Ophthalmic cream formulations and uses thereof

Abstract

Provided herein are gels, ointments, lotions, or cream formulations comprising an active pharmaceutical ingredient comprising a tropane moiety. The gel, lotion, or cream formulation may comprise at least one low molecular weight (LMW) compound, or a pharmaceutically acceptable salt thereof. Also provided herein are gel, ointment, lotion, or cream formulations comprising an active agent, such as atropine, pilocarpine, hyacinth bean alkali, or travoprost.

Description

Cross Reference to Related Applications

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 452,633, filed March 16, 2023, U.S. Provisional Application No. 63 / 605,955, filed December 4, 2023, and U.S. Provisional Application No. 63 / 549,789, filed February 5, 2024, the entire contents of which are incorporated herein by reference.

[0002] Tropane alkaloids include a class of bicyclo[3.2.1] alkaloids and secondary metabolites that contain a tropane ring in their chemical structure. Many tropane alkaloids occur naturally. Tropane alkaloids include cocaine, scopolamine, and atropine, among others. Tropane alkaloids can impart desirable pharmacological properties through their anticholinergic or stimulant activity.

[0003] Therapeutic uses of tropane alkaloids are diverse and include anesthetic, antiarrhythmic, antiemetic, antihistamine, antiparkinsonian, antispasmodic, bronchodilator, gastrointestinal, and ophthalmic uses. For example, atropine is a muscarinic receptor antagonist, an anticholinergic agent that blocks the activity of muscarinic acetylcholine receptors. By blocking the neurotransmitter acetylcholine at synapses in the central nervous system and peripheral nervous system, atropine has been used to treat poisoning by nerve agents and organophosphate insecticides that destroy acetylcholinesterase through phosphorylation and trigger harmful accumulation of acetylcholine in the body. Due to its cycloplegic and mydriatic effects, atropine has also been used to treat amblyopia, hyperopia, or myopia.

[0004] One challenge with tropane alkaloid therapeutics, including atropine therapeutics, is their chemical stability, including, for example, hydrolytic degradation. For example, atropine exhibits instability under basic, acidic, and oxidative conditions. Atropine degrades through hydrolysis to tropine and tropic acid, a degradation that is accelerated under strongly acidic or basic conditions — the rate of hydrolytic degradation of atropine is lowest in the pH range of about 3-4. Moreover, upon loss of a water molecule, atropine converts to apoatropine, which itself degrades through hydrolysis to tropine and atropic acid.

[0005] Accordingly, there is a need for stable formulations for therapeutic uses of tropane alkaloids that address both formulation physical stability and chemical instability of the tropane alkaloid in the formulation.

[0006] Travoprost is a prostaglandin used to treat glaucoma or open-angle high eye pressure.

[0007] Demodex mite-induced blepharitis is an inflammation of the eyelids and eyelashes. It typically occurs when tiny sebaceous glands / meibomian glands near the base of the eyelashes become blocked, causing inflammation, redness, and irritation of the eyelids. Demodex mites are often the underlying cause of Demodex blepharitis and other conditions associated with meibomian gland dysfunction and related ophthalmic disorders. Blepharitis typically affects the eye along the edge of the eyelid and eyelashes. Existing FDA-approved treatments for Demodex blepharitis include eye drops containing antiparasitic agents. However, existing treatments cause eye irritation, stinging, burning, contact dermatitis, and / or allergies, and their active pharmaceutical ingredients for killing Demodex mites have low efficacy. Therefore, improved treatments are needed for Demodex blepharitis. Brief description of the attached diagram Figure 1 This shows the change in the chemical stability of atropine in cream formulation 1 over time after exposure to 25 kGy electron beam sterilization and 40°C at 75% relative humidity. The dashed line represents the 95% prediction interval.

[0009] Figure 2 This shows the change in total impurities from atropine in cream formulation 1 over time after exposure to 25 kGy electron beam sterilization at 40°C and 75% relative humidity. The dashed line represents the 95% prediction interval.

[0010] Figure 3 This shows the change in the chemical stability of atropine in cream formulation 2 over time after exposure to 25 kGy electron beam sterilization and 40°C at 75% relative humidity. The dashed line represents the 95% prediction interval.

[0011] Figure 4 This shows the change in total impurities from atropine in cream formulation 2 over time after exposure to 25 kGy electron beam sterilization at 40°C and 75% relative humidity. The dashed line represents the 95% prediction interval.

[0012] Figure 5 This displays the mean atropine concentration in the aqueous humor target tissue following a single equimolar administration of atropine (eye drops), 0.15% w / w atropine (cream), or 1% w / w atropine (cream) formulations.

[0013] Figure 6 Display plotted on a logarithmic scale Figure 5 The same data as in [the original text].

[0014] Figure 7 The maximum pupil diameter over time is shown using an ointment (Formulation 1 in Table 1) and eye drops containing 0.15% atropine.

[0015] Figure 8Mean systemic concentration plotted on a log scale versus time for atropine topical ophthalmic solutions and creams (Formulation 2 in Table 1) for display.

[0016] Figure 9 Atropine chemical stability over time in cream formulation 23 following exposure of the cream to 25 kGy electron beam sterilization and 40 °C, 75% relative humidity is shown. Dashed lines represent 95% prediction intervals.

[0017] Figure 10 Free acid concentration of travoprost in the aqueous humor of Yucatan minipigs following treatment of glaucoma with cream formulations containing 0.004% to 0.0012% travoprost in a 14-day pharmacokinetic (PK) study is shown.

[0018] Figure 11A Tear break up time for pilocarpine cream formulations containing about 4% w / w to about 8% w / w pilocarpine compared to placebo in a human trial for dry eye disease is shown.

[0019] Figure 11B Improvement in vision for pilocarpine cream formulations containing about 4% w / w to about 8% w / w pilocarpine compared to placebo in a human trial for dry eye disease is shown.

[0020] Figure 12 Lethality of mites causing Demodex blepharitis using 1% physostigmine cream formulation with lotilaner 0.25% eye drop formulation is shown.

[0021] Figure 13 Atropine concentration in the aqueous humor of Yucatan minipigs following treatment of progressive myopia with 0.05% ophthalmic solution, and cream formulations containing 0.15% and 1% atropine in a 14-day repeat-dose pharmacokinetic (PK) study is shown.

[0022] Figure 14 Data from drug-excipient compatibility testing between travoprost and functional excipients is shown.

[0023] Figure 15 In vitro active pharmaceutical ingredient (API) release profiles for 0.5% w / w, 1% w / w, and 2% w / w physostigmine cream formulations are shown.

[0024] Figure 16AIn vitro permeation of atropine cream formulations comprising about 0.05% w / w to about 0.25% w / w atropine and about 0.05% w / w to about 5% w / w carbomer on synthetic skin membranes is shown.

[0025] Figure 16B Experimental set-up for in vitro permeation testing is shown.

[0026] Figure 17 Certain degradation pathways of physostigmine are shown.

[0027] Figure 18 Carbomer and SEPINEO ® Formulation viscosity relationships for P600.

[0028] Figure 19 Relationship between % content of physostigmine and formulation pH is shown.

[0029] Figure 20 Flow diagram for preparation of physostigmine formulations is shown.

[0030] Figure 21 Chemical stability trends for certain formulations of Example 13, PHY012 and PHY052 at 40°C are shown.

[0031] Figure 22 Total impurity profiles for certain formulations of Example 13, PHY012 and PHY052 at 40°C are shown.

[0032] Figure 23 Physical stability (pH) profile for formulation PHY052 of Example 13 at 40°C / 75% relative humidity (RH) is shown.

[0033] Figure 24 Physical stability (viscosity) for formulation PHY052 of Example 13 at 40°C / 75% RH is shown.

[0034] Figure 25A Stability studies and trend analysis for formulation screening and product shelf life determination are shown.

[0035] Figure 25B Appearance performance prediction and tube filling parameters are shown. DETAILED DESCRIPTION

[0036] Topical administration of active pharmaceutical ingredients can be performed by one of many composition types, including liquid agents, ointments, gels, lotions, and cream forms. Each topical administration form has its own advantages and disadvantages. For example, liquid agents are generally rapidly absorbed upon administration, but are limited to topical mucosal administration, where pH inconsistency with the pH of the mucosa for chemical stability can lead to administration discomfort - applying an acidic solution to a mucosa can cause a burning or stinging sensation. Creams are generally water-rich environments (particularly oil-in-water emulsion cream systems) and can subject the active pharmaceutical ingredient therein to hydrolytic or pH sensitive conditions. Ointments are oily and generally water-free, providing a protective barrier to the skin but not being absorbed themselves, leaving an oily residue at the target site. Importantly, topical formulations must also meet certain regulations regarding antimicrobial or antibacterial growth.

[0037] Stable cream formulations comprising tropane alkaloids have been discovered. Despite the aqueous nature of the cream formulations and the propensity of tropane alkaloids to hydrolytically degrade, the tropane alkaloids present in the cream are chemically stable for commercially relevant periods of time. It has also been discovered that the inclusion of at least one polycyclic nucleobase in the cream improves the stability of the cream formulation. It has further been discovered that the inclusion of low molecular weight compounds improves the stability of the cream formulation. Without being bound by theory, atropine can intercalate with the stabilizing agent and form steric hindrance around the atropine, and the steric hindrance protects the atropine from degradation to tropic acid. In addition to forming steric hindrance around the atropine molecule, the stabilizing agent can also effectively protect the atropine molecule from electron beam irradiation. Another benefit of the tropanyl creams provided herein is that they do not require conventional preservatives, such as benzalkonium chloride or parabens, to remain useful during commercially relevant storage. Additionally, the cream formulations have been found to impart improved pharmacokinetic profiles compared to alternative topical administration forms such as eye drops.

[0038] Other cream formulations are provided comprising atropine, pilocarpine, travoprost, or physostigmine. It has been discovered that the inclusion of one or more preservatives, at least one antioxidant partitioned into the appropriate phase (aqueous or oil phase) of the cream formulation and at least one antioxidant partitioned into the other phase (oil or aqueous phase) of the cream formulation improves the stability of the cream formulation. Furthermore, mixing the active agent (e.g., physostigmine) into the cream formulation as a last step during preparation after pre-adjusting the pH, as shown in Figure 20 improves the stability of the active agent (e.g., physostigmine) in the cream formulation.

[0039] The addition process of the antioxidant and / or preservative depends on the solubility in the respective solvent phase (oil or aqueous phase) and API solubility / stability. In addition to the enhanced stability of the finished pharmaceutical product, the co-mixing or co-dissolution of the antioxidant with the API during the formulation mixing process also protects the API from degradation during the manufacturing process.

[0040] Physostigmine is a reversible anticholinesterase that effectively increases the concentration of acetylcholine at cholinergic neurotransmission sites. Acetylcholine's effects are usually very short-lived because acetylcholine is hydrolyzed by an enzyme, acetylcholinesterase. Physostigmine inhibits the destructive action of acetylcholinesterase, thereby prolonging and exaggerating the effects of acetylcholine. Acetylcholinesterase inhibitors have been widely used as insecticides to kill arthropods such as Demodex mites by enhancing cholinergic neurotransmission, leading to persistent over-excitation of nerve-to-nerve and nerve-to-muscle communication, and ultimately paralysis and death. The levorotatory enantiomer of physostigmine (the laevorotatory isomer) has much higher efficacy (~100X to 1000X) in killing mites compared to its dextrorotatory counterpart. Advantageously, physostigmine in a topical cream formulation can treat demodicid blepharitis by directly contacting mites at the target site over a sustained period of time, as compared to eye drops. Accordingly, provided herein are salicylic acid physostigmine-based topical creams with minimal physostigmine degradation. The physostigmine-based cream formulations are physically and chemically stable for more than 4 months under accelerated stability conditions (e.g., 40°C and 75% relative humidity (RH)).

[0041] Physostigmine salicylate undergoes rapid degradation and oxidation in aqueous media. The degradation pathway of physostigmine salicylate in aqueous media is shown in Figure 17 Described herein are compositions and methods / processes for preparing salicylic acid physostigmine-based topical creams with minimal physostigmine degradation. The physostigmine-based cream formulations described herein are physically and / or chemically stable for more than 4 months under accelerated stability conditions (e.g., 40°C and 75% RH).

[0042] Definitions While the disclosure has been described in detail and with reference to specific embodiments thereof, it will be apparent to one of ordinary skill in the art that various changes and modifications can be made therein without departing from the spirit and scope thereof.

[0043] Groupings of alternative elements or embodiments of the application disclosed herein can be referenced herein individually or in any combination.

[0044] Unless defined otherwise, all technical and scientific terms used herein have the meaning commonly understood by one of ordinary skill in the art to which this application belongs.

[0045] Using only routine experimentation, those of skill in the art can recognize or be able to ascertain many equivalents of specific embodiments of the application described herein. Such equivalents are intended to be encompassed by the following claims.

[0046] Certain terms are defined below, whether used as a noun, verb, adjective, and / or adverb.

[0047] The articles "a" and "an" are used herein to refer to one or to more than one (i.e., to one or at least one) of the grammatical object of the article. By the use of the term "a" or "an", herein is intended to be a reference to one or to more than one (i.e., to one or at least one) of the grammatical object of the article.

[0048] Numerical values relating to measurements are affected by the error in measurement, which causes a limitation on their accuracy. For this reason, unless otherwise stated, all numerical values provided herein are to be understood as being modified in all instances by the term "about." Accordingly, the term "about" is meant to encompass a variance in the indicated value of ±10%. Otherwise, the numerical values provided herein are to be understood to be accurate to the last decimal place recited, or if no decimal places are recited, to the nearest practical value. The maximum range of values is determined by applying the rounding conventions to the last significant digits of the values, or when the values are given in a table, to the last significant digits of the table.

[0049] The term "alkanalyl" refers to a branched, cyclic, or straight chain, or combinations thereof, saturated hydrocarbon moiety comprising at least one aldehyde.

[0050] The term "alkanonyl" refers to a branched, cyclic, or straight chain, or combinations thereof, saturated hydrocarbon moiety comprising at least one ketone.

[0051] The term "alkenalyl" refers to a branched, cyclic, or straight chain, or combinations thereof, hydrocarbon moiety comprising at least one aldehyde and at least one carbon-carbon double bond.

[0052] The term "alkanolyl" refers to a branched, cyclic, or straight chain, or combinations thereof, saturated hydrocarbon moiety comprising at least one hydroxyl group.

[0053] The term "alkenonyl" refers to a branched, cyclic, or straight chain, or combinations thereof, hydrocarbon moiety comprising at least one ketone and at least one carbon-carbon double bond.

[0054] The term "alkenyl" refers to a branched, cyclic, or straight chain, or combinations thereof, hydrocarbon moiety comprising at least one carbon-carbon double bond.

[0055] The term "alkyl" refers to a branched, cyclic, or straight chain, or combinations thereof, saturated hydrocarbon moiety.

[0056] The term "halo" refers to a halogen.

[0057] The term "improving" refers to a lessening of the severity of at least one indicator of a disorder or disease, such as a delay or slowing of the progression of one or more indicators of the disorder or disease. The severity of the indicator can be determined by subjective or objective methods known to those of skill in the art.

[0058] The term "C e-k " refers to a moiety comprising e to k carbon atoms, wherein e and k are integers.

[0059] The terms "effective amount" and "therapeutically effective amount" refer to the amount of an active ingredient (such as a compound described herein) administered to an individual, as a single dose or as part of a series of doses, which will exert the desired effect. Generally, the effective amount can be estimated initially either in cell culture assays or in animal models, e.g., in non-human primates, mice, rabbits, dogs, or pigs. The animal model can also be used to determine the appropriate concentration range and route of administration. Such information can then be used to determine effective doses and routes of administration in non-human individuals and in humans.

[0060] The terms "cream" and "pharmaceutical cream" refer to a mixture of at least one active pharmaceutical ingredient described herein and a pharmaceutically acceptable carrier. The pharmaceutical cream facilitates administration of the at least one active pharmaceutical ingredient to a patient or individual.

[0061] The term "pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable material, composition or carrier, such as a liquid filler, solid filler, stabilizer, dispersing agent, suspending agent, diluent, excipient, thickening agent, solvent or encapsulating material, involved in carrying or transporting the at least one active pharmaceutical ingredient described herein into or within the patient's body or to the patient, such that the active ingredient can perform its intended function. A given carrier must be "acceptable" in the sense of being compatible with the other ingredients of the particular cream formulation (including the active pharmaceutical ingredient described herein) and not injurious to the patient. Other ingredients that can be included in the pharmaceutical cream described herein are known in the art and are described in, e.g., "Remington's Pharmaceutical Sciences" (Genaro (ed.), Mack Publishing Co., 1985), which is incorporated herein by reference in its entirety.

[0062] The term "pharmaceutically acceptable salt" refers to a derivative of a disclosed compound in which the parent compound is modified by converting an existing acid or base moiety to its salt form. The pharmaceutically acceptable salts can be synthesized from the parent compound that contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent or in a mixture of the two solvents. Lists of suitable salts are found in "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" (P. Henrich Stahl & Camille G. Wermuth (eds.), VHCA & Wiley-VCH, 2002), which is hereby incorporated by reference in its entirety. Reference to a type or class of compound herein is understood to include pharmaceutically acceptable salts of the compound.

[0063] The term "refractory disease" refers to a disease that continues to progress during treatment with a different pharmaceutical ingredient than the active pharmaceutical ingredient provided herein, is partially responsive to other treatments, or is transiently responsive to other treatments. This term can apply to each of the diseases mentioned herein.

[0064] The term "treatment" refers to the application of one or more specific procedures for the improvement of a disease. "Prophylactic" treatment refers to the reduction in the rate of progression, delay in the onset, or reduction in the severity of a disease or condition being treated.

[0065] The recitation of ranges of values herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range. Unless otherwise indicated herein, each individual value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein. The use of any and all examples, or exemplary language (e.g., "such as") provided herein, is intended merely to better illuminate the described subject matter and does not pose a limitation to the scope of the subject matter claimed. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the described subject matter.

[0066] Groupings of alternative elements or embodiments of the disclosure disclosed herein should not be construed as limitations. Each group member can be referred to and claimed individually or in any combination with other members of the group or other alternative elements disclosed herein. Further, the description herein of any alternatives in terms of a list of features or structural elements does not limit the subject matter disclosed herein to any particular alternative disclosed therein. Rather, the scope of the disclosure is to be understood as not limited to the disclosed alternatives, but rather to the subject matter of the claims.

[0067] Patent documents or other publications cited in this specification, if any, are incorporated herein by reference in their entirety for all purposes.

[0068] Embodiments of the present disclosure are illustrative. Thus, the present disclosure is not limited to the exact details shown and described.

[0069] Compositions In some embodiments, provided herein are certain compositions, which can be pharmaceutical compositions suitable for therapeutic use. The compositions can comprise one or more pharmaceutically acceptable carriers.

[0070] Thus, in some embodiments, the compositions provided herein comprise: one or more purified tropane alkaloids or pharmaceutically acceptable salts thereof; and one or more purified polycyclic nucleobases or pharmaceutically acceptable salts thereof. Such tropane alkaloids and polycyclic nucleobases are further described below. In some embodiments, the compositions comprise two different purified tropane alkaloids or pharmaceutically acceptable salts thereof, and one, two, or three purified polycyclic nucleobases or pharmaceutically acceptable salts thereof. In some embodiments, the pharmaceutical compositions can be provided as a pharmaceutical cream.

[0071] In some embodiments, provided herein are topical formulations comprising an active pharmaceutical ingredient comprising a tropane group. In some embodiments, the topical formulation is an ophthalmic formulation. In some embodiments, the topical formulation is a gel, a lotion, or a cream.

[0072] In some embodiments, the topical formulation has a viscosity of about 2000 centipoise (cP) to about 200,000 cP. In some embodiments, the topical formulation has a viscosity of about 2000 cP to about 70,000 cP. In some embodiments, the topical formulation has a viscosity of about 2000 cP to about 50,000 cP. In some embodiments, the topical formulation has a viscosity of about 10,000 cP to about 75,000 cP. In some embodiments, the topical formulation has a viscosity of about 10,000 cP to about 50,000 cP. In some embodiments, the topical formulation has a viscosity of about 10,000 cP to about 25,000 cP. In some embodiments, the topical formulation has a viscosity of about 25,000 cP to about 200,000 cP. In some embodiments, the topical formulation has a viscosity of about 25,000 cP to about 75,000 cP. In some embodiments, the topical formulation is an oil-in-water (o / w) formulation.

[0073] Creams, gels, and lotions Formulations have been discovered for slowing the hydrolysis of tropane alkaloids into their corresponding hydrolysis products, including tropine and the like. Thus, formulations, such as cream, gel, or lotion formulations, have been discovered that remain physically and chemically stable upon sustained exposure to storage conditions associated with commercial preparation, distribution, and consumer use. The formulations can be used to enable penetration of tropane alkaloids from the cream into the skin of an individual or patient and to facilitate their permeation, and subsequently deliver the tropane alkaloids to target tissues underneath the skin. In some embodiments, the target tissues can include a portion of the skin of the individual, or blood vessels, or ultimately systemic distribution through the vasculature. In some embodiments, the target tissues can be the eye or associated ocular structures, and embodiments include topical administration thereto.

[0074] Thus, in some embodiments, provided herein are gel formulations comprising an active pharmaceutical ingredient comprising a tropane moiety. In some embodiments, provided herein are lotion formulations comprising an active pharmaceutical ingredient comprising a tropane moiety. In some embodiments, provided herein are cream formulations comprising an active pharmaceutical ingredient comprising a tropane moiety. In some embodiments, the cream is an oil-in-water (o / w) emulsion cream, wherein the cream comprises at least 50% w / w or at least 60% w / w water. In some embodiments, provided herein are cream formulations comprising an active pharmaceutical ingredient comprising a tropane alkaloid. In some embodiments, the tropane alkaloid is contained in the oil phase of an oil-in-water emulsion, which can slow the hydrolysis or chemical degradation of the tropane alkaloid without being bound by theory. In some embodiments, provided herein are cream formulations comprising an active pharmaceutical ingredient comprising a tropinyl moiety. In some embodiments, the active pharmaceutical ingredient comprising a tropane moiety, a tropinyl moiety, or a tropane alkaloid is an anticholinergic compound. Anticholinergic agents and cholinergic agents generally have opposite effects in an individual, as the former blocks the effects of acetylcholine, while the latter mimics the effects of acetylcholine. For example, an anticholinergic agent can inhibit salivation or sweating, while a cholinergic agent can promote salivation or sweating. In some embodiments, the active pharmaceutical ingredient is atropine, benzatropine, cocaine, homatropine, hyoscyamine, scopolamine, tiotropium, tropane, trospium, or a pharmaceutically acceptable salt thereof.

[0075] In some embodiments, provided herein are gel formulations comprising an active pharmaceutical ingredient that is atropine. In some embodiments, provided herein are ointment formulations comprising an active pharmaceutical ingredient that is atropine. In some embodiments, provided herein are lotion formulations comprising an active pharmaceutical ingredient that is atropine.

[0076] 3-hydroxy-2-phenylpropionic acid (1R, 3r, 5S)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl ester (atropine) In some embodiments, the gel, ointment, lotion, or cream formulation comprises atropine, wherein the atropine comprises greater than 50% by weight of S )-3-hydroxy-2-phenylpropionic acid (1 R ,3 r ,5 S )-8-methyl-8-azabicyclo[3.2.1]oct-3-yl ester. In some embodiments, the gel, ointment, lotion, or cream formulation comprises atropine, wherein the atropine comprises greater than 50% by weight of R )-3-hydroxy-2-phenylpropionic acid (1 R ,3 r ,5 S )-8-methyl-8-azabicyclo[3.2.1]oct-3-yl ester. In some embodiments, the gel, ointment, lotion, or cream formulation comprises atropine, wherein the atropine comprises less than 10% by weight of S )-3-hydroxy-2-phenylpropionic acid (1 R ,3 r ,5 S )-8-methyl-8-azabicyclo[3.2.1]oct-3-yl ester. In some embodiments, the gel, ointment, lotion, or cream formulation comprises atropine, wherein the atropine comprises less than 10% by weight of R )-3-hydroxy-2-phenylpropionic acid (1 R ,3 r ,5 S )-8-methyl-8-azabicyclo[3.2.1]oct-3-yl ester.

[0077] In some embodiments, the gel, ointment, lotion, or cream formulation further comprises caffeine or a derivative thereof. In some such embodiments, the caffeine or derivative thereof can function as a chemical stabilizer and / or an emollient.

[0078] In some embodiments, the gel, ointment, lotion, or cream formulation further comprises a polycyclic nucleobase or a pharmaceutically acceptable salt thereof. In some embodiments, the nucleobase is a bicyclic or tricyclic nucleobase. In some embodiments, the gel, ointment, lotion, or cream formulation further comprises a heterocyclic compound having 9 or more ring atoms. In some embodiments, the 9 ring atoms comprise at least 5 carbon atoms. In some embodiments, the 9 ring atoms comprise at least 3 nitrogen atoms. In some embodiments, the 9 ring atoms comprise 4 nitrogen atoms. In some embodiments, the heterocyclic compound is an aromatic heterocyclic compound comprising a fused six-membered and five-membered ring system. In some embodiments, the heterocyclic compound is a purine compound. In some embodiments, the heterocyclic compound is an oxopurine (e.g., 8-oxopurine) compound. In some embodiments, the heterocyclic compound is a halogenated purine compound. In some embodiments, the heterocyclic compound is a thio purine compound. In some embodiments, the heterocyclic compound is a methyl purine or 8-oxomethyl purine. In some embodiments, the heterocyclic compound is a monomethyl purine, 8-oxomonomethyl purine, dimethyl purine, 8-oxodimethyl purine, trimethyl purine, or 8-oxotrimethyl purine compound. In some embodiments, the purine compound is azathioprine, adenine, 2-aminopurine, 2,6-diaminopurine, 2,6,8-triaminopurine, 2-amino-6-methoxypurine, 2-chloro-6-aminopurine, 2-fluoro-6-aminopurine, guanine, thioguanine, isoguanine, purine, mercaptopurine, hypoxanthine, xanthine, 1-methylxanthine, 3-methylxanthine, 7-methylxanthine, 1,3-dimethylxanthine (theophylline), 3,7-dimethylxanthine (theobromine), 1,7-dimethylxanthine (paraxanthine), 1,3,7-trimethylxanthine (caffeine), 8-chloro-1,3-dimethylxanthine, uric acid, 1-methyluric acid, 3-methyluric acid, 7-methyluric acid, 1,3-dimethyluric acid, 3,7-dimethyluric acid, 1,7-dimethyluric acid, and 1,3,7-trimethyluric acid.

[0079] In some embodiments, the heterocyclic compound has the following formula: or a pharmaceutically acceptable salt thereof, wherein a, b, c, d, e, f and g are each independently a single bond or a double bond; m, n, p, w, x, y, and z are each independently 0 or 1 ; R 1 3 7 9 each independently H, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-8 alkenyl, C 3-8 alkenyl, C 2-8 alkenyl, or C 4-8 alkenyl; R 2 6 8 each independently H, halogen, O-(C 1-3 alkyl), NH2, N(H)(C 1-3 alkyl), N(C 1-3 alkyl)(C 1-3 alkyl), S, or O.

[0080] In some embodiments: R 1 , R 3 , R 7 , and R 9 are each independently H or C 1-3 alkyl; and R 2 , R 6 , and R 8 are each independently H, F, CI, NH2, OCH3, N(H)(C 1-3 alkyl), N(C 1-3 alkyl)(C 1-3 alkyl), S, or O. In some embodiments of the heterocyclic compound formula, each alkyl is independently methyl, ethyl, propyl, or isopropyl.

[0081] In some embodiments, halo refers to F, CI, or I. In some embodiments, the haloalkyl moiety can be mono-, di-, tri-, tetra-, penta-, or hexa-haloalkyl, wherein each halo is independently selected from F or CI. In some embodiments, the haloalkyl includes a CFH2, CF2H, CF3, C2FH4, C2F2H3, C2F3H2, C2F4H, or CF5 moiety, or combinations thereof.

[0082] In some embodiments of the heterocyclic compound formula, R 1 , R 3 , R 7 , and R 9 are each independently H or methyl. In some embodiments, when R 1 ​​​​​H or C 1-3 alkyl (e.g., methyl) when, a is a single bond. In some embodiments, when R 3 H or C 1-3 alkyl (e.g., methyl) when, b is a single bond. In some embodiments, when R 7 H or C 1-3 alkyl (e.g., methyl) when, c is a single bond. In some embodiments, when R 9 H or C 1-3 alkyl (e.g., methyl) when, d is a single bond.

[0083] In some embodiments, when m is 0, a is a double bond. In some embodiments, when p is 0, b is a double bond. In some embodiments, when x is 0, c is a double bond. In some embodiments, when z is 0, d is a double bond.

[0084] In some embodiments, R 2 , R 6 , and R 8 are each independently H, NH2, S, or O. In some embodiments, when R 2 is S or O, f is a double bond and b is a single bond. In some embodiments, when R 6 is S or O, e is a double bond and a is a single bond. In some embodiments, when R 8 is S or O, g is a double bond, c is a single bond, and d is a single bond.

[0085] In some embodiments, the gel, ointment, lotion, or cream formulations described herein are physically and chemically stable, with stability lasting for a commercially relevant period of time, including at least 3 months, up to 6 months, or more. Example 2 describes such stability.

[0086] In some embodiments, one or more low molecular weight (LMW) compounds having one or more aromatic rings or having a conjugated structure can be included within the formulation. These LMW compounds can include histidine, sorbic acid (a conjugated molecule), benzoic acid, 2,5-dihydroxybenzoic acid, 2,5-dihydroxyterephthalic acid, 1,4-dihydroxy-2-naphthoic acid, 3,7-dihydroxy-2-naphthoic acid, their derivatives, and their pharmaceutically acceptable salt forms (i.e., sodium, potassium, ammonium, chloride, sulfate, magnesium, and / or calcium salts) can be used as stabilizers to stabilize (or help stabilize) the active pharmaceutical ingredient (API) in the cream formulation. The chemical structures of histidine and sorbic acid are shown below. In some embodiments, the pKa of the atropine stabilizer is similar to the desired pH of the gel, ointment, lotion, or cream formulation that includes atropine (e.g., a pKa of about 3 to about 6). By way of example only and not by way of limitation, the pKa of sorbic acid is about 4.76, and the pH of the gel, ointment, lotion, or cream formulation can be about 4.80. In some embodiments, the sorbic acid can be the free acid. In some embodiments, the sorbic acid can be a salt. In some embodiments, sorbic acid stabilizes atropine in the cream formulation as shown in Table 8 herein; similar for gel or lotion formulations. Advantageously, sorbic acid and its salts are a less expensive alternative to other stabilizers such as histidine, thereby being commercially beneficial.

[0087] In some embodiments, some LMW compounds such as sinapinic acid, a-cyano-4- hydroxycinnamic acid (HCCA), 4-chloro-a-cyanocinnamic acid, and their pharmaceutically acceptable salt forms (i.e., sodium, potassium, ammonium, magnesium, and / or calcium salts) can be used as chemical stabilizers to stabilize the API in the gel, ointment, lotion, or cream formulation. The chemical structure of HCCA is shown below: HCCA.

[0088] In some embodiments, the stabilizer can be a LMW compound having one or more aromatic ring structures, without a carboxylic acid functional group. These compounds can be used as chemical stabilizers to stabilize the API in the cream formulation. One such compound is geosmin, the chemical structure of which is shown below: Geosmin.

[0089] In some embodiments, the LMW compound has a molecular weight of about 50 g / mol to about 1000 g / mol, about 75 g / mol to about 900 g / mol, about 100 g / mol to about 800 g / mol, about 125 g / mol to about 700 g / mol, about 150 g / mol to about 600 g / mol, about 175 g / mol to about 500 g / mol, about 200 g / mol to about 400 g / mol, or about 225 g / mol to about 300 g / mol.

[0090] In some embodiments, the gel, ointment, lotion, or cream formulation can further comprise at least one low molecular weight compound or a pharmaceutically acceptable salt thereof. The at least one low molecular weight compound can comprise one or more aromatic ring structures. The LMW compound can be present as a salt, the salt comprising a salt selected from a sodium salt, a potassium salt, an ammonium salt, a magnesium salt, a calcium salt, or a combination thereof.

[0091] In some embodiments, the at least one low molecular weight compound or a pharmaceutically acceptable salt thereof stabilizes an active pharmaceutical ingredient (API) in the cream formulation.

[0092] In some embodiments, the at least one low molecular weight compound comprises caffeine, benzoic acid, sinapic acid, a-cyano-4-hydroxycinnamic acid, histidine, or geoporphyrin, or a pharmaceutically acceptable salt thereof, or a combination thereof. In some embodiments, the at least one low molecular weight compound comprises benzoic acid, sinapic acid, a-cyano-4-hydroxycinnamic acid, histidine, or geoporphyrin, or a pharmaceutically acceptable salt thereof, or a combination thereof. In some embodiments, the at least one low molecular weight compound is caffeine. In some embodiments, the at least one low molecular weight compound is histidine. In some embodiments, the at least one low molecular weight compound is a-cyano-4-hydroxycinnamic acid.

[0093] In some embodiments of the gel, ointment, lotion, or cream formulation, the at least one low molecular weight compound is present in the gel, ointment, lotion, or cream formulation in an amount of about 0.01% w / w to about 1% w / w.

[0094] In some embodiments of the gel, ointment, lotion, or cream formulation, the at least one low molecular weight compound is present in the gel, ointment, lotion, or cream formulation in an amount of about 0.05% w / w to about 0.7% w / w.

[0095] In some embodiments, the gel, ointment, lotion, or cream formulation comprises about 0.01% w / w to about 2.5% w / w of a tropane alkaloid or a pharmaceutically acceptable salt thereof. In some embodiments, the gel, ointment, lotion, or cream formulation comprises about 0.05% w / w to about 2.5% w / w of a tropane alkaloid or a pharmaceutically acceptable salt thereof. In some embodiments, the gel, ointment, lotion, or cream formulation comprises about 0.01% w / w, 0.05% w / w, 0.1% w / w, 0.15% w / w, 0.2% w / w, 0.3% w / w, 0.4% w / w, 0.5% w / w, 0.6% w / w, 0.7% w / w, 0.8% w / w, 0.9% w / w, 1% w / w, 1.1% w / w, 1.2% w / w, 1.5% w / w, or 2.5% w / w, or any range therebetween, of one or more tropane alkaloids or a pharmaceutically acceptable salt thereof. In some embodiments, the one or more tropane alkaloids or a pharmaceutically acceptable salt thereof is independently atropine, benztropine, cocaine, homatropine, hyoscyamine, scopolamine, tiotropium, trospium, or a pharmaceutically acceptable salt thereof. In some embodiments, the tropane alkaloid or a pharmaceutically acceptable salt thereof is atropine sulfate. In some embodiments, the gels, lotions, or creams described herein comprise about 0.01% w / w, 0.05% w / w, 0.08% w / w, 0.15% w / w, 0.5% w / w, or 1% w / w of atropine sulfate. As used herein, the % w / w of atropine is calculated as free base, regardless of the salt form used in the gel, ointment, lotion, or cream formulation.

[0096] In some embodiments, the gel, ointment, lotion, or cream formulations described herein can comprise about 0.01% w / w to about 0.3% w / w of a polycyclic nucleobase or a pharmaceutically acceptable salt thereof. In some embodiments, the gel, ointment, lotion, or cream formulations described herein can comprise about 0.05% w / w to about 0.3% w / w of a polycyclic nucleobase or a pharmaceutically acceptable salt thereof. In some embodiments, the gel, lotion, or cream described herein can comprise about 0.1% w / w to about 0.2% w / w of a polycyclic nucleobase or a pharmaceutically acceptable salt thereof. In some embodiments, the gel, lotion, or cream comprises about 0.16% w / w of 1,3,7-trimethylxanthine. In some embodiments, the gel, ointment, lotion, or cream formulation does not contain a polycyclic nucleobase (e.g., the cream does not comprise a polycyclic nucleobase or a pharmaceutically acceptable salt thereof, e.g., the gel, lotion, or cream does not comprise 1,3,7-trimethylxanthine).

[0097] In some embodiments, the gel, ointment, lotion, or cream formulation comprises about 0.0005% w / w to about 0.001% w / w of a polyquatemium-1 or a pharmaceutically acceptable salt thereof, and about 0.00025% w / w to about 0.0005% w / w of alexidine or a pharmaceutically acceptable salt thereof, wherein the gel, ointment, lotion, or cream formulation is preservative-free except for this, and wherein the gel, ointment, lotion, or cream formulation optionally comprises an active pharmaceutical ingredient.

[0098] In some embodiments, the gel, ointment, lotion, or cream formulation comprises a stabilizer selected from histidine, sorbic acid, or a- cinnamic acid or a pharmaceutically acceptable salt thereof, and comprises about 0.0005% w / w to about 0.001% w / w of a polyquatemium-1 or a pharmaceutically acceptable salt thereof, and about 0.00025% w / w to about 0.0005% w / w of alexidine or a pharmaceutically acceptable salt thereof, wherein the gel, ointment, lotion, or cream formulation is preservative-free except for this, and wherein the cream formulation optionally comprises an active pharmaceutical ingredient.

[0099] In some embodiments, the gel, lotion, or cream provided herein comprises less than about 0.25% w / w preservative. In some embodiments, the cream provided herein comprises no more than about 0.002% w / w preservative(s). In some embodiments, the preservative comprises a paraben, but does not comprise benzalkonium chloride (BAK). In some embodiments, the cream provided herein does not comprise BAK (i.e., BAK-free) or a paraben (e.g., methylparaben, ethylparaben, propylparaben, and butylparaben) (i.e., paraben-free). In some embodiments, the cream provided herein comprises about 0.001% w / w to about 0.003% w / w preservative. In some embodiments, the gel, lotion, or cream provided herein comprises about 0.002% w / w preservative, wherein the preservative comprises a biguanide compound (e.g., alexidine or a pharmaceutically acceptable salt thereof) and a polyquatemium compound (e.g., polyquatemium-1 or a pharmaceutically acceptable salt thereof (PQ-1)). In some embodiments, the gel, lotion, or cream provided herein comprises no more than about 0.0015% w / w preservative(s). In some embodiments, the gel, lotion, or cream provided herein comprises about 0.001% w / w PQ-1, about 0.0005% w / w alexidine or a pharmaceutically acceptable salt thereof, and 0% w / w paraben. In some embodiments, the gel, lotion, or cream provided herein comprises about 0.0005% w / w (e.g., about 5 PPM) PQ-1, about 0.00025% w / w (e.g., about 2.5 ppm) alexidine or a pharmaceutically acceptable salt thereof, and 0% w / w paraben. In some embodiments, the gel, lotion, or cream comprises PQ-1 and alexidine or a pharmaceutically acceptable salt thereof in a ratio of about 2: 1, respectively.

[0100] In some embodiments, the gel, lotion, or cream comprises a first pharmaceutically acceptable carrier that is a copolymer of acrylamide and sodium acryloyldimethyltaurate, isohexadecane, and polysorbate 80, which is marketed as SEPIPLUS® ®P-600 commercially available product. In some embodiments, the first pharmaceutically acceptable carrier is present at about 0.5% w / w to about 2% w / w, for example about 1% w / w. In some embodiments, the gel, lotion, or cream comprises a second pharmaceutically acceptable carrier that is a polymer of acrylic acid crosslinked with one or more polyol allyl ethers, which carrier is a component of a commercially available product sold as Carbomer homopolymer. In some embodiments, the second pharmaceutically acceptable carrier is present at about 1% w / w to about 3% w / w, for example about 2% w / w.

[0101] As used herein, Carbomer refers to a polyacrylic acid polymer. Carbomer can also be referred to as CARBOPOL ® CARBOPOL ® 980 refers to, for example, an excipient sold by Lubrizol, and which has a Chemical Abstracts Service Registry Number (CAS RN) of 139637-85-7. CARBOPOL ® 980 is described by Lubrizol as a homopolymer of acrylic acid crosslinked with allyl sucrose or allyl pentaerythritol, prepared using a co-solvent system of ethyl acetate and cyclohexane, and which has a viscosity of 40000 cP - 60000 cP (0.5 wt%, pH 7.5). Other homopolymers are contemplated within the embodiments provided herein, including but not limited to the CARBOPOL ® polymers in the table below.

[0102] 1 co-solvent system, prepared using cyclohexane and ethyl acetate As used herein, SEPINEO ® P600 refers to a copolymer sold by, for example, Seppic, and which copolymer is associated with the following CAS RN: 38193-60-1 (3 components: acrylamide - 2-acrylamido-2-methylpropane sulfonic acid sodium copolymer) / 93685-80-04 (isohexadecane) / 9005-65-6 (polyoxyethylene sorbitan monooleate). SEPINEO ® P600 is described by Seppic as a polymer of acrylamide / acryloyldimethyltaurate sodium copolymer, isohexadecane, and polysorbate 80.

[0103] In some embodiments, the gel, lotion, or cream comprises a buffer having a pK a of about 2.5 to 7. In some embodiments, the buffer has at least one pK aabout 3, 4, 5, 6, or 7, or any range therein. In some embodiments, the buffer has at least one pK a about 3 to 6.5. In some embodiments, the buffer is a citrate or citric acid buffer. In some embodiments, the buffer concentration is present in the cream at about 0.05% w / w to about 5% w / w. In some embodiments, the gel, ointment, lotion, or cream formulation comprises about 20% w / w to about 70% w / w water. In some embodiments, the gel, lotion, or cream comprises about 0.01% w / w to about 0.5% w / w sodium citrate, potassium citrate, magnesium citrate, or citric acid buffer. In some embodiments, the gel, lotion, or cream comprises about 0.05% w / w to about 0.5% w / w sodium citrate, potassium citrate, magnesium citrate, or citric acid buffer.

[0104] In some embodiments, the pH of the cream is about 4 to about 6, for example about 5, for example about 4.5, 4.6, 4.7, 4.8, or 4.9. In some embodiments, the pH of the gel, lotion, or cream is about 4.5 to about 5.

[0105] In some embodiments, the gel, lotion, or cream comprises a molar ratio of the tropane alkaloid or pharmaceutically acceptable salt thereof to the polycyclic nucleobase or pharmaceutically acceptable salt thereof of about (4-5): 1, for example about 4.2: 1.

[0106] Thus, in some embodiments, the gel, ointment, lotion, or cream formulation comprises: about 0.01% w / w to about 2.5% w / w of a tropane alkaloid or pharmaceutically acceptable salt thereof; and about 0.002% w / w to 0.5% w / w of one or more preservatives.

[0107] Thus, in some embodiments, the gel, ointment, lotion, or cream formulation comprises: about 0.01% w / w to about 2.5% w / w of a tropane alkaloid or pharmaceutically acceptable salt thereof; no more than about 0.002% w / w of one or more preservatives; a first pharmaceutically acceptable carrier that is a copolymer of acrylamide and sodium acryloyldimethyl taurate, isohexadecane, and polysorbate 80, the first pharmaceutically acceptable carrier being present at about 0.5% w / w to about 2% w / w; a second pharmaceutically acceptable carrier that is a polymer of acrylic acid crosslinked with one or more polyol allyl ethers, present at about 1% w / w to about 3% w / w; and pK a a buffer at about 2.5 to 7, present at about 0.01% w / w to about 5% w / w; and wherein the gel, ointment, lotion, or cream formulation optionally comprises about 0.05% w / w to about 0.3% w / w of a polycyclic nucleobase or a pharmaceutically acceptable salt thereof.

[0108] In some embodiments of the methods herein, the gel, ointment, lotion, or cream formulation comprises: about 0.05% w / w to about 2.5% w / w of a tropane alkaloid or a pharmaceutically acceptable salt thereof; no more than about 0.25% w / w of one or more preservatives; a first pharmaceutically acceptable carrier that is a copolymer of acrylamide and sodium acryloyldimethyl taurate, isohexadecane, and polysorbate 80, present at about 0.5% w / w to about 2% w / w; a second pharmaceutically acceptable carrier that is a polymer of acrylic acid crosslinked with one or more polyol allyl ethers, present at about 1% w / w to about 3% w / w; and pK a a buffer at about 2.5 to 7, present at about 0.01% w / w to about 5% w / w; and wherein the gel, ointment, lotion, or cream formulation optionally comprises about 0.01% w / w to about 0.3% w / w of a polycyclic nucleobase or a pharmaceutically acceptable salt thereof.

[0109] In some embodiments, the gel, ointment, lotion, or cream formulation comprises: about 0.01% w / w, 0.03% w / w, 0.05% w / w, 0.08% w / w, or 0.15% w / w of atropine sulfate; about 0.16% w / w of caffeine; about 1% w / w of a first pharmaceutically acceptable carrier that is a copolymer of acrylamide and sodium acryloyldimethyl taurate, isohexadecane, and polysorbate 80; about 2% w / w of a second pharmaceutically acceptable carrier that is a polymer of acrylic acid crosslinked with one or more polyol allyl ethers; and has a pH of about 4.5 to about 5.0 (e.g., about 4.7 to about 4.8, e.g., about 4.75).

[0110] In some embodiments, the gel, ointment, lotion, or cream formulation comprises: about 0.01% w / w, 0.03% w / w, 0.05% w / w, 0.08% w / w, or 0.15% w / w of atropine sulfate; about 0.16% w / w of caffeine; about 1% w / w of a first pharmaceutically acceptable carrier that is a copolymer of acrylamide and sodium acryloyldimethyl taurate, isohexadecane, and polysorbate 80; about 2% w / w of a second pharmaceutically acceptable carrier that is a polymer of acrylic acid crosslinked with one or more polyol allyl ethers; and has a pH of about 4.5 to about 5.0 (e.g., about 4.7 to about 4.8, e.g., about 4.75).

[0111] In some embodiments, the gel, ointment, lotion, or cream formulation comprises: about 0.01% w / w, 0.03% w / w, 0.05% w / w, 0.08% w / w, or 0.15% w / w of atropine sulfate; about 0.16% w / w of caffeine; about 1% w / w of a first pharmaceutically acceptable carrier that is a copolymer of acrylamide and sodium acryloyldimethyl taurate, isohexadecane, and polysorbate 80; about 2% w / w of a second pharmaceutically acceptable carrier that is a polymer of acrylic acid crosslinked with one or more polyol allyl ethers; and has a pH of about 4.5 to about 5.0 (e.g., about 4.7 to about 4.8, e.g., about 4.75).

[0112] In some embodiments, the gel, ointment, lotion, or cream formulation comprises: about 0.15% w / w atropine sulfate; 0% w / w polycyclic nucleobase or a pharmaceutically acceptable salt thereof (e.g., caffeine); about 1% w / w of a first pharmaceutically acceptable carrier that is a copolymer of acrylamide and sodium acryloyldimethyl taurate, isohexadecane, and polysorbate 80; about 2% w / w of a second pharmaceutically acceptable carrier that is a polymer of acrylic acid crosslinked with one or more polyol allyl ethers; and has a pH of about 4.5 to about 5.0 (e.g., about 4.7 to about 4.8, such as about 4.75).

[0113] In some embodiments, the gel, ointment, lotion, or cream formulation comprises: about 0.5% w / w atropine sulfate; 0% w / w polycyclic nucleobase or a pharmaceutically acceptable salt thereof (e.g., caffeine); about 1% w / w of a first pharmaceutically acceptable carrier that is a copolymer of acrylamide and sodium acryloyldimethyl taurate, isohexadecane, and polysorbate 80; about 2% w / w of a second pharmaceutically acceptable carrier that is a polymer of acrylic acid crosslinked with one or more polyol allyl ethers; and has a pH of about 4.5 to about 5.0 (e.g., about 4.7 to about 4.8, such as about 4.75).

[0114] In some embodiments, the gel, ointment, lotion, or cream formulation comprises: about 0.5% w / w atropine sulfate; 0% w / w polycyclic nucleobase or a pharmaceutically acceptable salt thereof (e.g., caffeine); 0% w / w p-hydroxybenzoic acid ester; about 1% w / w of a first pharmaceutically acceptable carrier that is a copolymer of acrylamide and sodium acryloyldimethyl taurate, isohexadecane, and polysorbate 80; about 2% w / w of a second pharmaceutically acceptable carrier that is a polymer of acrylic acid crosslinked with one or more polyol allyl ethers; and has a pH of about 4.5 to about 5.0 (e.g., about 4.7 to about 4.8, such as about 4.75).

[0115] In some embodiments, the gel, ointment, lotion, or cream formulation comprises about 5% w / w to about 7% w / w (e.g., about 6% w / w) of a sugar alcohol. In some embodiments, the sugar alcohol is sorbitol.

[0116] In some embodiments, the gel, ointment, lotion, or cream formulation comprises about 1% w / w to about 3% w / w (e.g., about 2% w / w) of a first non-ionic surfactant. In some embodiments, the first non-ionic surfactant is polysorbate 80.

[0117] In some embodiments, the gel, ointment, lotion, or cream formulation comprises about 0.01% w / w to about 0.5% w / w (e.g., about 0.2% w / w) of a metal chelator. In some embodiments, the metal chelator is ethylenediaminetetraacetic acid (EDTA).

[0118] In some embodiments, provided herein are gel, ointment, lotion, or cream formulations comprising an active pharmaceutical ingredient comprising a tropane group (e.g., atropine), pilocarpine, travoprost, donepezil, or ephedrine.

[0119] In some embodiments, the gel, ointment, lotion, or cream formulation has a water content of about 20% w / w to about 31% w / w. In some embodiments, the gel, ointment, lotion, or cream formulation has a water content of about 20% w / w to about 25% w / w. In some embodiments, the gel, ointment, lotion, or cream formulation has a water content of no more than about 31% w / w. In some embodiments, the gel, ointment, lotion, or cream formulation comprises a water content of at least about 15% w / w.

[0120] In some embodiments, the gel, ointment, lotion, or cream formulation has a pH of about 4.0 to about 5.5. In some embodiments, the gel, ointment, lotion, or cream formulation has a pH of about 4.7.

[0121] In some embodiments, the gel, ointment, lotion, or cream formulation comprises a viscosity modifier selected from the group consisting of a copolymer of acrylamide and sodium acryloyldimethyl taurate, isohexadecane, and polysorbate 80 (SEPINEO ® P600); or cross-linked polyacrylic acid (CARBOPOL, e.g., CARBOPOL 980); or a combination thereof. ® 980); or a combination thereof.

[0122] In some embodiments, the gel, ointment, lotion, or cream formulation comprises at least one antioxidant and at least one preservative. In some embodiments, the at least one antioxidant is selected from a parahydroxybenzoic acid ester (e.g., methyl paraben, propyl paraben), a bisbiguanide (e.g., alexidine), or a polyquatemium-1, or a combination thereof. In some embodiments, the at least one antioxidant is selected from butylated hydroxyanisole (BHA), ascorbyl palmitate, or a combination thereof.

[0123] In some embodiments, the gel, ointment, lotion, or cream formulation comprises: a co-solvent selected from diethylene glycol monoethyl ether (Transcutol ® ) or propylene glycol or a combination thereof in an amount of about 1% w / w to about 5% w / w; an emulsifier selected from polyoxyl 35 castor oil, polysorbate 80, PEG 8000, or cetyl alcohol, or a combination thereof in an amount of about 8.5% w / w to about 10% w / w; mineral oil in an amount of about 8% w / w to about 12% w / w; glycerin in an amount of about 4% w / w to about 8% w / w; at least one preservative in an amount of about 0.01% w / w to about 0.05% w / w; and at least one antioxidant in an amount of about 0.02% w / w to about 0.06% w / w.

[0124] In some embodiments, the gel, ointment, lotion, or cream formulation comprises about 1% w / w to about 3% w / w (e.g., about 2% w / w) of a polyether. In some embodiments, the polyether is a polyethylene glycol (PEG). In some embodiments, the polyether or PEG has an average molar mass of about at least 2000 g / mol, 4000 g / mol, 6000 g / mol, 8000 g / mol, 10000 g / mol, or 20000 g / mol. In some embodiments, the PEG is PEG 8000.

[0125] In some embodiments, the gel, ointment, lotion, or cream formulation comprises about 3% w / w to about 6% w / w (e.g., about 4% w / w to about 5% w / w, e.g., about 4.4% w / w) of a glycol. In some embodiments, the glycol has a molar mass of about 200 g / mol or less. In some embodiments, the glycol is propylene glycol.

[0126] In some embodiments, the gel, ointment, lotion, or cream formulation comprises about 5% w / w to about 15% w / w (e.g., about 8% w / w to about 12% w / w, e.g., about 9% w / w, 10% w / w, or 11% w / w) of an oil. In some embodiments, the oil is mineral oil.

[0127] In some embodiments, the gel, ointment, lotion, or cream formulation comprises about 3% w / w to about 7% w / w (e.g., about 4% w / w to about 6% w / w, e.g., about 5% w / w) of a second non-ionic surfactant. In some embodiments, the second non-ionic surfactant is a pegylated castor oil (e.g., the second non-ionic surfactant comprises a tri-ester of glycerol and ricinoleic acid that is pegylated). In some embodiments, the second non-ionic surfactant is polyoxyl 35 castor oil.

[0128] In some embodiments, the gel, ointment, lotion, or cream formulation comprises about 0.3% w / w to about 0.7% w / w (e.g., about 0.4% w / w to about 0.6% w / w, e.g., about 0.5% w / w) of a fatty alcohol. In some embodiments, the fatty alcohol is a C 4-30 alcohol, e.g., a C 6-24 alcohol, e.g., a C 16-18 alcohol. In some embodiments, the fatty alcohol is a C 4-30 alkyl-OH compound or a C 4-30 alkenyl-OH compound, e.g., a C 6-24 alkyl-OH, e.g., a C 16-18 alkyl-OH, or a C 6-24 alkenyl-OH, e.g., a C 16-18 alkenyl-OH. In some embodiments, the fatty alcohol is cetyl alcohol.

[0129] In some embodiments, the gel, ointment, lotion, or cream formulation comprises cream formulation 1, 2, 3, 4, or 5, as shown in Table 1 of Example 1.

[0130] In some embodiments, the cream formulation comprises cream formulation 6, 7, 8, 9, 10, or 11, as shown in Table 3 of Example 4. In some embodiments, the cream formulation comprises cream formulation 12, 13, or 14, as shown in Table 4 of Example 6. In some embodiments, the cream formulation comprises cream formulation 17, 18, 19, 20, or 21, as shown in Table 7 of Example 6. In some embodiments, the cream formulation comprises cream formulation PHY012, PHY038, PHY039, PHY040, PHY041, PHY042, PHY048, PHY049, PHY050, or PHY052, as shown in Table 14 of Example 13.

[0131] In some embodiments, the gel, lotion, or cream provided herein can comprise no more than about 5.0% w / w tropic acid, no more than about 0.2% w / w 7-hydroxy scopolamine, no more than about 0.2% w / w scopolamine, no more than about 0.2% w / w 6-hydroxy scopolamine, no more than about 0.3% w / w scopolamine related compound A (nortropine), no more than about 0.5% w / w littorine, or no more than about 0.2% w / w apomoφhine, or a combination thereof.

[0132] In some embodiments, the gel, lotion, or cream provided herein has an apparent viscosity of about 50k to about 200k centipoise (cps).

[0133] Provided herein are methods of making a gel, lotion, or cream comprising an active pharmaceutical agent, the method comprising: 1) preparing an aqueous phase comprising water; polysorbate 80; and a copolymer of acrylamide and sodium acryloyldimethyl taurate, isohexadecane, and polysorbate 80 (e.g., SEPI NEO ® P600); 2) adding a cross-linked polyacrylic acid (e.g., carbomer) to the aqueous phase mixture of step 1); 3) preparing an oil phase comprising PEG 8000, mineral oil, polyoxyl 35 castor oil, cetyl alcohol, BHA, methyl paraben, and propyl paraben; 4) mixing the oil phase of step 3) with the aqueous phase mixture of step 2) and homogenizing the mixture; 5) adjusting the pH of the homogenized mixture of step 4) to about pH 4.7; 6) preparing a solution phase comprising diethylene glycol monoethyl ether, propylene glycol, glycerin, and ascorbyl palmitate; 7) adding the active pharmaceutical agent to the solution phase of step 6); 8) adjusting the pH of the solution phase of step 7) to about pH 4.7; 9) mixing the solution phase of step 8) with the homogenized mixture of step 5) and homogenizing to obtain the gel, ointment, lotion, or cream formulation comprising physostigmine.

[0134] In some embodiments, the active pharmaceutical agent is selected from atropine, physostigmine, donepezil, pilocarpine, or travoprost.

[0135] Methods The gel, ointment, lotion, or cream formulations described herein can be used to deliver a therapeutically relevant amount of one or more tropane alkaloid or a pharmaceutically acceptable salt thereof through an individual's skin to an underlying tissue, structure, or organ of the individual. Accordingly, provided herein are methods of delivering one or more tropane alkaloid or a pharmaceutically acceptable salt thereof to an individual in need thereof, comprising topically administering to the individual an effective amount of a gel, ointment, lotion, or cream formulation described herein.

[0136] Also provided herein are methods of treating one or more ocular disease by delivering a therapeutically relevant amount of one or more tropane alkaloid through the skin (e.g., at least one eyelid) of an individual having one or more ocular disease. Accordingly, in some embodiments, provided herein are methods of treating an ocular disease in an individual in need thereof, comprising topically administering to the individual a therapeutically effective amount of a tropane alkaloid provided herein. In some embodiments, the ocular disease treated comprises one or more of age-related macular degeneration, allergic conjunctivitis, blepharitis, chorioretinitis, diabetic macular edema, diabetic retinopathy, dry eye disease, epicorneal scarring, geographic atrophy, glaucoma, graft versus host disease, inflammation caused by gene therapy vectors, injury-related ocular inflammation or dry eye syndrome, iritis, keratitis, keratoconjunctival xerosis, macular degeneration (wet or dry), meibomian gland dysfunction, myopia, non-infectious uveitis, ocular hyperemia, presbyopia (dry eye), primary or secondary Sjogren's syndrome, redness, retinal inflammation, retinal vein occlusion, sterile conjunctivitis, Thygeson's superficial punctate keratitis, uveitis, or

[0137] In some embodiments, provided herein are methods of improving delivery of a tropane alkaloid to a target tissue in an individual in need thereof, comprising topically administering to a portion of the individual's skin a dose of a gel, ointment, lotion, or cream formulation provided herein containing the tropane alkaloid; wherein the improved delivery is at least about 50%, 100%, 200%, 300%, 400%, 500%, or 1000% improved compared to a dose of an eye drop formulation topically administered containing the same molar amount of the tropane alkaloid as in the gel, ointment, lotion, or cream formulation. In some embodiments, the improved delivery is at least about 50% higher target tissue concentration of the tropane alkaloid compared to a dose of an eye drop formulation topically administered containing the same molar amount of the tropane alkaloid as in the gel, ointment, lotion, or cream formulation. In some embodiments, the portion of the skin is a portion described throughout the disclosure. In some embodiments, the target tissue is a tissue described throughout the disclosure. In some embodiments, the portion of the skin is a portion of an eyelid and the target tissue is the aqueous humor of an eye beneath the eyelid.

[0138] In some embodiments of the methods described herein, the gel, ointment, lotion, or cream formulation comprises tropane alkaloids or pharmaceutically acceptable salts thereof. In some embodiments of the methods described herein, the gel, ointment, lotion, or cream formulation comprises tropane alkaloids or pharmaceutically acceptable salts thereof, as well as polycyclic nucleobases or pharmaceutically acceptable salts thereof.

[0139] The gels, lotions, or creams described herein can be applied topically to a portion of an individual's skin. In some embodiments, the topical application is made on a portion of the hands, feet, face, neck, nose, or eyelids (e.g., the upper or lower eyelids, or a combination thereof, of one or both eyes of the individual). The gel, ointment, lotion, or cream formulations provided herein allow the one or more tropane alkaloids contained herein or their pharmaceutically acceptable salts to penetrate the skin, thereby delivering the one or more tropane alkaloids or their pharmaceutically acceptable salts to the tissues of the individual, including the individual's organs or internal tissues or regions. In some embodiments, after the gel, ointment, lotion, or cream formulation is applied to the individual's skin, the tropane alkaloids or their pharmaceutically acceptable salts therein are delivered to the individual's eyes.

[0140] In some embodiments of the methods described herein, the gel, ointment, lotion, or cream formulation comprises: About 0.01% w / w to about 2.5% w / w of tropane alkaloids or their pharmaceutically acceptable salts; One or more preservatives, not exceeding about 0.002% w / w; The first pharmaceutically acceptable carrier is a copolymer of acrylamide and sodium acryloyl dimethyl taurate, isohexadecane, and polysorbate 80, and the first pharmaceutically acceptable carrier is present at about 0.5% w / w to about 2% w / w; A second pharmaceutically acceptable carrier, wherein the second pharmaceutically acceptable carrier is a polymer crosslinked with acrylic acid and one or more polyol allyl ethers, and the second pharmaceutically acceptable carrier is present at about 1% w / w to about 3% w / w; and pK a It is a buffer of about 2.5 to 7, present at about 0.01% w / w to about 5% w / w; and The gel, ointment, lotion, or cream formulations thereof optionally contain about 0.01% w / w to about 0.3% w / w of a polycyclic nucleobase or a pharmaceutically acceptable salt thereof.

[0141] In some embodiments of the methods described herein, the gel, ointment, lotion, or cream formulation comprises: from about 0.05% w / w to about 2.5% w / w of a tropane alkaloid or a pharmaceutically acceptable salt thereof; no more than about 0.002% w / w of one or more preservatives; a first pharmaceutically acceptable carrier that is a copolymer of acrylamide and sodium acryloyldimethyl taurate, isohexadecane, and polysorbate 80, present at about 0.5% w / w to about 2% w / w; a second pharmaceutically acceptable carrier that is a polymer of acrylic acid cross-linked with one or more polyol allyl ethers, present at about 1% w / w to about 3% w / w; and pK a a buffer at about 2.5 to 7, present at about 0.01% w / w to about 5% w / w; and wherein the gel, ointment, lotion, or cream formulation optionally comprises about 0.01% w / w to about 0.3% w / w of a polycyclic nucleobase or a pharmaceutically acceptable salt thereof.

[0142] In some embodiments of the methods herein, the gel, ointment, lotion, or cream formulation comprises: from about 0.05% w / w to about 2.5% w / w of a tropane alkaloid or a pharmaceutically acceptable salt thereof; no more than about 0.25% w / w of one or more preservatives; a first pharmaceutically acceptable carrier that is a copolymer of acrylamide and sodium acryloyldimethyl taurate, isohexadecane, and polysorbate 80, present at about 0.5% w / w to about 2% w / w; a second pharmaceutically acceptable carrier that is a polymer of acrylic acid cross-linked with one or more polyol allyl ethers, present at about 1% w / w to about 3% w / w; and pK a a buffer at about 2.5 to 7, present at about 0.01% w / w to about 5% w / w; and wherein the gel, ointment, lotion, or cream formulation optionally comprises about 0.05% w / w to about 0.3% w / w of a polycyclic nucleobase or a pharmaceutically acceptable salt thereof.

[0143] In some embodiments of the methods herein, the cream formulation comprises a cream formulation as shown in the Examples below, e.g., Cream Formulation 1, 2, 3, 4, or 5 as shown in Table 1 of Example 1.

[0144] kit In some embodiments, provided herein are packaged gels, lotions, or creams comprising a container holding a therapeutically effective amount of at least one gel, ointment, lotion, or cream described herein, and a packaging assembly, optionally comprising instructions for using the at least one gel, ointment, lotion, or cream according to one or more methods provided herein. Such packaging assemblies can be referred to as kits, or as container closure systems.

[0145] The gels, lotions, or creams of the present application and related materials, e.g., packaging assemblies as container closure systems, etc., can be completed as a marketable product by the usual steps performed in the art, e.g., by appropriate sterilization and packaging steps. For example, the materials can be treated by UV / visible light irradiation (200-500 nm), e.g., using photoinitiators with different absorption wavelengths (e.g., Irgacure 184, Irgacure 2959, e.g., l-[4-(2-hydroxyethoxy)-phenyl]-2-hydroxy-2-methyl-l-propan-l-one), preferably water-soluble initiators (e.g., Irgacure 2959). Such irradiation is usually performed in an irradiation time of 1 min to 60 min, but depending on the specific method, longer irradiation times can be applied. The materials according to the present disclosure can finally be packaged aseptically in order to remain sterile until use and packaged (e.g., by adding a specific product information leaflet) into suitable containers (boxes, etc.).

[0146] According to further embodiments, the gels, lotions, or creams of the present application can also be provided in kit form in combination with other packaging assemblies necessary for administering the gels, ointments, lotions, or creams to a patient. For example, the disclosed kits, e.g., for the treatment of ocular diseases, can also comprise, e.g., administration materials, including spatulas, rulers, etc., and instructions.

[0147] These kits are designed in a variety of forms depending on the specific deficiency they are intended to treat.

[0148] Gels, lotions, or creams provided herein can be prepared and placed in a container for storage at ambient or elevated temperatures. Color change of the formulation can be reduced when the gels, lotions, or creams are stored in polyolefin plastic containers as compared to polyvinyl chloride plastic containers. Without wishing to be bound by theory, the containers can reduce exposure of the contents of the container to electromagnetic radiation, whether visible light (e.g., having a wavelength of about 380-780 nm) or ultraviolet (UV) light (e.g., having a wavelength of about 190-320 nm (UV B light) or about 320-380 nm (UV A light)). Some containers also have the ability to reduce adhesion or adsorption of the active agent to the surface of the container. Some containers also have the ability to reduce exposure of the contents of the container to infrared light, or contain a second component that has this ability. Containers that can be used include those made of polyolefins, such as polyethylene, polypropylene, polyethylene terephthalate, polycarbonate, polymethylpentene, polybutylene, or combinations thereof, particularly polyethylene, polypropylene, or combinations thereof. In some embodiments, the container is a glass container, and the user scoops the contents out of the container with a graduated spatula, spoon, or the like. In some embodiments, the container is malleable, which allows the user to squeeze the contents out of the container. The container can also be placed within a second container, such as one of paper, cardboard, paperboard, metal film or foil, or combinations thereof, to further reduce exposure of the contents of the container to UV light, visible light, or infrared light. Formulations provided herein benefit from reduced color change, decomposition, or both, during storage in such containers. Formulations provided herein can need to be stored for up to three months or more; in some cases, up to one year or more. The container can be in any form suitable for containing the contents; for example, a bag, a bottle, a tube, or a box.

[0149] The following examples further illustrate aspects of the present disclosure. They are in no way, however, a limitation of the teachings or disclosure as described herein.

[0150] Example Example 1: Cream Formulation and Method Certain embodiments of the creams described herein were prepared as described in Table 1. The formulations were mixed according to the following procedure: (a) weigh and dissolve the aqueous composition comprising sorbitol, polysorbate 80, SEPINEO P600 ®(a) Weigh and mix the water phase composition comprising sodium chloride, sodium phosphate dibasic, sodium phosphate monobasic, EDTA, caffeine, and carbomer, (b) Weigh and mix the oil and glycol composition comprising mineral oil, castor oil, propylene glycol, PEG 8000, cetyl alcohol, alexidine, and PQ-1, (c) Weigh and dissolve atropine sulfate in the buffer, (d) Add the oil / glycol mixture to the water phase mixture and mix until a homogenous mixture is obtained, (e) Add the atropine sulfate solution to the above mixture and mix until a homogenous formulation is subsequently obtained.

[0151] Table 1.

[0152] Concentrations calculated based on the free base form.

[0153] Example 2: Stability of Tropane Alkaloids in Cream Formulations The stability of Cream Formulations 1 and 2 of Table 1 was determined by exposure to 25 kilograys (kGy) of electron beam sterilization, followed by storage at 40 °C, 75% relative humidity for 3 months, and the results for chemical purity of atropine are shown in Figures Figure 1 and 2 (Figures generated using the same samples for Cream Formulation 1) and Figure 3 and 4 (Figures generated using the same samples for Cream Formulation 2). These data show that atropine does not degrade more than about 10% over the time period measured. Cream Formulations 1 and 2 remain chemically stable for up to 3 months and are expected to remain stable for at least 6 months under such conditions.

[0154] Example 3: Tropane Alkaloid Chemical Stability Base hydrolysis. When atropine sulfate was exposed to 0.05 N NaOH at room temperature for 10 minutes, about 17.5% degradation was observed. This indicates that atropine sulfate is sensitive to base.

[0155] Acid hydrolysis. When atropine sulfate was exposed to 5 N HC1 at room temperature for 3 days, about 14.2% degradation was observed. This indicates that atropine sulfate is sensitive to acid.

[0156] Oxidative degradation. When atropine sulfate was exposed to 30% H2O2 at room temperature for 7 days, followed by reflux at 60 °C for 24 hours, about 12.7% degradation was observed. This indicates that atropine sulfate is sensitive to oxidation.

[0157] Thermal degradation and photolytic degradation. No significant changes were observed under thermal and photolytic conditions. This indicates that atropine sulfate is stable to heat and light.

[0158] Example 4: Antimicrobial Effectiveness Test (AET) Cream formulations containing the preservatives shown in Table 2 were prepared and tested for antimicrobial effectiveness according to USP <51>.

[0159] Table 2.

[0160] Table 3. List of formulations containing preservatives

[0161] Concentrations calculated based on the free base form.

[0162] These data show that the combination of PQ-1 and allexicline is effective in inhibiting microbial growth in semisolid dosage forms over a range of preservative concentrations.

[0163] Example 5: Tissue Penetration Pharmacokinetics Three tropic alkaloid formulations were prepared, including a 0.15% w / w atropine topical ophthalmic cream (Formulation #1), a 1% w / w atropine topical ophthalmic cream (Formulation #2), and a 0.05% atropine topical ophthalmic eye drop (over-the-counter eye drop). The formulations were compared for target tissue (aqueous humor) penetration.

[0164] Figure 5 and Figure 6 ( Figure 5 The log-scale of the data) shows the average atropine concentration in the target tissue (aqueous humor) following a single molar equivalent dose of atropine with each formulation (a drop was administered to the eye (cornea) or 50 mg of the cream formulation was administered to the eyelid). These data show that the 0.15% atropine cream formulation provides target tissue (aqueous humor) exposure similar to the 0.05% atropine eye drop, indicating that the cream formulation is a viable alternative to the eye drop. For example, both the 0.05% solution and the 0.15% cream reached T max within 1-3 hours post-dose, indicating rapid drug absorption. A higher AUC 0-24 was observed in the 0.15% atropine topical ophthalmic cream dosing group compared to the 0.05% atropine eye drop dosing group, indicating more efficient utilization of the atropine administered.

[0165] These data also show an increase in aqueous humor exposure for the 0.15% to 1% atropine topical ophthalmic cream, indicating that a smaller volume of cream can be administered instead of a larger volume of cream containing a lower concentration of active pharmaceutical ingredient, which can address potential cosmetic issues with patient use and compliance.

[0166] Example 6: API stabilization with low molecular weight molecules (LMW) having one or more aromatic ring structures and / or conjugated structures Cream formulation with and without LMW molecules are shown in Table 4. The results of the assays before and after electron beam (25 kGy) irradiation are summarized in Table 5. The API stability of the LMW molecules was successfully demonstrated. It should be noted that formulations 12 and 13 are duplicate formulations to confirm reproducibility.

[0167] Table 4. Cream formulations with and without LMW molecules

[0168] Concentration based on free base form.

[0169] Formulation 13 is the same as formulation 12, demonstrating reproducibility in preparing the formulations described herein.

[0170] Table 5. Formulation assays with / without LMW molecules before and after electron beam (25 kGy) irradiation

[0171] The effect of caffeine on atropine stability after electron beam process was investigated. Cream formulations with and without caffeine were mixed and analyzed for content / total impurities by HPLC. The test results showed that after electron beam irradiation, the content of the formulation with caffeine decreased by 5.2% while the content of the formulation without caffeine decreased by 18.1% (Table 6). After electron beam irradiation, the total impurities increased to 1.7% for the formulation with caffeine while the formulation without caffeine increased to 8.4%. At the 3-month time point under the test conditions of 40°C and 75% relative humidity (RH), the presence of caffeine reduced the appearance of impurities. The amount of impurities was about 5 times lower for the formulation with caffeine compared to the formulation without caffeine.

[0172] Table 6. Atropine stability evaluation with and without caffeine

[0173] The effect of stabilizers on atropine stability after electron beam process was further investigated. The stabilizers included aromatic ring compounds (e.g., a-cyano-4-hydroxycinnamic acid) and heterocyclic compounds (e.g., histidine). Cream formulations were mixed with stabilizers (Table 7). The content / total impurities were analyzed by HPLC and the test results before and after electron beam process are summarized in Table 8.

[0174] The results showed that all the stabilizers tested herein were effective in preventing atropine degradation compared to the samples without stabilizers in Table 6.

[0175] Data showed a correlation between atropine stability and the amounts of α-cyano-4-hydroxycinnamic acid and histidine. Following electron beam processing, the amount of tropinic acid, an atropine degradation product, exhibited the same trend as in the atropine content analysis.

[0176] Table 7. Formulations containing multiple stabilizers at different concentrations

[0177] Table 8. Evaluation of the effect of stabilizers (caffeine substitutes) on the stability of atropine

[0178] Table 9. Cream formulations containing stabilizers

[0179] Concentration calculated based on free base form Example 7: Changes in pupil diameter A comparison was made between 0.15% atropine cream and 0.05% atropine eye drops. See [link / reference]. Figure 7 Based on clinical observation and dermal and ocular assessments, all dose levels were well tolerated. Similar pupillary dilation was observed with atropine cream and eye drops (+0.5 mm). The dilation was recorded after 14 days.

[0180] Example 8: Miniature Pig Plasma Exposure like Figure 8 As shown, the systemic exposure to atropine topical ophthalmic cream is 100 times or more lower than that to the systemic exposure to commercially approved atropine sulfate ophthalmic solution USP 1%.

[0181] Example 9: Moisture content of physostigmine preparation Five formulations containing 0% w / w to 25% w / w water were mixed (PHY038 to PHY042). As shown in Table 10, the test results indicate that formulations with a water content of 15% or less showed phase separation upon centrifugation, indicating poor physical stability. Formulations with a water content of 20% or higher showed no phase separation upon centrifugation, indicating ideal physical stability.

[0182] Table 10. Forced phase separation of formulations with different water contents by centrifugation (13500 rpm (~16800 RCF) for 5 min)

[0183] Formulations with low water content (10-15%) failed the physical stability test. Formulations PHY038, PHY039 and PHY040 with water content of 0%, 10% and 15% respectively were found to show phase separation in centrifuge test at 13500 rpm (~16800 RCF) for 5 min.

[0184] Formulations with high water content or high pH failed the chemical stability test. The physostigmine content of PHY030 was found to be = 94.4% before e-beam irradiation and = 85% after 25 kGy e-beam irradiation, and the total impurities were = 0.14% before e-beam irradiation and = 0.58% after 25 kGy e-beam irradiation.

[0185] Example 10: Physostigmine formulation antioxidant content Formulations were mixed with butylated hydroxyanisole (BHA), or a combination of BHA and ascorbyl palmitate at different concentrations (PHY048 to PHY052). The results of total impurities are summarized in Table 11.

[0186] Table 11. Change in total impurities over time for formulations containing different concentrations of antioxidants at 40°C / 75% RH

[0187] At 1 month (stored at accelerated 40°C / 75% RH conditions), formulations containing a combination of ascorbyl palmitate and BHA showed lower total impurities compared to formulations containing BHA only.

[0188] After 3 months at 40°C / 75 RH, formulations containing BHA only showed a darker cream color compared to formulations containing both BHA and ascorbyl palmitate, but had acceptable impurity levels. In other words, under accelerated stability conditions, the formulation color looked lighter (better appearance) when two antioxidants were used in the formulation.

[0189] Example 11: Physostigmine physical properties Formulation design experiments were performed to optimize the formulation composition to achieve ideal physical properties. The design of experiments is shown in Table 12, and the results of data analysis are shown in Figure 18 and Figure 19 .

[0190] Table 12. Design of experiments and results for the effect of formulation thickener and pH on cream viscosity

[0191] It was found that (a) when CARBOPOL ®980 The viscosity of the formulation increased as the concentration increased, (b) The viscosity of the formulation decreased as the pH increased, (c) Formulations containing 2% of SEPINEO P600 ® and 2% of CARBOPOL ® No phase separation was found for the formulation of 980 in the centrifuge test.

[0192] Example 12: Physostigmine excipient compatibility A drug excipient compatibility (DEC) study was performed to evaluate excipients, as shown in Table 13. All excipients used in the formulation were compatible with physostigmine before and after electron beam irradiation at 25 kGy. NaOH was used to adjust the pH of the cream and was added prior to mixing with physostigmine. The chemical stability of physostigmine in the formulation was stable at acidic pH environment (e.g., pH from about 3.5 to about 5.5).

[0193] Table 13. Drug-excipient compatibility - total impurities

[0194] N / A means no determination was made.

[0195] Example 13: Preparation of physostigmine formulations Formulations containing physostigmine were prepared according to the flowchart of Figure 20 Table 14 provides the different formulations prepared.

[0196] Table 14. Formulations of physostigmine topical cream

[0197] PHY012 contains 5 ppm of alexidine and 10 ppm of polyquaternium-1 The general preparation procedure for the formulations of Table 14 included gently dissolving physostigmine with ascorbyl palmitate in a mixture of propylene glycol and purified diethylene glycol monoethyl ether (or Transcutol) to minimize hydrolysis, oxidation, and thermal degradation during the preparation process. As shown in Figure 20 a water phase mixture was prepared, carbomer was added, an oil phase mixture was prepared, mixed, homogenized and pH adjusted, then the dissolved physostigmine solution as shown in Figure 20 was added to the cream base to minimize exposure time. The procedure described herein ensures that physostigmine is present in the oil / glycol phase and not in the water phase prior to addition to the cream base.

[0198] Example 14: Testing of physostigmine formulations Six sensory attributes were evaluated for the three formulations, such as appearance, spreadability, stickiness, comfort, greasiness / oily, and residue. PHY052 had the best overall sensory score. PHY048 was considered the most greasy, but was still acceptable to most of the subjects. PHY030 was considered the least greasy of the three formulations. For all three test formulations, no skin irritation, stinging, burning, or discomfort was detected by any of the 19 subjects.

[0199] The data in the above examples and figures indicate that certain physostigmine formulations are stable at 40°C / 75% RH for at least 3 months, and that the formulations provide desirable physostigmine release and permeation.

[0200] It will be appreciated that various modifications and changes can be made to the presently preferred embodiments described herein in light of the above teachings. Such modifications and changes, however, are intended to fall within the scope of the present subject matter, which is to be limited only by the appended claims. Accordingly, it is intended that the present subject matter cover all such modifications and changes as fall within the scope of the appended claims.

[0201] In instances where reference has been made in this specification to patents and printed publications, each of the above-referenced references and printed publications are individually incorporated herein by reference in their entirety.

Claims

1. A topical formulation comprising an active pharmaceutical ingredient, the active pharmaceutical ingredient comprising a tropane group.

2. The topical formulation of claim 1, wherein the topical formulation is a gel, lotion, ointment, or cream.

3. A gel, ointment, lotion, or cream formulation comprising an active pharmaceutical ingredient, the active pharmaceutical ingredient comprising a tropane group.

4. The gel, ointment, lotion, or cream formulation of claim 3, wherein the gel, ointment, lotion, or cream formulation is an oil-in-water emulsion cream formulation comprising at least 50% w / w water.

5. The gel, ointment, lotion, or cream formulation of claim 3 or 4, wherein the active pharmaceutical ingredient is a tropane alkaloid or a pharmaceutically acceptable salt thereof.

6. The cream formulation of one of claims 3-5, wherein the active pharmaceutical ingredient comprises atropine, benzatropine, cocaine, homatropine, hyoscyamine, scopolamine, tiotropium, trospendil, or trospium, or a pharmaceutically acceptable salt thereof.

7. The gel, ointment, lotion or cream formulation of any one of claims 3-6, wherein the active pharmaceutical ingredient is atropine or a pharmaceutically acceptable salt thereof, the active pharmaceutical ingredient comprising greater than 50% by weight of S )-3-hydroxy-2-phenylpropionic acid (1 R ,3 r ,5 S )-8-methyl-8-azabicyclo[3.2.1]oct-3-yl ester or a pharmaceutically acceptable salt thereof.

8. The gel, ointment, lotion or cream formulation of any one of claims 3-7, wherein the active pharmaceutical ingredient is atropine or a pharmaceutically acceptable salt thereof, the active pharmaceutical ingredient comprising less than 10% by weight of R )-3-hydroxy-2-phenylpropionic acid (1 R ,3 r ,5 S )-8-methyl-8-azabicyclo[3.2.1]oct-3-yl ester or a pharmaceutically acceptable salt thereof.

9. The gel, ointment, lotion or cream formulation of any one of claims 3-6, wherein the active pharmaceutical ingredient is atropine or a pharmaceutically acceptable salt thereof, the active pharmaceutical ingredient comprising greater than 50% by weight of R )-3-hydroxy-2-phenylpropionic acid (1 R ,3 r ,5 S )-8-methyl-8-azabicyclo[3.2.1]oct-3-yl ester, or a pharmaceutically acceptable salt thereof.

10. The gel, ointment, lotion or cream formulation of any one of claims 3-6 and 9, wherein the active pharmaceutical ingredient is atropine or a pharmaceutically acceptable salt thereof, the active pharmaceutical ingredient comprising less than 10% by weight of S )-3-hydroxy-2-phenylpropionic acid (1 R ,3 r ,5 S )-8-methyl-8-azabicyclo[3.2.1]oct-3-yl ester or a pharmaceutically acceptable salt thereof.

11. The gel, ointment, lotion, or cream formulation of one of claims 3-10, further comprising a heterocyclic compound having the formula: ###0001### or a pharmaceutically acceptable salt thereof, wherein m, n, p, w, x, y, and z are each independently 0 or 1.

12. The gel, ointment, lotion, or cream formulation of one of claims 3-10, further comprising a polycyclic nucleobase or a pharmaceutically acceptable salt thereof.

13. The gel, ointment, lotion, or cream formulation of claim 12, wherein the polycyclic nucleobase is azathioprine, adenine, 2-aminopurine, 2,6-diaminopurine, 2,6,8- triaminopurine, 2-amino-6-methoxypurine, 2-chloro-6-aminopurine, 2-fluoro-6- aminopurine, guanine, thioguanine, isoguanine, purine, mercaptopurine, hypoxanthine, xanthine, 1-methylxanthine, 3-methylxanthine, 7-methylxanthine, 1,3- dimethylxanthine, 3,7-dimethylxanthine, 1,7-dimethylxanthine, 1,3,7- trimethylxanthine, 8-chloro-1,3-dimethylxanthine, uric acid, 1-methyluric acid, 3- methyluric acid, 7-methyluric acid, 1,3-dimethyluric acid, 3,7-dimethyluric acid, 1,7- dimethyluric acid, or 1,3,7-trimethyluric acid, or a pharmaceutically acceptable salt thereof. a, b, c, d, e, f and g are each independently a single or double bond; 14. The gel, ointment, lotion, or cream formulation of one of claims 3-13, comprising atropine or a pharmaceutically acceptable salt thereof and 1,3,7-trimethylxanthine. R 1 , R 3 , R 7 , and R 9 are each independently H, C 1-6 alkyl, C 1-6 alkanol, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-8 alkanal, C 3-8 alkenal, C 2-8 alkanone, or C 4-8 alkenone; R 2 , R 6 , and R 8 are each independently H, halogen, O-(C 1-3 alkyl), NH2, N(H)(C 1-3 alkyl), N(C 1-3 alkyl)(C 1-3 alkyl), S, or O.

15. The cream formulation of claim 3, comprising: about 0.01% w / w to about 2.5% w / w of a tropane alkaloid or a pharmaceutically acceptable salt thereof; no more than about 0.25% w / w of one or more preservatives; ​ ​ ​ ​ ​ a first pharmaceutically acceptable carrier that is a copolymer of acrylamide and sodium acryloyldimethyl taurate, isohexadecane, and polysorbate 80, the first pharmaceutically acceptable carrier being present at about 0.5% w / w to about 2% w / w; a second pharmaceutically acceptable carrier that is a polymer of acrylic acid crosslinked with one or more polyol allyl ethers, the second pharmaceutically acceptable carrier being present at about 1% w / w to about 3% w / w; and pK a a buffering agent at about 2.5 to 7 present at about 0.01% w / w to about 5% w / w; and wherein the gel, ointment, lotion, or cream formulation optionally comprises about 0.01% w / w to about 0.3% w / w of a polycyclic nucleobase or a pharmaceutically acceptable salt thereof.

16. A composition comprising: one or more purified tropane alkaloids or a pharmaceutically acceptable salt thereof; and one or more purified polycyclic nucleobases or a pharmaceutically acceptable salt thereof.

17. The composition of claim 16, wherein the purified polycyclic nucleobase or a pharmaceutically acceptable salt thereof has the following formula: or a pharmaceutically acceptable salt thereof, wherein a, b, c, d, e, f and g are each independently a single or double bond; m, n, p, w, x, y, and z are each independently 0 or 1; R 1 , R 3 , R 7 , and R 9 are each independently H, C 1-6 alkyl, C 1-6 alkanol, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-8 alkanal, C 3-8 alkenal, C 2-8 alkanone, or C 4-8 alkenone; R 2 , R 6 , and R 8 are each independently H, halogen, O-(C 1-3 alkyl), NH2, N(H)(C 1-3 alkyl), N(C 1-3 alkyl)(C 1-3 alkyl), S, or O.

18. The gel, ointment, lotion, or cream formulation of any one of claims 3-13 and 15, further comprising at least one low molecular weight compound or a pharmaceutically acceptable salt thereof, wherein the at least one low molecular weight compound optionally comprises one or more aromatic ring structures.

19. The gel, ointment, lotion, or cream formulation of claim 18, wherein the at least one low molecular weight compound or a pharmaceutically acceptable salt thereof stabilizes an active pharmaceutical ingredient (API) in the gel, ointment, lotion, or cream formulation.

20. The gel, ointment, lotion, or cream formulation of claim 18, wherein the at least one low molecular weight compound is selected from caffeine, benzoic acid, sinapic acid, a- cyano-4-hydroxycinnamic acid, histidine, geoporphyrin, or a pharmaceutically acceptable salt thereof, or a combination thereof.

21. The gel, ointment, lotion, or cream formulation of any one of claims 18-20, wherein the at least one low molecular weight compound is present in the cream formulation in an amount of about 0.01% w / w to about 1% w / w.

22. The gel, ointment, lotion, or cream formulation of any one of claims 18-20, wherein the at least one low molecular weight compound is present in the cream formulation in an amount of about 0.05% w / w to about 0.7% w / w.

23. A cream formulation comprising atropine sulfate selected from Formulation #1, Formulation #2, Formulation #3, Formulation #4, Formulation #5, Formulation #6, Formulation #7, Formulation #8, Formulation #9, Formulation #10, Formulation #11, Formulation #12, Formulation #13, Formulation #14, Formulation #17, Formulation #18, Formulation #19, Formulation #20, or Formulation #21, each as described in the Examples section.

24. A gel, ointment, lotion or cream formulation comprising an active pharmaceutical ingredient, the active pharmaceutical ingredient comprising a tropane group, pilocarpine, travoprost or physostigmine.

25. The gel, ointment, lotion or cream formulation of claim 24 having a water content of about 20% w / w to about 31% w / w, or about 20% w / w to about 25% w / w.

26. The gel, ointment, lotion or cream formulation of claim 24 or 25 having a pH of about 4.0 to about 5.5, or about 4.

7.

27. The gel, ointment, lotion or cream formulation of any one of claims 24-26 comprising a viscosity modifier selected from the group consisting of a copolymer of acrylamide and sodium acryloyldimethyl taurate, isohexadecane and polysorbate 80; or cross-linked polyacrylic acid; or a combination thereof.

28. The gel, ointment, lotion or cream formulation of any one of claims 24-27 comprising at least one antioxidant and at least one preservative.

29. The gel, ointment, lotion or cream formulation of claim 28, wherein the at least one antioxidant is selected from the group consisting of a paraben, a bisbiguanide or a polyquatemium-1, or a combination thereof.

30. The gel, ointment, lotion or cream formulation of claim 28, wherein the at least one antioxidant is selected from the group consisting of butylated hydroxyanisole (BHA), ascorbyl palmitate, or a combination thereof.

31. The gel, ointment, lotion or cream formulation of any one of claims 24-30 comprising: a co-solvent selected from the group consisting of diethylene glycol monoethyl ether or propylene glycol, or a combination thereof, in an amount of about 1% w / w to about 5% w / w; an emulsifier selected from the group consisting of polyoxyl 35 castor oil, polysorbate 80, PEG 8000, or cetyl alcohol, or a combination thereof, in an amount of about 8.5% w / w to about 10% w / w; mineral oil in an amount of about 8% w / w to about 12% w / w; glycerin in an amount of about 4% w / w to about 8% w / w; at least one preservative in an amount of about 0.01% w / w to about 0.05% w / w; and at least one antioxidant in an amount of about 0.02% w / w to about 0.06% w / w.

32. The gel, ointment, lotion or cream formulation of any one of claims 24-31 selected from the group consisting of PHY012, PHY038, PHY039, PHY040, PHY041, PHY042, PHY048, PHY049, PHY050 or PHY052, each as described in the Examples section.

33. The gel, ointment, lotion or cream formulation of any one of claims 3-15, 18-23 or 24-32, or the composition of claim 16 or 17, contained in one or more containers, wherein at least one of the one or more containers comprises plastic.

34. A gel, ointment, lotion, or cream formulation comprising about 0.0005% w / w to about 0.001% w / w of polyquatemium-1 or a pharmaceutically acceptable salt thereof, and about 0.00025% w / w to about 0.0005% w / w of alexidine or a pharmaceutically acceptable salt thereof, wherein the gel, ointment, lotion, or cream formulation is otherwise free of preservatives, and wherein the cream formulation optionally comprises an active pharmaceutical ingredient.

35. A method comprising administering to an individual the gel, ointment, lotion, or cream formulation of any one of claims 3-15, 18-23, or 24-32, or the composition of claim 16 or 17.

36. A method of treatment comprising administering to an individual in need thereof the gel, ointment, lotion, or cream formulation of any one of claims 3-15, 18-23, or 24-32, or the composition of claim 16 or 17.

37. The method of any one of claims 35-36, wherein the individual has or is predisposed to having an ophthalmic condition (e.g., one or more of amblyopia, hyperopia, myopia, presbyopia, glaucoma, or demodex blepharitis).

38. The method of any one of claims 35-37, wherein the method comprises an anesthetic, antiarrhythmic, antiemetic, antihistamine, antiparkinsonian, antispasmodic, bronchodilatory, gastrointestinal, or ophthalmic treatment or method of use.

39. A method of modulating acetylcholine activity comprising administering to an individual in need thereof the gel, ointment, lotion, or cream formulation of any one of claims 3-15, 18-23, or 24-32, or the composition of claim 16 or 17.

40. The method of any one of claims 38-39, wherein the administering is topical administration.

41. A method of improving delivery of a tropane alkaloid to a target tissue in an individual in need thereof comprising topically administering to a portion of the individual’s skin a dose of the gel, ointment, lotion, or cream formulation of any one of claims 3-15, 18-23, or 24-32, or the composition of claim 16 or 17 containing the tropane alkaloid; wherein the improved delivery is a target tissue concentration of the tropane alkaloid that is at least about 50% higher than a target tissue concentration of a dose of an eye drop formulation topically administered, the eye drop formulation containing the same molar amount of the tropane alkaloid as in the gel, ointment, lotion, or cream formulation.

42. An article of manufacture comprising the gel, ointment, lotion, or cream formulation of any one of claims 3-15, 18-23, or 24-32, or the composition of claim 16 or 17, and instructions for use.

43. A method of making the gel, ointment, lotion, or cream formulation of any one of claims 24-32, the method comprising: 1) preparing an aqueous phase comprising water; polysorbate 80; and a copolymer of acrylamide and sodium acryloyldimethyl taurate, isohexadecane, and polysorbate 80; 2) adding cross-linked polyacrylic acid to the aqueous phase mixture of step 1); and 3) adding the following to the mixture of step 2): a preservative, a humectant, a thickening agent, a buffering agent, and a pH adjuster. 3) preparing an oil phase comprising PEG 8000, mineral oil, polyoxyl 35 castor oil, cetyl alcohol, BHA, methyl paraben, and propyl paraben; 4) mixing the oil phase of step 3) with the aqueous phase mixture of step 2) and homogenizing the mixture; 5) adjusting the pH of the homogenized mixture of step 4) to about pH 4.7; 6) preparing a solution phase comprising diethylene glycol monoethyl ether, propylene glycol, glycerin, and ascorbyl palmitate; 7) adding an active pharmaceutical agent to the solution phase of step 6); 8) adjusting the pH of the solution phase of step 7) to about pH 4.7; 9) mixing the solution phase of step 8) with the homogenized mixture of step 5) and homogenizing to obtain a gel, ointment, lotion, or cream formulation of any one of claims 24-32.

44. The method of claim 43, wherein the active pharmaceutical agent is selected from the group consisting of pilocarpine, atropine, donepezil, pilocarpine, or travoprost.

45. The formulation, composition, method, or article of any one of claims 1-44, which is an ophthalmic formulation, composition, method, or article.

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