Ophthalmic cream formulations and their use

Abstract

Gel, ointment, lotion, or cream formulations containing an active pharmaceutical ingredient including a tropanil portion are provided herein. The gel, lotion, or cream formulations may contain at least one low molecular weight (LMW) compound or a pharmaceutically acceptable salt thereof. Also provided herein are gel, ointment, lotion, or cream formulations containing active pharmaceutical ingredients such as atropine, pilocarpine, physostigmine, or travoprost.

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims the benefits of U.S. Provisional Application No. 63 / 452,633 filed on 16 March 2023, U.S. Provisional Application No. 63 / 605,955 filed on 4 December 2023, and U.S. Provisional Application No. 63 / 549,789 filed on 5 February 2024, which are incorporated herein by reference in their entirety.

[0002] Tropane alkaloids consist of a class of bicyclic [3.2.1] alkaloids and secondary metabolites that contain a tropane ring in their chemical structure. Many tropane alkaloids exist naturally. Notable examples of tropane alkaloids include cocaine, scopolamine, and atropine. Desirable pharmacological properties may be conferred through the anticholinergic or stimulant activity of tropane alkaloids.

[0003] Tropane alkaloids have a variety of therapeutic uses, including anesthetics, antiarrhythmics, antiemetics, antihistamines, antiparkinsonian drugs, anticonvulsants, bronchodilators, gastrointestinal drugs, and ophthalmic uses. For example, atropine is a muscarinic receptor antagonist, a type of anticholinergic agent that blocks the activity of muscarinic acetylcholine receptors. By blocking the neurotransmitter acetylcholine at synapses in the central and peripheral nervous systems, atropine has found uses in treating poisoning from nerve agents and organophosphate insecticides, which disrupt acetylcholinesterase through phosphorylation and induce harmful accumulation of acetylcholine in the body. Atropine has also found uses in treating amblyopia, hyperopia, or myopia due to its ciliary muscle paralysis and mydriatic effects.

[0004] One problem with tropane alkaloid therapeutic agents, including atropine therapeutic agents, is their chemical stability, including, for example, hydrolytic degradation. For example, atropine exhibits instability under basic, acidic, and oxidative conditions. Atropine decomposes via hydrolysis into tropine and tropic acid, and its decomposition is accelerated under strong acidic or basic conditions - the hydrolytic degradation rate of atropine is minimal in the pH range of approximately 3 - 4. Furthermore, due to the loss of a water molecule, atropine is converted into apoatropine, which itself decomposes via hydrolysis into tropine and tropic acid.

[0005] Therefore, with regard to the therapeutic use of tropane alkaloids, there is a need for stable formulations that address both the physical stability of the formulation and the chemical instability of the tropane alkaloids in the formulation.

[0006] Travoprost is a prostaglandin used to treat glaucoma or open-angle ocular hypertension.

[0007] Demodex-induced blepharitis is an inflammation of the eyelids and eyelashes. This usually occurs when small oil glands / Meibomian glands near the base of the eyelashes become clogged, causing eyelid inflammation, redness, and irritation. Demodex mites are often the underlying cause of Demodex blepharitis and other Meibomian gland dysfunctions and related eye diseases. Blepharitis generally has an adverse effect on the eye along the edges of the eyelids and eyelashes. Existing treatments for Demodex blepharitis approved by the FDA include eye drops containing antiparasitic drugs. However, existing treatments cause eye irritation, stinging, burning sensations, contact dermatitis, and / or allergies, and the effective rate of the active pharmaceutical ingredients used to kill Demodex mites is low. Therefore, an improved treatment for Demodex blepharitis is needed.

Brief Description of the Drawings

[0008] [Figure 1]Figure 1 shows the time course of the chemical stability of atropine in cream formulation 1 after the cream was sterilized by electron beam (eBeam) at 25 kGy and exposed to 40°C at 75% relative humidity. The dashed line represents the 95% prediction interval. [Figure 2] Figure 2 shows the total atropine-derived impurities in cream formulation 1 over time after exposure of the cream to electron beam sterilization at 25 kGy and 40°C at 75% relative humidity. The dashed line represents the 95% prediction interval. [Figure 3] Figure 3 shows the time course of the chemical stability of atropine in cream formulation 2 after exposure of the cream to electron beam sterilization at 25 kGy and 40°C at 75% relative humidity. The dashed line represents the 95% prediction interval. [Figure 4] Figure 4 shows the total atropine-derived impurities in cream formulation 2 over time after exposure of the cream to electron beam sterilization at 25 kGy and 40°C at 75% relative humidity. The dashed line represents the 95% prediction interval. [Figure 5] Figure 5 shows the mean atropine concentration in aqueous humor target tissue after a single dose of atropine on an equimolar basis using formulations containing 0.05% w / w atropine (ophthalmic solution), 0.15% w / w atropine (cream), or 1% w / w atropine (cream) (instilled into the eye or applied as a cream to the eyelid). [Figure 6] Figure 6 shows the same data from Figure 5 plotted on a logarithmic scale. [Figure 7] Figure 7 shows the time course of the maximum pupil diameter when using 0.15% atropine cream (formulation 1 in Table 1) and eye drops. [Figure 8] Figure 8 shows the mean systemic concentration over time plotted on a logarithmic scale when using 0.05% atropine ophthalmic topical solution and cream (formulation 2 in Table 1). [Figure 9] Figure 9 shows the time course of the chemical stability of atropine in cream formulation 23 after exposure of the cream to electron beam sterilization at 25 kGy and 40°C at 75% relative humidity. The dashed line represents the 95% prediction interval. [Figure 10]Figure 10 shows the free travoprost acid concentrations in aqueous humor during a 14-day pharmacokinetic (PK) study of Yucatan miniature pigs treated with cream formulations containing 0.004% to 0.0012% travoprost for glaucoma. [Figure 11A] Figure 11A shows the tear film breakup time for pilocarpine cream formulations containing approximately 4% to 8% w / w pilocarpine compared to placebo in human clinical trials for dry eye disease. [Figure 11B] Figure 11B shows the improvement in visual acuity with pilocarpine cream formulations containing approximately 4% to 8% w / w pilocarpine compared to placebo in human clinical trials for dry eye disease. [Figure 12] Figure 12 shows the mortality rates for mites causing Demodex blepharitis using a 1% physostigmine cream formulation versus a 0.25% lotilaner eye drop formulation. [Figure 13] Figure 13 shows the aqueous humor atropine concentrations in Yucatan miniature pigs during a 14-day repeated-dose pharmacokinetic (PK) study using 0.05% ophthalmic solution and cream formulations containing 0.15% and 1% atropine for the treatment of progressive myopia. [Figure 14] Figure 14 shows the data from drug excipient compatibility tests between travoprost and functional excipients. [Figure 15] Figure 15 shows the in vitro active ingredient (API) release profiles for 0.5% w / w, 1% w / w, and 2% w / w physostigmine cream formulations. [Figure 16A] Figure 16A shows the in vitro penetration of atropine cream formulations containing approximately 0.05% w / w to 0.25% w / w atropine and approximately 0.05% w / w to 5% w / w carbomer into synthetic skin membranes. [Figure 16B] Figure 16B shows the experimental setup for the in vitro penetration test. [Figure 17] Figure 17 shows a specific degradation pathway for physostigmine. [Figure 18] Figure 18 illustrates the relationship between the formulation viscosity of carbomer and SEPINEO® P600. [Figure 19] Figure 19 illustrates the relationship between the assay percentage of physostigmine and the pH of the formulation. [Figure 20] Figure 20 shows a flowchart of the preparation of physostigmine. [Figure 21] Figure 21 shows the chemical stability trends at 40°C for certain formulations from Example 13, namely PHY012 and PHY052. [Figure 22] Figure 22 shows the total impurity profiles at 40°C for certain formulations from Example 13, namely PHY012 and PHY052. [Figure 23] Figure 23 shows the physical stability (pH) profile of formulation PHY052 from Example 13 at 40°C / 75% relative humidity (RH). [Figure 24] Figure 24 shows the physical stability (viscosity) of formulation PHY052 from Example 13 at 40°C / 75%RH. [Figure 25A] Figure 25A shows stability studies and trend analyses for formulation screening and product shelf life determination. [Figure 25B] Figure 25B shows the predicted aesthetic performance and tube filling parameters.

[0009] Detailed explanation The topical application of active pharmaceutical ingredients can be via one of many compositional forms, including liquid, ointment, gel, lotion, and cream formats. Each topical application format has its own advantages and disadvantages. For example, liquids are often rapidly absorbed upon application but are limited to topical mucosal application, in which case discomfort may occur upon application due to pH imbalance with the mucous membrane for chemical stability—applying an acidic solution to a mucous membrane can cause a burning or stinging sensation. Creams are generally in a water-rich environment (particularly for oil-in-water emulsion cream systems), where the active pharmaceutical ingredients within are exposed to hydrolyzable or pH-sensitive conditions. Oily ointments, which are generally dehydrated, provide a protective barrier to the skin but leave a greasy residue at the target site without being absorbed by themselves. Importantly, topical formulations must also meet certain regulations regarding resistance to antimicrobial or antibacterial growth.

[0010] Stable cream formulations containing tropane alkaloids have been discovered. Despite the aqueous nature of the cream formulations and the susceptibility of tropane alkaloids to hydrolytic degradation, tropane alkaloids present in the creams are chemically stable over commercially meaningful periods. It has also been found that including at least one polycyclic nucleic acid base in the cream improves the stability of the cream formulation. Furthermore, it has been found that including low molecular weight compounds improves the stability of the cream formulation. Although not bound by theory, atropine may intercalate with stabilizers and form steric hindrance around the atropine molecule, which prevents the degradation of atropine to tropic acid. In addition to forming steric hindrance around the atropine molecule, stabilizers can effectively protect the atropine molecule from E-beam irradiation. A further advantage of the tropanil creams provided herein is that they do not require common preservatives such as benzalkonium chloride or parabens to remain usable for a commercially meaningful shelf life. In addition, the cream formulation was found to confer an improved pharmacokinetic profile compared to that from other topical application formats such as eye drops.

[0011] Further cream formulations containing atropine, pilocarpine, travopost, or physostigmine are provided. It has been found that the stability of the cream formulation is improved by including one or more preservatives, at least one antioxidant distributed in a suitable phase (aqueous or oil phase) of the cream formulation, and at least one antioxidant distributed in another phase (aqueous or aqueous phase) of the cream formulation. Furthermore, as shown in Figure 20, the stability of the activator (e.g., physostigmine) in the cream formulation is also increased by pre-adjusting the pH and then mixing it with an activator such as physostigmine in the final step of the manufacturing process.

[0012] The additive process for adding antioxidants and / or preservatives depends on the solubility and API solubility / stability in their respective solvent phases (either oil or aqueous). Co-mixing or co-dissolution of antioxidants and APIs in the formulation process can enhance the stability of the finished drug and prevent the degradation of APIs during the manufacturing process.

[0013] Physostigmine is a reversible anticholinesterase that effectively increases acetylcholine concentration at cholinergic neurotransmission sites. The effects of acetylcholine are normally very transient due to its hydrolysis by the enzyme acetylcholinesterase. Physostigmine inhibits the destructive action of acetylcholinesterase, thereby prolonging and amplifying the effects of acetylcholine. Acetylcholinesterase inhibitors are widely used as insecticides to kill arthropods such as Demodex mites by enhancing cholinergic neurotransmission, leading to intermittent hyperexcitation of nerve-to-nerve and nerve-to-muscle communication, ultimately resulting in paralysis and death. The levorotatory enantiomer (negative optical isomer) of physostigmine has significantly higher efficacy (approximately 100× to 1000×) in mite killing than its positive counterpart. Advantageously, physostigmine in topical cream formulations can treat Demodex blepharitis by providing prolonged direct contact with mites at the target site compared to eye drops. Accordingly, a physostigmine salicylate-based topical cream in which physostigmine degradation is minimized is provided herein. The physostigmine-based cream formulation is physically and chemically stable for 4 months under accelerated stability conditions (e.g., 40°C and 75% relative humidity (RH)).

[0014] Physostigmine salicylate undergoes rapid degradation and oxidation in aqueous media. The degradation pathway of physostigmine salicylate in aqueous media is shown in Figure 17. Compositions and methods / processes for producing physostigmine salicylate-based topical creams with minimal physostigmine degradation are described herein. The physostigmine-based cream formulations described herein are physically and / or chemically stable for 4 months under accelerated stability conditions (e.g., 40°C and 75% RH).

[0015] definition While this disclosure is described in detail with reference to specific embodiments thereof, it will be apparent to those skilled in the art that various changes and modifications can be made without departing from the spirit and scope of this disclosure.

[0016] Any group of alternative elements or embodiments disclosed herein may be referred to and claimed individually or in any combination with other members of the group or other elements found herein.

[0017] Unless otherwise defined, all technical and scientific terms used herein are given the meanings commonly known to those skilled in the art.

[0018] Those skilled in the art will be able to recognize or verify many equivalents of the specific embodiments of the invention described herein without resorting to excessive routine experimentation. Such equivalents are intended to be covered by the following claims.

[0019] For any given term, whether used alone, as part of a phrase, or as part of another term, it is defined as follows:

[0020] The articles "a" and "an" refer to one or more of the grammatical objects to which the article is applied.

[0021] Numerical values ​​related to measurements are subject to measurement errors, which limit their accuracy. Therefore, all numerical values ​​provided herein should be understood to be modified by the term "approximately" unless otherwise indicated. Thus, the term "approximately" refers to an error of ±10%. Otherwise, the degree of accuracy is indicated by the last decimal point of the numerical values ​​provided herein. Unless other error ranges are indicated, the maximum range is determined by rounding to the last decimal point or, if the given numerical value does not have decimals, to the last significant digit.

[0022] The term "alkanalyl" refers to a branched, cyclic, linear, or combination thereof saturated hydrocarbon moiety that contains at least one aldehyde.

[0023] The term "alkanonyl" refers to a branched, cyclic, linear, or combination thereof saturated hydrocarbon moiety that contains at least one ketone.

[0024] The term "alkenalyl" refers to a branched, cyclic, linear, or combination thereof hydrocarbon moiety that contains at least one aldehyde and at least one carbon-carbon double bond.

[0025] The term "alkanolyl" refers to a saturated hydrocarbon moiety that is branched, cyclic, linear, or a combination thereof, and contains at least one hydroxyl group.

[0026] The term "alkenonyl" refers to a branched, cyclic, linear, or combination thereof hydrocarbon moiety that contains at least one ketone and at least one carbon-carbon double bond.

[0027] The term "alkenyl" refers to a branched, cyclic, linear, or combination thereof hydrocarbon portion that contains at least one carbon-carbon double bond.

[0028] The term "alkyl" refers to a saturated hydrocarbon moiety that is branched, cyclic, linear, or a combination thereof.

[0029] The term "halo" refers to halogens.

[0030] The term "remission" means a reduction in the severity of at least one indicator of a condition or disease, such as a delay or slowing of the progression of one or more indicators of the condition or disease. The severity of an indicator may be determined by subjective or objective scales known to those skilled in the art.

[0031] "C ek The term "molecular" refers to a part containing e~k carbon atoms, where e and k are integers.

[0032] The terms “effective dose” and “therapeutic effective dose” refer to the amount of an active ingredient, such as a compound described herein, administered to a subject as a single dose or as part of a series of doses, that produces the desired effect. Generally, the effective dose can be estimated first in a cell culture assay or in a mammalian animal model, such as a non-human primate, mouse, rabbit, dog, or pig. Animal models may also be used to determine appropriate concentration ranges and routes of administration. Such information can then be used to determine doses and routes useful for administration to non-human and human subjects.

[0033] The terms “cream” and “medicinal cream” refer to a mixture of at least one active pharmaceutical ingredient as described herein and a pharmaceutically acceptable carrier. A medicinal cream facilitates the administration of at least one active pharmaceutical ingredient to a patient or subject.

[0034] The term “pharmaceutically acceptable carrier” means a pharmaceutically acceptable material, composition, or carrier, such as a liquid filler, solid filler, stabilizer, dispersant, suspending agent, diluent, excipient, thickener, solvent, or encapsulating material, that is involved in transporting or delivering at least one of the active pharmaceutical ingredients described herein into or to a patient so that the active pharmaceutical ingredient can perform its intended function. A given carrier must be “acceptable” in the sense that it is compatible with other components of a particular cream formulation containing the active pharmaceutical ingredient described herein and is not harmful to the patient. Other components that may be included in the medicinal creams described herein are known in the art, for example, as described in “Remington's Pharmaceutical Sciences” (Genaro (Ed.), Mack Publishing Co., 1985), the entire contents of which are incorporated herein by reference.

[0035] The term “pharmaceutically acceptable salt” refers to a derivative of a disclosed compound modified by converting an existing acidic or base moiety of the parent compound into its salt form. Pharmaceutically acceptable salts can be synthesized from parent compounds containing a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acidic or base form of these compounds with a stoichiometric amount of a suitable base or acid in water, an organic solvent, or a mixture of two solvents. A list of suitable salts can be found in “Handbook of Pharmaceutical Salts: Properties, Selection, and Use” (P. Henrich Stahl & Camille G. Wermuth (Eds.), VHCA & Wiley-VCH, 2002), the entire contents of which are incorporated herein by reference. References to any type or class of compounds herein should be understood to include pharmaceutically acceptable salts of that compound.

[0036] The term "refractory disease" refers to a disease that continues to progress during treatment with medicinal ingredients other than the active medicinal ingredients provided herein, or that responds partially or transiently to other treatments. This term may apply to each of the diseases referred to herein.

[0037] The terms "treatment" or "treating" refer to the application of one or more specific procedures used to bring a disease into remission. "Prophylactic" treatment refers to slowing the progression of the treated disease or condition, delaying its onset, or reducing the severity of its onset.

[0038] The enumeration of value ranges in this specification is intended solely as a concise way to refer individually to each of the distinct values ​​contained within that range. Unless otherwise indicated herein, each of the individual values ​​is incorporated herein as if it were individually enumerated. All methods described herein may be carried out in any preferred order unless otherwise indicated herein or unless it is clearly inconsistent with the context. Any examples or illustrative language provided herein (e.g., "such as") is intended solely to better illustrate the subject matter described herein and, unless otherwise claimed, does not impose any limitation on the scope of the subject matter. No language in this specification should be construed as indicating that any non-claimed element is essential to the carrying out of the subject matter described herein.

[0039] The grouping of alternative elements or embodiments of this disclosure should not be construed as limitation. Members of each group may be referred to and claimed individually or in any combination with other members of the group or other elements found herein. Furthermore, enumerated members of a group may be included in or excluded from another enumerated group for convenience or patentability reasons.

[0040] Where references are made in this Specified Publication to patent documents or other publications, the entire contents of such documents or publications shall be incorporated herein by reference.

[0041] The embodiments described herein are illustrative; therefore, this disclosure is not strictly limited to those shown or described.

[0042] composition In some embodiments, certain compositions that may be pharmaceutical compositions suitable for therapeutic use are provided herein. The compositions may comprise one or more pharmaceutically acceptable carriers.

[0043] Accordingly, in some embodiments, compositions comprising one or more purified tropane alkaloids or pharmaceutically acceptable salts thereof; and one or more purified polycyclic nucleic acid bases or pharmaceutically acceptable salts thereof are provided herein. Such tropane alkaloids and polycyclic nucleic acid bases are described further below. In some embodiments, the composition comprises two different purified tropane alkaloids or pharmaceutically acceptable salts thereof and one, two or three purified polycyclic nucleic acid bases or pharmaceutically acceptable salts thereof. In some embodiments, the pharmaceutical composition may be provided as a pharmaceutical cream.

[0044] In some embodiments, topical formulations comprising an active pharmaceutical ingredient containing a tropanil group are provided herein. In some embodiments, the topical formulation is an ophthalmic formulation. In some embodiments, the topical formulation is a gel, lotion, or cream.

[0045] In some embodiments, the topical formulation has a viscosity in the range of about 2,000 to about 200,000 centipoise (cP). In some embodiments, the topical formulation has a viscosity in the range of about 2,000 to about 70,000 centipoise (cP). In some embodiments, the topical formulation has a viscosity in the range of about 2,000 to about 50,000 centipoise (cP). In some embodiments, the topical formulation has a viscosity in the range of about 10,000 to about 75,000 centipoise (cP). In some embodiments, the topical formulation has a viscosity in the range of about 10,000 to about 50,000 centipoise (cP). In some embodiments, the topical formulation has a viscosity in the range of about 10,000 to about 25,000 centipoise (cP). In some embodiments, the topical formulation has a viscosity in the range of about 25,000 to about 200,000 centipoise (cP). In some embodiments, the topical formulation has a viscosity in the range of about 25,000 to about 75,000 centipoise (cP). In some embodiments, the topical formulation is an oil-in-water (o / w) formulation.

[0046] Creams, gels, and lotions Formulations have been discovered to mitigate the hydrolysis of tropane alkaloids to their corresponding hydrolysis products (including tropines, etc.). Thus, formulations that remain physically and chemically stable even when continuously exposed to storage conditions associated with commercial production, distribution, and consumer use, such as creams, gels, or lotions, have been discovered. These formulations are useful for enabling and facilitating the penetration of tropane alkaloids from a cream into the skin of a subject or patient, and subsequently delivering them to target tissues in the subcutaneous layers. In some embodiments, the target tissue may include a portion of the subject's skin, blood vessels, or ultimately systemic distribution through the vascular system. In some embodiments, the target tissue may be the eye or related anatomical structures of the eye, and this includes topical application thereto.

[0047] Accordingly, in some embodiments, gel formulations comprising an active pharmaceutical ingredient including a tropanil moiety are provided herein. In some embodiments, lotion formulations comprising an active pharmaceutical ingredient including a tropanil moiety are provided herein. In some embodiments, cream formulations comprising an active pharmaceutical ingredient including a tropanil moiety are provided herein. In some embodiments, the cream is an oil-in-water (o / w) emulsion cream, where the cream contains at least 50 or at least 60% w / w water. In some embodiments, cream formulations comprising an active pharmaceutical ingredient including a tropane alkaloid are provided herein. In some embodiments, the tropane alkaloid is contained in the oil phase of the oil-in-water emulsion, which, although not bound by theory, may mitigate hydrolysis or chemical decomposition of the tropane alkaloid. In some embodiments, cream formulations comprising an active pharmaceutical ingredient including a tropinyl moiety are provided herein. In some embodiments, the active pharmaceutical ingredient comprising a tropanil moiety, a tropinyl moiety, or a tropane alkaloid is an anticholinergic compound. Anticholinergics and cholinergics generally have opposite effects on the target organism, as the former blocks the action of acetylcholine and the latter mimics the action of acetylcholine. For example, anticholinergics may suppress saliva secretion or sweating, while cholinergics may promote saliva secretion or sweating. In some embodiments, the active pharmaceutical ingredient is atropine, benzatropine, cocaine, homatropine, hyoscyamine, scopolamine, tiotropium, tropisetron, or trospium, or a pharmaceutically acceptable salt thereof.

[0048] [ka]

[0049] In some embodiments, cream formulations containing atropine as an active pharmaceutical ingredient are provided herein. In some embodiments, gel formulations containing atropine as an active pharmaceutical ingredient are provided herein. In some embodiments, lotion formulations containing atropine as an active pharmaceutical ingredient are provided herein.

[0050] [ka] (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 3-hydroxy-2-phenylpropanoate (atropine)

[0051] In some embodiments, the gel, ointment, lotion, or cream formulation comprises atropine, wherein the atropine comprises more than 50% (by weight) of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl(S)-3-hydroxy-2-phenylpropanoate. In some embodiments, the gel, ointment, lotion, or cream formulation comprises atropine, wherein the atropine comprises less than 10% (by weight) of (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-yl(S)-3-hydroxy-2-phenylpropanoate.

[0052] In some embodiments, the gel, ointment, lotion, or cream formulation further comprises caffeine or a derivative thereof. In some such embodiments, caffeine or a derivative thereof may serve as a chemical stabilizer and / or emollient.

[0053] In some embodiments, the gel, ointment, lotion, or cream formulation further comprises a polycyclic nucleic acid base or a pharmaceutically acceptable salt thereof. In some embodiments, the nucleic acid base is a bicyclic or tricyclic nucleic acid base. In some embodiments, the gel, ointment, lotion, or cream formulation further comprises a heterocyclic compound having nine or more ring atoms. In some embodiments, the nine ring atoms contain at least five carbon atoms. In some embodiments, the nine ring atoms contain at least three nitrogen atoms. In some embodiments, the nine ring atoms contain four nitrogen atoms. In some embodiments, the heterocyclic compound is an aromatic heterocyclic compound comprising fused six-membered and five-membered ring systems. In some embodiments, the heterocyclic compound is a purine compound. In some embodiments, the heterocyclic compound is an oxo-purine (e.g., 8-oxo-purine) compound. In some embodiments, the heterocyclic compound is a halo-purine compound. In some embodiments, the heterocyclic compound is a thio-purine compound. In some embodiments, the heterocyclic compound is methylpurine or 8-oxomethylpurine. In some embodiments, the heterocyclic compound is monomethylpurine, 8-oxo-monomethylpurine, dimethylpurine, 8-oxo-dimethylpurine, trimethylpurine, or 8-oxo-trimethylpurine compound.In some embodiments, the purine compound is azathioprine, adenine, 2-aminopurine, 2,6-diaminopurine, 2,6,8-triaminopurine, 2-amino-6-methoxy-purine, 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.

[0054] In some embodiments, the heterocyclic compound has the following formula: [Chemical formula] [where [Chemical formula] each of which is independently a single bond or a double bond; each of m, n, p, w, x, y, and z is independently 0 or 1; R 1 、R 3 、R 7 、and R 9 each of which is independently H, C 1-6 alkyl, C 1-6 alkanoyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-8 alkanaryl, C 3-8 alkenaryl, C 2-8 alkanonyl, or C 4-8 alkenonyl; R 2 、R 6 、and R8 Each of these is independently H, Halo, O-(C) 1-3 Alkyl), NH2, N(H)(C 1-3 Alkyl), N(C 1-3 Alkyl)(C 1-3 [Alkyl, S, or O] or a pharmaceutically acceptable salt thereof.

[0055] In some embodiments:R 1 , R 3 , R 7 , and R 9 Each of these is independently H or C 1-3 It is alkyl; R 2 , R 6 , and R 8 Each of these is independently H, F, Cl, NH2, OCH3, N(H)(C) 1-3 Alkyl), N(C 1-3 Alkyl)(C 1-3 It is alkyl), S, or O. In some embodiments of the formula of the heterocyclic compound, each alkyl is independently methyl, ethyl, propyl, or isopropyl.

[0056] In some embodiments, halo refers to F, Cl, or I. In some embodiments, the haloalkyl moiety may be mono-, di-, tri-, tetra-, penta-, or hexa-haloalkyl, where each halogen is independently selected from F or Cl. In some embodiments, the haloalkyl moiety includes CFH2, CF2H, CF3, C2FH4, C2F2H3, C2F3H2, C2F4H, or CF5 moiety, or combinations thereof.

[0057] In some embodiments of the formula of the heterocyclic compound, R 1 , R 3 , R 7 , and R 9 Each of them is independently H or methyl. In some embodiments, R 1 is H or C 1-3 When it is alkyl (for example, methyl), [ka] It is a single bond. In some embodiments, R 3 is H or C 1-3 When it is alkyl (for example, methyl), [ka] It is a single bond. In some embodiments, R 7 is H or C 1-3 When it is alkyl (for example, methyl), [ka] It is a single bond. In some embodiments, R 9 is H or C 1-3 When it is alkyl (for example, methyl), [ka] It is a single bond.

[0058] In some embodiments, when m is 0, [ka] This is a double bond. In some embodiments, when p is 0, [ka] This is a double bond. In some embodiments, when x is 0, [ka] This is a double bond. In some embodiments, when z is 0, [ka] It is a double bond.

[0059] In some embodiments, R 2 , R 6 , and R 8 Each of these is independently H, NH2, S, or O. In some embodiments, R 2 When is S or O, [ka] It is a double bond, [ka] It is a single bond. In some embodiments, R 6 When is S or O, [ka] It is a double bond, [ka] It is a single bond. In some embodiments, R 8 When is S or O, [ka] It is a double bond, [ka] It is a single bond, [ka] It is a single bond.

[0060] In some embodiments, the gel, ointment, lotion, or cream formulations herein are physically and chemically stable, and their stability lasts for a commercially meaningful period of time, including at least three months, up to six months, or longer. Example 2 illustrates such stability.

[0061] In some embodiments, low molecular weight (LMW) compounds having one or more aromatic rings or compounds having a conjugated structure may be included in the formulation. These LMW compounds, which may include histidine, sorbic acid (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), may be used as stabilizers to stabilize (or contribute to the stabilization of) the active pharmaceutical ingredient (API) in the cream formulation. The chemical structures of histidine and sorbic acid are shown below. In some embodiments, the pK of the atropine stabilizer is used. a The pH is similar to the desired pH of the atropine-containing gel, ointment, lotion, or cream formulation (e.g., about 3 to about 6 pK). a ). As just one example, but not limited to, the pK of sorbic acid a The pH is approximately 4.76, and the pH of gel, ointment, lotion, or cream formulations may be approximately 4.80. In some embodiments, sorbic acid may be a free acid. In some embodiments, sorbic acid may be a salt. In some embodiments, sorbic acid stabilizes atropine in cream formulations as shown in Table 8 herein; the same applies to gel or lotion formulations. Advantageously, sorbic acid and its salts are inexpensive alternatives to other stabilizers such as histidine, and are therefore commercially beneficial.

[0062] [ka]

[0063] In some embodiments, several LMW compounds, such as sinapic acid, α-cyano-4-hydroxycinnamic acid (HCCA), 4-chloro-α-cyanocinnamic acid, and their pharmaceutically acceptable salt forms (i.e., sodium, potassium, ammonium, magnesium, and / or calcium), may be used as chemical stabilizers to stabilize APIs in gel, ointment, lotion, or cream formulations. The chemical structure of HCCA is shown below.

[0064] [ka]

[0065] In some embodiments, the stabilizer may be an LMW compound having one or more aromatic ring structures without carboxylic acid functional groups. These compounds can be used as chemical stabilizers to stabilize APIs in cream formulations. One such compound is ditranol, which is shown below.

[0066] [ka]

[0067] In some embodiments, the LMW compound has a molecular weight of approximately 50 g / mol to approximately 1000 g / mol, approximately 75 g / mol to approximately 900 g / mol, approximately 100 g / mol to approximately 800 g / mol, approximately 125 g / mol to approximately 700 g / mol, approximately 150 g / mol to approximately 600 g / mol, approximately 175 g / mol to approximately 500 g / mol, approximately 200 g / mol to approximately 400 g / mol, or approximately 225 g / mol to approximately 300 g / mol.

[0068] In some embodiments, the gel, ointment, lotion, or cream formulation may further comprise at least one low molecular weight compound or a pharmaceutically acceptable salt thereof. The at least one low molecular weight compound may comprise one or more aromatic ring structures. The LMW compound may exist as a salt comprising a salt selected from sodium, potassium, ammonium, magnesium, and calcium salts, or a combination thereof.

[0069] In some embodiments, at least one low molecular weight compound or a pharmaceutically acceptable salt thereof stabilizes the active pharmaceutical ingredient (API) in the cream formulation.

[0070] In some embodiments, at least one low molecular weight compound includes caffeine, benzoic acid, sinapic acid, α-cyano-4-hydroxycinnamic acid, histidine or ditranol, or a pharmaceutically acceptable salt thereof, or a combination thereof. In some embodiments, at least one low molecular weight compound includes benzoic acid, sinapic acid, α-cyano-4-hydroxycinnamic acid, histidine or ditranol, or a pharmaceutically acceptable salt thereof, or a combination thereof. In some embodiments, at least one low molecular weight compound is caffeine. In some embodiments, at least one low molecular weight compound is histidine. In some embodiments, at least one low molecular weight compound is α-cyano-4-hydroxycinnamic acid.

[0071] In some embodiments of the gel, ointment, lotion, or cream formulation, at least one low molecular weight compound is present in the gel, ointment, lotion, or cream formulation in an amount of about 0.01% to about 1% w / w.

[0072] In some embodiments of the gel, ointment, lotion, or cream formulation, at least one low molecular weight compound is present in the gel, ointment, lotion, or cream formulation in an amount of about 0.05% to about 0.7% w / w.

[0073] In some embodiments, the gel, ointment, lotion, or cream formulation contains about 0.01 to about 2.5% w / w tropane alkaloid or a pharmaceutically acceptable salt thereof. In some embodiments, the gel, ointment, lotion, or cream formulation contains about 0.05 to about 2.5% w / w tropane alkaloid or a pharmaceutically acceptable salt thereof. In some embodiments, the gel, ointment, lotion, or cream formulation contains one or more tropane alkaloids or a pharmaceutically acceptable salt thereof in any range between about 0.01, 0.05, 0.1, 0.15, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.5, or 2.5% w / w, or any range in between. In some embodiments, one or more tropane alkaloids or pharmaceutically acceptable salts thereof are, independently, atropine, benzatropine, cocaine, homatropine, hyoscyamine, scopolamine, tiotropium, tropisetron, or trospium, or pharmaceutically acceptable salts thereof. In some embodiments, the tropane alkaloid or pharmaceutically acceptable salt thereof is atropine sulfate. In some embodiments, the gels, lotions, or creams herein contain about 0.01, 0.05, 0.08, 0.15, 0.5, or 1% w / w of atropine sulfate. When used herein, the % w / w of atropine is calculated based on the free base, regardless of the salt form used in the gel, ointment, lotion, or cream formulation.

[0074] In some embodiments, the gel, ointment, lotion, or cream formulations described herein may contain about 0.01 to about 0.3% w / w of polycyclic nucleic acid bases or pharmaceutically acceptable salts thereof. In some embodiments, the gel, ointment, lotion, or cream formulations described herein may contain about 0.05 to about 0.3% w / w of polycyclic nucleic acid bases or pharmaceutically acceptable salts thereof. In some embodiments, the gel, lotion, or cream formulations described herein may contain about 0.1 to about 0.2% w / w of polycyclic nucleic acid bases or pharmaceutically acceptable salts thereof. In some embodiments, the gel, lotion, or cream contains about 0.16% w / w of 1,3,7-trimethylxanthine. In some embodiments, the gel, ointment, lotion, or cream formulation is polycyclic nucleic acid base-free (for example, the cream does not contain polycyclic nucleic acid bases or pharmaceutically acceptable salts thereof, for example, the gel, lotion, or cream does not contain 1,3,7-trimethylxanthine).

[0075] In some embodiments, the gel, ointment, lotion, or cream formulation comprises about 0.0005 to about 0.001% w / w of polyquaternium-1 or a pharmaceutically acceptable salt thereof, and about 0.00025 to about 0.0005% w / w of alexidine or a pharmaceutically acceptable salt thereof, wherein the gel, ointment, lotion, or cream formulation is otherwise preservative-free, and optionally contains an active pharmaceutical ingredient.

[0076] In some embodiments, the gel, ointment, lotion, or cream formulation contains a stabilizer selected from histidine, sorbic acid, or alpha-cinnamic acid, or a pharmaceutically acceptable salt thereof, about 0.0005 to about 0.001% w / w of polyquaternium-1 or a pharmaceutically acceptable salt thereof, and about 0.00025 to about 0.0005% w / w of alexidine or a pharmaceutically acceptable salt thereof, wherein the gel, ointment, lotion, or cream formulation is otherwise preservative-free, and the cream formulation optionally contains an active pharmaceutical ingredient.

[0077] In some embodiments, the gels, lotions, or creams provided herein contain less than about 0.25% w / w of preservatives. In some embodiments, the creams provided herein contain one or more preservatives at about 0.002% w / w or less. In some embodiments, the preservatives include parabens but do not include benzalkonium chloride (BAK). In some embodiments, the creams provided herein are BAK-free (i.e., BAK-free) or paraben-free (i.e., methylparaben, ethylparaben, propylparaben, and butylparaben). In some embodiments, the creams provided herein contain about 0.001 to about 0.003% w / w of preservatives. In some embodiments, the gels, lotions, or creams provided herein contain about 0.002% w / w preservatives, where the preservatives include biguanide compounds (e.g., alexidine or a pharmaceutically acceptable salt thereof) and polyquaternium compounds (e.g., polyquaternium-1 or a pharmaceutically acceptable salt thereof (PQ-1)). In some embodiments, the gels, lotions, or creams provided herein contain one or more preservatives in about 0.0015% w / w or less. In some embodiments, the gels, lotions, or creams provided herein contain about 0.001% w / w PQ-1, about 0.0005% w / w alexidine or a pharmaceutically acceptable salt thereof, and zero% w / w parabens. In some embodiments, the gels, lotions, or creams provided herein contain about 0.0005% w / w (e.g., about 5 PPM) of PQ-1, about 0.00025% w / w (e.g., about 2.5 ppm) of alexidine or a pharmaceutically acceptable salt thereof, and zero% w / w parabens. In some embodiments, the gels, lotions, or creams each contain PQ-1 and alexidine or a pharmaceutically acceptable salt thereof in a ratio of about 2:1.

[0078] In some embodiments, the gel, lotion, or cream contains a first pharmaceutically acceptable carrier, which is a copolymer of acrylamide and sodium acryloyldimethyltaurate, isohexadecane, and polysorbate 80, a component of a product marketed as SEPINEO® P-600. In some embodiments, the first pharmaceutically acceptable carrier is present in an amount of about 0.5 to about 2% w / w, for example, about 1% w / w. In some embodiments, the gel, lotion, or cream contains a second pharmaceutically acceptable carrier, which is a polymer of acrylic acid crosslinked with one or more allyl ethers of polyalcohols, a component of a product marketed as a carbomer homopolymer. In some embodiments, the second pharmaceutically acceptable carrier is present in an amount of about 1 to about 3% w / w, for example, about 2% w / w.

[0079] As used herein, carbomer refers to polyacrylic acid polymer. Carbomer may also be referred to as CARBOPOL®. CARBOPOL® 980 refers to an excipient marketed by Lubrizol, for example, with Chemical Information Retrieval Service Registration Number (CAS RN) 139637-85-7. CARBOPOL® 980 is described by Lubrizol as a homopolymer of acrylic acid crosslinked with allyl cellulose or allyl pentaerythritol, prepared using ethyl acetate and cyclohexane as a cosolvent system, having a viscosity cP of 40,000 to 60,000 (0.5 wt%) at pH 7.5. Other homopolymers, including but not limited to the CARBOPOL® polymers in the table below, are envisioned within the scope of the embodiments presented herein. Carbomer homopolymer type C refers to allyl pentaerythritol crosslinked polyacrylic acid.

[0080] [Table 1]

[0081] As used herein, SEPINEO® P600 refers to the copolymer sold by Seppic, for example, and is associated with CAS RN 38193-60-1 (3 components, acrylamide-sodium 2-acrylamide-2-methylpropanesulfonate copolymer) / 93685-80-04 (isohexadecane) / 9005-65-6 (polyoxyethylene sorbitan monooleate). SEPINEO® P600 is described by Seppic as a polymer of acrylamide / sodium acryloyldimethyltaurate copolymer / isohexadecane and polysorbate 80.

[0082] In some embodiments, the gel, lotion, or cream has a pH between approximately 2.5 and 7 pK a The buffer comprises a buffer having a pK of about 3, 4, 5, 6, or 7, or any range in between. In some embodiments, the buffer comprises a buffer having a pK of at least one pK of about 3, 4, 5, 6, or 7. a This includes. In some embodiments, the buffer has a pH of at least one pK between approximately 3 and 6.5. a This includes. In some embodiments, the buffer is citrate or citrate buffer. In some embodiments, the buffer concentration is present in the cream at about 0.05% to about 5% w / w. In some embodiments, the gel, ointment, lotion, or cream formulation contains about 20% w / w to about 70% w / w water. In some embodiments, the gel, lotion, or cream contains about 0.01% w / w to about 0.5% w / w sodium citrate, potassium citrate, magnesium citrate, or citrate buffer. In some embodiments, the gel, lotion, or cream contains about 0.05% w / w to about 0.5% w / w sodium citrate, potassium citrate, magnesium citrate, or citrate buffer.

[0083] In some embodiments, the pH of the cream is approximately 4 to approximately 6, for example, approximately 5, for example, approximately 4.5, 4.6, 4.7, 4.8, or 4.9. In some embodiments, the pH of the gel, lotion, or cream is approximately 4.5 to approximately 5.

[0084] In some embodiments, the gel, lotion, or cream contains a molar ratio of a tropane alkaloid or a pharmaceutically acceptable salt thereof to a polycyclic nucleic acid base or a pharmaceutically acceptable salt thereof, about (4-5):1, for example, about 4.2:1.

[0085] Therefore, in some embodiments, the gel, ointment, lotion, or cream formulation is Approximately 0.01 to approximately 2.5% w / w tropane alkaloids or their pharmaceutically acceptable salts; and Contains one or more preservatives in an amount of approximately 0.002% w / w to 0.5% w / w.

[0086] Therefore, in some embodiments, the gel, ointment, lotion, or cream formulation is Approximately 0.01 to 2.5% w / w tropane alkaloids or their pharmaceutically acceptable salts; One or more preservatives at approximately 0.002% w / w or less; A first pharmaceutically acceptable carrier, comprising a copolymer of acrylamide and sodium acryloyldimethyltaurate, isohexadecane, and polysorbate 80, present at approximately 0.5 to approximately 2% w / w; A second pharmaceutically acceptable carrier, which is a polymer of acrylic acid crosslinked with one or more allyl ethers of polyalcohols, present at about 1 to about 3% w / w; and Approximately 0.01 to 5% w / w, with pK values ​​between approximately 2.5 and 7. a Buffer containing Includes; Herein, the gel, ointment, lotion, or cream formulation optionally contains about 0.05 to about 0.3% w / w of polycyclic nucleic acid bases or pharmaceutically acceptable salts thereof.

[0087] In some embodiments of the methods described herein, the gel, ointment, lotion, or cream formulation is: Approximately 0.05 to 2.5% w / w tropane alkaloids or their pharmaceutically acceptable salts; One or more preservatives at approximately 0.25% w / w or less; A first pharmaceutically acceptable carrier, comprising a copolymer of acrylamide and sodium acryloyldimethyltaurate, isohexadecane, and polysorbate 80, present at approximately 0.5 to approximately 2% w / w; A second pharmaceutically acceptable carrier, which is a polymer of acrylic acid crosslinked with one or more allyl ethers of polyalcohols, present at about 1 to about 3% w / w; and Approximately 0.01 to 5% w / w, with pK values ​​between approximately 2.5 and 7. a Buffer containing Includes; Herein, the gel, ointment, lotion, or cream formulation optionally contains about 0.01 to about 0.3% w / w of polycyclic nucleic acid bases or pharmaceutically acceptable salts thereof.

[0088] In some embodiments, the gel, ointment, lotion, or cream formulation contains 0.01%, 0.03%, 0.05%, 0.08%, about 0.15%, about 0.5%, or about 1% w / w tropane alkaloids or pharmaceutically acceptable salts thereof; zero or about 0.1%, 0.15%, 0.16%, 0.17%, or 0.2% w / w polycyclic nucleic acid bases or pharmaceutically acceptable salts thereof; a first pharmaceutically acceptable carrier of about 1% w / w, which is a copolymer of acrylamide and sodium acryloyldimethyltaurate, isohexadecane, and polysorbate 80; a second pharmaceutically acceptable carrier of about 2% w / w, which is a polymer of acrylic acid crosslinked with one or more allyl ethers of polyalcohols; and a pH of about 4.5 to about 5.0 (e.g., about 4.7 to about 4.8, e.g., about 4.75).

[0089] In some embodiments, the gel, ointment, lotion, or cream formulation contains about 0.01%, 0.03%, 0.05%, 0.08%, or 0.15% w / w atropine sulfate; about 0.16% w / w caffeine; about 1% w / w first pharmaceutically acceptable carrier, which is a copolymer of acrylamide and sodium acryloyldimethyltaurate, isohexadecane, and polysorbate 80; about 2% w / w second pharmaceutically acceptable carrier, which is a polymer of acrylic acid crosslinked with one or more allyl ethers of polyalcohols; and a pH of about 4.5 to about 5.0 (e.g., about 4.7 to about 4.8, e.g., about 4.75).

[0090] In some embodiments, the gel, ointment, lotion, or cream formulation comprises about 1% w / w atropine sulfate; about 0.16% w / w caffeine; about 1% w / w a first pharmaceutically acceptable carrier, which is a copolymer of acrylamide and sodium acryloyldimethyltaurate, isohexadecane, and polysorbate 80; about 2% w / w a second pharmaceutically acceptable carrier, which is a polymer of acrylic acid crosslinked with one or more allyl ethers of polyalcohols; and a pH of about 4.5 to about 5.0 (e.g., about 4.7 to about 4.8, e.g., about 4.75).

[0091] In some embodiments, the gel, ointment, lotion, or cream formulation comprises about 0.15% w / w atropine sulfate; zero% w / w polycyclic nucleic acid bases or pharmaceutically acceptable salts thereof (e.g., caffeine); about 1% w / w of a first pharmaceutically acceptable carrier, which is a copolymer of acrylamide and sodium acryloyldimethyltaurate, isohexadecane, and polysorbate 80; about 2% w / w of a second pharmaceutically acceptable carrier, which is a polymer of acrylic acid crosslinked with one or more allyl ethers of polyalcohols; and a pH of about 4.5 to about 5.0 (e.g., about 4.7 to about 4.8, e.g., about 4.75).

[0092] In some embodiments, the gel, ointment, lotion, or cream formulation comprises about 0.5% w / w atropine sulfate; zero% w / w polycyclic nucleic acid bases or pharmaceutically acceptable salts thereof (e.g., caffeine); about 1% w / w of a first pharmaceutically acceptable carrier, which is a copolymer of acrylamide and sodium acryloyldimethyltaurate, isohexadecane, and polysorbate 80; about 2% w / w of a second pharmaceutically acceptable carrier, which is a polymer of acrylic acid crosslinked with one or more allyl ethers of polyalcohols; and a pH of about 4.5 to about 5.0 (e.g., about 4.7 to about 4.8, e.g., about 4.75).

[0093] In some embodiments, the gel, ointment, lotion, or cream formulation comprises about 0.5% w / w atropine sulfate; zero% w / w polycyclic nucleic acid bases or pharmaceutically acceptable salts thereof (e.g., caffeine); zero% w / w parabens; about 1% w / w of a first pharmaceutically acceptable carrier, which is a copolymer of acrylamide and sodium acryloyldimethyltaurate, isohexadecane, and polysorbate 80; about 2% w / w of a second pharmaceutically acceptable carrier, which is a polymer of acrylic acid crosslinked with one or more allyl ethers of polyalcohols; and a pH of about 4.5 to about 5.0 (e.g., about 4.7 to about 4.8, e.g., about 4.75).

[0094] In some embodiments, the gel, ointment, lotion, or cream formulation contains about 5 to about 7% w / w (e.g., about 6% w / w) of sugar alcohol. In some embodiments, the sugar alcohol is sorbitol.

[0095] In some embodiments, the gel, ointment, lotion, or cream formulation contains about 1 to about 3% w / w (e.g., about 2% w / w) of a first nonionic surfactant. In some embodiments, the first nonionic surfactant is polysorbate 80.

[0096] In some embodiments, the gel, ointment, lotion, or cream formulation contains about 0.01 to about 0.5% w / w (e.g., about 0.2% w / w) of a metal chelating agent. In some embodiments, the metal chelating agent is ethylenediaminetetraacetic acid (EDTA).

[0097] In some embodiments, gel, ointment, lotion, or cream formulations are provided herein that contain an active pharmaceutical ingredient comprising a tropanil group (e.g., atropine), pilocarpine, travoprost, donepezil, or physostigmine.

[0098] In some embodiments, the gel, ointment, lotion, or cream formulation contains a water content of about 20% to about 31% w / w. In some embodiments, the gel, ointment, lotion, or cream formulation contains a water content of about 20% to about 25% w / w. In some embodiments, the gel, ointment, lotion, or cream formulation contains a water content of about 31% w / w or less. In some embodiments, the gel, ointment, lotion, or cream formulation contains a water content of at least about 15% w / w.

[0099] 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.

[0100] In some embodiments, the gel, ointment, lotion, or cream formulation comprises a viscosity modifier selected from a copolymer of acrylamide and sodium acryloyldimethyltaurate, isohexadecane, and polysorbate 80 (SEPINEO® P600); or cross-linked polyacrylic acid (carbomer, e.g., CARBOPOL® 980); or a combination thereof.

[0101] 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 parabens (e.g., methylparaben, propylparaben), bis-biguanides (e.g., alexidine), or polyquaternium-1, or a combination thereof. In some embodiments, the at least one antioxidant is selected from butylated hydroxyanisole (BHA), ascorbic acid palmitate, or a combination thereof.

[0102] In some embodiments, the gel, ointment, lotion, or cream formulation is A cosolvent selected from diethylene glycol monoethyl ether (Transcutol®) or propylene glycol, or a combination thereof, in an amount of approximately 1% to approximately 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 approximately 8.5% to approximately 10% w / w; Mineral oil in an amount of approximately 8% to 12% w / w; Approximately 4% to 8% w / w of glycerin; At least one preservative in an amount of approximately 0.01 to approximately 0.05% w / w; and Contains at least one antioxidant in an amount of approximately 0.02% to 0.06% w / w.

[0103] In some embodiments, the gel, ointment, lotion, or cream formulation contains about 1 to about 3% w / w (e.g., about 2% w / w) of polyether. In some embodiments, the polyether is polyethylene glycol (PEG). In some embodiments, the polyether or PEG has an average molar mass of about at least 2,000, 4,000, 6,000, 8,000, 10,000, or 20,000 g / mol. In some embodiments, the PEG is PEG 8000.

[0104] In some embodiments, the gel, ointment, lotion, or cream formulation contains about 3 to about 6% w / w of the diol (e.g., about 4 to about 5% w / w, e.g., about 4.4% w / w). In some embodiments, the diol has a molar mass of about 200 g / mol or less. In some embodiments, the diol is propylene glycol.

[0105] In some embodiments, the gel, ointment, lotion, or cream formulation contains about 5 to about 15% w / w of oil (e.g., about 8 to about 12% w / w, e.g., about 9, 10, or 11% w / w). In some embodiments, the oil is mineral oil.

[0106] In some embodiments, the gel, ointment, lotion, or cream formulation contains about 3 to about 7% w / w (e.g., about 4 to about 6% w / w, e.g., about 5% w / w) of a second nonionic surfactant. In some embodiments, the second nonionic surfactant is PEGylated castor oil (e.g., the second nonionic surfactant contains PEGylated glycerol and ricinoleic acid triesters). In some embodiments, the second nonionic surfactant is polyoxyl 35 castor oil.

[0107] In some embodiments, the gel, ointment, lotion, or cream formulation contains about 0.3 to about 0.7% w / w (e.g., about 0.4 to about 0.6% w / w, e.g., about 0.5% w / w) of aliphatic alcohols. In some embodiments, the aliphatic alcohol is C 4-30 Alcohol, for example, C 6-24 Alcohol, for example, C 16-18 It is an alcohol. In some embodiments, the aliphatic alcohol is C 4-30 Alkyl-OH compounds or C 4-30 Alkenyl-OH compounds, for example, C 6-24 alkyl-OH, for example, C 16-18 Alkyl-OH, or C 6-24 Alkenyl-OH, for example, C 16-18It is an alkenyl-OH group. In some embodiments, the aliphatic alcohol is a cetyl alcohol.

[0108] In some embodiments, the gel, ointment, lotion, or cream formulation includes cream formulations 1, 2, 3, 4, or 5, as shown in Table 1 of Example 1.

[0109] In some embodiments, the cream formulation includes cream formulations 6, 7, 8, 9, 10, or 11 as shown in Table 3 of Example 4. In some embodiments, the cream formulation includes cream formulations 12, 13, or 14 as shown in Table 4 of Example 6. In some embodiments, the cream formulation includes cream formulations 17, 18, 19, 20, or 21 as shown in Table 7 of Example 6. In some embodiments, the cream formulation includes creams PHY012, PHY038, PHY039, PHY040, PHY041, PHY042, PHY048, PHY049, PHY050, or PHY052 as shown in Table 14 of Example 13.

[0110] In some embodiments, the gels, lotions, or creams provided herein may contain about 5.0% w / w or less of tropic acid, about 0.2% w / w or less of 7-hydroxyhyoscyamine, about 0.2% w / w or less of scopolamine, about 0.2% w / w or less of 6-hydroxyhyoscyamine, about 0.3% w / w or less of hyoscyamine-related compound A (norhyoscyamine), about 0.5% w / w or less of litrin, or about 0.2% w / w or less of apoatropine, or a combination thereof.

[0111] In some embodiments, the gels, lotions, or creams provided herein have an apparent viscosity of about 50 k to about 200 k centipoise (cps).

[0112] A method for manufacturing a gel, lotion, or cream containing an active pharmaceutical product, 1) A step of preparing an aqueous phase comprising water, polysorbate 80, and a copolymer of acrylamide and sodium acryloyldimethyltaurate, isohexadecane, and polysorbate 80 (e.g., SEPINEO® P600); 2) Adding cross-linked polyacrylic acid (e.g., carbomer) to the aqueous mixture from step 1); 3) A step of preparing an oil phase containing PEG 8000, mineral oil, polyoxyl 35 castor oil, cetyl alcohol, BHA, methylparaben, and propylparaben; 4) A step of mixing the oil phase from step 3) with the aqueous phase mixture from step 2) and homogenizing the mixture; 5) A step to adjust the pH of the homogenized mixture from step 4) to approximately pH 4.7; 6) A step of preparing a solution phase containing diethylene glycol monoethyl ether, propylene glycol, glycerin, and ascorbyl palmitate; 7) The step of adding the active pharmaceutical product to the solution phase of step 6); 8) A step to adjust the pH of the solution phase from step 7) to approximately pH 4.7; 9) The step of mixing and homogenizing the solution phase of step 8) with the homogenization mixture of step 5) to obtain a gel, ointment, lotion, or cream formulation containing physostigmine. Methods including the above are provided herein.

[0113] In some embodiments, the active pharmaceutical agent is selected from atropine, physostigmine, donepezil, pilocarpine, or travoprost.

[0114] method The gel, ointment, lotion, or cream formulations described herein are useful for delivering a therapeutically significant amount of one or more tropane alkaloids or pharmaceutically acceptable salts thereof to underlying tissues, structures, or organs in a subject through the skin of that subject. Accordingly, a method for delivering one or more tropane alkaloids or pharmaceutically acceptable salts thereof to a subject in need is provided herein, comprising topical administration of an effective amount of the gel, ointment, lotion, or cream formulation described herein to the subject.

[0115] Furthermore, methods for treating one or more eye diseases are also provided herein by delivering a therapeutically significant amount of one or more tropane alkaloids through the skin of a subject suffering from one or more eye diseases, for example, through at least one eyelid. Accordingly, in some embodiments, methods for treating eye diseases in a subject in need are provided herein, which include topical administration of a therapeutically effective amount of the tropane alkaloids provided herein to the subject. In some embodiments, the eye diseases treated include one or more of the following: age-related macular degeneration, allergic conjunctivitis, blepharitis, chorioretinitis, diabetic macular edema, diabetic retinopathy, dry eye disease, episcleritis, geographic atrophy, glaucoma, graft-versus-host disease, inflammation caused by gene therapy vectors, injury-related ocular inflammation or dry eye syndrome, iritis, keratitis, keratoconjunctivitis sicca, macular degeneration (exudative or atrophic), meibomian gland dysfunction, myopia, non-infectious uveitis, conjunctival hyperemia, presbyopia (dry eye), primary or secondary Sjögren's syndrome, erythema, retinitis, retinal vein occlusion, aseptic conjunctivitis, Tygeson's punctate superficial keratitis, uveitis, or Demodex blepharitis.

[0116] In some embodiments, a method is provided herein for improving the delivery of a tropane alkaloid to a target tissue in a subject requiring its use, comprising topically administering a dose of a gel, ointment, lotion, or cream formulation containing the tropane alkaloid to a portion of the skin of a subject, wherein the improved delivery is improved by at least about 50, 100, 200, 300, 400, 500, or 1000% compared to a dose of a topically administered eye drop formulation containing the same molar amount of tropane alkaloid in the gel, ointment, lotion, or cream formulation. In some embodiments, the improved delivery results in a target tissue concentration of the tropane alkaloid that is at least about 50% greater than that of a dose of a topically administered eye drop formulation containing the same molar amount of tropane alkaloid in the gel, ointment, lotion, or cream formulation. In some embodiments, the portion of skin is described throughout this disclosure. In some embodiments, the target tissue is described throughout this disclosure. In some embodiments, the portion of skin is a portion of the eyelid, and the target tissue is the aqueous humor of the eye beneath the eyelid.

[0117] In some embodiments of the methods described herein, the gel, ointment, lotion, or cream formulation comprises a tropane alkaloid or a pharmaceutically acceptable salt thereof. In some embodiments of the methods described herein, the gel, ointment, lotion, or cream formulation comprises a tropane alkaloid or a pharmaceutically acceptable salt thereof and a polycyclic nucleic acid base or a pharmaceutically acceptable salt thereof.

[0118] The gels, lotions, or creams provided herein may be applied topically to a portion of the skin of the subject. In some embodiments, topical application is to a portion of the hands, feet, face, neck, nose, or eyelids (e.g., the upper or lower eyelids of one or both eyes of the subject, or a combination thereof). The gel, ointment, lotion, or cream formulations provided herein allow one or more tropane alkaloids or pharmaceutically acceptable salts contained therein to penetrate the skin, thereby enabling the delivery of one or more tropane alkaloids or pharmaceutically acceptable salts thereof to the tissues of the subject, including organs or internal tissues or areas of the subject. In some embodiments, the gel, ointment, lotion, or cream formulations provided herein deliver the tropane alkaloids or pharmaceutically acceptable salts contained therein to the eyes of the subject following the application of the formulation to the skin of the subject.

[0119] In some embodiments of the methods described herein, the gel, ointment, lotion, or cream formulation is: Approximately 0.01 to 2.5% w / w tropane alkaloids or their pharmaceutically acceptable salts; One or more preservatives at approximately 0.002% w / w or less; A first pharmaceutically acceptable carrier, comprising a copolymer of acrylamide and sodium acryloyldimethyltaurate, isohexadecane, and polysorbate 80, present at approximately 0.5 to approximately 2% w / w; A second pharmaceutically acceptable carrier, which is a polymer of acrylic acid crosslinked with one or more allyl ethers of polyalcohols, present at about 1 to about 3% w / w; and Approximately 0.01 to 5% w / w, with pK values ​​between approximately 2.5 and 7. a Buffer containing Includes; Herein, the gel, ointment, lotion, or cream formulation optionally contains about 0.01 to about 0.3% w / w of polycyclic nucleic acid bases or pharmaceutically acceptable salts thereof.

[0120] In some embodiments of the methods described herein, the gel, ointment, lotion, or cream formulation is: Approximately 0.05 to 2.5% w / w tropane alkaloids or their pharmaceutically acceptable salts; One or more preservatives at approximately 0.002% w / w or less; A first pharmaceutically acceptable carrier, comprising a copolymer of acrylamide and sodium acryloyldimethyltaurate, isohexadecane, and polysorbate 80, present at approximately 0.5 to approximately 2% w / w; A second pharmaceutically acceptable carrier, which is a polymer of acrylic acid crosslinked with one or more allyl ethers of polyalcohols, present at about 1 to about 3% w / w; and Approximately 0.01 to 5% w / w, with pK values ​​between approximately 2.5 and 7. a Buffer containing Includes; Herein, the gel, ointment, lotion, or cream formulation optionally contains about 0.01 to about 0.3% w / w of polycyclic nucleic acid bases or pharmaceutically acceptable salts thereof.

[0121] In some embodiments of the methods described herein, the gel, ointment, lotion, or cream formulation is: Approximately 0.01 to 2.5% w / w tropane alkaloids or their pharmaceutically acceptable salts; One or more preservatives at approximately 0.25% w / w or less; A first pharmaceutically acceptable carrier, comprising a copolymer of acrylamide and sodium acryloyldimethyltaurate, isohexadecane, and polysorbate 80, present at approximately 0.5 to approximately 2% w / w; A second pharmaceutically acceptable carrier, which is a polymer of acrylic acid crosslinked with one or more allyl ethers of polyalcohols, present at about 1 to about 3% w / w; and Approximately 0.01 to 5% w / w, with pK values ​​between approximately 2.5 and 7. a Buffer containing Includes; Herein, the gel, ointment, lotion, or cream formulation optionally contains about 0.05 to about 0.3% w / w of polycyclic nucleic acid bases or pharmaceutically acceptable salts thereof.

[0122] In some embodiments of the methods described herein, the cream formulation includes cream formulations such as those shown throughout the following examples, for example, cream formulations 1, 2, 3, 4, or 5 as shown in Table 1 of Example 1.

[0123] kit In some embodiments, a packaged gel, lotion, or cream is provided herein, comprising a container and packaging component for containing at least one therapeutically effective amount of a gel, ointment, lotion, or cream as described herein, and optionally including instructions for using the at least one gel, ointment, lotion, or cream according to one or more of the methods provided herein. Such packaging component may be referred to as a kit or container closure system.

[0124] The gel, lotion, or cream and related materials, such as packaging components (e.g., in a container closure system), can be manufactured into a commercial product by conventional processes practiced in the art, such as appropriate sterilization and packaging processes. For example, the material can be treated by UV / visible light irradiation (200-500 nm) using a photoinitiator having various absorption wavelengths (e.g., Irgacure 184, 2959, e.g., 1-[4-(2-hydroxyethoxy)-phenyl]-2-hydroxy-2-methyl-1-propan-1-one), preferably a water-soluble initiator (e.g., Irgacure 2959). Such irradiation is usually carried out for irradiation times of 1-60 minutes, but longer irradiation times may be applied depending on the individual method. The materials relating to this disclosure can finally be aseptically packaged to maintain sterility until use and packaged in a suitable container (such as a box) (e.g., with a specific product information leaflet attached).

[0125] According to further embodiments, the gel, lotion, or cream may also be provided in the form of a kit combined with other packaging components necessary for administering the gel, ointment, lotion, or cream to a patient. For example, a kit disclosed for use in the treatment of eye diseases may further include, along with instructions, administration devices, such as spatulas and rulers.

[0126] The kits are designed in various forms based on the specific deficiencies they are designed to treat.

[0127] The gels, lotions, or creams provided herein may be prepared and stored in containers for storage at ambient temperature or at high temperatures. When gels, lotions, or creams are stored in polyolefin plastic containers compared to polyvinyl chloride plastic containers, discoloration of the formulation may be reduced. While not wishing to be bound by theory, containers may reduce the exposure of the container contents to electromagnetic radiation, whether visible light (e.g., having wavelengths of about 380–780 nm) or ultraviolet (UV) light (e.g., having wavelengths of about 190–320 nm (UV B) or about 320–380 nm (UV A)). Some containers also include the ability to reduce adhesion or adsorption of activators to the container surface. Some containers also include the ability to reduce the exposure of the container contents to infrared light, or a second component having such ability. Containers that may be used include those made from polyolefins, such as polyethylene, polypropylene, polyethylene terephthalate, polycarbonate, polymethylpentene, polybutene, or combinations thereof, in particular those made from polyethylene, polypropylene, or combinations thereof. In some embodiments, the container is a glass container, and the user scoops the contents from the container with a measuring spatula, spoon, etc. In some embodiments, the container is malleable, thereby allowing the user to squeeze the contents out of the container. The container may further be placed inside a second container, such as paper, cardboard, board, metal film or flakes, or a combination thereof, to further reduce the exposure of the container contents to UV light, visible light, or infrared light. The formulations provided herein benefit from discoloration, reduced decomposition, or both while stored in such a container. The formulations provided herein may require storage for up to three months or longer; in some cases, up to one year or longer. The container may be any form suitable for containing the contents; for example, a bag, bottle, tube, or box.

[0128] The following embodiments further illustrate aspects of the present disclosure. However, they are by no means limitations of the teachings or disclosures contained herein. [Examples]

[0129] Example 1: Cream formulation and process As shown in Table 1, certain examples of the cream described herein were prepared. The formulations were prepared according to the following steps: (a) an aqueous composition comprising sorbitol, polysorbate 80, SEPINEO P600®, EDTA, caffeine, and carbomer was weighed and dissolved in citrate buffer; (b) an oil and glycol composition comprising mineral oil, castor oil, propylene glycol, PEG 8000, cetyl alcohol, alexidine, and PQ-1 was weighed and mixed; (c) atropine sulfate was weighed and dissolved in buffer; (d) the oil / glycol mixture was added to the aqueous mixture and mixed until a homogeneous mixture was obtained; and (e) the atropine sulfate solution was added to the mixture and then mixed until a homogeneous formulation was obtained.

[0130] [Table 2]

[0131] Example 2: Stability of tropane alkaloids in cream formulations The stability of cream formulations 1 and 2 in Table 1 was assayed by exposure to electron beam sterilization at 25 kilogray (kGy) followed by storage at 40°C in 75% relative humidity for 3 months. The results are shown in Figures 1 and 2 (both figures created using the same sample of cream formulation 1) and Figures 3 and 4 (both figures created using the same sample of cream formulation 2) in terms of the chemical purity of atropine. These data indicate that there was no over-degradation of approximately 10% of atropine during the assay period. Cream formulations 1 and 2 remained chemically stable for up to 3 months and were expected to remain stable for at least 6 months under such conditions.

[0132] Example 3: Chemical stability of tropane alkaloids Base hydrolysis: When atropine sulfate was exposed to 0.05N NaOH at room temperature for 10 minutes, approximately 17.5% degradation was observed. This indicates that atropine sulfate is sensitive to bases.

[0133] Acid hydrolysis: When atropine sulfate was exposed to 5N HCl at room temperature for 3 days, approximately 14.2% degradation was observed. This indicates that atropine sulfate is sensitive to acid.

[0134] Oxidative decomposition: When atropine sulfate was exposed to 30% H2O2 at room temperature for 7 days, followed by reflux at 60°C for 24 hours, approximately 12.7% decomposition was observed. This indicates that atropine sulfate is susceptible to oxidation.

[0135] Thermal and photodegradation. No significant variations were observed under both thermal and light conditions. This indicates that atropine sulfate is stable to both heat and light.

[0136] Example 4: Antimicrobial efficacy test (AET) Prepare a cream formulation containing the preservatives shown in Table 2, and use USP <51> Antimicrobial efficacy tests were conducted according to the guidelines.

[0137] [Table 3]

[0138] [Table 4]

[0139] These data demonstrate that the combination of PQ-1 and alexidine is effective in inhibiting microbial growth across a wide range of preservative concentrations in a semi-solid dosage form.

[0140] Example 5: Tissue-penetrating pharmacokinetics Three tropane alkaloid preparations were prepared, including 0.15% w / w atropine ophthalmic topical cream (preparation #1), 1% w / w atropine ophthalmic topical cream (preparation #2), and 0.05% atropine ophthalmic topical eye drops (over-the-counter eye drops). These preparations were compared in terms of their penetration into target tissue (aqueous humor).

[0141] Figures 5 and 6 (logarithmic scale of data in Figure 5) show the mean atropine concentration in aqueous humor target tissue after a single dose of atropine on an equimolar basis using each formulation (eye drops into the eye (cornea) or 50 mg cream formulation applied to the eyelid). These data show that the 0.15% atropine cream formulation provided similar target tissue (aqueous humor) exposure as the 0.05% atropine eye drop solution, indicating that the cream formulation is a viable alternative to the eye drop. For example, the 0.05% solution and 0.15% cream each showed T1-3 hours after administration. max The AUC reached this point, indicating rapid absorption of the drug. The 0.15% atropine topical ophthalmic cream group had a higher AUC compared to the 0.05% atropine eye drop group. 0-24 This was observed, which indicates a more effective use of the administered atropine.

[0142] These data also show increased aqueous humor exposure between 0.15% and 1% atropine topical ophthalmic creams, indicating that smaller volumes of cream can be used instead of larger volumes of cream with lower concentrations of active ingredients, thereby addressing potential patient aesthetic concerns regarding use and medication adherence.

[0143] Example 6: API stabilized with one or more low molecular weight molecules (LMWs) having aromatic ring structures and / or conjugated structures Table 4 shows cream formulations with and without the LMW molecule. Table 5 summarizes the assay results of these formulations before and after electron beam (25 kGy) treatment. The API stability mediated by the LMW molecule was successfully demonstrated. It should be noted that cream formulations 12 and 13 are duplicate formulations for confirming reproducibility.

[0144] [Table 5]

[0145] [Table 6]

[0146] The effect of caffeine on atropine stability after electron beam processing was studied. Cream formulations were prepared with and without caffeine, and assay / total impurities were analyzed by HPLC. The results showed that the assay decreased by 5.2% in the caffeine-containing formulation after electron beam processing, compared to 18.1% in the caffeine-free formulation (Table 6). Total impurities increased to 1.7% in the caffeine-containing formulation after electron beam processing, compared to 8.4% in the caffeine-free formulation. The presence of caffeine reduced the appearance of impurities at 3 months under test conditions of 40°C and 75% relative humidity (RH). The amount of impurities was approximately five times lower in the caffeine-containing formulation compared to the caffeine-free formulation.

[0147] [Table 7]

[0148] The effect of stabilizers on atropine stability after electron beam processing was further investigated. Stabilizers include aromatic ring compounds (such as α-cyano-4-hydroxycinnamic acid) and heterocyclic compounds (such as histidine). Cream formulations were prepared with stabilizers (Table 7). Assay / total impurities were analyzed by HPLC, and the test results before and after electron beam processing are summarized in Table 8.

[0149] The results showed that all stabilizers tested in this specification effectively prevented the degradation of atropine compared to the samples in Table 6 without stabilizers.

[0150] The data showed a correlation between atropine stability and the amounts of α-cyano-4-hydroxycinnamic acid and histidine. The amount of tropic acid, a degradation product of atropine after the electron beam process, showed the same trend as in the atropine assay analysis.

[0151] [Table 8]

[0152] [Table 9]

[0153] [Table 10]

[0154] Example 7: Changes in pupil diameter Atropine cream 0.15% was compared with atropine eye drops 0.05%. See Figure 7. All dose levels were well tolerated based on clinical findings and skin and ocular evaluations. Pupillary dilation observed with atropine cream and eye drops was similar (+0.5 mm). Dilation was recorded at 14 days.

[0155] Example 8: Exposure to miniature pig plasma As shown in Figure 8, systemic exposure to atropine ophthalmic cream is more than 100 times lower than systemic exposure to commercially approved atropine sulfate ophthalmic solution USP 1%.

[0156] Example 9: Moisture content of physostigmine preparation Five formulations containing 0% to 25% w / w water were prepared (PHY038 to PHY042). As shown in Table 10, the test results clearly showed that formulations with a water content of 15% or less exhibited phase separation under centrifugation, which suggests the low physical stability of these formulations. Formulations with a water content of 20% or more did not exhibit phase separation under centrifugation, which suggests the desirable physical stability of these formulations.

[0157] [Table 11]

[0158] Formulations with low moisture content (10-15%) failed physical stability tests. Formulations PHY038, PHY039, and PHY040, with moisture content of 0%, 10%, and 15%, respectively, showed phase separation under centrifugation at 13,500 rpm (~16,800 RCF) for 5 minutes.

[0159] Formulations with high water content or high pH failed the chemical stability test. PHY030 was found to have 94.4% physostigmine before electron beam and 85% after 25 kGy electron beam in the physostigmine assay, and 0.14% total impurities before electron beam and 0.58% after 25 kGy electron beam.

[0160] Example 10: Antioxidant content of physostigmine preparation Formulations containing butylated hydroxyanisole (BHA) or a combination of BHA and ascorbyl palmitate at different concentrations (PHY048-PHY052) were prepared. The results for total impurities are summarized in Table 11.

[0161] [Table 12]

[0162] Formulations containing a combination of ascorbyl palmitate and BHA showed lower total impurities compared to BHA alone at 1 month (stored under accelerated conditions of 40°C / 75%RH).

[0163] Formulations containing BHA alone exhibited a slightly darker cream color compared to formulations containing both BHA and ascorbyl palmitate, but the impurity levels were acceptable during 3 months of accelerated stability at 40°C / 75RH. In other words, under accelerated stability conditions, when both antioxidants were used in the formulation, the formulation appeared lighter in color (better aesthetics).

[0164] Example 11: Physical properties of physostigmine To achieve the desired physical properties, formulation design experiments were conducted to optimize the formulation composition. The experimental design is shown in Table 12, and the data analysis results are shown in Figures 18 and 19.

[0165] [Table 13]

[0166] (a) The viscosity of the formulation increased when the concentration of CARBOPOL® 980 increased, (b) the viscosity of the formulation decreased when the pH increased, and (c) phase separation could not be confirmed by centrifugation tests in formulations containing 2% SEPINEO P600® and 2% CARBOPOL® 980.

[0167] Example 12: Compatibility with physostigmine excipients As shown in Table 13, drug excipient compatibility (DEC) studies were performed to evaluate the excipients. All excipients used in the formulation were compatible with physostigmine before and after 25 kGy electron beam treatment. NaOH was used to adjust the pH of the cream and was added before mixing with physostigmine. The chemical stability of physostigmine in the formulation is stable in an acidic pH environment (e.g., pH approximately 3.5 to 5.5).

[0168]

Table 14

[0169] Example 13: Preparation of Physostigmine Formulations Formulations containing physostigmine were prepared according to the flowchart of FIG. 20. Table 14 provides the various formulations prepared.

[0170]

Table 15

[0171] The general procedure for preparing the formulations in Table 14 involves gently dissolving physostigmine together with ascorbyl palmitate in a mixture of propylene glycol and purified diethylene glycol monoethyl ether (or Transcutol) in order to minimize hydrolytic degradation, oxidative degradation, and thermal degradation during the manufacturing process. As shown in FIG. 20, an aqueous phase mixture is prepared, carbomer is added, an oil phase mixture is prepared, mixed, homogenized and pH adjusted, and then the dissolved physostigmine solution is added to the base cream as shown in FIG. 20 to minimize the exposure time. The procedures described herein ensure that physostigmine is present in the oil / glycol phase rather than the aqueous phase until the time it is added to the base cream.

[0172] Example 14: Testing of Physostigmine Formulations Six functional properties such as appearance, spreadability, adhesiveness, comfort, greasiness / oiliness, and residue were evaluated for three formulations. PHY052 had the best overall functional score. PHY048 was the greasiest but was still judged to be acceptable to most subjects. PHY030 was judged to have the least oiliness among the three formulations. For all three test formulations, no skin irritation, stinging, burning, or discomfort was detected from any of the 19 subjects.

[0173] The data in the above examples and figures demonstrate that a particular physostigmine formulation is stable for at least 3 months at 40°C / 75%RH and that the formulation provides desirable release and penetration of physostigmine.

[0174] It should be understood that various changes and modifications to the currently preferred embodiments described herein will be obvious to those skilled in the art. Such changes and modifications can be made without departing from the spirit and scope of this subject matter and without impairing the intended advantages. Therefore, such changes and modifications are intended to be covered by the appended claims.

[0175] Wherever patents and printed publications are referenced throughout this Specified, each of the above references and printed publications is incorporated herein by individual reference.

Claims

1. A topical preparation containing an active pharmaceutical ingredient that includes a tropanil group.

2. A topical formulation according to claim 1, which is a gel, lotion, ointment, or cream.

3. A gel, ointment, lotion, or cream formulation containing an active pharmaceutical ingredient that includes a tropanil group.

4. The gel, ointment, lotion, or cream formulation according to claim 3, which is an oil-in-water emulsion cream formulation containing at least 50% w / w water.

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

6. A cream formulation according to any one of claims 3 to 5, wherein the active pharmaceutical ingredient comprises atropine, benzatropine, cocaine, homatropine, hyoscyamine, scopolamine, tiotropium, tropisetron, or trospium, or a pharmaceutically acceptable salt thereof.

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

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

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

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

11. formula: 【Chemistry 23】 [During the ceremony 【Chemistry 24】 Each of them is independently either a single bond or a double bond; Each of m, n, p, w, x, y, and z is independently either 0 or 1; R １－６ 、 R ３ 、 R ７ 、 and R ９ each is, independently, H, C １－６ alkyl, C １－６ alkanolyl, C １－６ haloalkyl, C ２－６ alkenyl, C ２－８ alkanalyl, C ３－８ alkenalyl, C ２－８ alkanonyl, or C ４－８ alkenonyl; R ２ , R ６ , and R ８ Each of these is independently H, Halo, O-(C) １－３ Alkyl), NH ２ , N(H)(C １－３ Alkyl), N (C １－３ (Alkyl) (C １－３ [It is alkyl, S, or O] A gel, ointment, lotion, or cream formulation according to one of claims 3 to 10, further comprising a heterocyclic compound having or a pharmaceutically acceptable salt thereof.

12. A gel, ointment, lotion, or cream formulation according to any one of claims 3 to 10, further comprising a polycyclic nucleic acid base or a pharmaceutically acceptable salt thereof.

13. Polycyclic nucleic acid bases include azathiopurine, 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, and 1,3-dimethylxane. The gel, ointment, lotion or cream formulation according to claim 12, wherein the compound is tin, 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.

14. A gel, ointment, lotion, or cream formulation according to any one of claims 3 to 13, comprising atropine or a pharmaceutically acceptable salt thereof and 1,3,7-trimethylxanthine.

15. Approximately 0.01 to 2.5% w / w tropane alkaloids or their pharmaceutically acceptable salts; One or more preservatives at approximately 0.25% w / w or less; A first pharmaceutically acceptable carrier, comprising a copolymer of acrylamide and sodium acryloyldimethyltaurate, isohexadecane, and polysorbate 80, present in an amount of approximately 0.5 to approximately 2% w / w; A second pharmaceutically acceptable carrier, which is a polymer of acrylic acid crosslinked with one or more allyl ethers of polyalcohols, present at about 1 to about 3% w / w; and Approximately 0.01% to 5% w / w, with pK levels between approximately 2.5 and 7. ａ Buffer containing Including; The cream formulation according to claim 3, wherein the gel, ointment, lotion, or cream formulation optionally comprises about 0.01 to about 0.3% w / w of a polycyclic nucleic acid base or a pharmaceutically acceptable salt thereof.

16. One or more purified tropane alkaloids or their pharmaceutically acceptable salts; and One or more purified polycyclic nucleic acid bases or their pharmaceutically acceptable salts. A composition containing the following:

17. A purified polycyclic nucleic acid base or a pharmaceutically acceptable salt thereof, of the formula: 【Chemistry 25】 [During the ceremony 【Chemistry 26】 Each of them is independently either a single bond or a double bond; Each of m, n, p, w, x, y, and z is independently either 0 or 1; R １ , R ３ , R ７ , and R ９ Each of these independently corresponds to H and C １－６ Alkyl, C １－６ Alkanoryl, C １－６ Haloalkyl, C ２－６ Alkenil, C ２－８ Arcanalil, C ３－８ Alkenaril, C ２－８ Alkanonyl, or C ４－８ It is alkenonil; R ２ , R ６ , and R ８ Each of these is independently H, Halo, O-(C) １－３ Alkyl), NH ２ , N(H)(C １－３ Alkyl), N (C １－３ (Alkyl) (C １－３ [It is alkyl, S, or O] The composition according to claim 16, or having a pharmaceutically acceptable salt thereof.

18. A gel, ointment, lotion, or cream formulation according to any one of claims 3 to 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 according to claim 18, wherein at least one low molecular weight compound or a pharmaceutically acceptable salt thereof stabilizes the active pharmaceutical ingredient (API) in the gel, ointment, lotion, or cream formulation.

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

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

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

23. A cream formulation containing 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, as described in the Examples section.

24. A gel, ointment, lotion, or cream formulation containing an active pharmaceutical ingredient including a tropanil group, pilocarpine, travoprost, or physostigmine.

25. A gel, ointment, lotion, or cream formulation according to claim 24, comprising a water content of approximately 20% to approximately 31% w / w or approximately 20% to approximately 25% w / w.

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

7.

27. A gel, ointment, lotion, or cream formulation according to any one of claims 24 to 26, comprising a copolymer of acrylamide and sodium acryloyldimethyltaurate, isohexadecane, and a viscosity modifier selected from polysorbate 80 or crosslinked polyacrylic acid, or a combination thereof.

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

29. The gel, ointment, lotion, or cream formulation according to claim 28, wherein at least one antioxidant is selected from parabens, bis-biguanides, polyquaternium 1, or a combination thereof.

30. The gel, ointment, lotion, or cream formulation according to claim 28, wherein at least one antioxidant is selected from butylated hydroxyanisole (BHA), ascorbic acid palmitate, or a combination thereof.

31. A cosolvent selected from diethylene glycol monoethyl ether or propylene glycol, or a combination thereof, in an amount of approximately 1% to approximately 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 approximately 8.5% to approximately 10% w / w; Mineral oil in an amount of approximately 8% to 12% w / w; Glycerin in an amount of approximately 4% to 8% w / w; At least one preservative in an amount of approximately 0.01 to approximately 0.05% w / w; and At least one antioxidant in an amount of approximately 0.02% to approximately 0.06% w / w A gel, ointment, lotion, or cream formulation according to any one of claims 24 to 30, comprising:

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

33. A gel, ointment, lotion, or cream formulation according to one of claims 3 to 15, 18 to 23, or 24 to 32, or a composition according to claim 16 or 17, comprising one or more containers, wherein at least one of the containers is made of plastic.

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

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

36. A method of treatment comprising administering a gel, ointment, lotion, or cream formulation according to any one of claims 3 to 15, 18 to 23, or 24 to 32, or a composition according to claim 16 or 17, to a subject requiring it.

37. The method according to one of claims 35 to 36, wherein the subject has or is prone to developing an ocular condition (e.g., amblyopia, hyperopia, myopia, presbyopia, glaucoma, or demodex blepharitis).

38. The method according to any one of claims 35 to 37, comprising an anesthetic, an antiarrhythmic agent, an antiemetic, an antihistamine, an antiparkinsonian, an anticonvulsant, a bronchodilator, a gastrointestinal agent, or a method of ophthalmic treatment or use.

39. A method for regulating acetylcholine activity, comprising administering a gel, ointment, lotion, or cream formulation according to any one of claims 3 to 15, 18 to 23, or 24 to 32, or a composition according to claim 16 or 17, to a subject requiring such regulation.

40. The method according to one of claims 38 to 39, wherein the administration is local.

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

42. A manufactured product comprising a gel, ointment, lotion, or cream formulation according to any one of claims 3 to 15, 18 to 23, or 24 to 32, or a composition according to claim 16 or 17, and instructions for use.

43. A method for preparing a gel, ointment, lotion, or cream formulation according to any one of claims 24 to 32, 1) A step of preparing an aqueous phase containing water, polysorbate 80, and a copolymer of acrylamide and sodium acryloyldimethyltaurate, isohexadecane, and polysorbate 80; 2) Adding crosslinked polyacrylic acid to the aqueous mixture from step 1); 3) A step of preparing an oil phase containing PEG 8000, mineral oil, polyoxyl 35 castor oil, cetyl alcohol, BHA, methylparaben, and propylparaben; 4) A step of mixing the oil phase from step 3) with the aqueous phase mixture from step 2) and homogenizing the mixture; 5) A step to adjust the pH of the homogenized mixture from step 4) to approximately pH 4.7; 6) A step of preparing a solution phase containing diethylene glycol monoethyl ether, propylene glycol, glycerin, and ascorbyl palmitate; 7) The step of adding the active pharmaceutical product to the solution phase of step 6); 8) A step to adjust the pH of the solution phase from step 7) to approximately pH 4.7; 9) A step of mixing and homogenizing the solution phase of step 8) with the homogenizing mixture of step 5) to obtain a gel, ointment, lotion, or cream formulation according to any one of claims 24 to 32. Methods that include...

44. The method according to claim 43, wherein the active pharmaceutical product is selected from physostigmine, atropine, donepezil, pilocarpine, or travoprost.

45. An ophthalmic preparation, composition, method, or product according to any of claims 1 to 44.

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