoprost sublingual tablet.

[0028] FIG. 3B shows the SAD PK data for the 2 mg bimatoprost liquid formulation.

[0029] FIG. 4A shows the Multiple Ascending Dose (MAD) PK data (Day 1) for the 0.6 mg bimatoprost sublingual tablet.

[0030] FIG. 4B shows the MAD PK data (Day 14) for the 0.6 mg bimatoprost sublingual tablet.

[0031] FIG. 5 A shows the MAD PK data (Day 1) for the 2 mg bimatoprost sublingual tablet.

[0032] FIG. 5B shows the MAD PK data (Day 14) for the 2 mg bimatoprost sublingual tablet.

[0033] FIG. 6 shows the LC-MS spectra for bimatoprost metabolites detected in human plasma.

[0034] FIG. 7 shows a visualization of the NRS scores collapsed into None, Mild, Moderate, and Severe groups, according to Example 10.

[0035] FIG. 8 shows the percentage pain relief across timepoints by treatment group (NRS 7+ Baseline subgroup).PCT / US25 / 47729 24 September 2025 (24.09.2025)Atty. Dkt. No.: 130856-0114DETAILED DESCRIPTION

[0036] Various embodiments are described hereinafter. It should be noted that the specific embodiments are not intended as an exhaustive description or as a limitation to the broader aspects discussed herein. One aspect described in conjunction with a particular embodiment is not necessarily limited to that embodiment and can be practiced with any other embodiment s).Definitions

[0037] As used herein, “about” will be understood by persons of ordinary skill in the art and will vary to some extent depending upon the context in which it is used. If there are uses of the term which are not clear to persons of ordinary skill in the art, given the context in which it is used, “about” will mean up to plus or minus 10% of the particular term.

[0038] The use of the terms “a” and “an” and “the” and similar referents in the context of describing the elements (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context.

[0039] “Sublingual administration” may be defined herein as the therapeutic administration of a pharmaceutical composition under the tongue. In some embodiments, the pharmaceutical composition refers to sublingual tablets. The tablet dosage form as per the present technology can be used for both sublingual or buccal administration or any of them. In some embodiments, the composition can be film-coated or uncoated. In some embodiments, the composition can be a scored or unscored tablet. Preferably, the pharmaceutical compositions as per the present technology are intended for use as a fast release tablet.

[0040] The term “pharmaceutically acceptable excipient” means a pharmacologically inactive component such as diluents, binders, fillers (including insoluble and / or soluble fillers), disintegrants, lubricants, glidants, surfactants, wetting agents, pH regulating agents, buffers, taste masking agents, water-soluble and / or water dispersible carrier materials, effervescent agents, salivating agents, antioxidants, permeation / penetration enhancers, solubilizing agents, crystallization inhibitors, co-crystal formers, plasticizers, acidulants,PCT / US25 / 47729 24 September 2025 (24.09.2025)Atty. Dkt. No.: 130856-0114 polymers, mucoadhesive agents, bioadhesive polymers, stabilizers, emulsifying agents, suspending agents, sweeteners, preservatives, flavoring and coloring agents, film forming agents, mouth feel improvers, solvents, cosolvents, and the like. Co-processed excipients are also covered under the scope of present technology. Excipients may be in the form of powder or in the form of dispersion. Combination of excipients performing the same function may also be used to achieve desired formulation characteristics. Excipients may be present in any part (intra and / or extra granular) of the composition in any proportion.

[0041] The term “patient” and / or “subject” are used interchangeably herein. In some embodiments, the patient or subject is a human. In some embodiments, the human can be of any age such as adult, adolescent, pediatric or geriatric.

[0042] The term “stable” in reference to the compositions of the present technology means the amount of the active ingredient of a formulation does not deviate from the initial amount by more than 10% (e.g., less than 10%, 8%, 6%, 4%, 2%, 1%, or 0.5%) of the initial content after being stored for at least 1 month, preferably for at least 2 months, preferably for at least 3 months, more preferably for at least 6 months, more preferably for at least 12 months or more preferably for at least 24 months. The stability of the composition may be evaluated at “long term” conditions 25° C / 60% RH, at intermediate condition 30° C / 65% RH, at “accelerated conditions” 40° C / 75% RH, in the final container measured as the loss in content of active ingredient. Stability testing may be conducted according to the current guidelines by ICH and FDA. In some embodiments of the technology, there is provided a solid pharmaceutical composition formulation for oral administration, wherein the total impurity is less than 5%, less than 3%, less than 2.5%, less than 2%, less than 1.5%, less than 1%, less than 0.9%, less than 0.8%, less than 0.7%, less than 0.6%, or less than 0.5%. In some embodiments of the technology, the total impurity is less than 1% or even less than 0.5%.

[0043] As used herein, the terms "treatment" and "treating" are used interchangeably herein. These terms refer to an approach for obtaining beneficial or desired results including, but not limited to, therapeutic benefit and / or a prophylactic benefit. A “therapeutic benefit” means eradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that anPCT / US25 / 47729 24 September 2025 (24.09.2025)Atty. Dkt. No.: 130856-0114 improvement is observed in the patient, notwithstanding that the patient can still be afflicted with the underlying disorder. For prophylactic benefit, the pharmaceutical compounds and / or compositions can be administered to a patient at risk of developing a disease, disorder, or condition, or to a patient reporting one or more of the physiological symptoms of a disease, disorder, or condition, even though a diagnosis thereof may not have been made.

[0044] The term “effective amount” or “a therapeutically effective amount” refers to an amount of an active agent being administered sufficient to prevent the disorder or prevent one or more symptoms of the disorder being treated. In certain embodiments, the term “effective amount” refers to that amount of an active agent being administered sufficient to reduce the risk of the disorder or one or more symptoms of the disorder.

[0045] Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein.

[0046] All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., “such as”) provided herein, is intended merely to better illuminate the embodiments and does not pose a limitation on the scope of the claims unless otherwise stated. No language in the specification should be construed as indicating any non-claimed element as essential.Pharmaceutical Compositions

[0047] In an aspect, provided herein is a pharmaceutical composition including a therapeutically effective amount of a prostaglandin F2a analog for treating a migraine and pharmaceutically acceptable excipients to stabilize the pharmaceutical composition.

[0048] In some embodiments, the prostaglandin F2a analog is selected from the group consisting of bimatoprost, latanoprost, travoprost, tafluprost, unoprostone, atanoprost, dinoprost, misoprostol, AS604872, BOL303259X, PF3187207, carboprost, and pharmaceutically acceptable salts, stereoisomers, solvates, co-crystals, polymorphs, or freePCT / US25 / 47729 24 September 2025 (24.09.2025)Atty. Dkt. No.: 130856-0114 acid forms thereof. In some embodiments, the prostaglandin F2a analog is bimatoprost or a pharmaceutically acceptable salt, stereoisomer, solvate, co-crystal, polymorph, or free acid form thereof.

[0049] Bimatoprost is a structural analog of prostaglandin F2a, and is characterized by the structural formula below:

[0050] In some embodiments, the prostaglandin F2a analog is a stereoisomer of bimatoprost characterized by the general structural formula below, where * denotes a chiral center:

[0051] In some embodiments, all of the chiral centers of the stereoisomer of bimatoprost are in the (R) configuration. In some embodiments, all of the chiral centers of the stereoisomer of bimatoprost are in the (S) configuration. In some embodiments, at least one, at least two, at least three, or at least four of the chiral centers of the stereoisomer of bimatoprost are in the (R) configuration. In some embodiments, at least one, at least two, at least three, or at least four of the chiral centers of the stereoisomer of bimatoprost are in the (S) configuration.PCT / US25 / 47729 24 September 2025 (24.09.2025)Atty. Dkt. No.: 130856-0114

[0052] In one aspect, provided herein is a pharmaceutical composition including a therapeutically effective amount of bimatoprost, or a pharmaceutically acceptable salt, stereoisomer, solvate, co-crystal, polymorph, or free acid form thereof, for treating a migraine and pharmaceutically acceptable excipients to stabilize the pharmaceutical composition.

[0053] In one aspect, provided herein is a solid pharmaceutical composition for oral administration including a therapeutically effective amount of bimatoprost, or a pharmaceutically acceptable salt, stereoisomer, solvate, co-crystal, polymorph, or free acid form thereof, for treating a migraine and pharmaceutically acceptable excipients to stabilize the solid pharmaceutical composition and provides oral release of bimatoprost, or the pharmaceutically acceptable salt, stereoisomer, solvate, co-crystal, polymorph, or free acid form thereof,.

[0054] In another aspect, the solid pharmaceutical compositions of the present disclosure include a therapeutically effective amount of bimatoprost, or a pharmaceutically acceptable salt, stereoisomer, solvate, co-crystal, polymorph, or free acid form thereof, for treating a migraine and pharmaceutically acceptable excipients to stabilize the solid pharmaceutical composition, where the pharmaceutical compositions are administered orally or to the oral mucosa and provide immediate release of bimatoprost, or the pharmaceutically acceptable salt, stereoisomer, solvate, co-crystal, polymorph, or free acid form thereof.

[0055] In some embodiments, the solid pharmaceutical composition includes a therapeutically effective amount of bimatoprost, or a pharmaceutically acceptable salt, stereoisomer, solvate, co-crystal, polymorph, or free acid form thereof, for treating a migraine; an effective amount of an antioxidant to provide a stable solid pharmaceutical composition; and one or more pharmaceutically acceptable excipients that provide oral release of bimatoprost, or the pharmaceutically acceptable salt, stereoisomer, solvate, cocrystal, polymorph, or free acid form thereof. In some embodiments, the solid pharmaceutical composition is stable for at least 3 months. In some embodiments, the solid pharmaceutical composition is stable for at least 6 months, at least 12 months, at least 18 months, or at least 24 months.

[0056] The pharmaceutical composition may include about 0.01 mg to about 8 mg, about 0.05 mg to about 8 mg, about 0.1 mg to about 8 mg, about 0.2 mg to about 8 mg, about 0.3PCT / US25 / 47729 24 September 2025 (24.09.2025)Atty. Dkt. No.: 130856-0114 mg to about 8 mg, about 0.4 mg to about 8 mg, about 0.5 mg to about 8 mg, about 0.6 mg to about 8 mg, about 0.7 mg to about 8 mg, about 0.8 mg to about 8 mg, about 0.9 mg to about 8 mg, about 1 mg to about 8 mg, about 1.1 mg to about 8 mg, about 1.2 mg to about 8 mg, about 1.3 mg to about 8 mg, about 1.4 mg to about 8 mg, about 1.5 mg to about 8 mg, about 1.6 mg to about 8 mg, about 1.7 mg to about 8 mg, about 1.8 mg to about 8 mg, about 1.9 mg to about 8 mg, about 2 mg to about 8 mg, about 2.1 mg to about 8 mg, about 2.2 mg to about 8 mg, about 2.3 mg to about 8 mg, about 2.4 mg to about 8 mg, about 2.5 mg to about 8 mg, about 2.6 mg to about 8 mg, about 2.7 mg to about 8 mg, about 2.8 mg to about 8 mg, about 2.9 mg to about 8 mg, about 3 mg to about 8 mg, about 3.1 mg to about 8 mg, about 3.2 mg to about 8 mg, about 3.3 mg to about 8 mg, about 3.4 mg to about 8 mg, about 3.5 mg to about 8 mg, about 3.6 mg to about 8 mg, about 3.7 mg to about 8 mg, about 3.8 mg to about 8 mg, about 3.9 mg to about 8 mg, about 4 mg to about 8 mg, about 4.1 mg to about 8 mg, about 4.2 mg to about 8 mg, about 4.3 mg to about 8 mg, about 4.4 mg to about 8 mg, about 4.5 mg to about 8 mg, about 4.6 mg to about 8 mg, about 4.7 mg to about 8 mg, about 4.8 mg to about 8 mg, about 4.9 mg to about 8 mg, about 5 mg to about 8 mg, about 5.1 mg to about 8 mg, about 5.2 mg to about 8 mg, about 5.3 mg to about 8 mg, about 5.4 mg to about 8 mg, about 5.5 mg to about 8 mg, about 5.6 mg to about 8 mg, about 5.7 mg to about 8 mg, about 5.8 mg to about 8 mg, about 5.9 mg to about 8 mg, about 6 mg to about 8 mg, about 6.1 mg to about 8 mg, about 6.2 mg to about 8 mg, about 6.3 mg to about 8 mg, about 6.4 mg to about 8 mg, about 6.5 mg to about 8 mg, about 6.6 mg to about 8 mg, about 6.7 mg to about 8 mg, about 6.8 mg to about 8 mg, about 6.9 mg to about 8 mg, about 7 mg to about 8 mg, about 7.1 mg to about 8 mg, about 7.2 mg to about 8 mg, about 7.3 mg to about 8 mg, about 7.4 mg to about 8 mg, about 7.5 mg to about 8 mg, about 7.6 mg to about 8 mg, about 7.7 mg to about 8 mg, about 7.8 mg to about 8 mg, or about 7.9 mg to about 8 mg of bimatoprost, or a pharmaceutically acceptable salt, stereoisomer, solvate, co-crystal, polymorph, or free acid form thereof.

[0057] The pharmaceutical composition may include about 0.01 mg to about 7 mg, about 0.05 mg to about 7 mg, about 0.1 mg to about 7 mg, about 0.2 mg to about 7 mg, about 0.3 mg to about 7 mg, about 0.4 mg to about 7 mg, about 0.5 mg to about 7 mg, about 0.6 mg to about 7 mg, about 0.7 mg to about 7 mg, about 0.8 mg to about 7 mg, about 0.9 mg to about 7 mg, about 1 mg to about 7 mg, about 1.1 mg to about 7 mg, about 1.2 mg to about 7 mg, about 1.3 mg to about 7 mg, about 1.4 mg to about 7 mg, about 1.5 mg to about 7 mg, aboutPCT / US25 / 47729 24 September 2025 (24.09.2025)Atty. Dkt. No.: 130856-0114 1.6 mg to about 7 mg, about 1.7 mg to about 7 mg, about 1.8 mg to about 7 mg, about 1.9 mg to about 7 mg, about 2 mg to about 7 mg, about 2.1 mg to about 7 mg, about 2.2 mg to about 7 mg, about 2.3 mg to about 7 mg, about 2.4 mg to about 7 mg, about 2.5 mg to about 7 mg, about 2.6 mg to about 7 mg, about 2.7 mg to about 7 mg, about 2.8 mg to about 7 mg, about 2.9 mg to about 7 mg, about 3 mg to about 7 mg, about 3.1 mg to about 7 mg, about 3.2 mg to about 7 mg, about 3.3 mg to about 7 mg, about 3.4 mg to about 7 mg, about 3.5 mg to about 7 mg, about 3.6 mg to about 7 mg, about 3.7 mg to about 7 mg, about 3.8 mg to about 7 mg, about 3.9 mg to about 7 mg, about 4 mg to about 7 mg, about 4.1 mg to about 7 mg, about 4.2 mg to about 7 mg, about 4.3 mg to about 7 mg, about 4.4 mg to about 7 mg, about 4.5 mg to about 7 mg, about 4.6 mg to about 7 mg, about 4.7 mg to about 7 mg, about 4.8 mg to about 7 mg, about 4.9 mg to about 7 mg, about 5 mg to about 7 mg, about 5.1 mg to about 7 mg, about 5.2 mg to about 7 mg, about 5.3 mg to about 7 mg, about 5.4 mg to about 7 mg, about 5.5 mg to about 7 mg, about 5.6 mg to about 7 mg, about 5.7 mg to about 7 mg, about 5.8 mg to about 7 mg, about 5.9 mg to about 7 mg, about 6 mg to about 7 mg, about 6.1 mg to about 7 mg, about 6.2 mg to about 7 mg, about 6.3 mg to about 7 mg, about 6.4 mg to about 7 mg, about 6.5 mg to about 7 mg, about 6.6 mg to about 7 mg, about 6.7 mg to about 7 mg, about 6.8 mg to about 7 mg, or about 6.9 mg to about 7 mg of bimatoprost, or a pharmaceutically acceptable salt, stereoisomer, solvate, co-crystal, polymorph, or free acid form thereof.

[0058] The pharmaceutical composition may include about 0.01 mg to about 6 mg, about 0.05 mg to about 6 mg, about 0.1 mg to about 6 mg, about 0.2 mg to about 6 mg, about 0.3 mg to about 6 mg, about 0.4 mg to about 6 mg, about 0.5 mg to about 6 mg, about 0.6 mg to about 6 mg, about 0.7 mg to about 6 mg, about 0.8 mg to about 6 mg, about 0.9 mg to about 6 mg, about 1 mg to about 6 mg, about 1.1 mg to about 6 mg, about 1.2 mg to about 6 mg, about 1.3 mg to about 6 mg, about 1.4 mg to about 6 mg, about 1.5 mg to about 6 mg, about 1.6 mg to about 6 mg, about 1.7 mg to about 6 mg, about 1.8 mg to about 6 mg, about 1.9 mg to about 6 mg, about 2 mg to about 6 mg, about 2.1 mg to about 6 mg, about 2.2 mg to about 6 mg, about 2.3 mg to about 6 mg, about 2.4 mg to about 6 mg, about 2.5 mg to about 6 mg, about 2.6 mg to about 6 mg, about 2.7 mg to about 6 mg, about 2.8 mg to about 6 mg, about 2.9 mg to about 6 mg, about 3 mg to about 6 mg, about 3.1 mg to about 6 mg, about 3.2 mg to about 6 mg, about 3.3 mg to about 6 mg, about 3.4 mg to about 6 mg, about 3.5 mg to about 6 mg, about 3.6 mg to about 6 mg, about 3.7 mg to about 6 mg, about 3.8 mg toPCT / US25 / 47729 24 September 2025 (24.09.2025)Atty. Dkt. No.: 130856-0114 about 6 mg, about 3.9 mg to about 6 mg, about 4 mg to about 6 mg, about 4.1 mg to about 6 mg, about 4.2 mg to about 6 mg, about 4.3 mg to about 6 mg, about 4.4 mg to about 6 mg, about 4.5 mg to about 6 mg, about 4.6 mg to about 6 mg, about 4.7 mg to about 6 mg, about 4.8 mg to about 6 mg, about 4.9 mg to about 6 mg, about 5 mg to about 6 mg, about 5.1 mg to about 6 mg, about 5.2 mg to about 6 mg, about 5.3 mg to about 6 mg, about 5.4 mg to about 6 mg, about 5.5 mg to about 6 mg, about 5.6 mg to about 6 mg, about 5.7 mg to about 6 mg, about 5.8 mg to about 6 mg, or about 5.9 mg to about 6 mg of bimatoprost, or a pharmaceutically acceptable salt, stereoisomer, solvate, co-crystal, polymorph, or free acid form thereof.

[0059] The pharmaceutical composition may include about 0.01 mg to about 5 mg, about 0.05 mg to about 5 mg, about 0.1 mg to about 5 mg, about 0.2 mg to about 5 mg, about 0.3 mg to about 5 mg, about 0.4 mg to about 5 mg, about 0.5 mg to about 5 mg, about 0.6 mg to about 5 mg, about 0.7 mg to about 5 mg, about 0.8 mg to about 5 mg, about 0.9 mg to about 5 mg, about 1 mg to about 5 mg, about 1.1 mg to about 5 mg, about 1.2 mg to about 5 mg, about 1.3 mg to about 5 mg, about 1.4 mg to about 5 mg, about 1.5 mg to about 5 mg, about 1.6 mg to about 5 mg, about 1.7 mg to about 5 mg, about 1.8 mg to about 5 mg, about 1.9 mg to about 5 mg, about 2 mg to about 5 mg, about 2.1 mg to about 5 mg, about 2.2 mg to about 5 mg, about 2.3 mg to about 5 mg, about 2.4 mg to about 5 mg, about 2.5 mg to about 5 mg, about 2.6 mg to about 5 mg, about 2.7 mg to about 5 mg, about 2.8 mg to about 5 mg, about 2.9 mg to about 5 mg, about 3 mg to about 5 mg, about 3.1 mg to about 5 mg, about 3.2 mg to about 5 mg, about 3.3 mg to about 5 mg, about 3.4 mg to about 5 mg, about 3.5 mg to about 5 mg, about 3.6 mg to about 5 mg, about 3.7 mg to about 5 mg, about 3.8 mg to about 5 mg, about 3.9 mg to about 5 mg, about 4 mg to about 5 mg, about 4.1 mg to about 5 mg, about 4.2 mg to about 5 mg, about 4.3 mg to about 5 mg, about 4.4 mg to about 5 mg, about 4.5 mg to about 5 mg, about 4.6 mg to about 5 mg, about 4.7 mg to about 5 mg, about 4.8 mg to about 5 mg, or about 4.9 mg to about 5 mg of bimatoprost, or a pharmaceutically acceptable salt, stereoisomer, solvate, co-crystal, polymorph, or free acid form thereof.

[0060] The pharmaceutical composition may include about 0.01 mg to about 4 mg, about 0.05 mg to about 4 mg, about 0.1 mg to about 4 mg, about 0.2 mg to about 4 mg, about 0.3 mg to about 4 mg, about 0.4 mg to about 4 mg, about 0.5 mg to about 4 mg, about 0.6 mg to about 4 mg, about 0.7 mg to about 4 mg, about 0.8 mg to about 4 mg, about 0.9 mg to about 4 mg, about 1 mg to 4 mg, about 1.1 mg to about 4 mg, about 1.2 mg to about 4 mg, aboutPCT / US25 / 47729 24 September 2025 (24.09.2025)Atty. Dkt. No.: 130856-01141.3 mg to about 4 mg, about 1.4 mg to about 4 mg, about 1.5 mg to about 4 mg, about 1.6 mg to about 4 mg, about 1.7 mg to about 4 mg, about 1.8 mg to about 4 mg, about 1.9 mg to about 4 mg, about 2 mg to about 4 mg, about 2.1 mg to about 4 mg, about 2.2 mg to about 4 mg, about 2.3 mg to about 4 mg, about 2.4 mg to about 4 mg, about 2.5 mg to about 4 mg, about 2.6 mg to about 4 mg, about 2.7 mg to about 4 mg, about 2.8 mg to about 4 mg, about 2.9 mg to about 4 mg, about 3 mg to about 4 mg, about 3.1 mg to about 4 mg, about 3.2 mg to about 4 mg, about 3.3 mg to about 4 mg, about 3.4 mg to about 4 mg, about 3.5 mg to about 4 mg, about 3.6 mg to about 4 mg, about 3.7 mg to about 4 mg, about 3.8 mg to about 4 mg, or about 3.9 mg to about 4 mg of bimatoprost, or a pharmaceutically acceptable salt, stereoisomer, solvate, co-crystal, polymorph, or free acid form thereof.

[0061] The pharmaceutical composition may include about 0.01 mg to about 3 mg, about 0.05 mg to about 3 mg, about 0.1 mg to about 3 mg, about 0.2 mg to about 3 mg, about 0.3 mg to about 3 mg, about 0.4 mg to about 3 mg, about 0.5 mg to about 3 mg, about 0.6 mg to about 3 mg, about 0.7 mg to about 3 mg, about 0.8 mg to about 3 mg, about 0.9 mg to about 3 mg, about 1 mg to 3 mg, about 1.1 mg to about 3 mg, about 1.2 mg to about 3 mg, about1.3 mg to about 3 mg, about 1.4 mg to about 3 mg, about 1.5 mg to about 3 mg, about 1.6 mg to about 3 mg, about 1.7 mg to about 3 mg, about 1.8 mg to about 3 mg, about 1.9 mg to about 3 mg, about 2 mg to about 3 mg, about 2.1 mg to about 3 mg, about 2.2 mg to about 3 mg, about 2.3 mg to about 3 mg, about 2.4 mg to about 3 mg, about 2.5 mg to about 3 mg, about 2.6 mg to about 3 mg, about 2.7 mg to about 3 mg, about 2.8 mg to about 3 mg, or about 2.9 mg to about 3 mg of bimatoprost, or a pharmaceutically acceptable salt, stereoisomer, solvate, co-crystal, polymorph, or free acid form thereof.

[0062] The pharmaceutical composition may include about 0.01 mg to about 2 mg, about 0.05 mg to about 2 mg, about 0.1 mg to about 2 mg, about 0.2 mg to about 2 mg, about 0.3 mg to about 2 mg, about 0.4 mg to about 2 mg, about 0.5 mg to about 2 mg, about 0.6 mg to about 2 mg, about 0.7 mg to about 2 mg, about 0.8 mg to about 2 mg, about 0.9 mg to about 2 mg, about 1 mg to 2 mg, about 1.1 mg to about 2 mg, about 1.2 mg to about 2 mg, about1.3 mg to about 2 mg, about 1.4 mg to about 2 mg, about 1.5 mg to about 2 mg, about 1.6 mg to about 2 mg, about 1.7 mg to about 2 mg, about 1.8 mg to about 2 mg, or about 1.9 mg to about 2 mg of bimatoprost, or a pharmaceutically acceptable salt, stereoisomer, solvate, co-crystal, polymorph, or free acid form thereof.PCT / US25 / 47729 24 September 2025 (24.09.2025)Atty. Dkt. No.: 130856-0114

[0063] In some embodiments, the pharmaceutical composition may include 0.01 mg to about 1 mg, about 0.05 mg to about 1 mg, about 0.1 mg to about 1 mg, about 0.2 mg to about 1 mg, about 0.3 mg to about 1 mg, about 0.4 mg to about 1 mg, about 0.5 mg to about 1 mg, about 0.6 mg to about 1 mg, about 0.7 mg to about 1 mg, about 0.8 mg to about 1 mg, or about 0.9 mg to about 1 mg bimatoprost, or a pharmaceutically acceptable salt, stereoisomer, solvate, co-crystal, polymorph, or free acid form thereof.

[0064] In some embodiments, the pharmaceutical composition may include about 0.01 mg to about 0.5 mg, about 0.02 mg to about 0.5 mg, about 0.03 mg to about 0.5 mg, about 0.04 mg to about 0.5 mg, about 0.05 mg to about 0.5 mg, about 0.06 mg to about 0.5 mg, about 0.07 mg to about 0.5 mg, about 0.08 mg to about 0.5 mg, about 0.09 mg to about 0.5 mg, about 0.1 mg to about 0.5 mg, about 0.2 mg to about 0.5 mg, about 0.3 mg to about 0.5 mg, or about 0.4 mg to about 0.5 mg bimatoprost, or a pharmaceutically acceptable salt, stereoisomer, solvate, co-crystal, polymorph, or free acid form thereof.

[0065] In some embodiments, the pharmaceutical composition may include about 0.01 mg to about 0.6 mg, about 0.02 mg to about 0.6 mg, about 0.03 mg to about 0.6 mg, about 0.04 mg to about 0.6 mg, about 0.05 mg to about 0.6 mg, about 0.06 mg to about 0.6 mg, about 0.07 mg to about 0.6 mg, about 0.08 mg to about 0.6 mg, about 0.09 mg to about 0.6 mg, about 0.1 mg to about 0.6 mg, about 0.2 mg to about 0.6 mg, about 0.3 mg to about 0.6 mg, about 0.4 mg to about 0.6 mg, or about 0.5 mg to about 0.6 mg bimatoprost, or a pharmaceutically acceptable salt, stereoisomer, solvate, co-crystal, polymorph, or free acid form thereof.

[0066] In some embodiments, the pharmaceutical composition may include about 0.01 mg to about 0.7 mg, about 0.02 mg to about 0.7 mg, about 0.03 mg to about 0.7 mg, about 0.04 mg to about 0.7 mg, about 0.05 mg to about 0.7 mg, about 0.06 mg to about 0.7 mg, about 0.07 mg to about 0.7 mg, about 0.08 mg to about 0.7 mg, about 0.09 mg to about 0.7 mg, about 0.1 mg to about 0.7 mg, about 0.2 mg to about 0.7 mg, about 0.3 mg to about 0.7 mg, about 0.4 mg to about 0.7 mg, about 0.5 mg to about 0.7 mg, or about 0.6 mg to about 0.7 mg bimatoprost, or a pharmaceutically acceptable salt, stereoisomer, solvate, co-crystal, polymorph, or free acid form thereof.

[0067] In some embodiments, the pharmaceutical composition may include about 0.01 mg, about 0.05 mg, about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg,PCT / US25 / 47729 24 September 2025 (24.09.2025)Atty. Dkt. No.: 130856-0114 about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1 mg, about 1.1 mg, about1.2 mg, about 1.3 mg, about 1.4 mg, about 1.5 mg, about 1.6 mg, about 1.7 mg, about 1.8 mg, about 1.9 mg, about 2 mg, about 2.1 mg, about 2.2 mg, about 2.3 mg, about 2.4 mg, about 2.5 mg, about 2.6 mg, about 2.7 mg, about 2.8 mg, about 2.9 mg, about 3 mg, about 3.1 mg, about 3.2 mg, about 3.3 mg, about 3.4 mg, about 3.5 mg, about 3.6 mg, about 3.7 mg, about 3.8 mg, about 3.9 mg, about 4 mg, about 4.1 mg, about 4.2 mg, about 4.3 mg, about 4.4 mg, about 4.5 mg, about 4.6 mg, about 4.7 mg, about 4.8 mg, about 4.9 mg, about 5 mg, about 5.1 mg, about 5.2 mg, about 5.3 mg, about 5.4 mg, about 5.5 mg, about 5.6 mg, about 5.7 mg, about 5.8 mg, about 5.9 mg, about 6 mg, about 6.1 mg, about 6.2 mg, about6.3 mg, about 6.4 mg, about 6.5 mg, about 6.6 mg, about 6.7 mg, about 6.8 mg, about 6.9 mg, about 7 mg, about 7.1 mg, about 7.2 mg, about 7.3 mg, about 7.4 mg, about 7.5 mg, about 7.6 mg, about 7.7 mg, about 7.8 mg, about 7.9 mg, or about 8 mg of bimatoprost, or a pharmaceutically acceptable salt, stereoisomer, solvate, co-crystal, polymorph, or free acid form thereof.

[0068] In some embodiments, the pharmaceutical composition may include about 0.5 mg, about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 3.5 mg, about 4 mg, about 4.5 mg, about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about 8.5 mg, about 9 mg, about 9.5 mg, about 10 mg, about 10.5 mg, about 11 mg, about 11.5 mg, about 12 mg, about 12.5 mg, about 13 mg, about 13.5 mg, about 14 mg, about 14.5 mg, about 15 mg, about 15.5 mg, or about 16 mg of bimatoprost, or a pharmaceutically acceptable salt, stereoisomer, solvate, co-crystal, polymorph, or free acid form thereof.

[0069] The present pharmaceutical compositions typically include an antioxidant. Suitable antioxidants may include an amino acid sulfite (e.g., L-lysine sulfite), ascorbic acid or any salts thereof, ascorbyl palmitate, benzoic acid or any salts thereof, benzotriazol, butylhydroxyanisole (BHA), butylhydroxytoluene (BHT), citric acid or any salts thereof, cysteine, cysteine hydrochloride, disodium calcium ethylenediaminetetraacetate, disodium ethylenediaminetetraacetate, dithiothreitol, DL-alpha-tocopherol, erythorbic acid or any salts thereof, ethoxyquin, ethylenediaminetetraacetic acid salts, folic acid or any salts thereof, fumaric acid or any salts thereof, glutathione, guaiac, homocysteine, hydroxypropyl-beta-cyclodextrin (HPpCD), sulfobutylether-beta-cyclodextrin (SBECD), gamma-cyclodextrins, alpha-cyclodextrins, isopropyl citrate, L-ascorbate stearate esters,PCT / US25 / 47729 24 September 2025 (24.09.2025)Atty. Dkt. No.: 130856-0114 malic acid or any salts thereof, monothioglycerol, nordihydroguaiaretic acid (NDGA), pentaerythrityl-tetrakis[3-(3,5-di-t-butyl-4-hydroxyphenyl)propionate]2- mercaptobenzimidazole, potassium dichloroisocyanurate, potassium sorbate, propionic acid or any salts thereof, propyl gallate, rongalite (CEEOHSChNa), sodium acetate, sodium bisulfite, sodium edetate, sodium hydrogen sulfite, sodium metabisulfite, sodium pyrosulfite 1,3-butylene glycol, sodium sulfite, sodium thioglycolate, sodium thiosulfate, sorbic acid, soybean lecithin, tert-butyl hydroquinone, thioglycerol, thiourea, TPGS (tocopherol polyethylene glycol succinate), vitamin A (i.e., beta carotene) and derivatives thereof, vitamin E and derivatives thereof, a-thioglycerin, or a combination of any two or more thereof. In some embodiments, the antioxidant is selected from the group consisting of butylated hydroxytoluene, citric acid, butylated hydroxy anisole, vitamin E TPGS, HPpCD, and combinations of any two or more thereof. In some embodiments, the antioxidant is selected from the group consisting of butylated hydroxytoluene, citric acid, butylated hydroxyanisole, and combinations of any two or more thereof. In some embodiments, the antioxidant comprises butylated hydroxytoluene.

[0070] The pharmaceutical composition may include about 0.001 to about 1 weight percent, about 0.005 to about 1 weight percent, about 0.01 to about 1 weight percent, about 0.05 to about 1 weight percent, about 0.1 to about 1 weight percent, about 0.2 to about 1 weight percent, about 0.3 to about 1 weight percent, about 0.4 to about 1 weight percent, about 0.5 to about 1 weight percent, about 0.6 to about 1 weight percent, about 0.7 to about 1 weight percent, about 0.8 to about 1 weight percent, or about 0.9 to about 1 weight percent of the antioxidant. In other embodiments, the pharmaceutical composition may include about 0.001 to about 0.9 weight percent, about 0.001 to about 0.8 weight percent, about 0.001 to about 0.7 weight percent, about 0.001 to about 0.6 weight percent, about 0.001 to about 0.5 weight percent, about 0.001 to about 0.4 weight percent, about 0.001 to about 0.3 weight percent, about 0.001 to about 0.2 weight percent, or about 0.001 to about 0.1 weight percent of the antioxidant. In some embodiments, the pharmaceutical composition may include about 0.001 weight percent, about 0.005 weight percent, about 0.01 weight percent, about 0.05 weight percent, about 0.1 weight percent, about 0.2 weight percent, about 0.3 weight percent, about 0.4 weight percent, about 0.5 weight percent, about 0.6 weight percent, about 0.7 weight percent, about 0.8 weight percent, about 0.9 weight percent, or about 1 weight percent of the antioxidant.PCT / US25 / 47729 24 September 2025 (24.09.2025)Atty. Dkt. No.: 130856-0114

[0071] In some embodiments, the pharmaceutically acceptable excipients include a filler and a disintegrant. The filler may include an insoluble filler and a soluble filler. In some embodiments, the pharmaceutically acceptable excipients further include a binder and / or a lubricant. In some embodiments, the pharmaceutically acceptable excipients include one or more of microcrystalline cellulose, mannitol, propylene glycol, croscarmellose sodium, and magnesium stearate. In some embodiments, the pharmaceutical composition comprises microcrystalline cellulose, mannitol, propylene glycol, croscarmellose sodium, and magnesium stearate. In some embodiments, one or more of the pharmaceutically acceptable excipients also function as a binder. In some embodiments, the insoluble filler, soluble filler, or both also function as a binder. In some embodiments, any of the pharmaceutical compositions described herein are substantially free of hydroxypropyl cellulose, i.e., including less than 1 weight percent hydroxypropyl cellulose. In some such embodiments, the pharmaceutical compositions are also free of antioxidant. In some embodiments, any of the pharmaceutical compositions described herein are free of hydroxypropyl cellulose. In some such embodiments, the pharmaceutical compositions are also free of antioxidant.

[0072] In some embodiments, the pharmaceutical composition includes about 40 to about 60 weight percent, about 45 to about 60 weight percent, about 50 to about 60 weight percent, about 40 to about 55 weight percent, about 40 to about 50 weight percent, or about 45 to about 55 weight percent of the insoluble filler. In some embodiments, the pharmaceutical composition includes about 40 weight percent, about 41 weight percent, about 42 weight percent, about 43 weight percent, about 44 weight percent, about 45 weight percent, about 46 weight percent, about 47 weight percent, about 48 weight percent, about49 weight percent, about 50 weight percent, about 51 weight percent, about 52 weight percent, about 53 weight percent, about 54 weight percent, about 55 weight percent, about 56 weight percent, about 57 weight percent, about 58 weight percent about 59 weight percent, or about 60 weight percent of the insoluble filler. In some embodiments, the insoluble filler is microcrystalline cellulose.

[0073] In some embodiments, the pharmaceutical composition includes about 30 to about50 weight percent, about 35 to about 50 weight percent, about 40 to about 50 weight percent, about 30 to about 45 weight percent, about 30 to about 40 weight percent, or about 35 to about 45 weight percent of the soluble filler. In some embodiments, the pharmaceutical composition includes about 30 weight percent, about 31 weight percent,PCT / US25 / 47729 24 September 2025 (24.09.2025)Atty. Dkt. No.: 130856-0114 about 32 weight percent, about 33 weight percent, about 34 weight percent, about 35 weight percent, about 36 weight percent, about 37 weight percent, about 38 weight percent, about 39 weight percent, about 40 weight percent, about 41 weight percent, about 42 weight percent, about 43 weight percent, about 44 weight percent, about 45 weight percent, about 46 weight percent, about 47 weight percent, about 48 weight percent about 49 weight percent, or about 50 weight percent of the soluble filler. In some embodiments, the soluble filler is mannitol.

[0074] In some embodiments, the pharmaceutical composition includes about 0 to about 10 weight percent, about 1 to about 9 weight percent, about 2 to about 8 weight percent, about 3 to about 7 weight percent, about 4 to about 6 weight percent, about 0 to about 8 weight percent, about 0 to about 6 weight percent, about 0 to about 4 weight percent, about 2 to about 10 weight percent, or about 4 to about 10 weight percent of a cosolvent. In some embodiments, the pharmaceutical composition includes about 0 weight percent, about 1 weight percent, about 2 weight percent, about 3 weight percent, about 4 weight percent, about 5 weight percent, about 6 weight percent, about 7 weight percent, about 8 weight percent, about 9 weight percent, or about 10 weight percent of a cosolvent. In some embodiments, the cosolvent is propylene glycol.

[0075] In some embodiments, the pharmaceutical composition includes about 1 to about 5 weight percent, about 2 to about 5 weight percent, about 3 to about 5 weight percent, about 1 to about 4 weight percent, or about 1 to about 3 weight percent of a disintegrant. In some embodiments, the pharmaceutical composition includes about 1 weight percent, about 2 weight percent, about 3 weight percent, about 4 weight percent, or about 5 weight percent of a disintegrant. In some embodiments, the disintegrant is croscarmellose sodium.

[0076] In some embodiments, the pharmaceutical composition includes about 0 to about 1 weight percent, about 0.1 to about 0.9 weight percent, about 0.2 to about 0.8 weight percent, about 0.3 to about 0.7 weight percent, about 0.4 to about 0.6 weight percent, about 0 to about 0.8 weight percent, about 0 to about 0.6 weight percent, about 0.2 to about 1 weight percent, or about 0.4 to about 1 weight percent of a lubricant. In some embodiments, the pharmaceutical composition includes about 0 weight percent, about 0.1 weight percent, about 0.2 weight percent, about 0.3 weight percent, about 0.4 weight percent, about 0.5 weight percent, about 0.6 weight percent, about 0.7 weight percent, about 0.8 weightPCT / US25 / 47729 24 September 2025 (24.09.2025)Atty. Dkt. No.: 130856-0114 percent, about 0.9 weight percent, or about 1 weight percent of a lubricant. In some embodiments, the lubricant is magnesium stearate.

[0077] In some embodiments, the pharmaceutical composition is a solid pharmaceutical composition for oral administration includes about 0.01 mg to about 2 mg bimatoprost; about 40 to about 60 weight percent of an insoluble filler; about 30 to about 50 weight percent of a soluble filler; 0 to about 10 weight percent cosolvent; about 0.001 to about 1 weight percent of an antioxidant; about 1 to about 5 weight percent of a disintegrant; and 0 to about 1 weight percent of a lubricant.

[0078] In some embodiments, the pharmaceutical composition is a solid pharmaceutical composition for oral administration includes about 45 to about 55 weight percent of the insoluble filler; about 35 to about 45 weight percent of the soluble filler; about 1 to about 5 weight percent cosolvent; about 0.001 to about 1 weight percent of the antioxidant; about 2 to about 4 weight percent of the disintegrant; and about 0.1 to about 0.8 weight percent of the lubricant.

[0079] In some embodiments, the pharmaceutical composition is a solid pharmaceutical composition for oral administration includes about 50 weight percent microcrystalline cellulose; about 40 weight percent mannitol; about 4 weight percent propylene glycol; about 0.3 weight percent butylated hydroxytoluene; about 3 weight percent croscarmellose sodium; and about 0.5 weight percent magnesium stearate.

[0080] In some embodiments, any of the pharmaceutical compositions described herein are formulated as a solid pharmaceutical composition. In some embodiments, the pharmaceutical composition is formulated as a liquid pharmaceutical composition.

[0081] In some embodiments, any of the pharmaceutical compositions described herein are formulated for oral administration. Non-limiting examples of oral administration include, but are not limited to, oral mucosal administration or oral administration that is absorbed via the gastrointestinal tract.

[0082] In some embodiments, any of the pharmaceutical compositions described herein are formulated for mucosal administration. Such administration routes include, but are notPCT / US25 / 47729 24 September 2025 (24.09.2025)Atty. Dkt. No.: 130856-0114 limited to, oral, otic, nasal, rectal, vaginal, conjunctival, sublingual, or transcutaneous mucosal administration.

[0083] In some embodiments, any of the solid pharmaceutical compositions described herein are formulated for oral mucosal release. In some embodiments, any of the solid pharmaceutical compositions described herein are formulated for sublingual release. In some embodiments, any of the solid pharmaceutical compositions described herein are formulated for buccal release. In some embodiments, any of the solid pharmaceutical compositions described herein are formulated for immediate release.

[0084] In some embodiments, any of the solid pharmaceutical compositions described herein releases at least 70% to 90% of bimatoprost, or the pharmaceutically acceptable salt, stereoisomer, solvate, co-crystal, polymorph, or free acid form thereof, within 2 minutes when measured in 500 mL of 0.05 M phosphate buffer with a pH of 6.8 using a USP II dissolution apparatus at a temperature of 37.0°C ± 0.5°C and a rotation speed of 75 RPM. In some embodiments, any of the solid pharmaceutical compositions described herein releases at least 80% to 100% of bimatoprost, or the pharmaceutically acceptable salt, stereoisomer, solvate, co-crystal, polymorph, or free acid form thereof, within 15 minutes when measured in 500 mL of 0.05 M phosphate buffer with a pH of 6.8 using a USP II dissolution apparatus at a temperature of 37.0°C ± 0.5°C and a rotation speed of 75 RPM.

[0085] In some embodiments, any of the solid pharmaceutical compositions described herein are about 85% to 100% dissolved within 2 minutes when measured in 500 mL of 0.05 M phosphate buffer with a pH of 6.8 using a USP II dissolution apparatus at a temperature of 37.0°C ± 0.5°C and a rotation speed of 75 RPM. In some embodiments, any of the solid pharmaceutical compositions described herein are about 90% to 100% dissolved within 5 minutes when measured in 500 mL of 0.05 M phosphate buffer with a pH of 6.8 using a USP II dissolution apparatus at a temperature of 37.0°C ± 0.5°C and a rotation speed of 75 RPM.

[0086] In some embodiments, the total weight any of the solid pharmaceutical compositions described herein is from about 50 mg to about 500 mg. In some embodiments, the total weight any of the solid pharmaceutical compositions described herein is about 100 mg.PCT / US25 / 47729 24 September 2025 (24.09.2025)Atty. Dkt. No.: 130856-0114

[0087] In some embodiments, the pharmaceutical composition is for oral mucosal administration. The pharmaceutical composition for oral mucosal administration can be administered in any pharmaceutical dosage form that can be held in the mouth for a suitable period of time and permits diffusion or erosion of the drug into the mouth cavity where the drug can be absorbed through the mucosa lining of the mouth. Such dosage forms include transmucosal dosage forms, tablets, fast disintegrating tablets, orally disintegrating tablets, lozenges, sublingual tablets, sublingual capsule, sublingual film, sublingual aerosol, sublingual solution, sublingual spray, buccal tablets, mucoadhesive tablets, bio adhesive tablets, troches, pastilles, pills, liquids, viscous liquids, pastes, drops, gels, patches, and the like. Depending on the intended mode of administration, the disclosed pharmaceutical compositions can be in solid, semi-solid or liquid dosage form, such as, for example, injectables, tablets, immediate release tablets, extended release tablets, suppositories, pills, time-release capsules, elixirs, tinctures, emulsions, syrups, powders, liquids, suspensions, or the like, sometimes in unit dosages and consistent with conventional pharmaceutical practices.Methods of Treatment

[0088] Any of the pharmaceutical compositions described herein may be used for the treatment of a migraine. In some embodiments, a method of treatment includes administering a therapeutically effective amount of a prostaglandin F2a analog, or a pharmaceutically acceptable salt, stereoisomer, solvate, co-crystal, polymorph, or free acid form thereof, in a pharmaceutical composition described herein to a subject suffering from or at risk of a migraine.

[0089] In some embodiments, a method of treatment includes administering a therapeutically effective amount of bimatoprost, or a pharmaceutically acceptable salt, stereoisomer, solvate, co-crystal, polymorph, or free acid form thereof, in any one of the solid pharmaceutical compositions described herein to a subject suffering from or at risk of a migraine.

[0090] In some embodiments, the methods of treatment include administering a therapeutically effective amount of bimatoprost, or a pharmaceutically acceptable salt, stereoisomer, solvate, co-crystal, polymorph, or free acid form thereof, in any one of the solid pharmaceutical compositions described herein to a subject suffering from or at risk ofPCT / US25 / 47729 24 September 2025 (24.09.2025)Atty. Dkt. No.: 130856-0114 a primary or secondary migraine. In some embodiments, the subject at risk of a migraine is experiencing other headache disorders.

[0091] In some embodiments, the pharmaceutical composition is administered as a single dose. In some embodiments, the pharmaceutical composition is administered as one or more doses. In some embodiments, the pharmaceutical composition is administered as a single dose daily. In some embodiments, the pharmaceutical composition is administered as one or more doses daily. In some embodiments, the pharmaceutical composition is administered as one dose, two doses, three doses, or four doses daily. In some embodiments, one or more doses are administered simultaneously.

[0092] In some embodiments, each dose in the one or more doses administered is the same dose. In some embodiments, each dose in the one or more doses administered daily is the same dose. In some embodiments, each dose in the one or more doses administered is a different dose. In some embodiments, each dose in the one or more doses administered daily is a different dose. Any combination of the provided doses may be administered to the subject for the treatment of a migraine.

[0093] In some embodiments, each dose is administered every one hour, every two hours, every four hours, every six hours, every eight hours, every twelve hours, every sixteen hours, every 20 hours, or every 24 hours. In some embodiments, one or more doses is administered every one hour, every two hours, every four hours, every six hours, every eight hours, every twelve hours, every sixteen hours, every 20 hours, or every 24 hours.

[0094] The present technology, thus generally described, will be understood more readily by reference to the following examples, which are provided by way of illustration and are not intended to be limiting of the present technology.EXAMPLESExample 1 : Composition and stability of comparative bimatoprost tablet formulation

[0095] Initial formulation prototypes (0.03 mg, 0.1 mg, and 0.3 mg bimatoprost tablets, Table 1) containing a hydroxypropylcellulose binder (HPC) were made at a 750 g scale. The process involved high shear blending and granulation, fluid bed drying, milling of granules, blending / lubrication, and tablet compression.PCT / US25 / 47729 24 September 2025 (24.09.2025)Atty. Dkt. No.: 130856-0114Table 1- Initial formulation composition of bimatoprost tablets developed with hydroxypropyl cellulose (HPC) binder’Purified water removed during processing 2Tablet weight for all three strengths is 100 mg

[0096] The prototypes were placed on stability in 30cc HPDE bottles (30 count tablets) at 5 °C, 25 °C / 60% RH (relative humidity) and 40 °C / 75% RH. The 3 month stability of all three strengths are shown in Tables 2, 3, and 4 below. Impurities were observed in the initial prototypes at time zero, including 15-keto, a known oxidative degradant, at > 0.10% (above the FDA reporting threshold), and various other RRTs related to oxidation (from forced degradation studies). The highest level of impurities was present in the 0.03 mg formulation, as the ratio of reactive excipients to drug is the highest. The rapid increase in the 0.03 mg tablet degradants (including 15-keto, known oxidative degradant) at 40 °C / 75% RH condition after 3 months indicates a high risk to allow for a stable room temperature formulation for greater than 6 months. The total related impurities for the 0.03 mg formulation ranged from 0.4-0.8% at 5 °C, 0.4-0.8% at 25 °C / 60%RH and 0.5-2.0% at 40 °C / 75%RH. The total related impurities for the 0.1 mg formulation ranged from 0.25-0.4% at 5 °C, 0.1-0.4% at 25 °C / 60%RH and 0.2-0.45% at 40 °C / 75%RH. The total relatedPCT / US25 / 47729 24 September 2025 (24.09.2025)Atty. Dkt. No.: 130856-0114 impurities for the 0.3 mg formulation ranged from -0.1% at 5 °C, 0.05-0.1% at 25 °C / 60%RH and 0.05-0.2% at 40 °C / 75%RH.Table 2- 5 °C stability data of initial prototype tablets, 0.03, 0. 1 and 0.3 mgTable 3- 25C / 60%RH stability data of initial prototype tablets, 0.03, 0. 1 and 0.3 mgPCT / US25 / 47729 24 September 2025 (24.09.2025)Atty. Dkt. No.: 130856-0114Table 4- 25C / 60%RH stability data of initial prototype tablets, 0.03, 0.1 and 0.3 mgExample 2: Preparation of comparative engineering batches of bimatoprost tablets from initial formulation

[0097] The initial formulation was scaled up from 750g to 4.2kg with the same process steps, but a different equipment process train. The manufacturing processes for prototype (750g) and engineering batch (4.2kg) scales are compared in Tables 6-10. The 0.03 mg strength batch was first made as a worst case scenario. The initial purity results (time zero) of the 0.03 mg batch were unexpected (Table 5), showing much higher degradation after processing compared to the prototypes. The process step responsible for degradation was identified as the large-scale fluid bed drying step. Degradants were mostly due to oxidative degradation, likely accelerated by exposure to heat and heavy air flow in the fluid bed dryer. The total amount of degradants at time zero for the 0.03 mg initial formulation engineering batch was 4.5%. The 15-keto known oxidative degradant was not present at time zero.PCT / US25 / 47729 24 September 2025 (24.09.2025)Atty. Dkt. No.: 130856-0114Table 5 - Time zero 0.03 mg initial engineering batch tablets (4.2kg scale)

[0098] Manufacturing process parameters for comparative prototype and engineering batches are shown in Table 6.Table 6. Granulation Scale and Parameter Comparison’Working volume (2 / 3 of nominal) represents target fill to efficiently use the chopper2% working volume fill calculated based on wet density value of 0.320 g / mL3Antioxidants incorporated into granulation fluid as needed.PCT / US25 / 47729 24 September 2025 (24.09.2025)Atty. Dkt. No.: 130856-0114Table 7. Fluid Bed Drying Scale and Parameter Comparison1% working volume fill calculated based on density value of milled granules of 0.422 g / mL from 11092-007-001Example 3 : Preparation bimatoprost formulations containing an antioxidant

[0099] Several formulations were screened for mitigating the time zero oxidation of bimatoprost as well as improving the long term stability profile (Table 8). HPC was removed from all formulations tested and a variety of antioxidants were tried in various formulations. Among the formulations tested, several were selected for further study based on the best balance of stability, bioavailability, and physical properties, including ease of manufacture and handling. Those include butylated hydroxytoluene (BHT), and butylated hydroxyanisole (BHA) / citric acid, for the reasons given below. New tablet prototypes were manufactured at a 750g scale (identical to the initial formulation) at the 0.03 mg strength (worst case).PCT / US25 / 47729 24 September 2025 (24.09.2025)Atty. Dkt. No.: 130856-0114Table 8- Bimatoprost tablet formulation prototypes (0.03 mg tablet strength) without HPC and with antioxidants

[0100] The different 0.03 mg tablet formulations, including a formulation without antioxidants, were evaluated for stability at 2 weeks at 50 °C / 75% RH condition. Stability results are shown below in Table 9. All formulations without HPC showed an improvement in the time zero purity profile compared to the initial formulation with HPC. The formulations containing BHT had the lowest impurities at time zero with less than or equal to 0.06% total impurities. The formulations containing citric acid / BHA had the lowest total impurities (< 0.3%) compared to the non-HPC formulation (0.37%) at 2 weeks, 50 °C / 75%RH and compared to the initial HPC formulation at 1 month, 40 °C / 75%RH (0.65%). The formulations that had the lowest 15-keto known oxidative degradant of bimatoprost at the 2 week timepoint were those containing the antioxidants: citric acid / BHAPCT / US25 / 47729 24 September 2025 (24.09.2025)Atty. Dkt. No.: 130856-0114 and BHT, which were below 0.10%. By comparison, the non-HPC formulation had a 15- keto level of 0.15% at 2 weeks, 50 °C / 75% RH and the initial formulation had a 15-keto level of 0.18% at 1 month, 40 °C / 75%RH. It was unexpected that each antioxidant combination would provide differentiation in performance between their time zero purity results and the growth of their impurities at accelerated conditions.Table 9 - New formulation prototypes (0.03 mg strength) with antioxidants- 0, 1-, 2-week stability at 50 °C / 75%RH accelerated conditions

[0101] The candidates selected as lead prototypes for further development were based on the following criteria: 1) processability / scalability, 2) low impurities at time zero, 3) stability at accelerated conditions, 4) little or no impact to bioavailability. Three prototype formulations were chosen: 1) non-HPC 2) Citric Acid / BHA, 3) BHT (see Table 10.)PCT / US25 / 47729 24 September 2025 (24.09.2025)Atty. Dkt. No.: 130856-0114Table 10 - Bimatoprost tablet formulation prototypes for stability* 0.1 mg tablets not manufactured as only 0.03 mg and 0.3 mg tablets were bracketed for stability.Example 4 - Engineering batches of new formulations

[0102] The formulations chosen for scale-up to engineering batches were the antioxidant formulations containing BHT and BHA / citric acid. 0.030 mg and 0.3 mg tablets were made at 4.2kg scale to bracket stability, using the same process train as the initial formulation engineering batches. Time zero purity for BHT and BHA / citric acid formulations are shown in Tables 11 and 12. The time zero impurity profiles of the 0.030 mg and 0.3 mg BHT engineering batches are superior to the BHA / citric acid batches. The total impuritiesPCT / US25 / 47729 24 September 2025 (24.09.2025)Atty. Dkt. No.: 130856-0114 for 0.03 mg BHT are about 1% and 0.03 mg BHA / citric acid 1.3%. Both 0.03 mg formulations are better than the 0.03 mg initial formulation engineering batch with total impurities at 4.5% (Table 5). The BHT formulation was chosen for clinical manufacturing (CTM) based on time zero purity. The BHT engineering batch stability data is shown in Table 16 up to 2 months. No major changes are noted for both 0.03 mg and 0.3 mg strength tablets at all storage conditions from 5 °C up to 40 °C / 75%RH. The total impurities for the 0.03 mg strength range between 0.5 to 1% over all conditions. The total impurities for the 0.3 mg strength remain less than 0.10% at all conditions.Table 11 - Time zero purity for BHT formulation engineering batch 0.03 and 0.3 mg tabletsTable 12 - Time zero purity for BHA / Citric Acid formulation engineering batch0.03 and 0.3 mg tabletsPCT / US25 / 47729 24 September 2025 (24.09.2025)Atty. Dkt. No.: 130856-0114Table 13 - 2 Month stability data for BHT formulation engineering batch 0.03 and 0.3 mg tabletsExample 5 - Clinical BatchesPCT / US25 / 47729 24 September 2025 (24.09.2025)Atty. Dkt. No.: 130856-0114

[0103] Clinical batches of the BHT formulation were manufactured at the same scale as the engineering batches (4.2kg scale). The purity profile at time zero is shown in Table 14, and ranges of properties are shown in Table 15. The purity profiles at time zero for CTM were similar to those for the engineering batches, demonstrating reproducibility.Table 14- Time zero purity profiles for 0.03, 0.1, and 0.3 mg BHT clinical batches (CTM)Table 15: Ranges for tablet propertiesExample 6 - Clinical Tablet Formulations with 0.6 mg and 2 mg Bimatoprost

[0104] The compositions of clinical tablets comprising 0.6 mg (600 pg) and 2 mg (2000 pg) of bimatoprost are shown in Table 16 and Table 17, respectively, below:Table 16: Composition of Bimatoprost 0.6 mg Sublingual TabletsPCT / US25 / 47729 24 September 2025 (24.09.2025)Atty. Dkt. No.: 130856-0114Table 17: Composition of Bimatoprost 2 mg Sublingual Tablets

[0105] The process of preparing the clinical tablets having 0.6 mg and 2 mg of bimatoprost differed compared to the process of preparing the 0.3 mg, 0.1 mg, and 0.3 mg bimatoprost tablets in that: 1) no water was used in the composition or wet granulation steps; 2) bimatoprost was dissolved in 100% propylene glycol, and this is used as the granulation fluid (i.e., no water); and 3) since water is not present in the formulation during granulation, the heated fluid bed drying step was eliminated.PCT / US25 / 47729 24 September 2025 (24.09.2025)Atty. Dkt. No.: 130856-0114

[0106] The physical property ranges for the 0.6 mg and 2 mg bimatoprost tablets are shown below in Table 18:Table 18: Physical property ranges of 0.6 mg and 2 mg bimatoprost tablets( ) = %RSDExample 7 - 3 Month Stability Testing for Bimatoprost Sublingual Tablets, 0.6 mg and 2 mg

[0107] The 0.6 mg and 2 mg bimatoprost sublingual tablets were placed on stability in 30cc HOPE bottles (30 count tablets) at 5 °C, 25 °C / 60% RH, and 40 °C / 75% RH. Table 19 shows the methods used to assess the tablets and the acceptance criteria for each method. The stability data for the 0.6 mg bimatoprost sublingual tablet are shown in Table 20 (5 °C, 0 month, 2 weeks, 1 month, and 3 months), Table 21 (25 °C / 60% RH, 2 weeks, 1 month, and 3 months), and Table 22 (40 °C / 75% RH, 2 weeks, 1 month, and 3 months). The stability data for the 2 mg bimatoprost sublingual tablet are shown in Table 23 (5 °C, 0 month, 2 weeks, 1 month, and 3 months), Table 24 (25 °C / 60% RH, 2 weeks, 1 month, and 3 months), and Table 25 (40 °C / 75% RH, 2 weeks, 1 month, and 3 months).

[0108] Table 26 shows the time zero (at release) quality attributes for the bimatoprost clinical tablets (0.3, 0.6 and 2 mg). Table 27 shows the 12 month stability data at 5°C for bimatoprost clinical tablets (0.3, 0.6 and 2 mg) stored at 30 count in 30cc HDPE bottles with 1 g desiccant. Table 28 shows the 12 month stability at 25°C / 60%RH for bimatoprost clinical tablets (0.3, 0.6 and 2 mg) stored at 30 count in 30cc HDPE bottles with 1 g desiccant. Table 29 shows the 6 month stability at 40°C / 75 %RH for bimatoprost clinical tablets (0.3, 0.6 and 2 mg) stored at 30 count in 30cc HDPE bottles with 1 g desiccant.Table 19: Test methods and acceptance criteria for bimatoprost tabletsPCT / US25 / 47729 24 September 2025 (24.09.2025)Atty. Dkt. No.: 130856-0114Table 20 - Stability at 5 °C, Bimatoprost Sublingual Tablets, 0.6 mgPCT / US25 / 47729 24 September 2025 (24.09.2025)Atty. Dkt. No.: 130856-0114Table 21 - Stability at 25 °C / 60% RH, Bimatoprost Sublingual Tablets, 0.6 mgPCT / US25 / 47729 24 September 2025 (24.09.2025)Atty. Dkt. No.: 130856-0114Table 22 - Stability at 40 °C / 75% RH, Bimatoprost Sublingual Tablets, 0.6 mgTable 23 - Stability at 5 °C, Bimatoprost Sublingual Tablets, 2 mgPCT / US25 / 47729 24 September 2025 (24.09.2025)Atty. Dkt. No.: 130856-0114Table 24 - Stability at 25 °C / 60% RH, Bimatoprost Sublingual Tablets, 2 mgPCT / US25 / 47729 24 September 2025 (24.09.2025)Atty. Dkt. No.: 130856-0114Table 25- Stability at 40 °C / 75% RH, Bimatoprost Sublingual Tablets, 2 mgPCT / US25 / 47729 24 September 2025 (24.09.2025)Atty. Dkt. No.: 130856-0114Table 26: Time zero (at release) quality attributes for bimatoprost clinical tablets (0.3, 0.6 and 2 mg)Table 27: 12 month stability at 5°C for bimatoprost clinical tablets (0.3, 0.6 and 2 mg) stored at 30 count in 30cc HDPE bottles with 1 g desiccantPCT / US25 / 47729 24 September 2025 (24.09.2025)Atty. Dkt. No.: 130856-0114Table 28: 12 month stability at 25°C / 60%RH for bimatoprost clinical tablets (0.3, 0.6 and 2 mg) stored at 30 count in 30cc HDPE bottles with 1 g desiccantPCT / US25 / 47729 24 September 2025 (24.09.2025)Atty. Dkt. No.: 130856-0114Table 29: 6 month stability at 40°C / 75 %RH for bimatoprost clinical tablets (0.3, 0.6 and 2 mg) stored at 30 count in 30cc HDPE bottles with 1 g desiccantExample 8 - Summary of Bimatoprost Sublingual Tablet Pharmacokinetic DataPCT / US25 / 47729 24 September 2025 (24.09.2025)Atty. Dkt. No.: 130856-0114

[0109] A double-blind placebo-controlled study was performed to characterize the pharmacokinetic (PK) profile of single ascending and multiple ascending sublingual doses of bimatoprost in healthy adult volunteers.

[0110] For the Single Ascending Dose (SAD) study, eight subjects were enrolled per dose cohort (6 subjects were randomized to be dosed with active drug, while 2 were randomized to placebo treatment in a blinded manner). Each subject was allocated to one dose level only. A minimum of 4 women and 2 men were enrolled in each cohort. In Cohort 5, each subject first received one dose of sublingual 2 mg bimatoprost tablet, followed by one dose of 2 mg bimatoprost solution. The subjects who received active tablets received active solution and the subjects who received tablet placebo received solution placebo. To avoid carryover, dosing was separated by 24 hours, which is greater than 5x the half-life of bimatoprost. In addition, detectable levels were not observed with the 0.03 mg, 0.1 mg, 0.3 mg, and 0.6 mg dose levels 24 hours post dose. A single dose of bimatoprost was administered sublingually (tablet or solution) the morning of Day 1 and Day 2, respectively, after an overnight fast of approximately 10 hours, followed by an additional 4 hours fast after dose for PK sampling.

[0111] The Multiple Ascending Dose (MAD) study was a randomized, double-blind, placebo-controlled study with a duration of 14 days dosing using the 0.6 mg and 2 mg bimatoprost sublingual tablet formulation. Eight subjects were enrolled per dose cohort (6 subjects were randomized to be dosed with active drug, while 2 were randomized to placebo treatment in a blinded manner). Each subject was allocated to one dose level only. A minimum of 4 women and 2 men were enrolled in each cohort. Subjects were dosed after overnight fast of approximately 10 hours followed by additional 4 hours fast after dose for PK sampling Days 1 and 14 and also dosed after overnight fast of approximately 10 hours on all the intermediate dosing days. Dosing was done once daily for 14 days from Day 1 to Day 14 inclusive.

[0112] Blood samples were collected at the pre-determined time points at pre- and postdosing to characterize the PK profile of plasma bimatoprost and capture appropriate PK parameters. PK sampling time points for SAD Cohorts 1 through 4 on Day 1 : pre-dose, 10, 20, 30, and 45 minutes, and 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, and 48 hours post-dose. PK sampling time points for SAD Cohort 5 on Day 1, Periods 1 and 2: pre-dose, 10, 20, 30, and 45 minutes, and 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, and 24 hours post-dose. PK samplingPCT / US25 / 47729 24 September 2025 (24.09.2025)Atty. Dkt. No.: 130856-0114 time points for MAD on Day 1 : pre-dose, 10, 20, 30, and 45 minutes, and 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, and 24 hours post-dose and on Day 14: pre-dose, 10, 20, 30, and 45 minutes and 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, and 48 hours post-dose. Trough PK sampling at pre-dose on Days 3, 5, 7, 9, 11, 12, and 13 (MAD).

[0113] Pharmacokinetic and statistical analysis were done using validated software (e.g., Phoenix® WinNonlin® version 8.0 or higher). For the SAD study, the PK data for the 0.03 mg and 0.1 mg bimatoprost sublingual tablets were all below the lower limit of quantitation (LLOQ). The PK datasets for the 0.3 mg up to the 2 mg bimatoprost sublingual tablets were above the LLOQ, and the plots of plasma concentrations (ng / mL) versus time for SAD subjects dosed with the tablets are shown in FIGs. 1 to 3 A. These datasets were suitable for calculating PK parameters such as AUC, Tmax, etc. (Tables 30 and 31).Table 30 - Summary of 0.6 mg Bimatoprost Sublingual Tablet SAD PK ParametersTable 31 - Summary of 2 mg Bimatoprost Sublingual Tablet SAD PK ParametersPCT / US25 / 47729 24 September 2025 (24.09.2025)Atty. Dkt. No.: 130856-0114

[0114] A liquid formulation (fully dissolved) versus solid formulation crossover study was conducted to understand whether the formulation bioavailability needed optimizing. The liquid formulation used water (70% by weight) and propylene glycol (30% by weight). The 2 mg bimatoprost sublingual tablet and the 2 mg bimatoprost solution unexpectedly had similar exposures and bioavailability sublingually, in comparing their plasma concentration versus time profiles as shown in FIGs. 3A and 3B, and PK parameters summarized in Table 31. Further, the sublingual tablets had dose proportional exposures up to 2 mg of bimatoprost.

[0115] Only the 0.6 mg and 2 mg bimatoprost sublingual tablets were used for the MAD studies. The plasma concentration versus time profiles for subjects on both Day 1 and Day 14 of the MAD studies are shown in FIGs. 4A and B after dosing 0.6 mg tablets and FIGs.5 A and B after dosing 2 mg tablets. For both sublingual tablet doses, the PK data were statistically similar between Day 1 and Day 14, as shown in Tables 32 and 33.Table 32 - Summary of 0.6 mg Bimatoprost Sublingual Tablet MAD PK ParametersPCT / US25 / 47729 24 September 2025 (24.09.2025)Atty. Dkt. No.: 130856-0114Table 33 - Summary of 2 mg Bimatoprost Sublingual Tablet MAD PK Parameters

[0116] Table 34 shows individual AUC and Cmax values for SAD cohorts 4 and 5 for the 0.6 mg and 2 mg bimatoprost sublingual tablets, with the dose normalized to compare sex / gender differences. Table 35 shows individual AUC and Cmax values for MAD cohorts 1 and 2 for the 0.6 mg and 2 mg bimatoprost sublingual tablets, with the dose normalized to compare sex / gender differences. It was found that females appeared to have higher exposure compared to males, and there was a general trend of higher dose- normalized AUC and Cmax observed in females compared to males, with high individual variability and some outliers.Table 34 - SAD Cohorts 4 and 5 - 0.6 mg and 2 mg bimatoprost sublingual tabletsPCT / US25 / 47729 24 September 2025 (24.09.2025)Atty. Dkt. No.: 130856-0114Table 35 - MAD Cohorts 1 and 2 - 0.6 mg and 2 mg bimatoprost sublingual tabletsPCT / US25 / 47729 24 September 2025 (24.09.2025)Atty. Dkt. No.: 130856-0114Example 9 - Bimatoprost Human Plasma Metabolite Identification

[0117] Pooled blood plasma from the SAD cohort was analyzed to identify bimatoprost metabolites present in plasma after sublingual administration of bimatoprost (Table 36). The proposed biotransformation of bimatoprost (MTX101) in human plasma after sublingual administration is shown below in Scheme 1:PCT / US25 / 47729 24 September 2025 (24.09.2025)Atty. Dkt. No.: 130856-0114Scheme 1PCT / US25 / 47729 24 September 2025 (24.09.2025)Atty. Dkt. No.: 130856-0114Table 36. Human metabolite identification in pooled blood plasma, 0.6 mg bimatoprost tablet SAD cohort* neutral moleculeThe liquid chromatography mass spectrometry (LC-MS) spectra of metabolites Ml through M7 detected in human plasma after dosing sublingual bimatoprost tablets are shown in FIG. 6.

[0118] Since the bimatoprost acid metabolite was not found in the clinical plasma PK samples (was below LLOQ), other metabolites found in the pooled blood plasma were tested for Prostaglandin F receptor (FP) / Prostaglandin E2 receptor 1 (EPl) activity:the de-ethylation product: Bimatoprost free amide; andPCT / US25 / 47729 24 September 2025 (24.09.2025)Atty. Dkt. No.: 130856-0114the oxidation product: 15-keto Bimatoprost.

[0119] Table 37 below shows the summary of the bimatoprost and bimatoprost metabolite FP / EP1 activity results. Bimatoprost acid and free amide showed significant activity at both FP and EPl receptors, and 15-keto bimatoprost showed no significant activity for either receptor. Bimatoprost and the observed bimatoprost metabolites were tested at 10 pM in duplicate in competition with EPl and FP radioligand binding.Table 37 FP and EPireceptor activity of bimatoprost and observed bimatoprost metabolitesExample 10. Clinical Efficacy of Bimatoprost Sublingual Tablets for Migraine Treatment

[0120] A migraine trial was conducted using MTX101 (2 mg bimatoprost sublingual tablet), utilizing an 11 -point numerical rating scale (NRS; 0 - 10). A strategy consistent with the U.S. Food and Drug Administration’s (FDA) meaningful score regions was used to coarsen the NRS into 4 ordinal categories (None, Mild, Moderate, Severe) by linking it to Function Disability Scale (No disability, Mildly impaired, Moderately impaired, Severely impaired) (FDA, 2023). One non-baseline, non-missing / imputed observation per subjectPCT / US25 / 47729 24 September 2025 (24.09.2025)Atty. Dkt. No.: 130856-0114 was randomly sampled for analyses. Descriptive statistics (N, mean, standard deviation, median, 25th / 75thpercentile, and minimum / maximum values) were calculated for NRS scores stratified by Functional Disability level. The 75thpercentiles for NRS scores at each Functional Disability were used to divide the NRS into 4 categories (None, Mild, Moderate, Severe). For example, if the “No disability” Functional Disability response category were found to have a range of NRS scores from 0 to 5 with a score of 2 found to be in the 75thpercentile of the distribution of scores, the value of 2 would be used to define the threshold to separate the “None” from “Mild” score ranges (with participants who have a score of 2 being classified in the “None” category). A similar process was used to define the cutvalues between subsequent Functional Disability response categories, resulting in nonoverlapping categories of each NRS score for groups defined by Functional Disability.

[0121] Pain Relief Definition. Headache pain relief was defined as a reduction from Baseline for an NRS score of 7+ to an NRS score of 0 to 3 at a subsequent time point.

[0122] Missing Data - Non-Response Imputation (NRI). If the NRS response was missing at a given timepoint, it was considered indeterminate and imputed as non-response (i.e., no relief).

[0123] Analytic Strategy. The primary method for analysis of headache pain relief was a generalized estimating equation (GEE) models with a logit link at each relevant timepoint (independent models fitted at each timepoint). Due to limited data and sparseness (i.e., few cases of relief at specific timepoints) the models included a limited number of predictors: predose Baseline NRS and treatment group. An exchangeable working correlation matrix was used for the repeated attacks within each participant. Note, when data are sparse (e.g., very few events, many cells with a frequency of zero, or very small clusters), estimates and standard errors can be biased or unstable in GEE. Odds ratios (ORs) of MTX101 relative to Placebo were estimated from the models and presented with p-values.

[0124] Results. The Spearman correlation between NRS scores and Functional Disability scores based on the randomly selected observations was 0.76, which supported the use of Functional Disability to divide NRS scores into None, Mild, Moderate, and Severe categories. Table 38 provides the summary statistics for the NRS scores stratified by Functional Disability level. Results suggest that for the “None” category NRS scores should range from 0 to 2, “Mild” NRS scores should range from 3 to 6, “Moderate” is comparablePCT / US25 / 47729 24 September 2025 (24.09.2025)Atty. Dkt. No.: 130856-0114 to an NRS score of 7, and for the “Severe” category NRS scores should range from 8 to 10. FIG. 7 is a visualization of the NRS scores collapsed into None, Mild, Moderate, and Severe groups.Table 38. NRS headache pain descriptive statistics stratified by Functional Disability (randomly selected post-baseline observation). n Mean 50 in 25th Pct I Median 75th Pctl Max

[0125] Based on these results, it is concluded that NRS scores from 7 to 10 can be categorized as Moderate or Severe.

[0126] Pain Relief. A summary of pain relief across time is provided in Table 39. From 1 hour through 24 hours MTX101 (see 2 mg bimatoprost formulation from Example 6, Table 17) showed numerically higher rates of pain relief relative to placebo. The most notable differences between treatment arms were between 1.5 hours and 4 hours post-baseline (GEE ORs ranged from 2.11 [4 hours] to 9.71 [2 hours]). Of note, at 2 hours post-baseline, n = 8 (22.2%) of MTX101 treated achieved pain relief compared to n = 1 (3.2%) for placebo (GEE: p = 0.0643). Further, at 3 hours post-baseline, there was a statistically significant difference between treatment arms based on the GEE model (p = 0.0340). FIG. 8 provides a visualization of differences in pain relief (% relief) by treatment group (MTX101 versus placebo) across timepoints up to 48 hours.Table 39. Summary of pain relief across timepoints by treatment group (NRS 7+ baseline subgroup).PCT / US25 / 47729 24 September 2025 (24.09.2025)Atty. Dkt. No.: 130856-0114Pain Relief at TimepointsNotes: Exact ~ exact log wistic reg wression. GEE ~ g -S3eneralized estimating equation. N ~ sample size, n ~ attacks with relief. OR odds ratio. P ~ pwalue.

[0127] While certain embodiments have been illustrated and described a person with ordinary skill in the art, after reading the foregoing specification, can effect changes, substitutions of equivalents and other types of alterations to the formulations of the present technology or derivatives, prodrugs, or pharmaceutical compositions thereof as set forth herein. Each aspect and embodiment described above can also have included or incorporated therewith such variations or aspects as disclosed in regard to any or all of the other aspects and embodiments.

[0128] The embodiments, illustratively described herein may suitably be practiced in the absence of any element or elements, limitation or limitations, not specifically disclosed herein. Thus, for example, the terms “comprising,” “including,” “containing,” etc. shall be read expansively and without limitation. Additionally, the terms and expressions employed herein have been used as terms of description and not of limitation, and there is no intention in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the claimed technology. Additionally, the phrase “consisting essentially of’ will be understood to include those elements specifically recited and those additional elements that do not materially affect the basic and novel characteristics of the claimed technology. The phrase “consisting of’ excludes any element not specified.PCT / US25 / 47729 24 September 2025 (24.09.2025)Atty. Dkt. No.: 130856-0114

[0129] The present technology is also not to be limited in terms of the particular aspects described herein, which are intended as single illustrations of individual aspects of the present technology. Many modifications and variations of this present technology can be made without departing from its spirit and scope, as will be apparent to those skilled in the art. Functionally equivalent formulations and methods within the scope of the present technology, in addition to those enumerated herein, will be apparent to those skilled in the art from the foregoing descriptions. Such modifications and variations are intended to fall within the scope of the appended claims. It is to be understood that this present technology is not limited to particular methods, formulations, reagents, compounds, compositions, or excipients, which can of course, vary. All formulations described herein may be prepared with equivalent excipients, except as otherwise indicated herein or otherwise clearly contradicted by context. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only, and is not intended to be limiting. Thus, it is intended that the specification be considered as exemplary only with the breadth, scope and spirit of the present technology indicated only by the appended claims, definitions therein and any equivalents thereof. No language in the specification should be construed as indicating any non-claimed element as essential.

[0130] The embodiments, illustratively described herein may suitably be practiced in the absence of any element or elements, limitation or limitations, not specifically disclosed herein. Thus, for example, the terms “comprising,” “including,” “containing,” etc. shall be read expansively and without limitation. Additionally, the terms and expressions employed herein have been used as terms of description and not of limitation, and there is no intention in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the claimed technology. Likewise, the use of the terms “comprising,” “including,” “containing,” etc. shall be understood to disclose embodiments using the terms “consisting essentially of’ and “consisting of.” The phrase “consisting essentially of’ will be understood to include those elements specifically recited and those additional elements that do not materially affect the basic and novel characteristics of the claimed technology. The phrase “consisting of’ excludes any element not specified.PCT / US25 / 47729 24 September 2025 (24.09.2025)Atty. Dkt. No.: 130856-0114

[0131] In addition, where features or aspects of the disclosure are described in terms of Markush groups, those skilled in the art will recognize that the disclosure is also thereby described in terms of any individual member or subgroup of members of the Markush group. Each of the narrower species and subgeneric groupings falling within the generic disclosure also form part of the technology. This includes the generic description of the technology with a proviso or negative limitation removing any subject matter from the genus, regardless of whether or not the excised material is specifically recited herein.

[0132] As will be understood by one skilled in the art, for any and all purposes, particularly in terms of providing a written description, all ranges disclosed herein also encompass any and all possible subranges and combinations of subranges thereof. Any listed range can be easily recognized as sufficiently describing and enabling the same range being broken down into at least equal halves, thirds, quarters, fifths, tenths, etc. As a nonlimiting example, each range discussed herein can be readily broken down into a lower third, middle third and upper third, etc. As will also be understood by one skilled in the art all language such as “up to,” “at least,” “greater than,” “less than,” and the like, include the number recited and refer to ranges which can be subsequently broken down into subranges as discussed above. Finally, as will be understood by one skilled in the art, a range includes each individual member, and each separate value is incorporated into the specification as if it were individually recited herein.

[0133] All publications, patent applications, issued patents, and other documents referred to in this specification are herein incorporated by reference as if each individual publication, patent application, issued patent, or other document was specifically and individually indicated to be incorporated by reference in its entirety. Definitions that are contained in text incorporated by reference are excluded to the extent that they contradict definitions in this disclosure.

[0134] Other embodiments are set forth in the following claims and include the full scope of equivalents to which such claims are entitled.

Claims

PCT / US25 / 47729 24 September 2025 (24.09.2025)Aty. Dkt. No.: 130856-0114WHAT IS CLAIMED IS:

1. A solid pharmaceutical composition for oral administration comprising a therapeutically effective amount of bimatoprost or a pharmaceutically acceptable salt, stereoisomer, solvate, co-crystal, polymorph, or free acid form thereof, and a pharmaceutically acceptable excipient that stabilizes the pharmaceutical composition and provides oral release of the bimatoprost or the pharmaceutically acceptable salt, stereoisomer, solvate, co-crystal, polymorph, or free acid form thereof.

2. A solid pharmaceutical composition for oral administration comprising: a therapeutically effective amount of bimatoprost or a pharmaceutically acceptable salt, stereoisomer, solvate, co-crystal, polymorph, or free acid form thereof; an effective amount of an antioxidant to provide a stable solid pharmaceutical composition; and a pharmaceutically acceptable excipient that provides oral release of the bimatoprost or the pharmaceutically acceptable salt, stereoisomer, solvate, co-crystal, polymorph, or free acid form thereof.

3. The solid pharmaceutical composition of claim 1 or claim 2, wherein the solid pharmaceutical composition comprises 0.01 mg to 8 mg bimatoprost or the pharmaceutically acceptable salt, stereoisomer, solvate, co-crystal, polymorph, or free acid form thereof.

4. The solid pharmaceutical composition of any one of claims 1-3, wherein the solid pharmaceutical composition comprises 0.01 mg to 4 mg bimatoprost or the pharmaceutically acceptable salt, stereoisomer, solvate, co-crystal, polymorph, or free acid form thereof.

5. The solid pharmaceutical composition of any one of claims 1-4, wherein the solid pharmaceutical composition comprises 0.01 mg to 2 mg bimatoprost or the pharmaceutically acceptable salt, stereoisomer, solvate, co-crystal, polymorph, or free acid form thereof.

6. The solid pharmaceutical composition of any one of claims 1-5, wherein the solid pharmaceutical composition comprises 0.01 mg to 1 mg bimatoprost or thePCT / US25 / 47729 24 September 2025 (24.09.2025)Aty. Dkt. No.: 130856-0114 pharmaceutically acceptable salt, stereoisomer, solvate, co-crystal, polymorph, or free acid form thereof.

7. The solid pharmaceutical composition of any one of claims 1-6, wherein the solid pharmaceutical composition comprises 0.02 mg to 0.7 mg bimatoprost or the pharmaceutically acceptable salt, stereoisomer, solvate, co-crystal, polymorph, or free acid form thereof.

8. The solid pharmaceutical composition of any one of claims 1-7, wherein the pharmaceutically acceptable excipients further comprise a filler and a disintegrant.

9. The solid pharmaceutical composition of claim 8, wherein the pharmaceutically acceptable excipients further comprise a binder and / or a lubricant.

10. The solid pharmaceutical composition of claim 8 or claim 9, wherein the filler comprises an insoluble filler and a soluble filler.

11. The solid pharmaceutical composition of any one of claims 2-10, wherein the antioxidant is selected from the group consisting of butylated hydroxytoluene, citric acid, butylated hydroxyanisole, vitamin E TPGS, HPpCD, and combinations of any two or more thereof.

12. The solid pharmaceutical composition of any one of claims 2-11, wherein the antioxidant is selected from the group consisting of butylated hydroxytoluene, citric acid, butylated hydroxyanisole, and combinations of any two or more thereof.

13. The solid pharmaceutical composition of any one of claims 2-12, wherein the antioxidant comprises butylated hydroxytoluene.

14. The solid pharmaceutical composition of any one of claims 2-13, wherein the pharmaceutically acceptable excipients comprise one or more of microcrystalline cellulose, mannitol, propylene glycol, croscarmellose sodium, and magnesium stearate.

15. The solid pharmaceutical composition of any one of claims 1-14, formulated for oral mucosal release.PCT / US25 / 47729 24 September 2025 (24.09.2025)Aty. Dkt. No.: 130856-011416. The solid pharmaceutical composition of any one of claims 1-15, formulated for sublingual release.

17. The solid pharmaceutical composition of any one of claims 1-15, formulated for buccal release.

18. The solid pharmaceutical composition of any one of claims 1-15, formulated for immediate release.

19. The solid pharmaceutical composition of any one of claims 1-18, wherein the solid pharmaceutical composition is stable for at least 3 months.

20. The solid pharmaceutical composition of any one of claims 1-19, wherein the solid pharmaceutical composition is stable for at least 6, at least 12, at least 18, or at least 24 months.

21. A solid pharmaceutical composition for oral administration comprising: about 0.01 mg to about 8 mg bimatoprost, or a pharmaceutically acceptable salt, stereoisomer, solvate, co-crystal, polymorph, or free acid form thereof; about 40 to about 60 weight percent of an insoluble filler; about 30 to about 50 weight percent of a soluble filler;0 to about 10 weight percent cosolvent; about 0.001 to about 1 weight percent of an antioxidant; about 1 to about 5 weight percent of a disintegrant; and 0 to about 1 weight percent of a lubricant.

22. The solid pharmaceutical composition of claim 21, comprising microcrystalline cellulose; mannitol; propylene glycol; butylated hydroxytoluene; croscarmellose sodium; and magnesium stearate.

23. The solid pharmaceutical composition of claim 21 or 22, wherein the solid pharmaceutical composition releases at least 70% to 90% of bimatoprost, or thePCT / US25 / 47729 24 September 2025 (24.09.2025)Aty. Dkt. No.: 130856-0114 pharmaceutically acceptable salt, stereoisomer, solvate, co-crystal, polymorph, or free acid form thereof, within 2 minutes when measured in 500 mL of 0.05 M phosphate buffer with a pH of 6.8 using a USP II dissolution apparatus at a temperature of 37.0°C ± 0.5°C and a rotation speed of 75 RPM.

24. The solid pharmaceutical composition of claim 21 or 22, wherein the solid pharmaceutical composition releases at least 80% to 100% of bimatoprost, or the pharmaceutically acceptable salt, stereoisomer, solvate, co-crystal, polymorph, or free acid form thereof, within 15 minutes when measured in 500 mL of 0.05 M phosphate buffer with a pH of 6.8 using a USP II dissolution apparatus at a temperature of 37.0°C ± 0.5°C and a rotation speed of 75 RPM.

25. The solid pharmaceutical composition of any one of claims 21-24 comprising: about 45 to about 55 weight percent of the insoluble filler; about 35 to about 45 weight percent of the soluble filler; about 1 to about 5 weight percent cosolvent; about 0.001 to about 1 weight percent of the antioxidant; about 2 to about 4 weight percent of the disintegrant; and about 0.1 to about 0.8 weight percent of the lubricant.

26. The solid pharmaceutical composition of any one of claims 21-25 comprising: about 50 weight percent microcrystalline cellulose; about 40 weight percent mannitol; about 4 weight percent propylene glycol; about 0.1 weight percent butylated hydroxytoluene; about 3 weight percent croscarmellose sodium; and about 0.5 weight percent magnesium stearate.

27. The solid pharmaceutical composition of any one of claims 21-26, wherein one or more ingredients also function as a binder.

28. The solid pharmaceutical composition of claim 27, wherein the insoluble filler, the soluble filler or both also function as a binder.PCT / US25 / 47729 24 September 2025 (24.09.2025)Aty. Dkt. No.: 130856-011429. The solid pharmaceutical composition of any one of claims 21-28, comprising about0.03 mg bimatoprost, or the pharmaceutically acceptable salt, stereoisomer, solvate, co-crystal, polymorph, or free acid form thereof.

30. The solid pharmaceutical composition of any one of claims 21-28, comprising about 0.1 mg bimatoprost, or the pharmaceutically acceptable salt, stereoisomer, solvate, cocrystal, polymorph, or free acid form thereof.

31. The solid pharmaceutical composition of any one of claims 21-28, comprising about 0.3 mg bimatoprost, or the pharmaceutically acceptable salt, stereoisomer, solvate, cocrystal, polymorph, or free acid form thereof.

32. The solid pharmaceutical composition of any one of claims 21-28, comprising about 0.5 mg bimatoprost, or the pharmaceutically acceptable salt, stereoisomer, solvate, cocrystal, polymorph, or free acid form thereof.

33. The solid pharmaceutical composition of any one of claims 21-28, comprising about 0.6 mg bimatoprost, or the pharmaceutically acceptable salt, stereoisomer, solvate, cocrystal, polymorph, or free acid form thereof.

34. The solid pharmaceutical composition of any one of claims 21-28, comprising about 1.2 mg bimatoprost, or the pharmaceutically acceptable salt, stereoisomer, solvate, cocrystal, polymorph, or free acid form thereof.

35. The solid pharmaceutical composition of any one of claims 21-28, comprising about 2 mg bimatoprost, or the pharmaceutically acceptable salt, stereoisomer, solvate, cocrystal, polymorph, or free acid form thereof.

36. The solid pharmaceutical composition of any one of claims 21-28, comprising about 3 mg bimatoprost, or the pharmaceutically acceptable salt, stereoisomer, solvate, cocrystal, polymorph, or free acid form thereof.

37. The solid pharmaceutical composition of any one of claims 21-28, comprising about 4 mg bimatoprost, or the pharmaceutically acceptable salt, stereoisomer, solvate, cocrystal, polymorph, or free acid form thereof.PCT / US25 / 47729 24 September 2025 (24.09.2025)Aty. Dkt. No.: 130856-011438. The solid pharmaceutical composition of any one of claims 21-28, comprising about 8 mg bimatoprost, or the pharmaceutically acceptable salt, stereoisomer, solvate, cocrystal, polymorph, or free acid form thereof.

39. The solid pharmaceutical composition of any preceding claim comprising less than 1 weight percent hydroxypropyl cellulose.

40. The solid pharmaceutical composition of any preceding claim that is free of hydroxypropyl cellulose.

41. The solid pharmaceutical composition of any preceding claim, wherein the pharmaceutical composition is formulated as a solid tablet.

42. The solid pharmaceutical composition of claim 41, wherein the total weight of the tablet is from about 50 mg to about 500 mg.

43. The solid pharmaceutical composition of claim 41 or 42, wherein the total weight of the tablet is about 100 mg.

44. A method of treating, ameliorating, or preventing headache or migraine in a subject in need thereof, the method comprising administering a therapeutically effective amount of bimatoprost, or a pharmaceutically acceptable salt, stereoisomer, solvate, co-crystal, polymorph, or free acid form thereof, in the form of a solid pharmaceutical composition of any preceding claim to the subject.

45. The method of claim 44, wherein the solid pharmaceutical composition is administered once daily.

46. The method of claim 44, wherein the solid pharmaceutical composition is administered twice daily.

47. The method of any one of claims 44-46 that is therapeutic.

48. The method of any one of claims 44-47, wherein the administration reduces a frequency of headache or migraine in the subject.

49. The method of any one of claims 44-47 for treating migraine in the subject.

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