Alimemazine for the treatment of pain associated with trigeminal neuralgia

Abstract

The present disclosure describes methods of using an alimemazine or a pharmaceutically acceptable salt thereof for treating pain associated with trigeminal neuralgia. The methods of the present disclosure can include administering to a patient in need thereof a therapeutically effective amount of an alimemazine or a pharmaceutically acceptable salt thereof, thereby treating the patient. The methods can include reducing pain in the patient, as determined by patient report or clinician-administered outcome assessments.

Description

[0001] Cross-references to related applications

[0002] This application claims priority to U.S. Provisional Patent Application No. 63 / 595,300, filed November 1, 2023, the entire contents of which are incorporated herein by reference. Background Technology

[0003] Trigeminal neuralgia (TN), also known as painful tic, is a chronic pain disorder affecting the trigeminal nerve, or the fifth cranial nerve (one of the most widely distributed nerves in the head). TN is a form of neuropathic pain (pain associated with nerve damage or neuropathy). The typical or “classic” form of the disorder (called “type 1” or TN1) causes extreme, sporadic, sudden burning or throbbing facial pain, with each attack lasting from a few seconds to two minutes. These attacks can occur rapidly in succession and last up to two hours. The “atypical” form of the disease (called “type 2” or TN2) is characterized by persistent aching, burning, or stabbing pain, slightly less intense than type 1. Both forms of pain can occur in the same person, sometimes simultaneously. The intensity of the pain can be physically and mentally debilitating.

[0004] The trigeminal nerve is the fifth cranial nerve (V), one of the 12 pairs of nerves attached to the brain. This nerve has three branches, originating from the semilunar ganglion, transmitting sensations from the upper, middle, and lower parts of the face, as well as the mouth, to the brain. The ophthalmic or superior branch (V1) supplies sensation to most of the scalp, forehead, and front of the head. The maxillary or middle branch (V2) innervates the cheek, palate, upper lip, teeth and gums, and the sides of the nose. The mandibular or inferior branch (V3) supplies the mandible, teeth and gums, and lower lip. More than one branch may be affected by the disease. In rare cases, both sides of the face may be affected at different times, or more rarely, simultaneously (called bilateral TN).

[0005] Pain varies depending on the type of TN, ranging from sudden, severe, stabbing pain to more persistent, aching, or burning sensations. Severe paroxysmal pain (paraxosymps) can be triggered by seemingly harmless stimuli that cause tremors or are triggered by contact with the cheek (such as when shaving, washing the face, or applying makeup), brushing teeth, eating, drinking, talking, or being exposed to wind. The pain may affect a small area of ​​the face or it may spread. Pain attacks rarely occur at night when the affected individual is sleeping. A typical characteristic of TN is that attacks stop for a period of time and then recur, but this can be progressive, with attacks often worsening over time and the pain-free periods before recurrence becoming shorter and less frequent. Eventually, the pain-free intervals disappear, and pain-controlling medications become ineffective, highlighting the need for more effective TN management and treatment options. Summary of the Invention

[0006] In some respects, it embodies a method for treating pain associated with trigeminal neuralgia, which involves administering a therapeutically effective amount of alimazine or a pharmaceutically acceptable salt thereof to a patient in need, thereby treating the patient's trigeminal neuralgia.

[0007] In some cases, a therapeutically effective amount of alimazine or a pharmaceutically acceptable salt thereof is administered once daily.

[0008] In some cases, a therapeutically effective amount of alimazine or a pharmaceutically acceptable salt thereof is administered twice daily.

[0009] In some respects, therapeutically effective amounts of alimazine or pharmaceutically acceptable salts thereof are administered via oral, intravenous (IV), intramuscular (IM), intrathecal, subcutaneous (SC), sublingual or buccal, rectal, vaginal, dermal, transdermal, nasal, or combinations thereof.

[0010] In some respects, therapeutically effective amounts of alimazine or its pharmaceutically acceptable salts are administered orally.

[0011] In some respects, therapeutically effective amounts of alimazine or its pharmaceutically acceptable salts are administered via oral thin film formulation.

[0012] In some respects, the therapeutically effective amount of alimazine or its pharmaceutically acceptable salt is about 0.5 mg to about 80 mg.

[0013] In some respects, the therapeutically effective amount of alimazine or its pharmaceutically acceptable salt is about 2.5 to about 5 mg.

[0014] In some respects, the therapeutically effective amount of alimazine or its pharmaceutically acceptable salt is about 0.5 to about 2.5 mg.

[0015] In some respects, treatment for pain associated with trigeminal neuralgia includes reducing the frequency of pain, reducing the duration of pain, reducing the intensity of pain, or any combination thereof.

[0016] In some respects, a reduction in the duration of pain includes a reduction in the duration of a single pain episode, a reduction in the duration of a series of pain episodes, and any combination thereof.

[0017] In some respects, a series of pain episodes includes at least two separate pain episodes.

[0018] In some respects, the pain associated with trigeminal neuralgia is stinging, tearing, throbbing, electric shock-like, persistent aches, burning, stinging with an intensity slightly less than that of type 1 TN, and any combination thereof.

[0019] In some respects, the reduction in pain frequency, the reduction in pain duration, the reduction in pain intensity, or any combination thereof, is measured using a patient diary, PGIC score, MSQ score, BNI pain intensity score, Penn-FPS-R score, Penn-FPS score, EQ-5D-5L score, WPAI score, or any combination thereof.

[0020] In some respects, administering a therapeutically effective amount of alimazine or a pharmaceutically acceptable salt thereof includes administering an initial dose between 2.5 and 5.0 mg.

[0021] In some respects, administering a therapeutically effective amount of alimazine or a pharmaceutically acceptable salt thereof includes administering an initial dose between 0.5 and 2.5 mg.

[0022] Some aspects further include administering an additional therapeutically effective amount of alimazine or a pharmaceutically acceptable salt thereof approximately every 30 minutes to approximately every 5 hours after the initial dose if treatment for pain associated with trigeminal neuralgia is not achieved.

[0023] In some respects, additional therapeutically effective amounts of alimazine or its pharmaceutically acceptable salts are increased approximately every 30 minutes to approximately every 5 hours until treatment of pain associated with trigeminal neuralgia is achieved.

[0024] In some respects, once treatment for pain associated with trigeminal neuralgia is achieved, an additional therapeutically effective amount of alimazine or a pharmaceutically acceptable salt thereof is maintained as the minimum effective level for treating pain associated with trigeminal neuralgia.

[0025] In some respects, the minimum effective level of therapeutically effective amount of alimazine or a pharmaceutically acceptable salt thereof is administered until treatment of pain associated with trigeminal neuralgia is no longer achieved. Thereafter, the minimum effective level of therapeutically effective amount of alimazine or a pharmaceutically acceptable salt thereof may be further increased until treatment of pain associated with trigeminal neuralgia is achieved again.

[0026] In some respects, at least every three months, the therapeutically effective amount of alimazine or a pharmaceutically acceptable salt thereof shall be reduced to the minimum effective level of a therapeutically effective amount of alimazine or a pharmaceutically acceptable salt thereof.

[0027] In some respects, the administration of a therapeutically effective amount of alimazine or a pharmaceutically acceptable salt thereof should be discontinued at least every 3 months. Attached Figure Description

[0028] The aspects, features, benefits, and advantages of the embodiments described herein will become apparent from the following description, the appended claims, and the accompanying drawings, wherein: Detailed Implementation

[0029] The various aspects will now be described more fully below. However, these aspects may be implemented in many different forms and should not be construed as limited to the examples set forth herein; rather, these examples are provided to make this disclosure thorough and complete and to fully convey its scope to those skilled in the art.

[0030] Where a numerical range is provided, it is intended that every intermediate value between the upper and lower limits of that range, as well as any other stated or intermediate value within that specified range, be included in this disclosure. For example, if a range of 1 mg to 8 mg is stated, it is also intended to explicitly disclose 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, and 7 mg, as well as numerical ranges greater than or equal to 1 mg and numerical ranges less than or equal to 8 mg.

[0031] Unless otherwise stated, all percentages, parts and ratios are based on the total weight of the topical composition, and all measurements were performed at approximately 25 °C.

[0032] Unless the context clearly specifies otherwise, the singular forms “a,” “an,” and “the / said” include plural references. Thus, for example, references to “polymer” include a single polymer as well as two or more identical or different polymers; references to “excipient” include a single excipient as well as two or more identical or different excipients, and so on.

[0033] When used immediately adjacent to a numerical value, the term "about" indicates a range of plus or minus 10% of that value, and also includes the exact value disclosed, such as "about 50" meaning 45 to 55, "about 25,000" meaning 22,500 to 27,500, etc., unless the context of this disclosure otherwise or is inconsistent with such interpretation. For example, in a series of numerical values ​​such as "about 49, about 50, about 55," "about 50" indicates a range extending to less than half the interval between the preceding and following values, such as greater than 49.5 to less than 52.5. Furthermore, expressions "less than about" or "greater than about" a value should be understood according to the definition of the term "about" provided herein.

[0034] As used in this article, the terms “administer,” “administering,” or “administration” refer to the direct administration of a compound (also known as a target agent) or a pharmaceutically acceptable salt or combination of a compound (target agent) to a subject.

[0035] The term “carrier” as used herein includes carriers, excipients, and diluents, and refers to the materials, compositions, or vehicles involved in carrying or transporting drugs, cosmetics, or other agents through tissue layers (such as the stratum corneum or stratum spinosum), such as liquid or solid fillers, diluents, excipients, solvents, or encapsulating materials.

[0036] Unless otherwise stated, the term “disorder” as used herein is used synonymously with and interchangeably with the terms disease, symptom or ailment.

[0037] The terms “effective amount” and “therapeutic effective amount”, used interchangeably in this disclosure, refer to the amount of a compound that, when administered to a subject, reduces the subject’s symptoms and / or improves the texture, appearance, color, sensation, and / or hydration of the intended treatment area. The actual amount constituting an “effective amount” or “therapeutic effective amount” will depend on a variety of conditions, including but not limited to the severity of the disorder, the size and health condition of the patient, the route of administration, and its combination. A skilled medical practitioner can readily determine an “effective amount” or “therapeutic effective amount” using methods known in the medical field.

[0038] As used herein, the term "modified release" refers to a pharmaceutical composition that does not release the entire active ingredient immediately by any other means. For example, it may release the active ingredient at a sustained or controlled rate over an extended period of time, or it may release the active ingredient after a delayed time following administration, or it may optionally be used in combination with an immediate-release composition. Modified release includes extended release, sustained release, controlled release, and delayed release. As used herein, the terms "extended release" or "sustained release" refer to a dosage form that makes the drug available over an extended period of time following administration, relative to a dose delivered entirely in an immediate form. As used herein, the term "delayed release" refers to a dosage form that releases the drug at a later time than immediately following administration. As used herein, the terms "oral," "oral route," and "oral administration" refer to a route of administration where the substance is ingested through the mouth.

[0039] As used herein, the phrase "pharmaceutically acceptable" refers to those target agents / compounds, salts, compositions, dosage forms, etc., that, within reasonable medical judgment, are suitable for use in contact with human and / or other mammalian tissues without excessive toxicity, irritation, allergic reactions, and / or other problems or complications, in proportion to a reasonable benefit / risk ratio. In some respects, "pharmaceutically acceptable" means approved by federal or state regulatory agencies, or listed in the United States Pharmacopeia or other recognized pharmacopoeias, for use in mammals (e.g., animals), more specifically for human use.

[0040] As used herein, the term "salt" includes pharmaceutically acceptable salts that are commonly used to form free acids and addition salts that form free bases. The properties of the salt are not critical, as long as it is pharmaceutically acceptable. The term "salt" also includes solvates of addition salts, such as hydrates, and polymorphs of addition salts. Suitable pharmaceutically acceptable acid addition salts can be prepared from inorganic or organic acids. Non-limiting examples of suitable inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, sulfuric acid, and phosphoric acid. Suitable organic acids can be selected from aliphatic, alicyclic, aromatic, aryl aliphatic, and heterocyclic acids containing carboxylic acids and sulfonic acids, such as formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, gluconic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, glucuronic acid, maleic acid, fumaric acid, pyruvic acid, aspartic acid, glutamic acid, benzoic acid, anthranilic acid, methanesulfonic acid, stearic acid, salicylic acid, p-hydroxybenzoic acid, phenylacetic acid, mandelic acid, embonic acid (pamoic acid), methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, pantothenic acid, toluenesulfonic acid, 2-hydroxyethanesulfonic acid, p-aminobenzenesulfonic acid, cyclohexylsulfamic acid, alginic acid, 3-hydroxybutyric acid, galactosic acid, and galacturonic acid.

[0041] As used herein, the terms “patient” and “subject” are interchangeable and can be understood as any organism that can be treated with the compounds disclosed herein. Therefore, the terms “patient” and “subject” can include, but are not limited to, any non-human mammal, primate, or human. In some aspects, a “patient” or “subject” is a mammal; exemplary mammals include: mice, rats, rodents other than mice and rats, rabbits, dogs, cats, pigs, cattle, sheep, horses, primates, or humans. In some aspects, a patient or subject is an adult, child, or infant. In some aspects, a patient or subject is a human.

[0042] As used herein, the term "treatment" refers, for example, to a method of treating a disorder or systemic condition, and generally includes the administration of a compound or composition that, compared to a subject who has not received the compound or composition, reduces the frequency of a medical condition or delays its onset or symptoms, and / or improves the texture, appearance, color, sensation, and / or hydration of the intended tissue treatment area on the subject's tissue surface. This can include reversing, alleviating, or suppressing the symptoms, clinical signs, and underlying pathology of the condition in a manner that improves or stabilizes the subject's condition. This can also include the administration of a compound or composition that results in a reduction in the frequency of pain, a reduction in the duration of pain, a reduction in the intensity of pain, or any combination thereof. In some embodiments, a reduction in the duration of pain includes a reduction in the duration of a single pain attack, a reduction in the duration of a series of pain attacks, or any combination thereof. In some aspects, a series of pain attacks includes at least two separate pain attacks. In some aspects, pain associated with trigeminal neuralgia is stabbing, tearing, throbbing, electric shock-like, persistent aching, burning, stabbing with an intensity slightly less than that of type 1 TN, or any combination thereof. In some respects, the reduction in pain frequency, the reduction in pain duration, the reduction in pain intensity, or any combination thereof, is measured using a patient diary, PGIC score, MSQ score, BNI pain intensity score, Penn-FPS-R score, Penn-FPS score, EQ-5D-5L score, WPAI score, or any combination thereof.

[0043] As used herein, the term "pharmaceutically acceptable carrier" refers to any standard pharmaceutical carrier, including but not limited to non-toxic solvents, phosphate-buffered saline solutions, water, emulsions (e.g., oil / water or water / oil emulsions), various types of wetting agents, any and all solvents, dispersion media, coatings, sodium lauryl sulfate, isotonic and absorption-retarding agents, disintegrants (e.g., potato starch or sodium carboxymethyl starch glycolate), etc. The composition may also include stabilizers and / or preservatives.

[0044] This right is reserved, by limiting clauses, to exclude or exclude any individual member of any such group, including any subscope or combination of subscopes within that group, which may be protected by scope or in any similar manner, for any reason, less than the entirety of this disclosure. Furthermore, this right is reserved, by limiting clauses, to exclude or exclude any individual substituent, analogue, compound, ligand, structure or group thereof, or any member of the claimed group, for any reason, less than the entirety of this disclosure.

[0045] For convenience, certain terms used in the specification, embodiments, and claims are collected herein. Unless otherwise defined, all technical and scientific terms used in this disclosure have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains.

[0046] Various aspects of this disclosure relate to phenothiazine-containing compositions for treating pain and methods of using such compositions to treat, prevent, and / or improve pain. Such compositions may further comprise various excipients that promote oral, topical, or both oral and topical administration. The compositions and methods described herein can reduce pain and other symptoms associated with chronic diseases.

[0047] Phenothiazines may include, for example, chlorpromazine, diethylprozine, ethylprozine, fluphenazine, methaqualone, perphenazine, prochlorperazine, promethazine, isoprozine, mesoridazine, thiotetramethazine, thioridazine, trifluoperazine, trifluprozine, alimazine, etc., various derivatives and salts thereof, and combinations thereof. In some respects, a phenothiazine may be one or more of diethylprozine, ethylprozine, methaqualone, isoprozine, thiotetramethazine, or alimazine, and in some respects, a phenothiazine may be alimazine or a pharmaceutically acceptable salt thereof.

[0048] Those skilled in the art will understand and appreciate the dosage and timing of the dose administered to a patient in need. The dosage and duration of treatment can vary and can be based on assessments made by those skilled in the art through monitoring and measuring improvement in the underlying condition. This assessment can be based on improved external physical signs, such as pain reduction. The dosage can also depend on the condition or disease being treated, the severity of the condition or disease being treated, and also on the patient's age and weight. In some aspects, the amount of phenothiazine administered using the exemplary method can vary and can be, for example, from about 0.05 mg / kg / day to about 5 mg / kg / day. In some aspects, the delivered amount of phenothiazine may be about 0.05 mg / kg / day to about 5 mg / kg / day, about 0.1 mg / kg / day to about 5 mg / kg / day, about 0.5 mg / kg / day to about 5 mg / kg / day, about 1 mg / kg / day to about 5 mg / kg / day, about 1.5 mg / kg / day to about 5 mg / kg / day, about 0.1 mg / kg / day to about 3 mg / kg / day, or any range or single value covered by these exemplary ranges. The administered composition may typically contain about 0.5 mg to about 80 mg of phenothiazine, about 0.5 mg to about 50 mg, about 1 mg to about 20 mg, about 1 mg to about 10 mg, about 1 mg to about 5 mg, or any range or single dose covered by these exemplary ranges. In some respects, the composition may be administered 1, 2, 3, 4 or more times daily, resulting in a total daily dose of about 0.5 mg to about 80 mg, about 0.5 mg to about 40 mg, about 1 mg to about 30 mg, about 1 mg to about 20 mg, or any single dose or range covered by these exemplary ranges.

[0049] The specific route of administration will depend on the indication. The choice of the specific route of administration and dosage regimen can be adjusted or titrated by the clinician according to methods known to the clinician to obtain the best clinical response. The amount of compound administered can be a therapeutically effective amount. The administered dose may depend on the characteristics of the subject being treated, such as the specific animal or human subject being treated, age, weight, health status, type of concurrent treatment (if any), and frequency of treatment, and can be readily determined by someone skilled in the art (e.g., by a clinician).

[0050] The exemplary pharmaceutical compositions described herein can be formulated for administration via a variety of different routes. Typically, the type of carrier is selected according to the method of administration. The compositions of various aspects can be formulated for systemic or local delivery to affected tissues. For example, in some aspects, the compositions can be formulated for systemic delivery via oral administration, intravenous (IV), intramuscular (IM), intrathecal, subcutaneous (SC), sublingual or buccal administration, rectal administration, vaginal administration, skin administration, percutaneous administration, nasal administration, and combinations thereof. In other aspects, the compositions described herein can be delivered locally, for example, using local administration.

[0051] For oral administration, these compounds can be readily formulated by combining them with pharmaceutically acceptable carriers known in the art. As used herein, the term "pharmaceutically acceptable carrier" means a non-toxic, inert solid or semi-solid liquid filler, diluent, encapsulating material, any type of formulation adjuvant, or a simple sterile aqueous medium, such as saline. Some examples of materials that can be used as pharmaceutically acceptable carriers include: sugars, such as lactose, glucose, and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; powdered tragacanth gum; malt, gelatin, and talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols, such as propylene glycol; polyols, such as glycerol, sorbitol, mannitol, and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffers, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethanol and phosphate buffers; and other non-toxic and compatible substances used in pharmaceutical preparations, and combinations thereof. Such carriers enable the compounds described herein to be formulated into tablets, pills, sugar-coated pills, capsules, liquids, gels, syrups, pastes, suspensions, etc., for oral ingestion by a patient seeking treatment. Oral pharmaceutical formulations can be obtained by adding a solid excipient, optionally grinding the resulting mixture, and processing the granular mixture after adding suitable excipients (if desired) to obtain tablets or sugar-coated pill cores. Suitable excipients include, but are not limited to, fillers, such as sugars, including but not limited to lactose, sucrose, mannitol, and sorbitol; cellulose formulations, such as, but not limited to, corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, and polyvinylpyrrolidone (PVP) and combinations thereof. If desired, disintegrants may be added, such as, but not limited to, croscarmellose, agar, or alginate or its salts (e.g., sodium alginate) and combinations thereof.

[0052] Sugar-coated pellet cores can be provided with a suitable coating. For this purpose, a concentrated sugar solution can be used, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, carbomer gel, polyethylene glycol, titanium dioxide, lacquer solution, and suitable organic solvents or solvent mixtures and combinations thereof. Dyes or pigments can be added to the coating of tablets or sugar-coated pellets to identify or characterize different combinations of active compound dosages.

[0053] Orally administered pharmaceutical formulations include, but are not limited to, push-in capsules made of gelatin and soft-sealable capsules made of gelatin and plasticizers (such as glycerin or sorbitol). Push-in capsules may contain an active ingredient mixed with a filler (such as lactose), a binder (such as starch), and / or a lubricant (such as talc or magnesium stearate), and optionally a stabilizer. In soft capsules, the active compound may be dissolved or suspended in a suitable liquid, such as fatty oils, liquid paraffin, or liquid polyethylene glycol, or combinations thereof. Additionally, stabilizers may be added. All formulations intended for oral administration should be at a dosage suitable for such administration.

[0054] Oral formulations may also be presented as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent (such as calcium carbonate, calcium phosphate, or kaolin), or as soft gelatin capsules in which the active ingredient is mixed with water or an oily medium (such as peanut oil, liquid paraffin, or olive oil).

[0055] Syrups and elixirs can be formulated with sweeteners, including, for example, glycerol, propylene glycol, sorbitol, sucrose, and combinations thereof. Such formulations may also contain modifiers, preservatives, flavoring agents, coloring agents, and combinations thereof.

[0056] For buccal or sublingual administration, the composition may be in the form of tablets, flashmelt, or lozenges formulated in any conventional manner.

[0057] In addition to the formulations described above, the compounds described herein can also be formulated as depot preparations. Such long-acting formulations can be administered via implantation (e.g., subcutaneous or intramuscular) or intramuscular injection.

[0058] Reservoir-type injectable formulations can be administered at intervals of about 1 to about 6 months or longer. Thus, for example, the compound can be formulated with suitable polymers or hydrophobic materials (e.g., as an emulsion in an acceptable oil) or ion exchange resins, or as a slightly soluble derivative, such as as a slightly soluble salt.

[0059] In transdermal application, the compounds described herein, for example, can be applied to plasters or administered via transdermal therapeutic systems and ultimately delivered to the organism.

[0060] In some aspects, exemplary pharmaceutical compositions may be associated with fibers. For example, in some aspects, a fiber-containing composition may include an electrospun polymer having a phenothiazine associated with it. In some aspects, the phenothiazine may be dispersed within the electrospun polymer and may exclude the drug from the outer surface of the fiber formed by the electrospun polymer. The drug dispersed within the electrospun polymer may provide the additional benefit of resisting accidental and / or unintended removal of the phenothiazine from the fiber. In other aspects, the phenothiazine may additionally or alternatively be associated with the outer surface of the fiber by, for example, impregnating, spraying, or otherwise treating the outer surface of the fiber with the drug.

[0061] In some aspects, the electrospun polymer may include one or more polymers. In some aspects, the polymer may be a water-soluble polymer or a combination of water-soluble polymers. In certain aspects, one or more polymers may include a combination of synthetic polymers and natural polymers, having any combination and / or compositional proportions.

[0062] In some respects, the phenothiazine associated with the polymer can be dispersed or dissolved in an oil, such as oil selected from: hemp oil, cannabidiol (CBD) oil, olive oil, sesame oil, canola oil, palm oil, vegetable oils, their derivatives, or combinations thereof. In some respects, the drug can be in a crystalline form. In a further respects, the phenothiazine can be crystals dispersed or dissolved in an oil or solution.

[0063] Pharmaceutical and therapeutic compositions of compounds may also include suitable solid or gel phase carriers or excipients. Examples of such carriers or excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars, starch, cellulose derivatives, gelatin, polymers such as polyethylene glycol, and combinations thereof.

[0064] In various embodiments, the composition may further include pharmaceutically and / or cosmetically acceptable carriers, excipients, diluents, fillers, disintegrants, desiccants, binders, lubricants, surfactants, hydrophobic carriers, water-soluble carriers, emulsifiers, buffers, humectants, wetting agents, solubilizers, preservatives, colorants, plasticizers, carriers, or combinations thereof. Those skilled in the art may refer to various pharmacological references, such as Modern Pharmaceutics, Banker & Rhodes, Marcel Dekker, Inc. (1979) and Goodman & Gilman's The Pharmaceutical Basis of Therapeutics, 6th Edition, MacMillan Publishing Co, New York (1980), to guide the determination of the amounts of such components in the compositions and formulations of each aspect. Any of the aforementioned carriers, excipients, diluents, fillers, disintegrants, desiccants, adhesives, lubricants, surfactants, hydrophobic carriers, water-soluble carriers, emulsifiers, buffers, humectants, wetting agents, solubilizers, preservatives, colorants, plasticizers, and combinations thereof may be incorporated into such compositions.

[0065] In some aspects, exemplary topical compositions may include solvents such as: water, isopropanol, dipropylene glycol methyl ether, butylated hydroxytoluene dipropylene glycol monomethyl ether, 1-methoxy-2-propanol (glysolv PM / lcinol PM), ethylene glycol monobutyl ether, diethylene glycol monobutyl ether (butyl diglysolv 1), diethylene glycol monoethyl ether (transcutol), propylene glycol (PG), N-methyl-2-pyrrolidone (NMP), dichloromethane, ether, ethanol, acetonitrile, ethyl acetate, benzyl alcohol, combinations of natural oils, ethylene glycol, propylene glycol, dimethylpolysiloxane (DMPX), oleic acid, octanoic acid, 1-octanol, ethanol (denatured or anhydrous), liposome compositions, suitable vegetable oils (e.g., aloe vera derivatives or sesame oil and / or their derivatives), ethosomes, azones, castor oil derivatives (e.g., ethoxylated castor oil), jojoba oil derivatives, corn oil derivatives, emu oil derivatives, and combinations thereof. The solvent may be present at any suitable concentration. For example, in some aspects, the solvent may be present at about 5 wt.% to about 99.9 wt.%, about 10 wt.% to about 95 wt.%, about 25 wt.% to about 90 wt.%, about 20 wt.% to about 80 wt.% of the total composition, or at any range or individual solvent concentration covered by these example ranges.

[0066] In some aspects, the topical composition may include a polar water-miscible solvent, such as an alcohol and / or glycol. Polar water-miscible solvents can improve skin penetration and solvation of the active agent. Polar water-miscible solvents may include, for example, C1-C4 alcohols, polyethylene glycol, ethylene glycol, propylene glycol, butylene glycol, pentanediol, glycerin, diethylene glycol monoethyl ether, propylene carbonate, and combinations and mixtures thereof. The total amount of the polar water-miscible solvent may be less than about 10 wt.% of the total composition weight, or about 0.5 wt.% to about 10 wt.%, about 1 wt.% to about 5 wt.%, about 0.5 wt.% to about 5 wt.%, or any range or individual solvent concentration covered by these exemplary ranges.

[0067] In some aspects, the composition may contain a surfactant. The surfactant may be incorporated into the oil phase, the aqueous phase, or both. Suitable surfactants include, for example, alkyl polyglycol ethers, alkyl polyglycol esters, ethoxylated alcohols, polysorbates, polyoxyethylene fatty acid esters, ionic or nonionic surfactants, hydrogenated castor oil / polyethylene glycol adducts, castor oil / polyethylene glycol adducts, sorbitan fatty acid esters (such as Span 20 or Span 80), block copolymers of ethylene oxide and propylene oxide (such as Pluronic L121 or Pluronic F68), polymeric surfactants having acrylic crosslinked copolymers (such as Pemulen Tr-1 and Pemulen Tr-2), and combinations and mixtures thereof. The composition may contain a surfactant at a concentration of about 0.1 wt.% to about 5 wt.%, about 0.5 wt.% to about 3 wt.%, about 0.7 wt.% to about 2 wt.%, or any range or individual solvent concentration covered by these exemplary ranges.

[0068] In some aspects, the composition may contain an antioxidant. Such antioxidants may be, for example, butylated hydroxytoluene, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, 2,4,5-trihydroxyphenylbutanone, 4-hydroxymethyl-2,6-di-tert-butylphenol, isoascorbic acid, guaiac resin, propyl gallate, thiodipropionic acid, dilauryl thiodipropionate, tert-butylhydroquinone, tocopherol, and pharmaceutically acceptable salts or esters thereof, or combinations thereof. The antioxidant may be present at a concentration of about 0.01 wt.% to about 1 wt.% of the total composition or at any single concentration covered by the example range.

[0069] In some aspects, the composition may include an emulsifier, such as various monoglycerides, diglycerides, triglycerides, and mixtures thereof, at a concentration of about 3 wt.% to about 10 wt.% of the total composition.

[0070] In some aspects, the composition may further comprise analgesics, such as methyl salicylate, codeine, morphine, methadone, meperidine, buprenorphine, hydromorphone, levonorgestrel, oxycodone, fentanyl, nonsteroidal anti-inflammatory drugs (NSAIDs), and combinations thereof. The amount of the analgesic in such compositions may be from about 0.01 wt.% to about 5 wt.% of the total composition.

[0071] In some aspects, the composition may further include a humectant. Examples of humectants used in exemplary compositions include propylene glycol, glycerin, and combinations thereof. The amount of the humectant in such compositions may be from about 0.01 wt.% to about 10 wt% of the total composition.

[0072] In some aspects, the composition may further comprise a pharmaceutically acceptable buffer sufficient to adjust and maintain the pH of the composition described herein in the range of about 7.0 to about 14.0, or about 8.5 to about 12.0. Typically, suitable buffers include citrates, phosphates, glycine, and combinations thereof. The amount of buffer in such compositions may be from about 0.01 wt.% to about 10 wt.% of the total composition.

[0073] In some aspects, the exemplary compositions may further contain minerals, mineral salts, or combinations thereof. Exemplary minerals used include, but are not limited to, selenium, sulfur, zinc, iron, chlorine, cobalt, copper, manganese, molybdenum, and iodine. The amount of minerals or mineral salts in the exemplary topical formulations includes any therapeutically effective amount. For example, the concentration of the mineral or mineral salt may be from about 0.01 wt.% to about 5 wt.% relative to the total amount of the composition, from about 0.1 wt.% to about 1 wt.% relative to the total amount of the composition, or any range or individual concentration covered by these example ranges.

[0074] In some aspects, the composition may further comprise vitamins or combinations of vitamins. Vitamins are organic molecules and nutrients essential for the maintenance of normal biological functions and metabolism in organisms. Examples used include, but are not limited to: vitamin A, vitamin B1, vitamin B2, vitamin B3, vitamin B4, vitamin B5, vitamin B6, vitamin B7, vitamin B8, vitamin B9, vitamin Bio, vitamin B11, vitamin B12, vitamin C, vitamin D, vitamin E, and vitamin K. The amount of vitamins in a topical formulation can be any therapeutically effective amount. For example, the concentration of vitamins can be from about 0.01 wt.% to about 5 wt.% relative to the total amount of the composition, from about 0.1 wt.% to about 1 wt.% relative to the total amount of the composition, or any range or individual concentration covered by these example ranges.

[0075] In some aspects, exemplary compositions may further comprise: anti-inflammatory compounds such as hyaluronic acid, curcumin, glutathione, methotrexate, tofacitinib, 6-mercaptopurine, azathioprine, sulfasalazine, mesalazine, oxalazine, chloroquine / hydroxychloroquine, penicillamine, sodium aurethimide malate (intramuscular and oral), azathioprine, colchicine, corticosteroids (oral, inhalation, and local injection), β-2 adrenergic receptor agonists (salbutamol, terbutaline, salmeterol), xanthine (theophylline, aminophylline), cromoglycate, nedolomethin, ketotifen, ipratropium, and oxitropium. Cyclosporine, FK506, rapamycin, mycophenolate mofetil, leflunomide, NSAIDs (e.g., ibuprofen), corticosteroids (e.g., prednisolone), phosphodiesterase inhibitors, adenosine agonists, antithrombotic agents, complement inhibitors, adrenergic agents, agents that interfere with the signaling of pro-inflammatory cytokines (e.g., NIK, IKK, p38, or MAP kinase inhibitors), IL-1 converting enzyme inhibitors, T cell signaling inhibitors (e.g., kinase inhibitors), metalloproteinase inhibitors, sulfasalazine, 6-mercaptopurine, angiotensin-converting enzyme inhibitors, soluble cytokine receptors (e.g., soluble p55 or p75). TNF receptor and its derivatives p75TNFRigG (etanercept) and p55TNFRigG (lenarcept), siL-1RI, siL-1RII, siL-6R, anti-inflammatory cytokines (e.g., IL-4, IL-10, IL-11, IL-13, and TGF), celecoxib, folic acid, hydroxychloroquine sulfate, rofecoxib, etanercept, infliximab, adalimumab, sertocilizumab, tocilizumab, abatacept, naproxen, vardicoxib, sulfasalazine, methylprednisolone, meloxicam, methylprednisolone acetate, disodium aurethiobutane, aspirin, triamcinolone acetonide, propoxyphene / acetaminophen naphthalenesulfonate. Folic acid, nabumetone, diclofenac, piroxicam, etodoxacin, diclofenac sodium, oxapazine, oxycodone hydrochloride, hydrocodone bitartrate / acetaminophen, diclofenac sodium / misoprostol, fentanyl, analgesin, tramadol hydrochloride, salsalate, sulindac, cyanocobalamin / folic acid / pyridoxine, acetaminophen, alendronate sodium, prednisolone, cortisone, betamethasone, morphine sulfate, lidocaine hydrochloride, indomethacin, glucosamine sulfate / chondroitin, amitriptyline hydrochloride, sulfadiazine, oxycodone HCV Acetaminophen, olopatadine hydrochloride, misoprostol, naproxen sodium, omeprazole, cyclophosphamide, rituximab, IL-1 TRAP, MRA, CTLA4-IG, IL-18BP, anti-IL-12, anti-IL1S, BIRB-796, SCIO-469, VX-702, AMG-548, VX-740, roflumilast, IC-485, CDC-801, S1PI agonists (such as FTY720), PKC family inhibitors (such as rubesta or AEB-071) or mesoplan, budesonide, epidermal growth factor, corticosteroids, cyclosporine, sulfasalazine, aminosalicylic acid, 6-mercaptopurine, azathioprine, metronidazole, lipoxygenase inhibitors, mesalazine, olsalazine, balsalazine, antioxidants, thromboxane inhibitors, IL-1 receptor antagonists, anti-IL-1 monoclonal antibodies Antibodies, anti-IL-6 monoclonal antibodies, growth factors, elastase inhibitors, pyridylimidazole compounds, antibodies or antagonists against other human cytokines or growth factors (e.g., TNF, LT, IL-1, IL-2, IL-6, IL-7, IL-8, IL-12, IL-15, IL-16, IL-23, EMAP-II, GM-CSF, FGF, and PDGF), cell surface molecules (e.g., CD2, CD3, CD4, CD8, CD25, CD28, CD30, CD40, CD45, CD69, or CD90 or their ligands), methotrexate, cyclosporine, FK506, rapamycin Mycotoxin, mycophenolate mofetil, leflunomide, NSAIDs (e.g., ibuprofen), corticosteroids (e.g., prednisolone), phosphodiesterase inhibitors, adenosine agonists, antithrombotic agents, complement inhibitors, adrenergic agents, agents that interfere with the signaling of pro-inflammatory cytokines such as TNF5 or IL-1 (e.g., NIK, IKK, or MAP kinase inhibitors), IL-1 converting enzyme inhibitors, TNF converting enzyme inhibitors, T cell signaling inhibitors such as kinase inhibitors, metalloproteinase inhibitors, sulfasalazine, azathioprine, 6-mercaptopurine, angiotensin-converting enzyme inhibitors, soluble cytokine receptors (e.g., soluble p55 or p75 TNF receptors, s... Anti-inflammatory agents, such as iL-1RI, siL-1RII, siL-6R, anti-inflammatory cytokines (e.g., IL-4, IL-10, IL-11, IL-13, or TGF), and therapeutic agents targeting intrinsic checkpoint blockade, such as genes encoding cytokine-induced SH2-containing proteins, antibodies BGB-A317, nivolumab or pembrolizumab, atezolizumab, avelumab, durvalumab, ipilimumab, and combinations thereof. The amount of the anti-inflammatory agent includes any therapeutically effective amount. For example, in some aspects, the amount of the anti-inflammatory agent may be from about 0.01 wt.% to about 5 wt.% relative to the total amount of the composition, or from about 0.1 wt.% to about 1 wt.% relative to the total amount of the formulation.wt.%, or any range or individual concentration covered by these example ranges.

[0076] Depending on the condition being treated, exemplary compositions may contain steroids, antihistamines, sympathomimetics, beta-blockers, parasympathomimetics, parasympatholytics, prostaglandins, nonsteroidal anti-inflammatory drugs (NSAIDs), antibiotics, antifungals, local anesthetics, and combinations thereof.

[0077] Further aspects of this disclosure include methods for treating pain by administering a therapeutically effective amount of any composition described or considered herein. The administration can be performed by any method, including but not limited to oral administration, intravenous (IV), intramuscular (IM), intrathecal administration, subcutaneous (SC), sublingual or buccal administration, rectal administration, vaginal administration, skin administration, percutaneous administration, and combinations thereof. In some aspects, administration can be performed orally or topically. In some aspects, the administration can be performed once or twice per hour, once daily, twice or three times daily, once weekly, twice, three times, four times or more, etc., depending on the duration of exposure or the severity of symptoms.

[0078] In some aspects, the method may include the steps of applying any of the exemplary compositions described herein, as well as co-applying one or more additional active agents or anti-inflammatory agents, and combinations thereof. Such additional active agents and anti-inflammatory agents, and combinations thereof, may be applied in separate doses via any route of administration. For example, the compositions described herein may be applied topically, while additional active agents, anti-inflammatory agents, and combinations thereof may be applied topically, orally, and / or by injection, respectively.

[0079] Compositions and methods of various aspects can be used to treat patients suffering from various types of pain, including, for example, acute pain, chronic pain, neuropathic pain, inflammatory pain, headache, somatic pain, visceral pain, and / or referred pain. As used herein, the term "pain" refers to any unpleasant sensory experience, usually associated with a physical disturbance. The physical disturbance may or may not be obvious to the clinician. There are two types of pain: chronic and acute. Acute pain is pain that is short in duration and has a sudden onset. Chronic pain is pain other than acute pain. Chronic pain includes neuropathic pain, inflammatory pain, headache, somatic pain, visceral pain, and referred pain.

[0080] In some respects, the compositions disclosed herein can be used to treat pain caused by or otherwise associated with neuropathic pain conditions. Neuropathic pain refers to abnormal sensory input from the peripheral nervous system, the central nervous system, or both, resulting in discomfort. Symptoms of neuropathic pain include persistent spontaneous pain, atypical pain (painful response to normally painless stimuli), hyperalgesia (an enhanced response to painful stimuli that normally cause only mild discomfort, such as a needle prick), and / or hyperalgesia (transient discomfort turning into prolonged, severe pain). Neuropathic pain can be caused by, for example, the following: traumatic injury, such as nerve compression injury (e.g., nerve crush, nerve stretching, nerve entrapment, or incomplete nerve transection); spinal cord injury (e.g., spinal cord resection); limb amputation; contusion; inflammation (e.g., myelitis); surgery; ischemic events, including, for example, stroke and / or heart attack; exposure to toxins, such as drugs, alcohol, heavy metals (e.g., lead, arsenic, mercury), industrial agents (e.g., solvents, glue fumes), and / or nitrous oxide; diseases, such as inflammatory diseases, neoplasms, acquired immunodeficiency syndrome (AIDS), Lyme disease, herpes zoster, varicella-zoster virus infection, leprosy, metabolic diseases, peripheral nerve disorders (e.g., neuroma), mononeuropathy, and / or polyneuropathy.

[0081] This category encompasses various types of neuropathic pain, including, for example, neuralgia (pain radiating along the pathway of one or more specific nerves, usually without any demonstrable pathological changes in neurostructure). Types of neuralgia include trigeminal neuralgia, postherpetic neuralgia, glossopharyngeal neuralgia, sciatica, and atypical facial pain. Various types of neuralgia typically cause brief, intense pain that can be described in many ways, such as "lancinating," "stabbing," "sharp," "lightning-like," "burning," "like an electric shock," and "itchy." Neuralgia can occur after infections (such as shingles, varicella-zoster virus infection, syphilis, Lyme disease), depression, diabetes, chronic renal insufficiency, porphyria, medication use, and combinations thereof.

[0082] In some respects, exemplary compositions can be used to treat deafferentation. Deafferentation refers to the loss of sensory input from a part of the body, which may be caused by interruption of peripheral sensory fibers or nerves from the central nervous system. Deafferentation pain syndromes include, for example, pain associated with brain or spinal cord injury, post-stroke pain, phantom pain, paraplegia, brachial plexus avulsion injuries, lumbar radiculopathy, and combinations thereof.

[0083] In some respects, the exemplary composition can be used to treat complex regional pain syndrome (CRPS). CRPS is a chronic pain syndrome caused by sympathetic maintenance pain and can exist in two forms. CRPS 1 is a chronic neurological disorder that most commonly occurs in the arm or leg after minor or severe injury. CRPS 1 is associated with severe pain; changes in the nails, bones, and skin; and increased sensitivity to touch in the affected limb. CRPS 2 arises from identified nerve damage.

[0084] In some respects, exemplary compositions can be used to treat neuropathy. Neuropathy is a functional or pathological alteration of nerves, clinically characterized by abnormalities in sensory or motor neurons. Central neuropathy is a functional or pathological alteration of the central nervous system. Peripheral neuropathy is a functional or pathological alteration of one or more peripheral nerves that transmit information from the central nervous system (brain and spinal cord) to muscles and other organs, and from the skin, joints, and other organs back to the brain. Risk factors for neuropathy include diabetes, alcoholism, genetic predisposition, exposure to certain chemicals and drugs, and chronic compression of nerves. Neuropathy can affect any one or a combination of sensory, motor, and autonomic nerves. Symptoms also depend on whether the condition affects the whole body or only a single nerve (e.g., due to injury). For example, the methods disclosed herein can be used to treat diabetic neuropathic pain (DNP), chemotherapy-induced neuropathic pain (CINP), and combinations thereof.

[0085] Peripheral neuropathy can be caused by, for example, genetic disorders, peroneal muscular atrophy, Friedreich ataxia, systemic or metabolic diseases, diabetes (diabetic neuropathy), multiple sclerosis, dietary deficiencies (especially vitamin B-12), excessive alcohol consumption (alcoholic neuropathy), uremia (caused by kidney failure), cancer, infectious or inflammatory conditions, HIV / AIDS, hepatitis, Colorado tick fever, diphtheria, and Guillain-Barré syndrome. Leprosy, Lyme disease, herpes zoster, varicella-zoster virus infection, polyarteritis nodosa, rheumatoid arthritis, sarcoidosis, Sjögren's syndrome, syphilis, systemic lupus erythematosus, amyloidosis, exposure to toxic compounds, heavy metals (lead, arsenic, mercury, etc.), ischemia (reduced oxygen / blood flow), prolonged exposure to hypothermia, and combinations thereof.

[0086] Polyneuropathy is a peripheral neuropathy involving loss of motor or sensory function in a specific area due to damage or destruction of multiple peripheral nerves. Polyneurotic pain can occur in conditions such as post-polio syndrome, postmastectomy syndrome, diabetic neuropathy, alcoholic neuropathy, amyloidosis, toxins, AIDS, hypothyroidism, uremia, vitamin deficiency, chemotherapy-induced pain, 2',3'-dideoxycytidine (ddC) treatment, Guillain-Barré syndrome, or Fabry disease.

[0087] Mononeuropathy is a peripheral neuropathy involving loss of motor or sensory function in a specific area due to injury or destruction of a single peripheral nerve or nerve group. Mononeuropathy is most commonly caused by localized injury or trauma, although occasionally systemic disorders can lead to isolated nerve damage (such as polyneuritis). Causes may include trauma, prolonged compression of the nerve, compression of the nerve by swelling or damage to nearby body structures, and damage leading to destruction of the myelin sheath or part of the nerve cell. Examples of mononeuropathy-related pain include sciatic nerve dysfunction, peroneal nerve dysfunction, radial nerve dysfunction, ulnar nerve dysfunction, cranial mononeuropathy VI, cranial mononeuropathy VI, cranial mononeuropathy VII, cranial mononeuropathy VII, cranial mononeuropathy III (compression type), cranial mononeuropathy III (diabetic type), axillary nerve dysfunction, carpal tunnel syndrome, femoral nerve dysfunction, tibial nerve dysfunction, Bell's palsy, thoracic outlet syndrome, sixth (abducens) nerve palsy, and combinations thereof.

[0088] Generalized peripheral neuropathy is symmetrical and usually results from various systemic diseases and disease processes affecting the peripheral nervous system. Generalized peripheral neuropathy includes distal axonopathy, caused by certain metabolic or toxic disorders of neurons, often due to conditions such as diabetes, renal failure, deficiency syndromes (e.g., malnutrition), and alcoholism, or the effects of toxins or drugs; myelopathy caused by attack on the myelin sheath, resulting from acute inflammatory demyelinating polyneuropathy (AIDP; also known as Guillain-Barré syndrome), chronic inflammatory demyelinating syndrome (CIDP), inherited metabolic diseases (e.g., leukodystrophy), or acute failure of impulse conduction caused by toxins; neuropathy, caused by damage to peripheral nervous system (PNS) neurons due to motor neuron disease, sensory neuron disease (e.g., herpes zoster), toxins, neurotoxins, autonomic dysfunction, or infection; and focal entrapment neuropathy, such as carpal tunnel syndrome.

[0089] In some respects, the exemplary compositions can be used to treat inflammatory pain. For example, the exemplary compositions can be used to treat arthritic diseases such as: rheumatoid arthritis; juvenile rheumatoid arthritis; systemic lupus erythematosus (SLE); gouty arthritis; scleroderma; osteoarthritis; psoriatic arthritis; ankylosing spondylitis; Reiter's syndrome (reactive arthritis); adult-onset Still's disease; arthritis caused by viral infections; arthritis caused by bacterial infections, such as gonococcal arthritis and non-gonococcal bacterial arthritis (suppurative arthritis); stage III Lyme disease; tuberculous arthritis; arthritis caused by fungal infections, such as blastomycosis, and combinations thereof. In some aspects, the exemplary compositions can be used to treat autoimmune diseases, such as Guillain-Barré syndrome, Hashimoto's thyroiditis, pernicious anemia, Addison's disease, type 1 diabetes, systemic lupus erythematosus, dermatomyositis, Sjogren's syndrome, lupus erythematosus, multiple sclerosis, myasthenia gravis, Reiter's syndrome, Graves' disease, Mogellons disease, and combinations thereof. In some aspects, the exemplary compositions can be used to treat connective tissue diseases, such as spondyloarthritis, dermatomyositis, fibromyalgia, and combinations thereof. In some aspects, the exemplary compositions can be used to treat injuries and inflammation resulting from injuries, such as crushing, puncture, or stretching of a joint or joint-related tissue. In some aspects, the exemplary compositions can be used to treat neuritis, an inflammatory process affecting a nerve or group of nerves, with symptoms including pain, paresthesia, paresis, or hypoesthesia (numbness). Examples of neuritis include brachial neuritis, retrobulbar neuropathy, optic neuropathy, vestibular neuritis, and combinations thereof.

[0090] In some respects, exemplary compositions may be used to treat headaches, including, for example, muscular / myogenic headaches, tension headaches, episodic tension headaches, chronic tension headaches, vascular headaches, migraines (including migraine without aura (common migraine), migraine with aura (classical migraine), menstrual migraine, migraine equivalent (migraine without headache), complex migraine, abdominal migraine, and mixed tension migraine), cluster headaches, hypertensive headaches, traction and inflammatory headaches, steroid headaches, rebound headaches, chronic sinusitis headaches (caused by, for example, bacterial infection, fungal infection, viral infection, allergy, or autoimmune disease of the sinuses), organic headaches, ictal headaches, and combinations thereof.

[0091] In some respects, the exemplary compounds can be used to treat pain caused by or otherwise associated with somatic pain conditions, such as excessive muscle tension, sprains, strains, repetitive movement disorders (e.g., caused by overuse of the hands, wrists, elbows, shoulders, necks, backs, hips, knees, feet, legs, or ankles), and muscle diseases (e.g., caused by polymyositis, dermatomyositis, lupus, fibromyalgia, polymyalgia rheumatica). Rhabdomyolysis (and other diseases caused by rheumatica), myalgia, infections (including, for example, muscle abscesses, trichinosis, influenza, Lyme disease, malaria, Rocky Mountain spotted fever, avian influenza, the common cold, community-acquired pneumonia, meningitis, monkeypox, severe acute respiratory syndrome, toxic shock syndrome, trichinosis, typhoid fever, upper respiratory tract infection, etc.), drugs (including, for example, cocaine, statins used to lower cholesterol (such as atorvastatin, simvastatin, and lovastatin), ACE inhibitors used to lower blood pressure (such as enalapril and captopril), etc.), and combinations thereof.

[0092] In some respects, exemplary compositions can be used to treat visceral pain originating from internal organs or viscera, including, for example, functional visceral pain such as pain associated with irritable bowel syndrome, chronic functional abdominal pain (CFAP), functional constipation, functional dyspepsia, non-cardiac chest pain (NCCP), and chronic abdominal pain; chronic gastrointestinal inflammation such as gastritis, Crohn's disease, ulcerative colitis, microscopic colitis, diverticulitis, gastroenteritis, interstitial cystitis, intestinal ischemia, cholecystitis, appendicitis, gastroesophageal reflux, ulcers, kidney stones, urinary tract infection, pancreatitis, hernia, etc.; autoimmune pain such as sarcoidosis and vasculitis; organic visceral pain such as pain caused by traumatic, inflammatory, or degenerative lesions of the gut or pain caused by tumors compressing sensory nerve innervations; treatment-induced visceral pain such as pain associated with chemotherapy or radiotherapy, and combinations thereof.

[0093] In some respects, the exemplary compositions can be used to treat pain caused by or otherwise associated with referred pain conditions, such as pain associated with herniated discs, compressed nerves (e.g., compressed nerves in the thigh, knee, or foot), myocardial ischemia, and combinations thereof.

[0094] In any of the embodiments described herein, the compositions and methods of this disclosure relate to treating trigeminal neuralgia and reducing and / or controlling the pain associated therewith. In some embodiments, a method for treating trigeminal neuralgia is provided, comprising administering a therapeutically effective amount of alimazine or a pharmaceutically acceptable salt thereof to a patient in need, thereby treating the patient's trigeminal neuralgia.

[0095] In some embodiments, a therapeutically effective amount of alimazine or a pharmaceutically acceptable salt thereof is administered once daily. In some embodiments, a therapeutically effective amount of alimazine or a pharmaceutically acceptable salt thereof is administered twice daily. A therapeutically effective amount of alimazine or a pharmaceutically acceptable salt thereof may be administered by any of the methods described herein, such as oral administration, intravenous administration (IV), intramuscular administration (IM), intrathecal administration, subcutaneous administration (SC), sublingual or buccal administration, rectal administration, vaginal administration, skin administration, transdermal administration, or a combination thereof. In some embodiments, a therapeutically effective amount of alimazine or a pharmaceutically acceptable salt thereof is administered orally. In some embodiments, a therapeutically effective amount of alimazine or a pharmaceutically acceptable salt thereof is administered sublingually.

[0096] In some implementations, the therapeutically effective amount of alimazine or a pharmaceutically acceptable salt thereof is from about 0.5 mg to about 20 mg, such as about 0.5 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, or any range or value thereof. In some embodiments, a therapeutically effective amount of alimazine or a pharmaceutically acceptable salt thereof is from about 0.05 mg / kg to about 5 mg / kg, such as about 0.05 mg / kg, about 0.06 mg / kg, about 0.07 mg / kg, about 0.08 mg / kg, about 0.09 mg / kg, about 0.1 mg / kg, about 0.5 mg / kg, about 1 mg / kg, about 1.5 mg / kg, about 2 mg / kg, about 2.5 mg / kg, about 3 mg / kg, about 3.5 mg / kg, about 4 mg / kg, about 4.5 mg / kg, about 5 mg / kg, or any range or value thereof.

[0097] Trigeminal neuralgia can be type 1 or type 2, or a combination thereof. Type 1 TN can present as intense, brief, sudden, and / or blazing facial pain that can last from seconds to minutes. Type 2 TN can present as persistent stinging, aching, or burning soreness, which may be relatively less intense than type 1. Patients may experience both type 1 and type 2 TN simultaneously or periodically. Further classifications of TN include primary, caused by vascular compression of the nerve; secondary, usually caused by neurological disorders such as multiple sclerosis or tumors or cysts near the trigeminal nerve; and idiopathic, where the cause is unknown.

[0098] In some implementations, treatment for trigeminal neuralgia includes reducing the patient's pain. Pain relief can be assessed using any method known to those skilled in the art, including pain assessment scales such as OPQRST, QISS TAPED, SOCRATES, Pain Risk Factors Assessment Form, Numerical Rating Scale, Visual Analog Scale, Penn Facial Pain Scale (Penn-FPS), Penn Facial Pain Scale Revised (Penn-FPS-R), Brief Pain Inventory – ShortForm (BPI-SF), Brief Pain Inventory Pain Interference Index (BPI-PII), Patient Global Impression of Change (PGIC), Faces Pain Scale – Revised (FPS-R), Burchiel Questionnaire, and McGill Pain Questionnaire. The Questionnaire, the Barrow Neurological Institute (BNI) pain intensity score, and other patient-reported outcomes (PROs) and clinician-transmitted assessments familiar to those skilled in the art may also be used. Other assessments evaluating the impact of pain on a patient's ability to perform daily activities may also be employed, such as the EuroQoL 5-Dimension 5 Level (EQ-5D-5L), Work Productivity and Activity Impairment (WPAI), etc. Treatment of a patient with trigeminal neuralgia may include improving and / or preventing an increase in one or more of the assessments described herein.

[0099] In some implementations, reducing patient pain includes improving patient pain as measured by the Penn-FPS-R score, the Penn-FPS score, or a combination thereof. In some implementations, reducing patient pain includes preventing an increase in patient pain as measured by the Penn-FPS-R score, the Penn-FPS score, or a combination thereof.

[0100] In some implementations, treatment of trigeminal neuralgia includes improvement of the patient's Penn-FPS-R score, Penn-FPS score, PGIC score, EQ-5D-5L score, WPAI score, or a combination thereof. In some implementations, treatment of trigeminal neuralgia includes preventing increases in the patient's Penn-FPS-R score, PGIC score, Penn-FPS score, EQ-5D-5L score, BNI pain intensity score, or WPAI score, preventing low PGIC scores, or a combination thereof.

[0101] The Penn-FPS-R scale asks patients to circle a number that best describes the severity of their pain interference. Interference items include eating, touching the face (including brushing loose hair, hugging, kissing, itching), brushing teeth or using dental floss, smiling or laughing, speaking, opening the mouth wide, biting or chewing, self-care (including washing face or hair, shaving, applying makeup), activities involving temperature changes (including moving between outdoors and air-conditioned rooms), daily activities (including work, exercise, housework), mood (the patient's feelings), and interpersonal relationships (with friends, family, partners, etc.). Endpoints for treating TN include a reduction in the overall severity and duration of facial pain, a reduction in the frequency and severity of paroxysmal excruciating pain (intense pain associated with TN), and a reduction in the dosage of existing standards of care for TN analgesics, including discontinuation of existing standards of care for TN analgesics.

[0102] In some implementations, a method for treating pain associated with trigeminal neuralgia is specifically embodied, which includes administering a therapeutically effective amount of alimazine or a pharmaceutically acceptable salt thereof to a patient in need, thereby treating the patient's trigeminal neuralgia.

[0103] In some implementations, a therapeutically effective amount of alimazine or a pharmaceutically acceptable salt thereof is administered once daily.

[0104] In some implementations, a therapeutically effective amount of alimazine or a pharmaceutically acceptable salt thereof is administered twice daily.

[0105] In some implementations, a therapeutically effective amount of alimazine or a pharmaceutically acceptable salt thereof is administered via oral, intravenous (IV), intramuscular (IM), intrathecal, subcutaneous (SC), sublingual or buccal, rectal, vaginal, dermal, transdermal, nasal, or a combination thereof.

[0106] In some implementations, a therapeutically effective amount of alimazine or a pharmaceutically acceptable salt thereof is administered orally.

[0107] In some implementations, a therapeutically effective amount of alimazine or a pharmaceutically acceptable salt thereof is administered via an oral film formulation.

[0108] In some implementations, the therapeutically effective amount of alimazine or a pharmaceutically acceptable salt thereof is about 0.5 mg to about 20 mg.

[0109] In some implementations, the therapeutically effective amount of alimazine or a pharmaceutically acceptable salt thereof is about 2.5 to about 5 mg.

[0110] In some implementations, the therapeutically effective amount of alimazine or a pharmaceutically acceptable salt thereof is about 0.5 to about 2.5 mg.

[0111] In some implementations, treatment for pain associated with trigeminal neuralgia includes reducing the frequency of pain, reducing the duration of pain, reducing the intensity of pain, or any combination thereof.

[0112] In some implementations, the reduction in pain duration includes a reduction in the duration of a single pain attack, a reduction in the duration of a series of pain attacks, or any combination thereof.

[0113] In some implementations, a series of pain episodes includes at least two separate pain episodes.

[0114] In some implementations, the pain associated with trigeminal neuralgia is stinging, tearing, throbbing, electric shock-like, persistent aches, burning, stinging with an intensity slightly less than that of type 1 TN, and any combination thereof.

[0115] In some implementations, the reduction in pain frequency, the reduction in pain duration, the reduction in pain intensity, or any combination thereof, is measured using a patient diary, PGIC score, MSQ score, Penn-FPS-R score, Penn-FPS score, EQ-5D-5L score, Barrow Neurological Institute Pain Intensity Scale, WPAI score, or any combination thereof.

[0116] In some implementations, administering a therapeutically effective amount of alimazine or a pharmaceutically acceptable salt thereof includes an initial dose between 2.5 and 5.0 mg.

[0117] In some embodiments, administering a therapeutically effective amount of alimazine or a pharmaceutically acceptable salt thereof includes administering an initial dose between about 0.5 mg and about 2.5 mg, such as about 0.5 mg, about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, or any value contained within the range formed by any two of the foregoing values.

[0118] Some implementation schemes further include administering an additional therapeutically effective amount of alimazine or a pharmaceutically acceptable salt thereof approximately every 30 minutes to approximately every 5 hours after the initial dose if treatment for pain associated with trigeminal neuralgia is not achieved.

[0119] In some embodiments, an additional therapeutically effective amount of alimazine or a pharmaceutically acceptable salt thereof is increased approximately every 30 minutes to approximately every 5 hours until treatment of pain associated with trigeminal neuralgia is achieved. For example, the initial dose may be approximately 0.5 mg, followed by a dose of approximately 1 mg after approximately 30 minutes. In some embodiments, the initial dose may be approximately 1 mg, followed by a dose of approximately 2.5 mg after approximately 2 hours. Various combinations are considered, i.e., an initial dose of approximately 0.5 to approximately 2.5 mg, followed by an additional dose (greater than the initial dose) administered approximately 30 minutes to approximately 5 hours after the initial dose.

[0120] In some implementations, once treatment for pain associated with trigeminal neuralgia is achieved, an additional therapeutically effective amount of alimazine or a pharmaceutically acceptable salt thereof is maintained as the minimum effective level for treating pain associated with trigeminal neuralgia.

[0121] In some implementations, the minimum effective level of therapeutically effective amount of alimazine or a pharmaceutically acceptable salt thereof is administered until treatment of pain associated with trigeminal neuralgia is no longer achieved. Thereafter, the minimum effective level of therapeutically effective amount of alimazine or a pharmaceutically acceptable salt thereof may be further increased until treatment of pain associated with trigeminal neuralgia is achieved again.

[0122] In some implementations, at least every three months, the applied therapeutically effective amount of alimazine or a pharmaceutically acceptable salt thereof is reduced to a minimum effective level of alimazine or a pharmaceutically acceptable salt thereof.

[0123] In some implementations, administration of a therapeutically effective amount of alimazine or a pharmaceutically acceptable salt thereof is discontinued at least every three months.

[0124] A method for relieving pain in a patient suffering from trigeminal neuralgia is provided, comprising administering a therapeutically effective amount of alimazine or a pharmaceutically acceptable salt thereof to a patient in need, thereby relieving the patient's pain. The method for relieving pain in a patient suffering from trigeminal neuralgia may utilize any composition, formulation, or dosing regimen of any embodiment described herein.

[0125] In some implementations, reducing patient pain includes improving patient pain as measured by the Penn-FPS score compared to pre-treatment patient pain as measured by the Penn-FPS score. In some implementations, reducing patient pain includes preventing an increase in patient pain as measured by the Penn-FPS score compared to pre-treatment patient pain as measured by the Penn-FPS score.

[0126] In some implementations, reducing patient pain includes improving patient pain as measured by the Penn-FPS-R score compared to pre-treatment patient pain as measured by the Penn-FPS-R score. In some implementations, reducing patient pain includes preventing an increase in patient pain as measured by the Penn-FPS-R score compared to pre-treatment patient pain as measured by the Penn-FPS-R score.

[0127] In some implementations, reducing patient pain includes improving the patient's PGIC score at the end of the treatment period. In other implementations, reducing patient pain includes preventing a low PGIC score at the end of the treatment period.

[0128] Self-reported changes in Patient Overall Impression (PGIC) reflect patients' perceptions of treatment effectiveness. The PGIC is a 7-point scale describing patients' ratings of overall improvement. Patients rate their changes as “very significant improvement,” “significant improvement,” “minor improvement,” “no change,” “slight worsening,” “significant worsening,” or “very significant worsening.” As used herein, a low PGIC score is considered to be a score of “slight worsening,” “significant worsening,” or “very significant worsening” at the end of the treatment period. Therefore, the method of treating trigeminal neuralgia and alleviating associated pain according to the present invention includes preventing scores of “slight worsening,” “significant worsening,” or “very significant worsening” at the end of the treatment period. Improvement in the patient's PGIC score at the end of the treatment period is defined as a score of “very significant improvement,” “significant improvement,” or “slight improvement.”

[0129] A method for treating pain in a patient is provided, comprising administering to the patient a therapeutically effective amount of alimazine or a pharmaceutically acceptable salt thereof, thereby treating the patient's pain. In some embodiments, the therapeutically effective amount of alimazine or a pharmaceutically acceptable salt thereof is from about 0.5 mg to about 80 mg, such as about 0.5 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 70 mg, about 75 mg, about 80 mg, or any range or value thereof.

[0130] In some embodiments, the pain may be caused by any acute, chronic, neuropathic, or other pain source disclosed herein. For example, in some embodiments, the pain may be caused by trigeminal neuralgia, postherpetic neuralgia, neuritis, brachial plexus neuritis, retrobulbar neuropathy, optic neuropathy, vestibular neuritis, glossopharyngeal neuralgia, sciatica, atypical facial pain, afferent nerve block pain syndrome, complex regional pain syndrome (CRPS), central neuropathy, peripheral neuropathy, diabetic neuropathic pain (DNP), chemotherapy-induced neuropathic pain (CINP), polyneuropathy, mononeuropathy, generalized peripheral neuropathy, or combinations thereof.

[0131] In some implementations, the pain may be caused by arthritic diseases such as: rheumatoid arthritis; juvenile rheumatoid arthritis; systemic lupus erythematosus (SLE); gouty arthritis; scleroderma; osteoarthritis; psoriatic arthritis; ankylosing spondylitis; Reiter's syndrome (reactive arthritis); adult-onset Still's disease; arthritis caused by viral infections; arthritis caused by bacterial infections, such as gonococcal arthritis and non-gonococcal bacterial arthritis (suppurative arthritis); stage III Lyme disease; tuberculous arthritis; arthritis caused by fungal infections, such as blastomycosis, or combinations thereof.

[0132] In some implementations, the pain may be caused by an autoimmune disease, such as Guillain-Barré syndrome, Hashimoto's thyroiditis, pernicious anemia, Addison's disease, type 1 diabetes, systemic lupus erythematosus, dermatomyositis, Sjögren's syndrome, multiple sclerosis, myasthenia gravis, Reiter's syndrome, Graves' disease, Mogellons' disease, or a combination thereof.

[0133] In some implementations, the pain may be caused by connective tissue diseases, such as spondyloarthritis, dermatomyositis, fibromyalgia; injury and inflammation caused by trauma, such as compression, puncture, stretching of the joint or joint-related tissues, or a combination thereof.

[0134] In some implementations, the pain may be caused by muscular / myogenic headache, tension headache, episodic tension headache, chronic tension headache, vascular headache, migraine (including migraine without aura (common migraine), migraine with aura (classical migraine), menstrual migraine, migraine equivalent (migraine without headache), complex migraine, abdominal migraine, and mixed tension migraine), cluster headache, hypertensive headache, traction and inflammatory headache, steroid headache, rebound headache, chronic sinusitis headache caused by, for example, bacterial infection, fungal infection, viral infection, allergy, or autoimmune disease of the sinuses, or a combination thereof.

[0135] In some implementations, the pain may be caused by somatic pain conditions, such as excessive muscle tension, sprains, strains, repetitive movement disorders (e.g., caused by overuse of the hand, wrist, elbow, shoulder, neck, back, hip, knee, foot, leg, or ankle) or a combination thereof.

[0136] In some implementations, the pain may be caused by muscle diseases (e.g., polymyositis, dermatomyositis, lupus, fibromyalgia, polymyalgia rheumatica, and rhabdomyolysis), myalgia, infections (including, for example, muscle abscess, trichinosis, influenza, COVID-19, Lyme disease, malaria, Rocky Mountain spotted fever, avian influenza, the common cold, community-acquired pneumonia, meningitis, monkeypox, severe acute respiratory syndrome, toxic shock syndrome, trichinosis, typhoid fever, upper respiratory tract infection) or a combination thereof.

[0137] In some implementations, the pain may be caused by visceral pain originating from internal organs or viscera, including, for example, functional visceral pain such as pain associated with irritable bowel syndrome, chronic functional abdominal pain (CFAP), functional constipation, functional dyspepsia, non-cardiac chest pain (NCCP), and chronic abdominal pain; chronic gastrointestinal inflammation such as gastritis, Crohn's disease, ulcerative colitis, microscopic colitis, diverticulitis, gastroenteritis, interstitial cystitis, intestinal ischemia, cholecystitis, appendicitis, gastroesophageal reflux, ulcers, kidney stones, urinary tract infections, pancreatitis, hernias, and combinations thereof.

[0138] In some implementations, pain may be caused by autoimmune pain such as sarcoidosis and vasculitis, organic visceral pain such as pain caused by traumatic, inflammatory or degenerative intestinal injury or pain caused by tumor compression of sensory nerve innervation, treatment-induced visceral pain such as pain associated with chemotherapy or radiotherapy, and combinations thereof.

[0139] In some implementations, the pain may be caused by referred pain conditions, such as pain or combinations thereof related to herniated discs, compressed nerves (e.g., compressed nerves in the thigh, knee, or foot), myocardial ischemia, etc.

[0140] In any of these implementations, alleviating patient pain may include reducing and / or preventing an increase in patient pain as assessed by patient-reported outcomes (PROs) or by an assessment familiar to a clinician skilled in the art. There are no particular limitations on the assessments used to evaluate pain; they may be any assessment disclosed herein or any assessment known to a person skilled in the art, including but not limited to assessments relating to the pain condition and source disclosed herein.

[0141] As described herein, the methods disclosed herein can replace, or be used in conjunction with, existing standard care treatments for trigeminal neuralgia or any acute pain, chronic pain, neuropathic pain, inflammatory pain, headache, somatic pain, visceral pain, and / or referred pain disclosed herein to further alleviate the symptoms described herein. Not wishing to be bound by theory, this document provides examples of existing standard care treatments.

[0142] Pain from any of the conditions described in this article can be treated with a variety of medications. For example, medications used for the conditions described in this article and their associated pain may include anticonvulsants such as gabapentin and pregabalin; tricyclic antidepressants such as amitriptyline and nortriptyline; serotonin-norepinephrine reuptake inhibitors such as duloxetine, venlafaxine, and desvenlafaxine; opioids such as tramadol and tapentadol ER; opioids such as oxycodone, hydrocodone, tramadol, codeine, and morphine; topical medications such as lidocaine patches, capsaicin creams and patches, isosorbide dinitrate spray, and compound gels containing baclofen, amitriptyline, and ketamine; and selective serotonin reuptake inhibitors (SSRIs), such as... Citalopram, paroxetine, and escitalopram; nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin, ibuprofen, and naproxen sodium; N-methyl-D-aspartate (NMDA) receptor agonists such as ketamine, dextromethorphan, memantine, and amantadine; and opioids such as methadone, dextropropoxyphene, and ketobemidone, which are also NMDA receptor antagonists; acetaminophen; neurostimulation, including local or spinal nerve stimulation; psychological support, such as cognitive behavioral therapy; steroid injections, including betamethasone; and local anesthetics such as lidocaine and bupivacaine hydrochloride. Other medications for the conditions described herein may also be used, as is known to those skilled in the art. The methods and compositions of the present invention may be used in place of or in combination with the other medications disclosed herein.

[0143] Additional examples of other medicaments and exemplary dosing regimens that can be used to treat the conditions disclosed herein are also described. It is not intended to limit one to theory; the medicaments disclosed herein can be used to treat a variety of pain conditions (such as those disclosed herein) and can be used in place of or in combination with the compositions and methods of this disclosure to effectively treat a variety of pain sources.

[0144] Carbamazepine can be administered at an initial dose of approximately 200 mg, for example, two to four times daily. The dosage range is from approximately 200 mg to approximately 1200 mg, titrated with approximately 200 mg every 3 days. Dose reduction can be done with 200 mg every 7 days. Potential side effects include dizziness, drowsiness, fatigue, ataxia, diplopia, nausea, cognitive slowing, hyponatremia, leukopenia, thrombocytopenia, skin reactions, and abnormal liver function tests. Carbamazepine can be used to treat conditions including, but not limited to, trigeminal neuralgia. Carbamazepine is approved in the European Union for trigeminal neuralgia and diabetic peripheral neuropathic pain, and in the United States for trigeminal neuralgia. Carbamazepine stabilizes the membrane at voltage-gated sodium channels on nociceptive neurons in the PNS and CNS and reduces the spontaneous activity of these neurons.

[0145] Oxcarbazepine can be administered as an initial dose of about 300 mg, for example, four times daily. The dosage range is from about 300 mg to about 1800 mg, titrated with about 300 mg every 3 days. The dose can be reduced to 300 mg every 7 days. Potential side effects include dizziness, drowsiness, fatigue, nausea, ataxia, hyponatremia, and skin reactions. Oxcarbazepine can be used to treat conditions including, but not limited to, trigeminal neuralgia.

[0146] Lamotrigine can be administered as an initial dose of about 25 mg, for example, twice daily. The dose range is from about 25 mg to about 400 mg, with a titration regimen of about 25 mg for 2 weeks, 50 mg for 1 week, and then increasing by about 50 mg weekly. Tapering can be done at 50 mg every 7 days. Potential side effects include dizziness, drowsiness, fatigue, headache, gastrointestinal symptoms, irritability, sleep disturbances, tremor, cognitive impairment, and rash. Lamotrigine can be used to treat conditions including, but not limited to, trigeminal neuralgia.

[0147] Gabapentin can be administered at an initial dose of approximately 300 mg, for example, three times daily. The dosage range is from approximately 300 mg to approximately 3600 mg, titrated with approximately 300 mg every 3 days. Tapering can be done with 300 mg every 7 days. Potential side effects include dizziness, confusion, fatigue, ataxia, drowsiness, suicidal behavior, increased frequency of withdrawal-induced seizures, multi-organ hypersensitivity, peripheral edema, ataxia or gait disturbance, diarrhea, increased risk of infection, gastrointestinal symptoms, and weight gain; caution should be exercised when used in combination with opioids. Gabapentin is an anticonvulsant / anti-epileptic drug approved by the FDA for the treatment of PHN in adults, and may also be used to treat conditions including, but not limited to, trigeminal neuralgia and DNP. Gabapentin is approved in the EU for peripheral neuropathic pain. Structurally associated with the GABA neurotransmitter, it acts by binding to the α2-δ site of voltage-gated calcium channels, thereby reducing the release of excitatory neurotransmitters.

[0148] Pregabalin can be administered as an initial dose of approximately 150 mg, for example, twice daily. The dosage range is from approximately 150 mg to approximately 600 mg, titrated with approximately 150 mg every 3 days. Dose reduction can be done in 100 mg every 7 days. Potential side effects include dizziness, confusion, ataxia, increased risk of infection, gastrointestinal symptoms, and weight gain. Pregabalin is an FDA-approved medication for the treatment of postherpetic neuralgia (PHN) and can also be used to treat conditions including, but not limited to, trigeminal neuralgia. Pregabalin is also approved in the United States for diabetic peripheral neuropathy and neuropathic pain associated with spinal cord injury, and in the European Union for peripheral and central neuropathic pain. Its action is similar to gabapentin, binding to calcium channels and affecting neurotransmitter release, but it is more potent and requires a lower dose. Adverse reactions include dizziness, water retention, visual disturbances, drowsiness, ataxia, euphoria, and vertigo. A Japanese study reported that pregabalin's analgesic effect in PHN is six times that of gabapentin. Although pain is relieved, the dosage should be increased gradually and cautiously to prevent adverse reactions.

[0149] Baclofen can be administered as an initial dose of about 15 mg, for example, three times daily. The dosage range is from about 15 mg to about 90 mg, titrated with about 15 mg every 3 days. Tapering can be done with 15 mg every 7 days. Potential side effects include confusion, dizziness, drowsiness, gastrointestinal symptoms, euphoria, and hallucinations. Baclofen can be used to treat conditions including, but not limited to, trigeminal neuralgia. Baclofen may act through a combined mode of action, namely GABAergic modulation, blocking sodium channels and glutamatergic (NMDA) receptors.

[0150] Botulinum toxin type A can be administered at an initial dose of approximately 25-195 units, for example, once every 12 weeks. The dosage range is approximately 25 units to approximately 195 units. Potential side effects include temporary facial asymmetry, temporary bruising at the injection site, temporary drooling, and difficulty chewing. Botulinum toxin type A can be used to treat conditions including, but not limited to, trigeminal neuralgia. Botulinum toxin type A (BTX-A) is a toxin produced by Clostridium botulinum and has been used to treat a variety of conditions, including dystonia, spasticity, cerebral palsy, strabismus, and chronic pain of various origins, including PHN. Its mechanism of action is not fully understood. It primarily works by inhibiting the release of pain mediators at nerve endings and dorsal root ganglia, reducing inflammation around nerve endings, inactivating sodium channels, and exhibiting axonal transport. In a study of 58 patients, BTX-A was found to effectively reduce pain in 18 cases (31%) and showed significant effects in 27 cases (46.6%) of PHN symptoms. Side effects of BTX-A treatment are mild, including pain at the injection site, which usually disappears within a week without any treatment.

[0151] Duloxetine is a selective serotonin and norepinephrine reuptake inhibitor (SNRI) that increases the levels of these neurotransmitters in the brain and spinal cord, helping to modulate pain transmission. The starting dose of duloxetine is 30 mg daily, titrated to a maximum dose of 60 mg daily. Representative doses range from approximately 60 mg to approximately 120 mg daily. Adverse reactions may include nausea, dry mouth, dizziness, fatigue, constipation, xerostomia, decreased appetite, drowsiness, sweating, gastrointestinal discomfort, and insomnia. Duloxetine can be used to treat conditions including, but not limited to, PHN, DNP, and CIPN. Duloxetine is a potent inhibitor of neuronal serotonin and norepinephrine reuptake and a weaker inhibitor of dopamine reuptake. Duloxetine has no significant affinity for dopaminergic, adrenergic, cholinergic, histaminergic, opioid, glutamate, or GABA receptors. Duloxetine's effects on the spinal cord are also related to its modulation of pain. Increases the concentration of serotonin and norepinephrine in the dorsal horn of the spinal cord, by activating 5-HT 1A 5-HT 1B 5-HT 1D It activates 5-HT2, 5-HT3, α1-adrenergic, and α2-adrenergic receptors, increasing descending inhibition of pain.

[0152] Venlafaxine can be used to treat conditions including, but not limited to, DNP and CIPN. Representative doses range from approximately 75 mg to approximately 225 mg daily. Potential side effects include drowsiness, dizziness, and mild gastrointestinal problems. The exact mechanism of action of venlafaxine in treating various mental illnesses has not been fully elucidated; however, it is understood that venlafaxine and its active metabolite, O-desmethylvenlafaxine (ODV), effectively and selectively inhibit the reuptake of serotonin and norepinephrine at the presynaptic terminals.

[0153] Lidocaine is a local anesthetic used topically to provide surface analgesia for chronic pain conditions including, but not limited to, PHN and DNP. It is formulated as a patch containing 5% lidocaine and applied once daily to undamaged skin for 12 hours, with a 12-hour interval between patches. Up to three 5% lidocaine patches can be applied once daily to intact skin for 12 hours. Lidocaine acts as a mechanical barrier against irritation in areas of abnormal pain. Lidocaine is continuously released after application, with only 3% of the drug entering the systemic circulation, well below toxic concentrations. Lidocaine is extensively metabolized in the liver and excreted via the kidneys. Adverse reactions observed after lidocaine patch treatment include local skin reactions such as itching, erythema, rash, burning sensation, and edema. Lidocaine is well tolerated in individuals of all ages with minimal adverse reactions and is better tolerated than systemic treatment with pregabalin. Lidocaine is approved for use in PHN in the EU and the US. Lidocaine reduces ectopic discharges in damaged afferent pain receptors by partially inhibiting voltage-gated calcium channels (blocking dysfunctional (sensitized) Nav1.7 and Nav1.8 sodium channels in skin nociceptors) and may also have anti-inflammatory properties by modulating T cell activity and inhibiting nitric oxide production.

[0154] Capsaicin is a selective agonist of the TRPV1 channel found in skin nociceptors. Exposure to capsaicin activates TRPV1, leading to calcium influx and inhibiting electron transport, resulting in loss of cell integrity and long-term loss of function of nociceptor nerve fibers, thereby reducing pain. A high-concentration 8% capsaicin transdermal patch is used to treat neuropathic pain, with a single application lasting up to 3 months. This patch contains 8% capsaicin (640 mcg / cm2), with a total of 179 mg of capsaicin per patch. Adverse reactions such as burning sensation, erythema, pain, dryness, edema, and itching can be managed with local anesthetics such as lidocaine. Capsaicin cream can also be used, for example, 0.075% applied four times daily. Skin-site side effects may occur. Capsaicin can be used to treat conditions including, but not limited to, diabetic peripheral neuropathy (DNP). In the European Union, capsaicin is approved for the topical treatment of peripheral neuropathic pain, as a monotherapy or in combination with other pharmaceutical products. In the United States, capsaicin is approved for postherpetic neuralgia (PHN) and diabetic peripheral neuropathy (DNP) pain. Cream formulations of capsaicin may selectively activate TRPM8, which is also activated after damage to cold-sensing and sensory nerves.

[0155] Clonidine gel can be used to treat conditions including, but not limited to, DNP. A single dose of 0.65 g of gel can be applied three times daily. Skin site reactions may occur. Topical clonidine is a presynaptic α-2 adrenergic receptor agonist with antinociceptive activity and has been associated with pain relief in DNP in a few low- to moderate-quality studies.

[0156] Alpha-lipoic acid gel can be used to treat conditions including, but not limited to, DNP. A representative dose may be approximately 600-1800 mg orally or 600 mg intravenously daily for 3 weeks, excluding weekends. Potential side effects include nausea, vomiting, abdominal discomfort, and diarrhea. Alpha-lipoic acid is a natural thiol with potent antioxidant properties and is used as a dietary supplement.

[0157] Opioids, such as oxycodone, hydrocodone, and morphine, have good analgesic effects; however, their use in PHN is controversial due to concerns about addiction and dependence. Opioids modulate pain by interacting with μ, κ, and δ opioid receptors present in both the central and peripheral nervous systems during the inflammatory response. These receptors are coupled to inhibitory G proteins, and when activated, they lead to the closure of voltage-gated calcium channels, causing potassium efflux and hyperpolarization, and reducing the production of cyclic adenosine monophosphate. These mechanisms result in a reduction in neuronal excitatory and nociceptive impulse transmission, thereby altering the response to pain. Multiple clinical studies have demonstrated the effectiveness of opioids in treating neuropathic pain, including PHN. Adverse effects of opioids include nausea, itching, drowsiness, constipation, and sedation, and caution should be exercised in patients with a history of drug abuse. Opioids are often used as second- or third-line drugs and as adjunctive therapy at lower doses, providing immediate pain relief while titrating other first-line drugs to reach their therapeutic dose. The maximum dose of oxycodone can be approximately 120 mg daily, divided into two doses. Long-term use may lead to tolerance, frequent dose escalations, and hyperalgesia. Oxycodone and its active metabolites selectively bind to μ-opioid receptors, as well as κ and δ-opioid receptors in the central and peripheral nervous systems, and induce G protein-coupled receptor signaling pathways. Activation of μ-opioid receptors inhibits N-type voltage-gated calcium channels, thereby suppressing the pain response. Some opioids also act on the descending nervous system (pain suppression) by inhibiting norepinephrine and serotonergic reuptake. Opioids are approved in the United States and the European Union for moderate to severe pain.

[0158] Cannabinoids can be used for off-label treatment of pain as described in this article. Cannabinoids are agonists of CB1 receptors in the central nervous system (CNS), spinal cord, and peripheral nerves, and may act by inhibiting neuronal excitability. Some cannabinoid compounds are psychoactive, and synthetic cannabinoid receptor agonists may have a higher potential to induce psychosis than natural cannabis and should be considered with caution.

[0159] Tapentadol can be used to treat conditions including, but not limited to, DNP. Representative doses range from approximately 100 mg to approximately 500 mg daily. Potential side effects include dizziness, drowsiness, headache, fatigue, and gastrointestinal problems. Tapentadol is a centrally acting synthetic analgesic that binds to μ-opioid receptors with 18 times less potency than morphine. It also increases norepinephrine concentrations in the rat brain by inhibiting norepinephrine reuptake.

[0160] Tramadol is a weak opioid that acts on μ receptors and inhibits the reuptake of serotonin and norepinephrine. The maximum daily dose is 400 mg, titrated in 50-100 mg increments. Tramadol is considered a mild opioid and has been shown to be less effective in PHN than other opioids, but it is better tolerated and a safer alternative. It may be a better choice for patients with a history of drug abuse or heart problems. Adverse reactions include nausea, drowsiness, constipation, dizziness, headache, vertigo, and an increased risk of seizures at high doses. Caution is advised when using tramadol in patients with a history of seizures or those taking medications that lower the seizure threshold.

[0161] Other medications may also be used as standard of care for TN or other pain-causing conditions described in this article. For example, pimozide, a dopamine receptor antagonist, is primarily used to treat Tourette syndrome. It was found to be effective in a randomized, double-blind, crossover trial in 48 patients with treatment-resistant TN.

[0162] Topiramate is another medication that can be used to treat TN. The exact mechanism of action of topiramate is not fully understood. However, its pain-modulating effect may be related to its ability to block voltage-gated sodium channels and enhance GABA activity by binding to non-benzodiazepine sites on GABAA receptors. In a study of eight patients with classic TN, topiramate (100-400 mg / day) was found to be effective in 75% of the patients.

[0163] Levetiracetam has been tested in TN. Its exact mechanism of action is unclear, but it is believed to target high-pressure N-type calcium channels and synaptic vesicle protein 2A (SV2A); in this way, it blocks transsynaptic impulse transmission. Evidence for its use in TN is scarce. Recently, two open-label pilot studies investigated the efficacy and tolerability of levetiracetam in TN patients. One study involving 10 patients reported a 50-90% improvement. Another study involving 23 patients reported a 62% reduction in daily seizure frequency in patients receiving levetiracetam as add-on therapy.

[0164] Other medications that have shown limited benefit in treating TN were also disclosed. For example, phenytoin, and intravenous phenytoin, is an anticonvulsant used to prevent and control various types of seizures.

[0165] Fosphenytoin is a water-soluble phenytoin prodrug used only in hospitals to treat seizures. It works by slowing the impulses in the brain that trigger seizures. Its main mechanism is to block frequency-dependent, use-dependent, and voltage-dependent neuronal sodium channels, thereby limiting the repetitive firing of action potentials. Fosphenytoin can be used to treat conditions including, but not limited to, trigeminal neuralgia.

[0166] Clonazepam is a long-acting benzodiazepine with an intermediate onset time, commonly used to treat panic disorder, severe anxiety, and seizures. Clonazepam can also be used to treat conditions including, but not limited to, trigeminal neuralgia.

[0167] Valproic acid is an anticonvulsant used to control complex partial seizures as well as simple and complex absence seizures. Valproic acid can also be used to treat conditions including, but not limited to, trigeminal neuralgia.

[0168] Misoprostol is a prostaglandin E1 analog used to reduce the risk of NSAID-induced gastric ulcers and for termination of pregnancy. Misoprostol can also be used to treat conditions including, but not limited to, trigeminal neuralgia.

[0169] Tocarib is an orally active class Ib antiarrhythmic drug that interferes with the heart's sodium channels and is commonly used to treat ventricular arrhythmias. Tocarib can also be used to treat conditions including, but not limited to, trigeminal neuralgia.

[0170] Topical capsaicin cream is a local analgesic used to relieve symptoms of neuropathic pain associated with postherpetic neuralgia, as well as other muscle and joint pain.

[0171] Intranasal lidocaine is a local anesthetic used in various superficial and invasive procedures. It ultimately induces numbness by blocking sodium channels, temporarily preventing neurons in the local tissue from transmitting sensory signals to the brain. Intranasal lidocaine can be used to treat conditions including, but not limited to, trigeminal neuralgia.

[0172] Tizanidine is an alpha-2 adrenergic agonist used for short-term treatment of muscle spasms. Tizanidine can also be used to treat conditions including, but not limited to, trigeminal neuralgia.

[0173] Sumatriptan is a serotonin receptor agonist used to treat migraines and cluster headaches. Sumatriptan can also be used to treat conditions including, but not limited to, trigeminal neuralgia.

[0174] Amitriptyline is a tricyclic antidepressant (TCA) with analgesic properties, widely used to treat depression and neuropathic pain. Amitriptyline, nortriptyline, and desipramine are commonly used off-label for the treatment of PHN and CIPN. They provide analgesia by inhibiting the reuptake of serotonin and norepinephrine at presynaptic nerve endings, thereby reducing sensory perception between the brainstem and spinal cord. TCAs should be started at a low dose of 10-25 mg at bedtime and titrated gradually at 10-25 mg every 3-7 days, depending on patient tolerance, up to a maximum daily dose of 150 mg. TCAs are associated with adverse reactions such as sedation, dry mouth, blurred vision, constipation, urinary retention, QT prolongation, sexual dysfunction, dry mouth, water retention, increased appetite, weight gain, constipation, dizziness, and orthostatic hypotension. Caution should be exercised when prescribing TCAs to patients at risk of suicide and overdose. Amitriptyline is the most widely prescribed neurotransmitter, but it has a high anticholinergic effect. Nortriptyline and desipramine are better tolerated and more effective than amitriptyline. The mechanism of action of TCAs is not fully understood. It is believed that amitriptyline inhibits the membrane pump mechanism responsible for the reuptake of neurotransmitter amines (such as norepinephrine and serotonin), thereby increasing their concentration in the synaptic cleft of the brain.

[0175] Other pain conditions treatable with the compositions and methods described herein include complex regional pain syndrome and phantom limb pain. Complex regional pain syndrome can be treated with NSAIDs, anticonvulsants, tricyclic antidepressants, opioids, neurostimulation, psychological support, and combinations thereof; these treatments may be used in place of or in combination with the compositions and methods disclosed herein. Phantom limb pain can be treated with tricyclic antidepressants, serotonin-norepinephrine reuptake inhibitors, opioids and opioids, anticonvulsants, NMDA receptor agonists, local anesthetics, and combinations thereof; these treatments may be used in place of or in combination with the compositions and methods disclosed herein.

[0176] Various formulations of active agents for treating trigeminal neuralgia are considered for use in the methods of this disclosure. For example, oral, sublingual, topical, and injectable formulations may be used in the methods of this disclosure.

[0177] Liquid formulations are considered. A typical liquid formulation may contain 6 mg / ml of the active ingredient, but other doses reflecting tablet dosages, such as 2.5 mg / ml or 5 mg / ml, may also be used. The exact dose can be determined in a Phase III study for a specific indication if needed. Other concentrations of the active ingredient may be used to facilitate administration or reduce the volume of inactive ingredients. Other inactive ingredients may include sucrose, apricot flavor (No. 1NS), 96% ethanol, anhydrous citric acid, sodium citrate, sodium benzoate, anhydrous sodium sulfite (E221), sodium metabisulfite (E223), ascorbic acid, and purified water, which are commonly used in syrup formulations. Substitutions and variations in the formulation can be investigated, such as reducing or eliminating sucrose. For example, a liquid formulation may contain a methanol solution of 1 mg / mL alimazine tartrate.

[0178] Nasal spray formulations were also considered. The intranasal route is a very useful administration route when the CNS / brain region is the therapeutic target. Medications for nasal decongestion, rhinitis, and migraine have been successfully delivered via the intranasal route. First-generation antihistamines such as alimazine or their pharmaceutically acceptable salts can cross the blood-brain barrier (BBB), unlike second-generation antihistamines, and they are not substrates of the P-glycoprotein efflux pump in the brain endothelial cells located at the BBB.

[0179] Other first-generation antihistamines include ethylenediamines (such as mepyramine, chloropyramine, antazoline, and tripelennamine), which were the first group of clinically effective H1-antihistamines developed.

[0180] Pyrilamine targets the H1 receptor. It is a first-generation antihistamine. However, it penetrates the brain rapidly, often causing drowsiness as a side effect. It has been found in over-the-counter combination products for treating cold and menstrual symptoms, but is considered an unapproved prescription drug for coughs, colds, or allergies.

[0181] Clopidogrel is a first-generation antihistamine used in Eastern European countries to treat bronchial asthma, as well as allergic rhinitis, allergic conjunctivitis, and other allergic reactions. It is also indicated for Quincke's edema, allergic reactions to insect bites, food and drug allergies, and anaphylactic shock.

[0182] Ametazolin is a first-generation antihistamine with anticholinergic activity. It is used to relieve nasal congestion. It is also formulated with naphazoline as eye drops to relieve allergic conjunctivitis.

[0183] Triprine is a histamine H1 antagonist with low sedative effects but often causes gastrointestinal irritation. It is used to treat asthma, hay fever, urticaria, and rhinitis; it is also used in veterinary medicine. Triprine is administered via various routes, including topical application.

[0184] Other first-generation antihistamines include ethanolamines (such as diphenhydramine, carbizamine, doxylamine, olphenadrine, bromazine, clemastine, and dimenhydrinate).

[0185] Diphenhydramine is the original drug in this group. Significant anticholinergic adverse reactions and sedative effects were observed in this group, but the incidence of gastrointestinal adverse reactions was relatively low. Diphenhydramine (perhaps best known as its brand-name formulation Benadryl) is a first-generation H1 receptor antihistamine widely used to treat seasonal allergies, insect bites and stings, and rashes. However, it also has antiemetic, antitussive, hypnotic, and anti-Parkinson's disease properties. Because histamine receptors are present in both the peripheral and central nervous systems, diphenhydramine has been shown to cause sedation due to its competitive antagonism of histamine H1 receptors in the central nervous system. Although its use in the treatment of allergies is sometimes unpopular due to its sedative effects, diphenhydramine has been reintroduced in many over-the-counter sleep aids and cold and cough medicines marketed for "nighttime" use. Diphenhydramine is also used in combination with 8-chlorotheophylline as an anti-nausea drug, diphenhydramine, where it primarily works by antagonizing H1 histamine receptors in the vestibular system. Diphenhydramine has also been shown to be involved in many neurotransmitter systems affecting behavior, including dopamine, norepinephrine, serotonin, acetylcholine, and opioids. Therefore, diphenhydramine is being investigated for its anxiolytic and antidepressant properties.

[0186] Carbixamine is a first-generation antihistamine that competes with free histamine for binding to HA receptor sites. This antagonizes the effect of histamine on HA receptors, thereby reducing the negative symptoms caused by histamine binding to HA receptors. The product label for carbixamine as an over-the-counter cough and cold medicine is being revised to state "Do not use in children under 4 years of age" to prevent and reduce misuse, as many unapproved carbixamine-containing formulations contain inappropriate labeling that promotes unapproved uses (including treatment of congestion, cough, the common cold, and for children under 2 years of age), which could lead to serious health risks.

[0187] Doxylamine is a histamine H1 antagonist with significant sedative properties. It is used for allergies, as well as as an antitussive, antiemetic, and hypnotic. Doxylamine has also been used in veterinary applications and has been used to treat Parkinson's disease.

[0188] Ophenazine is a muscarinic antagonist used to treat drug-induced Parkinson's disease and relieve pain caused by muscle spasms. Ophenazine antagonizes H1 receptors and N-methyl-D-aspartate receptors (NMDA receptors), but not selectively antagonizes muscarinic acetylcholine receptors (hence its use as an anticholinergic). It also blocks potassium channels in the human Ether-à-go-go-related gene (HERG) and sodium channels in Nav1.7, Nav1.8, and Nav1.9, and is an inhibitor of norepinephrine and dopamine reuptake.

[0189] Bromodiphenhydramine (also known as bromomidine) is an ethanolamine antihistamine with antibacterial properties. Bromodiphenhydramine is used to control skin allergies. Ethanolamine antihistamines produce a significant sedative effect in most patients. Bromodiphenhydramine competes with free histamine for binding to HA receptor sites. This antagonizes the effect of histamine on HA receptors, thereby reducing the negative symptoms caused by histamine binding to HA receptors.

[0190] Clomastine is an ethanolamine derivative, a first-generation histamine H1 antagonist used to treat hay fever, rhinitis, allergic dermatitis, and pruritus. It causes drowsiness. Clomastine is a selective histamine H1 antagonist that binds to histamine H1 receptors. This blocks the action of endogenous histamine, thus temporarily relieving the negative symptoms caused by histamine.

[0191] Dimenhydrinate is a medication used to prevent and treat nausea, vomiting, dizziness, and motion sickness. Early research on dimenhydrinate focused on its role as an antihistamine for treating urticaria; its treatment of motion sickness was a serendipitous discovery. Dimenhydrinate is a theobromine chlorate that breaks down into diphenhydramine and 8-chlorotheophylline. While the exact mechanism of action is unclear, it is theoretically believed that diphenhydramine reduces balance disturbances through muscarinic action or histamine H1 antagonism. 8-chlorotheophylline may reduce diphenhydramine-induced drowsiness by blocking adenosine receptors to produce an excitatory effect.

[0192] Other first-generation antihistamines include alkylamines (such as feniramine, chlorpheniramine, dextrochlorpheniramine, dextrobromopheniramine, bromopheniramine, triprolidine, dimethinidine, and avastin). Isomerism is an important factor in the activity of this group of drugs. For example, E-triprolidine is 1000 times more potent than Z-triprolidine. This difference is related to the positioning and fit of the molecules at the histamine H1 receptor binding site. Alkylamines are considered to have relatively fewer sedative and gastrointestinal adverse reactions, but a relatively higher incidence of paradoxical central nervous system (CNS) excitation.

[0193] Fenipamine is a first-generation antihistamine in the alkylamine class, similar to brompheniramine and chlorpheniramine. It is used in combination with other medications in some over-the-counter allergy and cold / flu products. Its use as an antihistamine has been largely superseded by second-generation antihistamines such as cetirizine and loratadine. Fenipamine competes with histamine for histamine H1 receptors, and once bound, acts as an inverse agonist. Reduced H1 receptor activity leads to reduced itching and decreased vasodilation and capillary leakage, thus reducing redness and edema. This can be seen in the inhibition of histamine-induced wheals (swelling) and flare (vasodilation). The inverse agonist effect of H1 receptors in the CNS is also the reason why first-generation antihistamines like fenipamine produce a sedative effect. The binding of fenipamine to H4 receptors and subsequent inverse agonist effect may also help reduce itching by antagonizing inflammation.

[0194] Chlorpheniramine is a histamine H1 antagonist used for allergic reactions, hay fever, rhinitis, urticaria, and asthma. It has also been used in veterinary applications. As one of the most widely used classic antihistamines, it generally causes less drowsiness and sedation than promethazine. Chlorpheniramine binds to histamine H1 receptors. This blocks the action of endogenous histamine, thus temporarily relieving the negative symptoms caused by histamine.

[0195] Dextrochlorpheniramine is an enantiomer of chlorpheniramine, used to treat sunburn, insect bites, and allergic skin reactions. Dextrochlorpheniramine is the effective S-enantiomer of chlorpheniramine. The active ingredient, in the form of dextrochlorpheniramine maleate salt, is available as a prescription drug for the adjunctive treatment of allergies and anaphylactic reactions. It is an antihistamine with anticholinergic (dryness) and sedative effects. It disrupts histamine signaling by competing with histamine for receptor sites on effector cells.

[0196] Dexbromin maleate is an antihistamine used to treat allergic conditions such as hay fever or urticaria. Dexbromin competitively binds to histamine H1 receptors. It competes with histamine for normal H1 receptor sites on effector cells in the gastrointestinal tract, blood vessels, and respiratory tract. This blocks the effects of endogenous histamine, thus temporarily relieving the negative symptoms caused by histamine.

[0197] Brompheniramine is a histamine H1 antagonist used to treat cough, upper respiratory symptoms, and nasal congestion associated with allergies and the common cold. Brompheniramine is an H1 histamine receptor antagonist with moderate antimuscarinic activity, similar to other common antihistamines such as diphenhydramine. Due to its anticholinergic effects, brompheniramine may cause drowsiness, sedation, dry mouth, dry throat, blurred vision, and increased heart rate.

[0198] Triptloridine is a first-generation histamine H1 antagonist used for allergic rhinitis, asthma, and urticaria. It is an ingredient in cough and cold medicines. It may cause drowsiness. Triptloridine is a histamine H1 antagonist that competes with histamine for normal H1 receptor sites on effector cells in the gastrointestinal tract, blood vessels, and respiratory tract. It effectively and temporarily relieves sneezing, watery and itchy eyes, and runny nose caused by hay fever and other upper respiratory allergies. Triptloridine has anticholinergic and sedative effects.

[0199] Dimethylindidine is an antihistamine / anticholinergic drug used orally and topically as an antipruritic. Dimethylindidine exists in racemic mixtures. (S)-(+)-dimethylindidine is a potent M2-selective muscarinic receptor antagonist (with lower affinity for M1, M3, and M4 muscarinic receptors). The (R)-(-)-enantiomer is the preferred enantiomer (responsible for biological activity) that binds to histamine H1 receptors. Dimethylindidine is a selective histamine H1 antagonist that binds to histamine H1 receptors. This blocks the action of endogenous histamine, thereby temporarily relieving the negative symptoms caused by histamine.

[0200] Avastin is a triprolidine analog antihistamine used to treat allergies and hay fever. As an H1 receptor antagonist, it works by blocking the action of histamine on this receptor, thereby preventing symptoms associated with histamine release, such as itching, vasodilation, hypotension, edema, bronchoconstriction, and tachycardia.

[0201] Other first-generation antihistamines include piperazines (such as cycladine, bucrorazine, clocycline, hydroxyzine, meclorazine, and ketotifen). These compounds are structurally related to ethylenediamines and ethanolamines and produce significant anticholinergic side effects, except for hydroxyzine, which has a very low affinity for muscarinic acetylcholine receptors, thus producing negligible anticholinergic side effects. Compounds in this group are commonly used to treat motion sickness, vertigo, nausea, and vomiting. The second-generation H1-antihistamine cetirizine also belongs to this chemical group.

[0202] Cyclazine is a histamine H1 antagonist, administered orally or parenterally, used to control postoperative and drug-induced vomiting and motion sickness. Cyclazine is a piperazine derivative antihistamine used as an antivertigo / antiemetic. Cyclazine is used to prevent and treat nausea, vomiting, and dizziness associated with motion sickness. Additionally, it has been used to treat vertigo in diseases affecting the vestibular system. While the mechanism by which cyclazine exerts its antiemetic and antivertigo effects is not fully elucidated, its central anticholinergic properties are partly responsible. The drug inhibits labyrinthine excitability and vestibular stimulation and may affect the medullary chemoreceptor trigger zone. It also possesses anticholinergic, antihistamine, central nervous system depressant, and local anesthetic effects. Cyclazine works by blocking histamine receptors in the vomiting center, thereby reducing the activity of these pathways. Furthermore, due to its anticholinergic properties, muscarinic receptors are also blocked.

[0203] Bucrolizine is an antihistamine with antiemetic and anticholinergic effects. When administered as a syrup, it is touted as an effective appetite stimulant for children; however, this indication has not been validated. In addition to the aforementioned conditions, bucrolizine has been investigated for the treatment of migraine attacks and nausea and vomiting during pregnancy. Bucrolizine works by blocking histamine receptors in the vomiting center, thereby reducing the activity of these pathways. Furthermore, due to its anticholinergic properties, muscarinic receptors are also blocked.

[0204] Chlorcyclorhizine is a first-generation phenylpiperazine antihistamine used to treat urticaria, rhinitis, itching, and other allergic symptoms. Chlorcyclorhizine also possesses some local anesthetic, anticholinergic, and antiserotonergic properties and can be used as an antiemetic.

[0205] Hydroxyzine is a first-generation histamine H1 receptor antagonist of the diphenylmethane and piperazine classes, possessing sedative, anxiolytic, and antiemetic properties. Hydroxyzine blocks histamine activity to relieve allergic symptoms such as itching. Its off-target effects also make it suitable for use as a sedative, anxiolytic, and antiemetic in certain disease states. Hydroxyzine is a potent inverse agonist of the histamine H1 receptor—a substance considered to have a “negative efficacy,” meaning it actively inhibits receptor activity rather than simply blocking it. This inverse agonistic effect on these receptors is why hydroxyzine is effective in treating histamine-induced edema, flushing, and itching. Hydroxyzine is not a cortical depressant, therefore its sedative properties may occur at the subcortical level of the CNS. These sedative properties contribute to its anxiolytic activity. The antiemetic effect is likely due to secondary effects of its off-target activity. It is also an inhibitor of member 2 of the potassium voltage-gated channel subfamily H.

[0206] Meclopramide is a histamine H1 antagonist with antiemetic and antivertigo properties. It is used for the symptomatic treatment of motion sickness and to control vertigo associated with vestibular disorders. It also has anticholinergic, central nervous system depressant, and local anesthetic effects. Through its antagonistic effect on H1 receptors, meclopramide primarily works by inhibiting the signal transduction pathway from the vestibular nucleus and nucleus of the solitary tract (NTS) to the chemoreceptor trigger zone (CTZ) and the medullary vomiting center via histaminergic neurotransmission. In addition to histamine H1 receptors, it is also an inverse agonist of nuclear receptor subfamily 1 group I member 3.

[0207] Ketotifen is a benzocycloheptathiophene derivative with potent antihistamine and mast cell stabilizing properties. Its structure is similar to some other first-generation antihistamines such as cyproheptadine and atazatadine. The exact mechanism by which ketotifen exerts its therapeutic effect is unclear. Ketotifen is a potent, non-competitive antagonist of the H1 histamine receptor, which may be an important reason for its anti-allergic activity. Furthermore, ketotifen stabilizes mast cells and has been shown in vitro to inhibit the release of allergic and inflammatory mediators such as histamine, leukotrienes C4 and D4 (i.e., SRS-A), and platelet-activating factor (PAF).

[0208] Other first-generation antihistamines include tricyclic and tetracyclic antihistamines (such as promethazine, alimemazine, cyproheptadine, and mequintazine). These compounds differ from phenothiazine antipsychotics in ring substitution and chain characteristics. They are also structurally related to tricyclic (and tetracyclic) antidepressants, which explains the adverse effects of H1-antihistamines in these three classes and the poor tolerability of tricyclic H1-antihistamines. The second-generation H1-antihistamine loratadine is derived from compounds in this group.

[0209] Promethazine is a first-generation antihistamine. It antagonizes multiple receptors, making it suitable for a variety of indications, including allergic reactions, pain, sedation, nausea, and vomiting. Promethazine is an antagonist of histamine H1, postsynaptic mesolimbic dopamine, alpha-adrenergic, muscarinic, and N-methyl-D-aspartate (NMDA) receptors. Its antihistamine effect is used to treat allergic reactions. Its antagonism of muscarinic and NMDA receptors allows it to be used as a soporific and for anxiety and tension. Its antagonism of histamine H1, muscarinic, and dopamine receptors in the medullary vomiting center allows promethazine to be used to treat nausea and vomiting.

[0210] Alimemazine (also known as Trimepazine) is a first-generation antihistamine used to prevent and relieve allergic conditions that cause itching and other allergic skin conditions, including urticaria. Alimemazine competes with free histamine for binding to HA receptor sites. This antagonizes the effect of histamine on HA receptors, thereby reducing the negative symptoms caused by histamine binding to HA receptors.

[0211] Cyproheptadine is a potent competitive antagonist of serotonin and histamine receptors. It is primarily used to treat allergy symptoms, although it may be better known for its appetite stimulant and off-label use in treating serotonin syndrome. Cyproheptadine appears to exert its antihistamine and antiserotonin effects by competitively binding to their respective receptors with free histamine and serotonin. Antagonism of serotonin in the hypothalamic appetite center may explain cyproheptadine's appetite-stimulating effect. In addition to histamine H1 receptors, cyproheptadine is also an antagonist of serotonin receptors 2A, 2C, H2, and 2B, as well as muscarinic acetylcholine receptors M1, M2, M3, and 7.

[0212] Mequitazine is a histamine H1 antagonist (antihistamine). It competes with histamine for normal H1 receptor sites on effector cells in the gastrointestinal tract, blood vessels, and respiratory tract. It can effectively and temporarily relieve sneezing, watery and itchy eyes, and runny nose caused by hay fever and other upper respiratory allergies.

[0213] Formulating compounds such as alimazine into nasal sprays allows for more direct drug delivery to the brain and more effective targeting of brain regions involved in the perception of neuropathic pain in the target indication (dorsal root ganglia and semilunar ganglia). This may also have the potential advantage of reducing the dose required for a therapeutic response compared to CNS side effects (such as drowsiness) of compounds like alimazine. Compounds such as alimazine will be easier to formulate into nasal sprays. In some embodiments, alimazine has a LogP of 4.71, making the compound lipophilic, and according to Lipinski's rule of 5, compounds with LogP > 5 can cross the BBB without being bound by physics. Formulations of compounds like alimazine using similar carriers to azelastine (benzalkonium chloride, disodium edetate, hydroxypropyl methylcellulose, citrate, disodium hydrogen phosphate, sodium chloride, and purified water) can be used.

[0214] Sublingual dissolving film formulations are also considered. "Oral thin film," "OTF," "oral dissolving film," "oral dissolvable film," "oral drug strip," or "oral strip" refers to a product intended for administration of an active ingredient via oral (buccal or sublingual), gastric (gastrically), and / or small intestine (enterically) absorption. Oral films are edible and pharmaceutically acceptable. Films are typically prepared using hydrophilic polymers that rapidly dissolve in the tongue or mouth upon contact with a liquid, delivering the active ingredient into systemic circulation through dissolution. Oral films can also be used for adhesion to mucosal tissues (e.g., at least one of the mouth, nose, eyes, vagina, and rectum) for local delivery of the active ingredient. Therefore, it should be understood that those skilled in the art appreciate that references to oral films for use on mucosal tissues (such as the nose, eyes, vagina, and rectum) are appropriate and acceptable. When placed on the tongue, such films immediately disintegrate, releasing the drug, which dissolves in saliva. Some of the drug is absorbed from the mouth, pharynx, and esophagus as it travels down to the stomach with the saliva. In this case, the bioavailability of the drug is significantly higher than that observed in conventional tablets. For the treatment of TN, oral film formulations such as alimazine or pharmaceutically acceptable salts thereof would be possible and could have useful advantages such as ease of administration / convenience (especially for elderly patients) compared to side effects, water-free administration, the potential for rapid absorption, and the potential for achieving therapeutic effects with lower doses. For the paroxysmal pain characteristic of TN, oral film formulations such as alimazine or pharmaceutically acceptable salts thereof may be useful. In some embodiments, sublingual dissolving film formulations comprise oral films. In some embodiments, when placed on the tongue, such films immediately disintegrate, releasing the drug, which dissolves in saliva and is then absorbed directly into the systemic circulation through the oral mucosa. In this context, oral films can bypass the first-pass metabolism effect, thereby improving the bioavailability of the active ingredient. In some cases, the bioavailability of the drug is significantly higher than that observed in conventional tablet formulations (50%). Some drugs are absorbed from the mouth, pharynx, and esophagus as they descend into the stomach with saliva, and are then absorbed through the gastrointestinal system as with conventional oral dosage forms. For the treatment of TN, oral films will be particularly useful given their drug delivery characteristics. In some embodiments, the oral film may contain about 1 mg to about 5 mg of alimazine or a pharmaceutically acceptable salt thereof in one or more layers constituting the oral film formulation.

[0215] In some implementations, the use of an oral film for the treatment of TN containing alimazine or a pharmaceutically acceptable salt thereof may produce a local anesthetic effect (e.g., numbing sensation in the mouth near the two branches of the trigeminal nerve (V2, V3)), which may have additional therapeutic benefits.

[0216] In some implementations, oral films for treating TN containing alimazine or a pharmaceutically acceptable salt thereof offer the advantage of ease of administration for TN patients experiencing TN pain attacks, as TN patients may be unable to swallow, open their mouths wide, drink water, and may have a fear of choking, making the use of conventional oral formulations difficult. In some implementations, oral films for treating TN containing alimazine or a pharmaceutically acceptable salt thereof may be particularly convenient for elderly patients with TN who may have limited ability to swallow conventional oral formulations due to TN and other comorbidities affecting the swallowing reflex, such as Alzheimer's disease.

[0217] In some implementations, treatment of TN with an oral film containing alimazine or a pharmaceutically acceptable salt thereof does not require water at the time of administration.

[0218] In some implementations, oral films for treating TN containing alimazine or a pharmaceutically acceptable salt thereof have the potential to be rapidly absorbed into the systemic circulation and thus provide rapid pain relief.

[0219] In some embodiments, the use of oral films for treating TN containing alimazine or a pharmaceutically acceptable salt thereof allows for the use of lower doses of alimazine or a pharmaceutically acceptable salt thereof while still maintaining the therapeutic effect of treating TN pain. By way of non-limiting example, a lower dose (i.e., lower than the dose level used in tablet form of alimazine or a pharmaceutically acceptable salt thereof) can reduce the degree of drowsiness while maintaining the same therapeutic effect. For example, a typical dose of alimazine or a pharmaceutically acceptable salt thereof (5 mg BID) may cause drowsiness, while in some embodiments, the use of oral films for treating TN containing alimazine or a pharmaceutically acceptable salt thereof, containing approximately 0.5 mg to 2.5 mg of alimazine or a pharmaceutically acceptable salt thereof twice daily, may completely avoid drowsiness. In some embodiments, a lower dose can achieve the same therapeutic effect in treating TN pain while reducing the degree of dizziness in elderly patients.

[0220] In some implementations, an oral film containing alimazine or a pharmaceutically acceptable salt thereof for the treatment of TN will be bioequivalent to a conventional oral tablet formulation of alimazine or a pharmaceutically acceptable salt thereof.

[0221] In some embodiments, an oral film containing alimazine or a pharmaceutically acceptable salt thereof for treating TN may contain about 0.5 mg to about 2.5 mg of alimazine or a pharmaceutically acceptable salt thereof. In some embodiments, an oral film containing alimazine or a pharmaceutically acceptable salt thereof for treating TN may contain about 0.5 mg to about 2.5 mg of alimazine or a pharmaceutically acceptable salt thereof per film. In some embodiments, an oral film containing alimazine or a pharmaceutically acceptable salt thereof for treating TN will have higher bioavailability in the brain. When administered using an oral film containing alimazine or a pharmaceutically acceptable salt thereof for treating TN, alimazine or a pharmaceutically acceptable salt thereof is rapidly absorbed via the mucosal route, enters the systemic circulation, and exerts a therapeutic effect on TN pain through H1 histamine receptors in the brain (primarily the tuberous papillary nucleus). This can produce a therapeutic effect without some of the common side effects of alimazine or a pharmaceutically acceptable salt thereof, such as, but not limited to, drowsiness.

[0222] In some implementations, the oral film containing alimazine or a pharmaceutically acceptable salt thereof for treating TN is designed to provide a slower-absorbed therapeutic dose through the dissolution of the inner layer, allowing the drug to be absorbed from the mouth, pharynx, and esophagus as it moves down into the stomach with saliva, and then absorbed via the GI system as with conventional oral dosage forms.

[0223] In some implementations, oral films for treating TN containing alimazine or a pharmaceutically acceptable salt thereof are multilayer oral films designed to provide a more rapid initial therapeutic effect via a mucosal route, followed by a second “dose” and therapeutic effect via a conventional gastric route. Overall, this may reduce the total dose required to achieve a therapeutic effect compared to side effects, and offers patients the advantage of taking fewer oral films.

[0224] In some embodiments, oral films for treating TN containing alimazine or a pharmaceutically acceptable salt thereof may further contain one or more polymers (including but not limited to water-soluble polymers), plasticizers, surfactants, sweeteners, saliva stimulants, superdisintegrants, colorants, flavoring agents, stabilizers and thickeners, refreshing agents, antioxidants, mucoadhesives, plasticizers, or any combination thereof. In some embodiments, the polymer is selected from gum polysaccharides (e.g., gum arabic, sodium alginate), gelatin, maltodextrin, water-soluble cellulose derivatives such as, but not limited to, hydroxypropyl methylcellulose (HPMC), hydroxyethyl cellulose, hydroxypropyl cellulose, polyvinyl alcohol (PVA), polyethylene oxide (PEO), polyvinylpyrrolidone (PVP), chitosan, kollicoat, sodium alginate, pectin, rosin, water-soluble cellulose derivatives, copovidone (a copolymer of 1-vinyl-2-pyrrolidone and vinyl acetate); copolymers of other vinylpyrrolidones; other polymers or copolymers of substituted vinylpyrrolidones; derivatives of polyvinylpyrrolidone; polyethylene oxide, carboxymethyl cellulose; polyvinyl alcohol; natural gums, including xanthan gum, tragacanth, guar, acacia, and gum arabic; and water-soluble polyacrylates. Examples of substituted vinylpyrrolidones include, but are not limited to, N-vinyl-3-methyl-2-pyrrolidone, N-vinyl-4-methyl-2-pyrrolidone, N-vinyl-5-methyl-2-pyrrolidone, N-vinyl-5,5-dimethyl-2-pyrrolidone, and N-vinyl-3,3,5-trimethyl-2-pyrrolidone. Examples of monomers that can copolymerize with vinylpyrrolidone or substituted vinylpyrrolidones include vinyl aromatic monomers, such as styrene, and acrylate or methacrylate monomers, such as methyl methacrylate and 2-dimethylaminoethyl methacrylate, or any combination thereof. In some embodiments, the polymer may be an agent that enhances the dissolution of the oral film in the oral cavity and minimizes tensile strength. In some embodiments, the plasticizer is selected from polyethylene glycol, propylene glycol, glycerol and polyols, citric acid, phthalates, glycerol, diethylene glycol, bis(2-ethylhexyl) phthalate, ethylene glycol, tributyl citrate, triethyl citrate, or any combination thereof. In some implementations, plasticizers are agents that improve the stability and brittleness of oral films. Specifically, the term "surfactant" is intended to refer to an amphiphilic compound that reduces the surface tension of a liquid, the interfacial tension between two liquids, or the interfacial tension between a liquid and a solid. Combinations of surfactants may be used.In some embodiments, the surfactant is selected from sodium lauryl sulfate, polysorbate, poloxamer 407, polyoxyethylene sorbitan fatty acid ester, α-hydro-co-hydroxypoly(oxyethylene) poly(oxypropylene) poly(oxyethylene) block copolymer, polyoxyethylene allyl ether, polyoxyethylene, castor oil derivative diol, glycerol, erythritol, threitol, arabinitol, xylitol, ribitol, mannitol, sorbitol, galactitol, fucitol, iditol, inositol, volemitol, isomaltitol, maltitol, lactitol, maltotetraitol, maltotetraitol, or any combination thereof. In some embodiments, the surfactant is an agent that acts as a wetting or dispersing agent, enabling the oral film to rapidly melt and release alimazine or a pharmaceutically acceptable salt thereof. In some embodiments, the sweetener is selected from acesulfame potassium, aspartame, aspartan-acesulfame salt, cyclamate, erythritol, glycerol, glycyrrhizin, hydrogenated starch hydrolysate, isomaltitol, lactitol, maltitol, mannitol, neotame, polydextrose, saccharin, sorbitol, sucralose, tagatose, xylitol, dextrose, glucose, fructose, honey, xylose, ribose, caffeine, sucrose, maltose, steviol glycosides, sodium or calcium saccharin salts, thomatase I and II, aspartame, fructose, sorbitol, mannitol, or any combination thereof. In some embodiments, the sweetener is an agent capable of increasing the palatability of the oral film. In some embodiments, the salivary stimulant is selected from citric acid, malic acid, lactic acid, ascorbic acid, tartaric acid, or any combination thereof. In some embodiments, the salivary stimulant is an agent capable of accelerating the disintegration of the oral film by increasing saliva production. In some embodiments, the superdisintegrating agent is an agent that causes rapid disintegration of the oral film through a combined effect of swelling and water absorption. In some embodiments, the colorant is selected from FD&C-licensed colorants (FD&C Yellow #6 and titanium dioxide are examples), EU colors, natural colorants, pigments, or any combination thereof.In some embodiments, the flavoring agent may be selected from isoamyl acetate (banana flavor), benzaldehyde (cherry flavor), cinnamaldehyde (cinnamon flavor), ethyl propionate (fruit flavor), methyl anthranilate (grape flavor), limonene (orange flavor), ethyl sebadienoate (pear flavor), allyl hexanoate (pineapple flavor), ethyl maltol, ethyl vanillin (vanilla flavor), methyl salicylate (wintergreen flavor), menthol, chloroform, certain salts, or any combination thereof. In some embodiments, the stabilizer and thickener may be selected from natural gums (e.g., but not limited to xanthan gum, locust bean gum, carrageenan), cellulose derivatives, or combinations thereof. In some embodiments, the stabilizer and thickener enhance the viscosity and strength of the dispersion or suspension of the oral film preparation solution before casting. In some embodiments, the cooling agent may be a chemical substance that triggers a cooling sensation in cold-sensitive receptors. In some embodiments, the cooling agent is selected from menthol, thymol, camphor, eucalyptol, or combinations thereof. In some embodiments, the antioxidant is selected from sulfites, such as sodium sulfite, sodium bisulfite, sodium metabisulfite, and similar salts of potassium and calcium, or combinations thereof. In some embodiments, the oral film may advantageously employ antioxidants or oxygen scavengers to prevent or reduce oxidative degradation of the active ingredient before use. In some embodiments, the mucosal adhesive may be selected from sodium alginate, sodium carboxymethyl cellulose, guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, karya gum, methyl cellulose, polyethylene oxide, retene, tragacanth gum, or combinations thereof. In some embodiments, the mucosal adhesive promotes adhesion of the oral film to the oral mucosa.

[0225] Traditional tablet formulations are also considered. An exemplary amount may be approximately 2.5 mg to approximately 10 mg of active agent per tablet. Such tablets may be administered once, twice, or three times daily, or other suitable dosing regimens. Other inactive ingredients may include microcrystalline cellulose, lactose, colloidal anhydrous silica, magnesium stearate, sodium carboxymethyl starch, hydroxypropyl methylcellulose, polyethylene glycol (macrogol) 200, indigo E132, and titanium dioxide E171. For example, a tablet may contain 5 mg of alimazine or a pharmaceutically acceptable salt thereof (e.g., alimazine tartrate).

[0226] Modified release formulations, including but not limited to sustained release, sustained action, prolonged action, controlled release, time-released, and long-acting dosage forms of alimazine or its pharmaceutically acceptable salts, are considered. In some embodiments, modified release formulations maintain consistent serum drug concentrations (SDCs) to achieve a balance between therapeutic efficacy and potential side effects or adverse events. In some embodiments, modified release formulations of alimazine or its pharmaceutically acceptable salts for the treatment of TN may be used as maintenance therapy and optionally in combination with oral film formulations that can be used to treat acute exacerbations of TN. In some embodiments, the formulations described herein are selected from modified release formulations of prolonged release, sustained release, controlled release, or delayed release formulations.

[0227] In some embodiments, the modified release formulations described herein are inert solid carriers or matrices in which the drug is uniformly suspended, including in the form of tablets or small beads. In some embodiments, the matrix is ​​a gelling material, including gelatin, methylcellulose, tragacanth gum, veegum, and alginate. In some embodiments, the matrix is ​​a polymer, including polylactic acid copolymers, polyacrylates, methacrylates, polyesters, ethylene-vinyl acetate copolymers (EVA), polyglycolic acid, polylactide, and silicone. In some embodiments, the modified release formulation is a sustained-release pellet, bead, or granule. In some embodiments, the modified release formulation is an extended-release tablet in which the solubility of the drug is modified to achieve prolonged release. In some embodiments, the extended-release tablet is formed using a non-ionic base or acid form of the drug. In some embodiments, extended-release tablets are formed by granulating the drug together with excipients, including stearic acid, castor wax, high molecular weight polyethylene glycol (Carbowax), glyceryl monostearate, beeswax, cetyl oil, magnesium stearate, and hydrogenated vegetable oil (Sterotex), to reduce the water solubility of the drug. In some embodiments, modified-release formulations are ion-exchange formulations, wherein anionic or cationic drugs are complexed with ion-exchange resins of opposite charge to form insoluble, non-absorbable resin-drug complexes.

[0228] In some embodiments, the modified release formulations described herein further comprise one or more pharmaceutically acceptable excipients. Examples of pharmaceutically acceptable excipients that may be present in the composition include, but are not limited to, fillers / carriers, solvents / co-solvents, preservatives, antioxidants, suspending agents, surfactants, defoamers, buffers, chelating agents, sweeteners, flavoring agents, binders, extenders, disintegrants, diluents, lubricants, fillers, wetting agents, glidants, and combinations thereof.

[0229] In some embodiments, the modified release formulations described herein may further comprise one or more exemplary fillers. Examples of exemplary fillers include cellulose and cellulose derivatives, such as microcrystalline cellulose, powdered cellulose; dextrin; starch, such as dry starch, hydrolyzed starch, and starch derivatives, such as corn starch; cyclodextrin; sugars, such as powdered sugar and sugar alcohols, such as lactose, mannitol, sucrose, and sorbitol; inorganic fillers, such as aluminum hydroxide gel, calcium carbonate (granules or powder), precipitated calcium carbonate, carbonates, magnesium aluminum metasilicate, calcium hydrogen phosphate; and sodium chloride, silicon dioxide, silicic acid, titanium dioxide, titanium oxide, calcium dihydrogen phosphate dihydrate, calcium sulfate, alumina, kaolin, talc, or combinations thereof.

[0230] In some embodiments, the modified release formulation described herein further comprises one or more disintegrants. Examples of disintegrants include starch, alginate, cross-linked polymers such as croscarmellose, croscarmellose sodium carboxymethyl cellulose, potassium starch glycolate, sodium starch glycolate, clay, cellulose, starch, gum, or combinations thereof.

[0231] In some embodiments, the modified release formulations described herein further comprise one or more binders, including but not limited to cellulose such as hydroxypropyl cellulose, methylcellulose, and hydroxypropyl methylcellulose; starch such as corn starch, pregelatinized starch, and hydroxypropyl starch; waxes and natural and synthetic gums such as acacia gum, tragacanth gum, and sodium alginate; synthetic polymers such as polymethyl methacrylate and polyvinylpyrrolidone; and povidone, dextrin, pullulan, agar, gelatin, tragacanth gum, polyethylene glycol (macrogol), or combinations thereof.

[0232] In some embodiments, the modified release formulations described herein further comprise one or more wetting agents, including but not limited to oleic acid, glyceryl monostearate, sorbitan monooleate, sorbitan monolaurate, triethanolamine oleate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monolaurate, sodium oleate, sodium lauryl sulfate, poloxamer, poloxamer 188, polyoxyethylene ether, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene fatty acid ester, polyethylene glycol fatty acid ester, polyoxyethylene hardened castor oil, polyoxyethylene alkyl ether, polysorbate, cetyl alcohol, glyceryl fatty acid ester (e.g., glyceryl triacetate, glyceryl monostearate, etc.), polyoxymethylene stearate, sodium lauryl sulfate, sorbitan fatty acid ester, sucrose fatty acid ester, benzalkonium chloride, polyethoxylated castor oil, and combinations thereof.

[0233] In some embodiments, the modified release formulation described herein further comprises one or more lubricants, including but not limited to stearic acid, magnesium stearate, calcium hydroxide, talc, corn starch, sodium stearoyl fumarate, alkali metal and alkaline earth metal salts, waxes, boric acid, sodium benzoate, sodium acetate, sodium chloride, leucine, polyethylene glycol (PEG), methoxy polyethylene glycol, propylene glycol, sodium oleate, glyceryl behenate, glyceryl palmitostearate, glyceryl benzoate, magnesium lauryl sulfate, sodium lauryl sulfate, and combinations thereof.

[0234] In some embodiments, the modified release formulation described herein further comprises one or more flow aids, including but not limited to silica (colloidal anhydrous), starch, talc, magnesium stearate, calcium stearate, zinc stearate, calcium hydrogen phosphate, magnesium carbonate, magnesium oxide, calcium silicate, silica, silica, colloidal silica, talc, sodium lauryl sulfate, natural starch, or combinations thereof.

[0235] In some embodiments, the modified release formulation described herein may be a tablet and further comprises a top coating, such as a hydroxypropyl methylcellulose coating or a polyvinyl alcohol coating, and is available under the trade name Opadry, such as Opadry White, Opadry II (Opadry is a registered trademark of BPSI Holdings LLC, Wilmington, DE, USA).

[0236] In some embodiments, the modified release formulation described herein may further comprise one or more preservatives. Examples of preservatives include sodium benzoate, parabens, methylparaben, ethylparaben, butylparaben, and propylparaben, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid, benzalkonium chloride (BKC), benzyl chloride, phenol, phenylmercuric nitrate, thimerosal, or combinations thereof. The preservative may be contained in a liquid dosage form. The amount of preservative may be sufficient to extend the shelf life or storage stability of the liquid dosage form, or both.

[0237] In some embodiments, the modified release formulation described herein may further comprise one or more flavoring agents. Examples of flavoring agents include synthetic flavoring oils and flavoring aromatics and / or natural oils, extracts from plant leaves, flowers, fruits, etc., or any combination thereof. Other examples include cinnamon oil, wintergreen oil, peppermint oil, clove oil, laurel oil, anise oil, eucalyptus oil, thyme oil, cedarwood leaf oil, nutmeg oil, sage oil, bitter almond oil, and cinnamon oil, etc., or any combination thereof. Also suitable as flavoring agents are vanilla, citrus oils (including lemon, orange, grape, lime, and grapefruit) and fruit flavorings (including apple, banana, pear, peach, strawberry, raspberry, cherry, plum, pineapple, apricot, strawberry flavor, tutti-fruity flavor, and peppermint flavor), or any combination thereof.

[0238] In some implementations, modified-release formulations can typically be in any physical form suitable for treating the subject. These forms can be referred to as unit dosage forms, such as single pellets or tablets. In some examples, the pharmaceutical composition can be formulated as tablets, capsules, granules, powders, liquids, suspensions, gels, syrups, pastes, suppositories, patches, nasal sprays, aerosols, injections, implantable sustained-release formulations, or mucosal adhesive films. In some examples, the pharmaceutical formulation can be formed as tablets, bilayer tablets, capsules, multigranules, drug-coated microspheres, matrix tablets, or multicore tablets. The physical form can be selected based on the desired therapeutic effect.

[0239] In some embodiments, the modified release formulations described herein can be manufactured using a variety of conventional methods, such as conventional mixing, dissolving, granulation, dragee-making, levigating, emulsifying, encapsulating, entrapping, or lyophilizing. Modified release formulations can be formulated in a conventional manner using one or more physiologically acceptable carriers, diluents, excipients, or adjuvants that facilitate the processing of the active agent into a pharmaceutically acceptable formulation. A suitable formulation can be selected based on the chosen route of oral administration.

[0240] In some embodiments, the modified release formulations described herein are core tablets, or tablet-within-a-tablet, wherein the inner core is used for the slow release of the drug ingredient, while the outer shell contains a rapidly releasing dose of the drug. In some embodiments, the modified release formulation is achieved through microencapsulation, wherein microscopic drug particles are encapsulated with a special coating material (such as ethyl cellulose). In some embodiments, the modified release formulation is a permeation drug delivery system in the form of a tablet comprising an outer semi-permeable membrane and an inner core filled with a mixture of the drug and a permeabilizer (saline solution). In some embodiments, the modified release formulation is a gastric retention system that can remain in the stomach for several hours and prolong the gastric residence time of the drug. In some embodiments, the modified release formulation is a combination of any of the above embodiments.

[0241] In some embodiments, the modified release formulations described herein are for oral administration. These modified release formulations can combine alimazine or a pharmaceutically acceptable salt thereof with another pharmaceutical reagent and one or more pharmaceutically acceptable carriers well known in the art. Such carriers facilitate formulation into tablets, pills, sugar-coated pills, capsules, liquids, gels, syrups, pastes, suspensions, etc., for oral ingestion by a patient to be treated. For oral solid dosage forms, such as powders, capsules, and tablets, suitable excipients include fillers such as sugars, such as lactose, sucrose, mannitol, and sorbitol; cellulose preparations such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, and / or polyvinylpyrrolidone (PVP); granulating agents; and binders. If desired, disintegrants such as croscarmellose, agar, or alginate or its salts, such as sodium alginate, can be added. If desired, the solid dosage form can be sugar-coated or enteric-coated using standard techniques.

[0242] In some embodiments, the modified release formulation described herein may comprise a matrix selected from microcrystalline cellulose, sodium carboxymethyl cellulose, hydroxyalkyl celluloses such as hydroxypropyl methyl cellulose and hydroxypropyl cellulose, polyethylene oxide, alkyl celluloses such as methyl cellulose and ethyl cellulose, polyethylene glycol, polyvinylpyrrolidone, cellulose acetate, cellulose acetate butyrate, cellulose acetate phthalate, cellulose acetate trimellitate, polyvinyl acetate phthalate, polyalkylmethacrylates, polyvinyl acetate, and mixtures thereof.

[0243] Topical formulations such as creams, lotions, and drops are also considered. Compounds such as alimazine or pharmaceutically acceptable salts thereof can be formulated into lotions or creams for topical application to the skin to treat pain in conditions such as postherpetic neuralgia (PHN), trigeminal neuralgia (TN), diabetic neuropathic pain (DNP), and chemotherapy-induced neuropathic pain (CIPN). Standard methods for formulating creams, lotions, or liquids, such as those commonly found in antihistamines and capsaicin creams, can be used. Other local delivery systems, such as patches, are also being further considered. Patches typically consist of an adhesive material containing an active substance (in an aqueous or other form of matrix), applied to a nonwoven polyester felt backing and covered with a polyethylene terephthalate (PET) film release liner. Patches typically contain, but are not limited to, the following inactive ingredients: aluminum dihydroxyaminoacetate, disodium EDTA, gelatin, glycerin, kaolin, methylparaben, polyacrylic acid, polyvinyl alcohol, propylene glycol, propylparaben, sodium carboxymethyl cellulose, sodium polyacrylate, D-sorbitol, tartaric acid, and urea. Compounds such as alimazine or pharmaceutically acceptable salts thereof can be formulated into patches for topical application to the skin to treat pain associated with conditions such as PHN, TN, DNP, and CIPN. Compounds absorbed through the skin may also have systemic effects as well as local pain-relieving effects.

[0244] Subcutaneous or intrathecal injection is also considered. Compounds such as alimazine or pharmaceutically acceptable salts thereof can be formulated for subcutaneous injection to treat pain in PHN, DNP, TN, and CIPN. Standard formulations and syringes / needles suitable for subcutaneous injection can be used. There is evidence that intrathecal injection of drugs such as methylprednisolone and lidocaine can suppress pain in PHN because these drugs work by reducing pain signal transmission from afferent nerves to the dorsal root ganglion (DRG). Compounds such as alimazine or pharmaceutically acceptable salts thereof can be formulated for intrathecal administration using common formulations and delivery techniques (pumps, needles, etc.). Preclinical and clinical formulation, efficacy, and dosage studies are needed to demonstrate therapeutic value (pain relief).

[0245] The inventors of this disclosure have determined that off-label treatments effective in postherpetic neuralgia (PHN) may be effective in treating trigeminal neuralgia (TN), as both are neuropathic pain conditions. Both conditions can be driven by latent infections such as herpes zoster virus (Herpes zoster) and Borrelia burgdorferi (Lyme disease). PHN involves the dorsal root ganglion. Trigeminal neuralgia involves the trigeminal ganglion (TG). Both the dorsal root ganglion (DRG) and TG are involved in the perception of itch and pain. The thalamus plays a crucial role in transmitting pain and itch sensations from the DRG and, particularly, TN pain via the TG. The DRG and TG share similar pathways and signaling molecules associated with pain and itch. In the presence of alimazine, the DRG, TG, and thalamus express histamine receptors. Direct neuromodulation of the DRG has shown promising results in the treatment of PHN and painful diabetic peripheral neuropathy (DPN). Direct neuromodulation of TG using various methods (e.g., chemical, electrical, surgical, and pharmacological approaches) is also a promising strategy for treating TN, as it involves thalamic neuromodulation. There is considerable overlap in the cellular signaling pathways involved in itching and pain. For example, transient receptor potential ion channels—V1 isoform (TRPV1) and A1 isoform (TRPA1)—as well as Toll-like receptors (TLRs) and protease-activated receptors (PARs) are involved in both sensations.

[0246] The applicant has demonstrated the efficacy of alimazine in successfully treating TN patients (n=7) and has provided supporting clinical evidence (non-randomized clinical trials) for this disclosure.

[0247] To avoid being bound by theory, the following principles are hypothesized as the potential mechanism of action of alimazine in trigeminal neuralgia.

[0248] Pathological mechanisms of trigeminal neuralgia

[0249] Trigeminal neuralgia (TN) originates from damage or inflammation of the trigeminal nerve or its branches, involving dysfunction of both the peripheral nervous system (PNS) and the central nervous system (CNS). The pathophysiology of TN is complex and multifactorial, involving multiple molecular and cellular processes. A key mechanism involves an inflammatory response triggered by damage to the tissues surrounding the trigeminal nerve in the PNS, leading to peripheral sensitization and the hallmark symptoms of atypical pain and hyperalgesia.

[0250] Peripheral sensitization is driven by inflammatory mediators such as prostaglandin E2 (PGE2), cytokines, and neuropeptides like brain-derived neurotrophic factor (BDNF), released by immune cells including macrophages, neutrophils, and mast cells. Histamine released by mast cells plays a crucial role in sensitizing peripheral nerve endings by depolarizing nociceptors. Alterations in the expression of nociceptive receptors (such as transient receptor potential vanilloid 1 (TRPV1) and transient receptor potential cation channel subfamily A member 1 (TRPA1)) lead to increased excitability in trigeminal neurons. Furthermore, alterations in the activity of sodium, potassium, and calcium channels result in the activation and proliferation of satellite glial cells (SGCs), further amplifying neuronal excitability. This increased excitability in trigeminal ganglion (TG) neurons enhances the release of neuropeptides such as substance P (SP) and calcitonin gene-related peptide (CGRP) into the brainstem.

[0251] Peripheral sensitization may also involve demyelination of the trigeminal nerve due to nerve compression, which can lead to ephaptic transmission and associated symptoms of abnormal pain and hyperalgesia. The inability of the nerve to remyelinate can be exacerbated by abnormal inflammatory responses, potentially reinforcing the sensitization cycle, particularly in patients with diseases such as multiple sclerosis.

[0252] Enhanced trigeminal neuronal sensitization in the peripheral nervous system (PNS) triggers changes in neuronal plasticity and hyperexcitability in central neurons, leading to central sensitization. Many molecular processes of central sensitization are similar to those in the peripheral nervous system. Sustained and enhanced input from the central terminals of the trigeminal nerve increases synaptic release of glutamate, SP, and CGRP in the caudal subnucleus of the trigeminal spinal nucleus, which also activates glial cells, particularly astrocytes. Simultaneously, reduced GABA and glycine signaling within local circuits, along with altered expression of potassium chloride cotransporter 2 (KCC2) and GABA transporters, weaken inhibitory control and enhance neuronal excitability. Furthermore, reduced descending inhibitory regulation from somatosensory efferents further promotes central sensitization.

[0253] antihistamines

[0254] Alimazine tartrate, like many first-generation antihistamines, is a potent blocker of the histamine H1 (H1) receptor. Similar to other members of the G protein-coupled receptor (GPCR) family, the histamine H1 receptor acts as a cellular switch, existing in a state of equilibrium between inactivation ("off") and activity ("on"). Unlike histamine, first-generation antihistamines are structurally independent of histamine and do not compete for the same binding sites. Instead, they bind to alternative sites on the receptor, producing the opposite effect. Therefore, H1-antihistamines are not merely receptor antagonists but act as inverse agonists, stabilizing the receptor in its inactive conformation and reducing the likelihood of overstimulation by histamine.

[0255] In addition to blocking histamine activity, H1-antihistamines also inhibit NF-κB transcription factors involved in the immune response through the phospholipase C and phosphatidylinositol (PIP2) signaling pathways. This leads to reduced antigen presentation and decreased expression of pro-inflammatory cytokines, cell adhesion molecules, and chemokines. Furthermore, by reducing intracellular calcium concentration, H1-antihistamines promote mast cell stability, thereby reducing further histamine release.

[0256] Due to their off-target effects, including antimuscarinic, anti-alpha-adrenergic, and anti-serotonergic activities, as well as their ability to cross the blood-brain barrier (BBB), first-generation antihistamines such as alimazine have therapeutic applications beyond managing H1-histamine-mediated allergic reactions. These effects also make them suitable for use as antitussives, antiemetics, antinausea medications, sedatives, and treatments for Parkinson's disease.

[0257] The role of histamine and histamine H1 receptors (H1R) in neuropathic pain

[0258] Histamine plays a crucial role in various physiological processes, including inflammatory responses, allergic reactions, and pain modulation. The histamine H1 receptor (H1R) is a G protein-coupled receptor (GPCR) and one of the four histamine receptor subtypes (H1R, H2R, H3R, and H4R). It is primarily involved in mediating pro-inflammatory responses, including pain.

[0259] When histamine binds to H1R, it induces a conformational change in the receptor, leading to activation of the associated Gq / 11 protein. This activation triggers the dissociation of the G protein into its subunits Gαq / 11 and Gβγ, thereby initiating a downstream signaling cascade. The Gαq / 11 subunit activates phospholipase C-β (PLC-β), which hydrolyzes phosphatidylinositol 4,5-bisphosphate (PIP2) in the cell membrane into two second messengers: inositol 1,4,5-triphosphate (IP3) and diacylglycerol (DAG). IP3 binds to its receptor on the endoplasmic reticulum (ER), resulting in the release of calcium ions (Ca). 2+ Intracellular Ca2+ is released into the cytoplasm, a key event in H1R-mediated signaling.2+ The increase in [amount] activates calcium-dependent enzymes, including protein kinase C (PKC), and Ca [amount] [is affected]. 2+ It also forms a complex with calmodulin. Calmodulin, in turn, inhibits the activity of potassium voltage-gated channels type 7 (Kv7) and sensitizes transient receptor potential vanillic acid isoform 1 (TRPV1) receptors. DAG is retained in the plasma membrane and interacts with Ca2+. 2+ Synergistic activation of PKC, a key player in regulating ion channels, gene expression, and nociceptive neuron sensitization.

[0260] PKC activation leads to phosphorylation of various proteins, including ion channels and receptors involved in nociception, such as TRPV1, sodium channels, and potassium channels. This phosphorylation enhances the sensitivity of nociceptive neurons to painful stimuli, resulting in pain perception. This process is particularly relevant in neuropathic pain, where these pathways may be aberrantly activated. Activation of TRPV1 (a non-selective cation channel) allows influxes of sodium, potassium, and calcium ions, leading to neuronal depolarization and increased excitability, manifested as enhanced pain perception.

[0261] The inflammatory processes underlying neuropathic pain, such as those caused by tissue damage, injury, or infection (e.g., herpes zoster), activate resident immune cells (e.g., mast cells) and recruited immune cells (e.g., polymorphonuclear leukocytes (PMNLs), as well as other cell types, including epithelial cells, Schwann cells, fibroblasts, and postganglionic sympathetic neurons (SPGNs). In particular, mast cells release histamine, which binds to H1Rs in peripheral afferent nerves, as well as in the dorsal root ganglion (DRG) and trigeminal ganglion (TG). This activates TRPV1, forming a perpetuating feedback loop of inflammation and pain. Furthermore, H1R activation in peripheral nerves can lead to neurogenic inflammation, where the release of neuropeptides such as substance P further sensitizes pain pathways.

[0262] In the central nervous system (CNS), histamine acts on H1 receptors in the DRG, TG, and thalamus, promoting central sensitization, a hallmark of chronic neuropathic pain. Central sensitization involves the amplification of synaptic transmission within pain pathways, leading to an overreaction to normally painless (abnormal pain) or mildly painful stimuli (hyperalgesia)—a key characteristic of trigeminal neuralgia.

[0263] Commonalities between itching and pain

[0264] Although itching and pain are distinct sensations, they share significant commonalities. Pain is known to suppress itching, while analgesics like morphine paradoxically induce itching. Both chronic pain and chronic pruritus exhibit similar pathological mechanisms, particularly in long-term conditions. These sensations are detected by primary sensory neurons located in the dorsal root ganglion (DRG) and trigeminal ganglion. Pruritus receptors (itch receptors) and nociceptors (pain receptors) overlap within the DRG, with pruritus receptors representing a subset of C-fiber nociceptors.

[0265] There is considerable overlap in the cellular signaling pathways involved in itching and pain. For example, transient receptor potential ion channels—the V1 isoform (TRPV1) and the A1 isoform (TRPA1)—as well as Toll-like receptors (TLRs) and protease-activated receptors (PARs) are involved in both sensations. However, some receptors, such as the G protein-coupled receptor (GPCR) MrgprA3 (MAS-associated GPR, member A3) and the thymic stromal lymphopoietin (TSLP) receptor, are specific to itching. TRPV1 plays a crucial role in histamine (the most well-known endogenous pruritogen)-induced pruritus. Histamine type 1 receptor (H1R) is co-expressed with TRPV1 in pruritogenic nociceptors, and its signaling is coupled to TRPV1 activation, inducing membrane depolarization and activation of Ca2+-dependent intracellular cascades.

[0266] Conditions such as neuropathy and dermatitis that alter the sensitization of the peripheral nervous system (PNS) and central nervous system (CNS) (brainstem, spinal cord, and cortical neurons) can lead to pain and itching. For example, central sensitization is the basis for touch-evoked pain (abnormal pain sensation) and touch-evoked itch (abnormal pruritus). Both sensations are also influenced by the immune system, as inflammatory mediators released in response to tissue damage or injury (such as insect bites (itching) or infection (such as shingles)) can directly activate or sensitize pruritus and nociceptive neurons, leading to increased sensitivity to itching and pain. Oxidative stress is closely associated with the pathogenesis of chronic pain and has also been shown to induce histamine-dependent pruritus by activating TRPA1.

[0267] Sodium channels play a crucial role in both itching and pain. Gain-of-function and loss-of-function mutations in the sodium channel subunit Nav1.7, as well as Nav1.8 and Nav1.9, are closely related to pain sensation in humans. Notably, Nav1.7 has also been reported to be involved in paroxysmal pruritus.

[0268] Chronic pain is a recognized hypersensitivity state resulting from both peripheral and central sensitization. Similarly, chronic pruritus and chronic cough are increasingly understood as hypersensitivity syndromes. As previously mentioned, first-generation antihistamines have a wide range of therapeutic applications, particularly for pruritus, due to their central and peripheral antihistamine effects. Their off-target effects, including antimuscarinic, anti-alpha-adrenergic, and antiserotonergic activities, also make them suitable for managing chronic cough and pain. For example, alimazine has been used for pruritus, as a mild sedative, and as an antiemetic.

[0269] The role of transient receptor potential vanilloid type-1 (TRPV1) in pain

[0270] Transient receptor potential vanillic acid isoform 1 (TRPV1) cation channels are crucial in the perception and modulation of pain. TRPV1 receptors are activated by a variety of stimuli, including harmful heat, pH changes (acidity and alkalinity), voltage changes, and endogenous compounds such as endocannabinoids and lipoxygenase products. Capsaicin and resiniferatoxin are two of the most well-known activators of TRPV1. Activation of TRPV1 in primary sensory neurons of the trigeminal nerve in rodents and humans releases pain-related neuropeptides—such as calcitonin gene-related peptide (CGRP) and substance P (SP)—from peripheral and central nerve endings. These neuropeptides then bind to their respective receptors on effector cells, leading to neurogenic inflammation and sensitization of nociceptors.

[0271] TRPV1 is involved in a variety of pain conditions, including inflammatory, cancer-related, and neuropathic pain. Specifically, TRPV1 has been reported to play a role in orofacial pain conditions such as pulpitis, temporomandibular disorder (TMD), oral cancer, and traumatic pain caused by inferior alveolar nerve (IAN) injury. These findings suggest that TRPV1 may play an important role in neuropathic pain, particularly trigeminal neuralgia.

[0272] Nociceptor activation and sensitization can occur through direct and indirect pathways. TRPV1 can be directly activated by elevated temperatures or by chemical mediators released from immune cells (such as resident mast cells (e.g., histamine) and polymorphonuclear leukocytes (PMNLs)) as well as epithelial cells, Schwann cells, fibroblasts, and postganglionic sympathetic neurons (SPGNs). Crosstalk between signaling pathways plays a crucial role in TRPV1 regulation. For example, TRPV1 can be activated or sensitized by the release of inositol triphosphate (IP3) from phosphatidylinositol 4,5-bisphosphate (PIP2) mediated by phospholipase C. The release of diacylglycerol (DAG) and calcium ions (Ca) from intracellular reservoirs... 2+ The combined action of these enzymes can activate classic protein kinase C (PKC) isoenzymes, such as PKCδ. Intracellular Ca... 2+ The increase in [something] also activates Ca²⁺ / calmodulin-dependent protein kinase II (CaMKII), further sensitizing TRPV1.

[0273] Furthermore, activation of adenylate cyclase via G protein-coupled receptor (GPCR) leads to activation of protein kinase A (PKA), which can sensitize TRPV1. Another pathway involves PKCε, which is activated via the cAMP-dependent guanine exchange factor (EPAC) mechanism. The EPAC-dependent pathway plays a crucial role in nociceptor sensitization, particularly during periods of persistent inflammation, and is thought to contribute to the "memory" of previously damaged tissues, potentially prolonging pain sensitivity.

[0274] The role of muscarinic receptors in neuropathic pain

[0275] First-generation antihistamines are known to exhibit antimuscarinic effects. Muscarinic receptors are also G protein-coupled receptors involved in the parasympathetic nervous system, named for their increased sensitivity to muscarinic alkaloids (compounds found in certain fungi). The muscarinic receptor family consists of five subtypes: M1, M2, M3, M4, and M5. These receptors are activated by the neurotransmitter acetylcholine. Similar to histamine receptors (H1, H2, and H3), muscarinic receptors M1, M3, and M5 are excitatory, coupled to Gq proteins, and activate phospholipase C (PLC) and protein kinase C (PKC). PLC produces the second messengers diacylglycerol (DAG) and inositol triphosphate (IP3), thereby increasing intracellular calcium and PKC activation, leading to an excitatory cellular response. Conversely, the M2 and M4 receptors are inhibitory, coupled with the Gi protein, inhibiting adenylate cyclase, reducing protein kinase A (PKA) activity and cyclic adenosine monophosphate (cAMP) levels, leading to an inhibitory response.

[0276] Several studies have shown that the cholinergic system, particularly muscarinic receptors, is involved in neuropathic pain. Central muscarinic M2 receptors have been shown to modulate neuropathic pain induced by traumatic nerve injury, and activation of these receptors in the insular cortex alleviates oxaliplatin-induced neuropathic pain in male rats. Electrophysiological studies have further shown that presynaptic muscarinic receptors in the dorsal root ganglion (DRG) and trigeminal ganglion regulate primary afferent input to neurons in the dorsal horn of the spinal cord or medulla oblongata. Recent studies using in vivo siRNA knockdown in rats have shown that M2 and M4 receptors primarily mediate nociceptive responses, while M1 and M3 receptors show little involvement. Notably, M2 and M4 receptors are expressed at primary afferent terminals, and the M4 subtype appears to be particularly relevant in chronic pain states, such as diabetic neuropathy, where its expression is upregulated.

[0277] Dimethindene is a first-generation antihistamine with antimuscarinic properties, used orally and topically as an antipruritic. It exists in racemic mixture form, where the (S)-(+)-dimethindene enantiomer is a potent M2-selective muscarinic receptor antagonist, while the (R)-(-)-enantiomer is the bioactive agent for histamine H1 receptor binding. Several H1 receptor antagonists, such as mequinatazine, cyproheptadine, clomastine, diphenhydramine, promethazine, homochlorcyclizine, and alimazine, have also been shown to have high affinity for muscarinic receptors (Ki = 5.0–38 nM).

[0278] A key aspect of trigeminal neuralgia (TN), particularly in classic or idiopathic cases, is the compression of the nerve by blood vessels, such as the superior cerebellar artery. This compression leads to focal demyelination of the trigeminal nerve, causing aberrant nerve signaling, including transsynaptic transmission, where impulses “jump” between neurons. This erroneous discharge of the trigeminal nerve produces spontaneous pain. Recent research has highlighted the role of the M1 receptor (M1R) in remyelination, positioning it as a potential therapeutic target for diseases such as multiple sclerosis (MS). MS is driven by an abnormal inflammatory response and myelin destruction resulting from the inability to effectively remyelinate, due to the loss of oligodendrocytes responsible for axonal myelination. Although oligodendrocyte precursor cells (OPCs) can migrate to the lesion site, they often fail to differentiate, leading to persistent demyelination over time.

[0279] M1R antagonists, such as clomastine (a first-generation antihistamine), have been shown to promote the differentiation of OPCs into oligodendrocytes, leading to remyelination. Due to demyelination, MS patients frequently suffer from neuropathic pain, including TN. Although clomastine has shown modest improvement in remyelination during MS progression through M1R inhibition, the use of drugs with muscarinic activity, such as alimazine, may provide sufficient remyelination to alleviate TN pain through a similar mechanism.

[0280] Proposed mechanism of action (MOA) of alimazine tartrate in trigeminal neuralgia

[0281] Trigeminal neuralgia (TN) is a chronic neuropathic pain condition characterized by hypersensitivity driven by peripheral and central sensitization. The pathophysiology of TN is complex and multifactorial, involving numerous molecular and cellular mechanisms. Various therapeutic interventions have been targeted at these mechanisms, but clinical outcomes have been inconsistent. Current standard-of-care treatments for TN, such as carbamazepine and oxcarbazepine, primarily target overactive sodium channels in trigeminal neurons of the peripheral nervous system (PNS). However, these treatments are often associated with significant side effects and diminished efficacy, leaving many patients suffering from persistent, debilitating pain.

[0282] The applicant has demonstrated the efficacy and durability of alimazine tartrate in relieving postherpetic neuralgia (PHN) and TN pain. While these clinical observations are not from randomized clinical trials and may be subject to placebo effects and other confounding factors, they provide a promising finding for this devastating facial pain condition.

[0283] TN is a multifaceted disease, and therapies targeting a single pathway (such as sodium channels) may not be optimally managed. Current drug therapies for TN do not alter disease progression and primarily provide symptom relief. Microvascular decompression (MVD) remains the only treatment that can alter disease progression, providing significant long-term pain relief for patients with nerve compression. However, TN patients without nerve compression, or those for whom MVD is unsuccessful, must rely on long-term drug therapy, often involving multiple medications, with limited efficacy.

[0284] Like many first-generation antihistamines, alimazine has a wide range of therapeutic applications, including relieving itching, sedation, antiemetic, and antitussive activity. Its diverse pharmacological effects are attributed to its central and peripheral antihistamine properties as well as “off-target” effects, including antimuscarinic, anti-alpha-adrenergic, and antiserotonergic effects. Alimazine is proposed to be a first-generation antihistamine capable of crossing the blood-brain barrier (BBB) ​​to relieve TN pain by modulating multiple mechanisms involved in the central nervous system (CNS) and peripheral nervous system (PNS). This unique multipharmacological activity makes alimazine a promising new therapeutic agent for relieving TN pain by modulating multiple molecular pathways behind its complex pathophysiology.

[0285] Alimazine has been widely used as an antipruritic, and there is a shared mechanism between itching and pain, including mechanisms involving histamine. Therefore, it is proposed that the primary mechanism of action (MOA) of alimazine in the TN involves the stabilization of its H1 receptor (H1R) in an inactive conformation. This would reduce the stimulation of trigeminal afferent neurons and neurons in the CNS (dorsal root ganglion [DRG], trigeminal ganglion [TG], dorsal horn of the spinal cord, and thalamus) by excess histamine. This effect may occur through a signaling cascade of PLCβ3, PIP2, DAG, IP3, and PKC, which regulate ion channels such as TRPV1, thereby reducing neuronal sensitization.

[0286] Several first-generation H1 receptor antihistamines have been investigated as potential analgesics and have shown promise in preclinical and clinical models; however, the discovery and subsequent widespread use of nonsteroidal anti-inflammatory drugs (NSAIDs) appear to have dampened interest in antihistamines as analgesics. The mixed results of preclinical studies targeting H2 and H3 receptors, along with the newly discovered role of the H4 receptor in pain, necessitate further investigation, particularly regarding the interactions between histamine receptors, before antihistamines regain attention in pharmaceutical companies' pain programs. We believe that clinical data on the efficacy of alimazine, although obtained in a small number of TN patients, coupled with planned preclinical and clinical trials, will provide valuable insights into the role of first-generation antihistamines in neuropathic pain.

[0287] The role of TRPV1 in nociception is central to our hypothesis because histamine signaling is closely associated with TRPV1 activation in both itching and pain. TRPV1 is involved in various neuropathic pain conditions (e.g., PHN, diabetic neuropathy, chemotherapy-induced pain) and may also play a role in trigeminal neuralgia. TRPV1 can be activated or sensitized via PLC-mediated release of IP3 from PIP2, and DAG and intracellular Ca2+ further activate PKC isoenzymes such as PKCδ, which phosphorylate TRPV1. This cascade reaction, including Ca... 2+- Activation of calmodulin-dependent protein kinase II (CaMKII) leads to TRPV1 sensitization and the perception of pain.

[0288] Alimazine's modulation of these pathways (via PKC) may reduce overexcitation of trigeminal neurons, thereby alleviating TN pain. Targeting TRPV1 to relieve pain and itching has shown promise, particularly with the use of capsaicin, an agonist that desensitizes TRPV1 and has analgesic, antipruritic, and anti-inflammatory effects. An 8% capsaicin patch has been approved for PHN and painful diabetic neuropathy. The clinical efficacy of capsaicin has led to the development of various oral TRPV1 antagonists and desensitizing agonists for a variety of TRPV1-mediated pain and itching conditions. However, due to unwanted side effects (hyperthermia) in Phase I trials and a lack of efficacy in Phase II trials, no drugs have been approved for clinical use, resulting in a lack of further development by pharmaceutical companies. Interestingly, the focus has shifted from optimizing highly selective and potent TRPV1 antagonists to so-called “milder” drug approaches, which use molecules based on the capsaicin skeleton but designed to be enzymatically modified in the affected tissue to modulate TRPV1 and apply them topically to reduce local side effects such as burning sensations and systemic effects, particularly hyperthermia.

[0289] Furthermore, the modulation of H1R by alimazine may influence the inflammatory process. Tissue damage, injury, or infection involving trigeminal neurons (e.g., Herpes zoster) triggers an immune response, including the activation of resident mast cells and the recruitment of polymorphonuclear leukocytes (PMNLs), epithelial cells, Schwann cells, fibroblasts, and postganglionic sympathetic neurons (SPGNs). In particular, mast cells release histamine, which binds to H1R in peripheral afferent nerves, DRGs, and TGs, further sensitizing TRPV1 and exacerbating pain. Alimazine may contribute to overall pain relief by reducing this histamine-driven sensitization through stabilizing H1R and modulating the immune response.

[0290] The ability of alimazine to modulate pain via H1R may also involve the inhibition of NF-κB immune response transcription factors through the PLC and PIP2 signaling pathways. This inhibition leads to reduced antigen presentation, decreased expression of pro-inflammatory cytokines, and downregulation of cell adhesion molecules and chemokines. Furthermore, by stabilizing calcium levels, alimazine may promote mast cell stability, further reducing histamine release. These effects collectively reduce neuronal sensitization and peripheral inflammatory processes, ultimately suppressing CNS sensitization and pain.

[0291] Off-target effects of alimazine on muscarinic receptors may further enhance its analgesic properties. Both M2 and M4 muscarinic receptor subtypes mediating nociceptive responses are expressed at primary afferent terminals. The M4 receptor is of particular interest in chronic pain conditions due to its increased expression in neuropathic pain states such as diabetic neuropathy.

[0292] The high affinity of alimazine for muscarinic receptors (shared with other H1 receptor antagonists) may contribute to its analgesic effect in TN.

[0293] In the applicant's study of a small subset of TN patients treated with alimazine, two out of seven patients experienced long-term pain relief with no symptom recurrence for more than 12 months. This suggests a potential disease-modifying effect, possibly mediated by alimazine's influence on inflammatory pathways. Furthermore, recent studies have highlighted the role of the M1 muscarinic receptor in remyelination, which may be particularly relevant in TN cases associated with nerve compression and demyelination. The potential of alimazine to promote remyelination through M1 receptor modulation could provide long-term, potentially disease-altering therapeutic benefits.

[0294] In summary, while the exact mechanism of action of alimazine in TN remains to be fully elucidated, current hypotheses suggest that, due to its multipharmacological properties, the drug acts through multiple pathways to reduce pain and potentially alter disease course. Ongoing studies aim to further characterize these mechanisms as part of efforts to repurpose and reformulate alimazine for TN. Early clinical observations indicate that alimazine provides significant pain relief in patients with TN.

[0295] Example

[0296] Although the invention has been described in considerable detail with reference to certain aspects thereof, other versions are possible. Therefore, the spirit and scope of the appended claims should not be limited to the versions described and exemplified herein. Various aspects of the invention will be described with reference to the following non-limiting embodiments.

[0297] The table below briefly summarizes the examples, describing seven patients with TN and their clinical outcomes, along with comments related to each patient. In each case, administration of alimazine reduced or alleviated the patient's pain, as further described in the examples.

[0298]

[0299] Example 1

[0300] A middle-aged man suffers from typical trigeminal neuralgia (Type I), characterized by sharp, tearing, and intense pain in the left side of his face, triggered by bathing, eating, facial expressions, touching his facial skin and nose, and brushing his teeth. Attacks are triggered by these stimuli, immediately halting all other activities until the pain subsides after a few seconds. He has altered his behavior to avoid these stimuli, even affecting the way he speaks and eats. He has had previous MRI scans, which showed no vascular compression as a diagnostic indicator. His daily activities are entirely dominated by the fear of triggering another attack.

[0301] He did not take carbamazepine (Tegretol) for fear that it would disqualify him from holding a pilot's license. He did not take any painkillers. Before receiving treatment with alimazine, he had no way to relieve these terrible pains.

[0302] The patient began treatment with alimazine, 5 mg twice daily. On the second day of treatment, the intensity and frequency of attacks began to decrease. After four days of medication, all pain had disappeared. Since then, he has noticed some discomfort in his face, but not the sharp, almost unbearable pain he previously experienced. This has been successfully relieved by taking half to one 5 mg tablet once or twice daily. He now doesn't need medication most days. Aside from drowsiness after taking the medication, there have been no other side effects. He noted that drowsiness is a common side effect for him if a medication has the potential to cause it.

[0303] Example 2

[0304] The patient, a 76-year-old male, had a history of Lyme disease affecting the V1 and V2 distribution areas of the right trigeminal nerve. The disease had previously caused numbness of the skin in his right forehead and cheek, which resolved with successful antibiotic treatment. Approximately 19 years after the initial Lyme disease episode, he began noticing lightning-like pain in his right cheek. These were brief and usually occurred with skin irritation, such as during showering, occurring about once or twice a year. Twenty-two years after his initial Lyme disease episode, he experienced a severe trigeminal neuralgia (TN) attack affecting his right cheek (Type 1). He experienced an average of eight sharp, stabbing pains per day, triggered by facial expressions, touch, opening his mouth to eat, brushing his teeth, or even a gust of cold wind. Fearing a recurrence of Lyme disease, he self-treated with doxycycline. His attacks subsided after 14 days, and he became asymptomatic. He then received alimazine, which he took 5 mg twice daily when sharp pain recurred at 7 and 11 months after the TN attack, successfully stopping all recurrent pain immediately. There has been no recurrence of TN in the 12 months since the last treatment with alimazine.

[0305] Example 3

[0306] The patient was an elderly man with type 1 TN that had not been successfully controlled with carbamazepine and gabapentin. He was in so much pain that he couldn't even brush his teeth without triggering a severe attack of pain. He started taking 5 mg of alimazine twice daily and tolerated the medication well, except for some drowsiness. The pain began to subside, and by ten days after starting treatment, he was essentially pain-free and able to eat, talk, and brush his teeth without fear of triggering acute TN pain. This relief was long-lasting. He discontinued carbamazepine and gabapentin.

[0307] Example 4

[0308] The patient was a 77-year-old male with metastatic leukemia (TN), which began 3 years prior after dental surgery. TN presented as sharp, tearing pain (Type 1) in the left mandible. These pains were paroxysmal, triggered by stimuli such as brushing teeth, occurring at least once daily, with each susceptible period lasting 3-4 weeks, and occurring 3-4 times per year. His mother had also had TN with the same pattern. He was also taking pregabalin when he started taking alimazine. After 10 days of the first course of treatment with 5 mg alimazine twice daily, his mandibular pain disappeared, but a sensitive area remained on the side of his head above his ear. This completely disappeared after a few days of treatment with the second course of 5 mg alimazine twice daily.

[0309] Example 5

[0310] The patient is a young woman suffering from severe ocular shingles affecting her right face and right eye. She has extensive ocular involvement and has required medication for a full year. Her corneal problems are accompanied by severe, persistent neuropathic pain (Type 2) in the affected ophthalmic nerve branch region (trigeminal nerve), which torments her every waking hour. She is taking 12 medications, including carbamazepine 200 mg twice daily (BID), pregabalin 150 mg three times daily (TID), ophthalmic medications, and oxycodone as needed to relieve pain. She started taking alimazine and noticed some improvement after about 5 days of starting, then requested more medication to continue treatment. About four months later, she reported, “My maximum pain now is probably 5, and the average is 2, which is fantastic!” She had persistent facial pain in the ophthalmic branch region of her trigeminal nerve, but the pain had lessened. She is considering starting a second course of alimazine at a dose of 10 mg BID, double the dose she took initially.

[0311] Example 6

[0312] The patient had shingles on her forehead, followed by persistent neuralgia in the affected ophthalmic branch of the trigeminal nerve. She experienced persistent pain (TN Type 2) for approximately six months, although not as severe as in patient 5. The patient was able to function normally. Six days after starting a 5 mg BID of alimazine, she reported: “Yes, I’m taking the medication, and it really helps my head. Only a few pills left. It’s such a relief not to have a headache!” She did not undergo a second course of medication. She experiences occasional residual pain, which is well controlled with Tylenol.

[0313] Example 7

[0314] A representative clinical protocol for treating trigeminal neuralgia is outlined below.

[0315] Number of patients: 80-100.

[0316] Study duration: 12-18 months (12-week treatment period).

[0317] Study Design: Randomized, double-blind (DB) withdrawal study compared to standard of care. Studies may include a screening period, a 7-day adjustment period, a 4- or 6-week single-blind dose optimization period, or a screening period, a 7-day adjustment period, a 4-week open-label period, and a 14-week double-blind period. Long-term extension studies may be conducted for patients who complete the double-blind period.

[0318] Primary endpoint: The proportion of participants classified as responders at week 12 of the double-blind period.

[0319] Secondary endpoints: safety indicators, quality of life, and population pharmacokinetic assessments.

[0320] Number of sites: 10

[0321] Primary outcome measure: frequency and duration of pain attacks recorded in the pain diary.

[0322] Secondary outcome measures: Penn-FPS-R quality of life index, PGIC, and the number of times patients used "emergency medications" (e.g., existing SOC medications, opioids, etc.).

[0323] Inclusion criteria: age ≥18 years, diagnosed with typical, pure paroxysmal TN ≥3 months prior to enrollment in the study, and experiencing ≥3 pain episodes per day.

[0324] Trial endpoints: Based on patient-reported outcome measures, using pain attack frequency and duration recorded in pain diaries, Patient Global Impression Change (PGIC) score and Penn-Facial-Pain-Score-Revised, EuroQoL 5-Dimensions 5-Level version (EQ-5D-5L) score, and Work Productivity and Activity Impairment (WPAI) score. Changes in rescue medication use before and after treatment in each group.

[0325] Alimazine formulations: 5 mg alimazine sulfate or alimazine tartrate twice daily. For most patients, the dose will be 1 x 5 mg oral film (OTF) twice daily, morning and evening. Alternative doses for older patients (especially those experiencing dizziness) can be achieved by titration, starting with 1 x 2.5 mg OTF or 1 x OTF tablet once daily at night to manage potential side effects such as dizziness.

[0326] Treatment can be discontinued based on a decrease in pain intensity and frequency. For example, in the case of TN (Total Neuralgia), once the frequency and intensity of pain attacks drop to zero, the patient can stop treatment and restart it if the pain recurs. However, in other cases presenting as more persistent pain, such as PHN (Profound Neuralgia), treatment may be continued for a long time. Depending on the indication, medications can be used prophylactically to control the intensity and frequency of pain, especially because they may act on sensory ganglia involved in pain perception (dorsal root ganglia (PHN, CIPN, DNP) or semilunar ganglia (TN)), without being bound by theory.

[0327] Example 8

[0328] A representative clinical protocol for treating postherpetic neuralgia is summarized below.

[0329] Postherpetic neuralgia (PHN) is the most common long-term complication of varicella-zoster virus (VZV) (also known as human herpesvirus type 3 (HHV-3)). This reactivation of dormant VZV is called herpes zoster (or shingles). VZV is the pathogen of varicella (chickenpox), a childhood disease.

[0330] The hallmark of PHN is unilateral dermatome pattern of tearing / burning pain that lasts for three months or longer after a herpes zoster (HZ) outbreak.

[0331] Postherpetic neuralgia (PHN) occurs in a subset of people who have experienced an acute herpes zoster (HZ) outbreak. Established risk factors for the progression of an acute HZ outbreak to PHN include age, severe immunosuppression, the presence of a prodromal phase, intense pain during a shingles outbreak, unusual pain, ocular involvement, and diabetes.

[0332] Persistent (≥3 months) tearing / burning pain, paresthesia, paresthesia, itching, dysesthesias, and / or hyperalgesia in or near the rash area are characteristic of PHN. PHN also interferes with patients' quality of life, and sleep disturbance is a common complaint. Pain-related sleep disturbances, in turn, can aggravate pain and / or decrease pain tolerance.

[0333] The treatment endpoint will be a reduction in overall pain intensity and / or elimination of PHN pain, as well as improved sleep (reduction of PHN pain-related sleep disturbances). Pain is described as tearing / burning pain, paresthesia, paresthesia, itching, hypoesthesia, and / or hyperalgesia in or near the HZ rash area. Sleep is also affected.

[0334] Number of patients: 100-120.

[0335] Study duration: 12-18 months (12-week treatment period).

[0336] Study Design: Randomized, double-blind, placebo-controlled, efficacy study. Treatment group: 5 mg dose twice daily during treatment. Placebo comparator: Placebo (sugar pill) twice daily during treatment.

[0337] Primary endpoint: Change in mean daily pain intensity score over the past 7 days (week 8 or final visit) compared to baseline.

[0338] Secondary endpoints: pain scale, sleep score, quality of life, and emotional state profile.

[0339] Number of centers: 20.

[0340] Country: United States only.

[0341] Primary outcome measure: Basic Pain Inventory (BPI) (PHN version).

[0342] Secondary outcome measures: BPI, McGill Short Form pain scale, changes in clinician and patient overall impressions, EuroQoL 5D-5L score, sleep diary, mood, and number of times the patient used "emergency medications" (e.g., existing SOC medications, opioids, etc.).

[0343] Inclusion criteria: Male and female participants aged ≥50 years with postherpetic neuralgia whose pain had persisted for >3 months after the shingles rash had healed. Female participants were infertile (e.g., sterilized, postmenopausal).

[0344] The trial endpoint will be based on pain reduction (based on BPI score) compared to baseline at week 8 or the final visit. Additional secondary endpoints will be based on pain reduction compared to baseline at each visit, changes in clinician and patient overall impression scores compared to baseline, EuroQoL 5-dimensional, 5-level (EQ-5D-5L) scores, mood scores, and sleep scores. Changes in emergency medication use before and after treatment in each group will also be considered.

[0345] Example 9

[0346] A representative clinical protocol for treating diabetic neuropathic pain is outlined below.

[0347] Diabetic neuropathy is the most common complication of diabetes mellitus (DM), affecting up to 50% of patients with type 1 and type 2 DM. Diabetic neuropathic pain (DNP) is clinically defined as pain in diabetic patients caused by damage to peripheral, autonomic, focal, or proximal nerves. It most commonly affects the distal extremities of the hands and feet and can occur in patients diagnosed with either type 1 (T1D) or type 2 (T2D) diabetes. The prevalence of painful neuropathy in type 2 diabetes is more than twice that seen in type 1 diabetes.

[0348] Most patients experience moderate to severe pain, and most find it difficult to articulate the characteristics of their pain. Common descriptive terms for neuropathic pain, such as “burning,” “electric shock,” “shooting / stabbing” radiating to the legs, “pins and needles” and “numbness,” can be elicited upon further questioning. Patients may also have evoked pain characteristics, such as atypical pain (a painful response to non-painful stimuli) and hyperalgesia (a stronger response to stimuli that normally cause pain), which can significantly impact daily activities. The pain typically occurs in the feet and may ascend to affect the lower extremities and occasionally the hands. The pain usually worsens at night, leading to sleep disturbances and fatigue.

[0349] Pain, coupled with physical disability resulting from other long-term complications of diabetes, severely impairs quality of life. Patients with neuropathic pain score significantly lower across all domains of quality of life, including enjoyment of life, sleep, physical activity, self-care, and energy levels.

[0350] The treatment endpoints will be a reduction in overall pain, a decrease in sleep disturbances, and an improvement in quality of life and mood scores for DNP.

[0351] Number of patients: more than 200.

[0352] Study duration: 12-18 months (12-week treatment period).

[0353] Study design: randomized, double-blind, placebo-controlled, parallel group, efficacy study.

[0354] Treatment group: 5 mg dose twice daily during treatment.

[0355] Placebo control group: Two placebos (sugar pills) were administered daily during the treatment period.

[0356] Primary endpoint: Change in mean daily pain intensity score from baseline (day 7–day 1) compared to the mean pain intensity score at week 12 (the last week).

[0357] Secondary endpoints: pain scale, sleep score, quality of life, and emotional state profile.

[0358] Number of centers: 20.

[0359] Country: United States only.

[0360] Primary outcome measure: 11-point numerical pain rating scale (PI-NRS).

[0361] Secondary outcome measures: PI-NRS, changes in clinician and patient overall impressions, EuroQoL 5D-5L score, sleep diary, and mood.

[0362] Inclusion criteria: Male and female subjects aged >18 years and <80 years with type 1 or type 2 diabetes for at least 6 months, and with optimized and stable glycemic control in the 3 months prior to screening. Douleur Neuropathique 4 (DN4) score >=4, and the number of times the patient used "emergency medications" (e.g., existing SOC medications, opioids, etc.).

[0363] The trial endpoint will be based on pain reduction (based on PI-NRS) compared to baseline at week 8 or the final visit. Additional secondary endpoints will be based on pain reduction compared to baseline at each visit (or patient self-report), changes in clinician and patient overall impression scores compared to baseline, EuroQoL 5-dimensional 5-level version (EQ-5D-5L) scores, mood scores, and sleep scores. Changes in emergency medication use before and after treatment in each group will also be considered.

[0364] Example 10

[0365] A representative clinical protocol for treating chemotherapy-induced neuropathic pain is outlined below.

[0366] Chemotherapy-induced neuropathic pain (CINP) is one of the most serious side effects of anticancer drugs (such as platinum and taxane derivatives (oxaliplatin, cisplatin, carboplatin, and paclitaxel)). It is mainly caused by damage to the somatosensory nervous system after anticancer drug treatment and is one of the main causes of neuropathic pain in cancer patients in clinical practice.

[0367] Sensory symptoms typically manifest as spontaneous or evoked abnormal sensations, such as paraesthesia, hypoesthesia, numbness, burning, piercing, tingling, or electric shock sensations, as well as abnormal pain or hyperalgesia triggered by mechanical or thermal stimuli. Symptoms usually affect the extremities of the upper and lower extremities ("stocking and glove" distribution) and extend towards the proximal areas of the body.

[0368] Chemotherapy-induced neuropathic pain initially presents as an acute pain syndrome, with sensory symptoms appearing immediately during or after drug administration, and progresses to chronic neuropathy after repeated treatment cycles.

[0369] However, acute neuropathy usually resolves during treatment breaks, while chronic neuropathy can last for months or years. 47% of patients receiving anticancer drug treatment still experience peripheral neuropathy symptoms six years after treatment discontinuation. Chronic pain from CINP severely impairs the quality of life for cancer patients.

[0370] CINP patients report paresthesia, hypoesthesia, numbness, burning, piercing or electric shock sensations, as well as abnormal pain or hyperalgesia caused by mechanical or thermal stimuli. These sensations affect the extremities of the upper and lower extremities ("stocking-glove" distribution) and extend to proximal areas of the body.

[0371] The treatment endpoint will be the reduction of overall CINP pain and quality of life indicators.

[0372] Number of patients: 25-30.

[0373] Study design: randomized, double-blind, placebo-controlled, parallel group, efficacy study.

[0374] Treatment group: 5 mg dose twice daily during treatment.

[0375] Placebo control group: Two placebos (sugar pills) were administered daily during the treatment period.

[0376] Primary endpoint: Comparison of pain intensity scores reported by patients in the two groups after the treatment period (12 weeks).

[0377] Secondary endpoints: Pain Scale (NPSI), indicators of cancer-related symptoms (e.g., FACT-paclitaxel), and changes in “emergency medication” use.

[0378] Number of centers: up to 10.

[0379] Country: United States only.

[0380] Primary outcome measure: Brief Pain Scale (BPI).

[0381] Secondary outcome measures: Neuropathic Pain Symptom Scale (NPSI), FACT-Taxane, FACT-GOG-NTX or the appropriate FACT tool used for the chemotherapy administered, and the number of times the patient used "emergency medications" (e.g., existing SOC medications, opioids, etc.).

[0382] Inclusion criteria: Patients must be at least 18 years old. Patients must experience moderate to severe peripheral neuropathic pain. Patients must have chronic peripheral neuropathic pain, defined as chemotherapy-related pain lasting 3 months or longer. Patients will primarily have bilateral peripheral neuropathic pain symptoms affecting both feet. Patients must have cancer (at any stage).

[0383] The trial endpoint will be based on the reduction of pain (based on BPI score) at the end of treatment (week 12). Additional secondary endpoints will be based on the reduction of pain (using NPSI, FACT-XXX) compared to baseline at the end of treatment in each trial group. Changes in emergency medication use before and after treatment in each group will also be considered.

[0384] Example 11

[0385] Bioavailability, safety and efficacy of alimazine in the treatment of trigeminal neuralgia (PhI / II)

[0386] The typical or “classic” form of this disorder (known as “Type 1” or TN1) causes extreme, sporadic, sudden burning or throbbing facial pain, with each episode lasting from a few seconds to two minutes. These episodes can occur rapidly and consecutively, lasting up to two hours.

[0387] The “atypical” form of the disease (called “type 2” or TN2) is characterized by persistent aches, burning, and stinging pain, which is slightly less intense than type 1.

[0388] Both forms of pain can occur in the same person, sometimes simultaneously. The intensity of the pain can be physically and mentally debilitating.

[0389] The trigeminal nerve is one of 12 pairs of nerves that attach to the brain. It has three branches originating from the semilunar ganglion, transmitting sensations from the upper, middle, and lower parts of the face, as well as the mouth, to the brain. The ophthalmic or superior branch supplies sensation to most of the scalp, forehead, and front of the head. The maxillary or middle branch innervates the cheek, palate, upper lip, teeth and gums, and the sides of the nose. The mandibular or inferior branch supplies sensation to the mandible, teeth and gums, and lower lip. More than one branch may be affected by the disease. In rare cases, both sides of the face may be affected at different times, or more rarely, both sides may be affected simultaneously (a condition known as bilateral TN).

[0390] The pain varies depending on the type of TN, ranging from sudden, intense, stabbing to more persistent, aching, or burning sensations. Severe paroxysmal pain (paroxysmal attacks) can be triggered by seemingly harmless stimuli that cause tremors or are triggered by contact with the cheek (such as when shaving, washing the face, or applying makeup), brushing teeth, eating, drinking, talking, or being exposed to wind. The pain may affect a small area of ​​the face or it may spread. Pain attacks rarely occur at night when the affected individual is sleeping. TN is characterized by recurrence after a period of cessation, but this condition can be progressive. Attacks typically worsen over time, with shorter and fewer pain-free periods before recurrence. Eventually, the pain-free periods disappear, and medications for pain control become less effective.

[0391] Example 12

[0392] Study Design Summary: This study is designed as a Phase I(b) / II(b) bioequivalence and proof-of-concept efficacy study to evaluate the bioequivalence, formulation characteristics, safety, dosing regimen (in healthy volunteers), and efficacy of alimazine in patients with trigeminal neuralgia who have not responded adequately to current pain management therapies. Phase I(b)-A will evaluate the bioequivalence and safety of alimazine in tablet and oral film (OTF) forms in healthy volunteers. Phase I(b)-B will be an open-label, multi-dose escalation study of alimazine in the OTF form in healthy volunteers to determine the maximum tolerated dose (MTD). The Phase II(b) study will evaluate the efficacy of alimazine in the OTF form at the MTD, compared to the control group, in patients with trigeminal neuralgia in a randomized controlled trial.

[0393] Phase 1(b) - Part A

[0394] Primary objective: Bioequivalence / safety of tablet / oral film (OTF) formulations in healthy volunteers.

[0395] Allocation: Randomized, controlled, crossover study comparing tablet and OTF formulations of drugs.

[0396] Intervention models: random, crossover

[0397] Alimazine tablets

[0398] Alimazine OTF

[0399] Blindness: None - Open Label

[0400] Subjects: n=52 (total of Part A and Part B)

[0401]

[0402] Phase 1(b) – Part B

[0403] Primary objective: To determine the maximum tolerated dose (MTD) of alimazine in the OTF form in healthy volunteers.

[0404] Distribution: Open-label, multi-dose escalation OTFs

[0405] Intervention Model: Parallel Allocation

[0406] Alimazine OTF

[0407] Blindness: None, Open Label

[0408]

[0409] Phase II(b)

[0410] Primary objective: A proof-of-concept study to determine the efficacy of alimazine in the OTF form in patients with TN.

[0411] Allocation: Randomized, controlled, comparing alimazine OTF with placebo.

[0412] Intervention Model: Parallel Allocation

[0413] Medication: Alimazine OTF

[0414] Medication: Placebo (matched to alimazine OTF)

[0415] Blinding: Double-blind (participant / researcher)

[0416] Subjects: n=40

[0417]

[0418] end

[0419] Main ending

[0420]

[0421] Secondary outcome indicators

[0422]

[0423] Other outcome indicators

[0424]

[0425] Research queue description

[0426] Health queue

[0427] Summary of included standards

[0428] 1. The ability and willingness to provide written informed consent and comply with research procedures.

[0429] 2. Proficient in the language of researchers, research staff, and informed consent forms.

[0430] 3. Age 45-75 years (similar to the age range of TN patients).

[0431] 4. All participants must use effective contraception during the study period and be willing and able to continue using contraception for 90 days after receiving the study treatment.

[0432] 5. Based on the researcher's judgment, medical history, and screening assessment, the candidate must be in good health.

[0433] Exclusion criteria

[0434] 1. Any clinically significant history of cardiac, endocrine, gastrointestinal, hematological, hepatic, immunological, metabolic, urinary, pulmonary, neurological, dermatological, psychiatric, or renal disease, or other major medical conditions, as determined by the investigator.

[0435] 2. Previous exposure to alimazine.

[0436] 3. Other unspecified reasons that the researcher or sponsor deems the subject unsuitable for enrollment.

[0437] Trigeminal neuralgia cohort

[0438] Summary of inclusion criteria:

[0439] 1. The ability and willingness to provide written informed consent and comply with research procedures.

[0440] 2. Proficient in the language of researchers, research staff, and informed consent forms.

[0441] 3. Age 18-75 years old.

[0442] 4. Diagnosed with primary trigeminal neuralgia (TN) according to the ICHD3 criteria confirmed by the research neurologist.

[0443] 5. Experiencing pain due to TN, and at baseline, experiencing at least 3 episodes per day with a pain intensity of 4 or higher (on the numerical pain intensity rating scale (PI-NRS)) in the past 7 days.

[0444] 6. Female patients must be infertile or menopausal. For female patients of childbearing age, they must not be pregnant or breastfeeding (using appropriate contraception and having a negative pregnancy test).

[0445] Exclusion criteria summary:

[0446] Patients meeting any of the following criteria will be excluded from this study:

[0447] 1. Current or past history of any major psychiatric diagnosis unrelated to TN. Patients with TN-related depressive symptoms are permitted.

[0448] 2. Current or past history of manic or psychotic episodes.

[0449] 3. A history of substance dependence (DSM-5, Diagnostic and Statistical Manual for Mental Disorders, 5th edition) and / or substance abuse, excluding nicotine, within the past six months [180 days].

[0450] 4. Known allergic reaction to the investigational drug or any of its components.

[0451] 5. Patients with secondary TN according to ICHD3 criteria.

[0452] Medication history:

[0453] 1. Previous treatment with alimazine, unless prior consent is obtained from a medical monitor.

[0454] 2. Receive antipsychotic medication within six months (180 days) prior to screening.

[0455] 3. Use of any investigational drug within 90 days prior to the start of the investigational drug.

[0456] Medical condition:

[0457] 1. Evidence of clinically significant, uncontrolled, unstable medical conditions or newly diagnosed cardiovascular disease (such as ischemic heart disease, coronary artery spasm, and cerebral ischemia). Subjects who have experienced myocardial infarction, acute coronary syndrome, percutaneous coronary intervention, cardiac surgery, stroke, or transient ischemic attack within 6 months prior to screening.

[0458] 2. Subjects with a history of gastric or small bowel surgery (including gastric bypass, gastric banding, gastric sleeve, gastric balloon, etc.) are considered by researchers to have malabsorption potential or to have gastrointestinal diseases that lead to malabsorption.

[0459] 3. Body Mass Index (BMI) > 39 kg / m² 2

[0460] Efficacy Calculation

[0461] Calculating efficacy in pain trials is notoriously difficult and depends heavily on the study design.

[0462] However, in TN, particularly Type 1 (characterized by multiple stabbing attacks per day), we selected a reduction in the number of daily attacks as the primary endpoint. Most patients experience an average of 7–10 pain attacks per day, and a 30% (from 7–10 attacks to 5–7 attacks per day) to 50% (from 7–10 attacks to 3–5 attacks per day) reduction in the number of attacks would be clinically significant for patients.

[0463] Therefore, the number of participants was calculated using the following parameters. We assumed two independent study groups from parallel allocations (treatment group vs. placebo group), and we considered the clinically meaningful outcome of the drug to be a 30% reduction in daily pain attacks, i.e., 3 fewer attacks compared to baseline.

[0464] Each group has n=16 participants, and considering a 10% dropout rate, the total number of participants is 16 / (1-0.1)=17.

[0465] A total of 35 participants are needed to demonstrate efficacy for the trial.

[0466] Example 13

[0467] Pharmaceutical formulations: Quality Target Product Overview (QTPP).

[0468] The formulation of alimazine has been evaluated in an in vitro oral model. The quality objectives for this formulation are outlined in the table below.

[0469]

[0470] This disclosure is not limited to the specific systems, devices, and methods described, as these may vary. The terminology used in this specification is for the purpose of describing a particular version or embodiment only and is not intended to be limiting.

[0471] This disclosure is not limited to the specific embodiments described herein, which are intended to be illustrative of various aspects. Many modifications and variations can be made without departing from its spirit and scope, as will be apparent to those skilled in the art. In addition to those listed herein, functionally equivalent methods and apparatus within the scope of this disclosure will be apparent to those skilled in the art from the foregoing description. These modifications and variations are intended to fall within the scope of the appended claims. This disclosure is limited only by the terms of the appended claims and the full scope of their equivalents. It should be understood that this disclosure is not limited to specific methods, reagents, compounds, compositions, or biological systems, which are of course subject to variation. It should also be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.

[0472] Regarding the use of virtually any plural and / or singular terms in this document, those skilled in the art may convert plural to singular and / or singular to plural as needed by the context and / or application. For clarity, various singular / plural permutations may be explicitly presented herein.

[0473] Those skilled in the art will understand that, in general, the terms used herein, particularly those used in the appended claims (e.g., the body of the appended claims), are generally intended to be “open-ended” terms (e.g., the term “comprising” should be interpreted as “including but not limited to,” the term “having” should be interpreted as “having at least,” the term “comprising” should be interpreted as “including but not limited to,” etc.). While various compositions, methods, and apparatuses are described as “comprising” various components or steps (interpreted as “including but not limited to”), compositions, methods, and apparatuses may also consist “substantially” or “composed of” these various components and steps, and such terms should be interpreted as defining substantially closed groups of members. Those skilled in the art will further understand that if there is an intention to introduce a particular number of claim statements, such intention will be explicitly stated in the claims, and without such statements, such intention does not exist.

[0474] For example, to aid understanding, appended claims may include the use of introductory phrases “at least one” and “one or more” to introduce the claim statement. However, the use of such phrases should not be construed as implying that a claim statement introduced by the indefinite article “a” or “an” limits any particular claim containing such an introduced claim statement to containing only one embodiment of such a statement, even if the same claim includes the introductory phrases “one or more” or “at least one” and indefinite articles such as “a” or “an” (e.g., “a” and / or “an” should be interpreted as “at least one” or “one or more”); the same applies to the use of definite articles used to introduce the claim statement.

[0475] Furthermore, even when the specific number of claims in the introduced claims is explicitly stated, those skilled in the art will recognize that such a statement should be interpreted as indicating at least the number of claims (e.g., a simple statement of "two claims" without other modifiers indicates at least two claims, or two or more claims). Additionally, in the case of using conventions such as "at least one of A, B, and C," the intention of this construction is generally that those skilled in the art understand the meaning of the convention (e.g., "a system having at least one of A, B, and C" will include, but is not limited to, systems having only A, only B, only C, having A and B together, having A and C together, having B and C together, and / or having A, B, and C together, etc.). In the case of using conventions such as "at least one of A, B, or C," the intention of this construction is generally that those skilled in the art understand the meaning of the convention (e.g., "a system having at least one of A, B, or C" will include, but is not limited to, systems having only A, only B, only C, having A and B together, having A and C together, having B and C together, and / or having A, B, and C together, etc.). Those skilled in the art will further understand that any transition words and / or phrases presenting two or more alternative terms, whether in the specification, claims, or drawings, should be understood to include the possibility of including one, any, or both terms. For example, the phrase "A or B" will be understood to include the possibility of including "A" or "B" or "A and B".

[0476] Furthermore, where the disclosed features or aspects are described in terms of the Markush group, those skilled in the art will recognize that this disclosure is therefore also described in terms of any individual member or subgroup of the Markush group.

[0477] As those skilled in the art will understand, for any and all purposes, such as in providing a written description, all scopes disclosed herein also encompass any and all possible subscopes and combinations thereof. Any listed scope can be readily considered adequately descriptive and such that the scope can be decomposed into at least equal halves, thirds, quarters, fifths, tenths, etc. As a non-limiting example, each scope discussed herein can be readily decomposed into a lower third, a middle third, and an upper third, etc. As those skilled in the art will also understand, all language such as “up to,” “at least,” etc., includes the stated number and refers to a scope that can be subsequently decomposed into subscopes as described above. Finally, as those skilled in the art will understand, a scope includes each individual member. Thus, for example, a group having 1-3 compounds means a group having 1, 2, or 3 compounds. Similarly, a group having 1-5 cells means a group having 1, 2, 3, 4, or 5 compounds, etc.

[0478] The various features and functions disclosed above, or their alternatives, can be combined into many other different systems or applications. Those skilled in the art can then make various alternatives, modifications, variations, or improvements that are not currently foreseeable or anticipated, each of which is also intended to be covered by the disclosed embodiments.

Claims

1. A method for treating pain associated with trigeminal neuralgia, comprising administering a therapeutically effective amount of alimazine or a pharmaceutically acceptable salt thereof to a patient in need, thereby treating the patient's trigeminal neuralgia.

2. The method according to claim 1, wherein, The therapeutically effective amount of alimazine or a pharmaceutically acceptable salt thereof is administered once daily.

3. The method according to claim 1, wherein, The therapeutically effective amount of alimazine or a pharmaceutically acceptable salt thereof is administered twice daily.

4. The method according to claim 1, wherein, The therapeutically effective amount of alimazine or a pharmaceutically acceptable salt thereof may be administered orally, intravenously (IV), intramuscularly (IM), intrathecally, subcutaneously (SC), sublingually or buccally, rectally, vaginally, dermally, transdermally, nasally, or in combination thereof.

5. The method according to claim 1, wherein, The therapeutically effective amount of alimazine or a pharmaceutically acceptable salt thereof is administered orally.

6. The method according to claim 1, wherein, The therapeutically effective amount of alimazine or a pharmaceutically acceptable salt thereof is administered via an oral film formulation.

7. The method according to claim 1, wherein, The therapeutically effective amount of alimazine or a pharmaceutically acceptable salt thereof is about 0.5 mg to about 80 mg.

8. The method according to claim 1, wherein, The therapeutically effective amount of alimazine or a pharmaceutically acceptable salt thereof is about 2.5 mg to about 5 mg.

9. The method according to claim 1, wherein, The therapeutically effective amount of alimazine or a pharmaceutically acceptable salt thereof is about 0.5 mg to about 2.5 mg.

10. The method according to claim 1, wherein, The treatment for pain associated with trigeminal neuralgia includes a reduction in pain frequency, a reduction in pain duration, a reduction in pain intensity, or any combination thereof.

11. The method according to claim 10, wherein, A reduction in pain duration includes a reduction in the duration of a single pain episode, a reduction in the duration of a series of pain episodes, and any combination thereof.

12. The method according to claim 11, wherein, A series of pain episodes includes at least two separate pain episodes.

13. The method according to claim 1, wherein, The pain associated with trigeminal neuralgia is described as stabbing, tearing, throbbing, electric shock-like, persistent aches, burning sensations, stabbing pain with intensity slightly less than that of type 1 TN, and any combination thereof.

14. The method according to claim 11, wherein, The reduction in pain frequency, the reduction in pain duration, the reduction in pain intensity, or any combination thereof, was measured using a patient diary, PGIC score, MSQ score, BNI pain intensity score, Penn-FPS-R score, Penn-FPS score, EQ-5D-5L score, WPAI score, or any combination thereof.

15. The method according to claim 1, wherein, Administering a therapeutically effective amount of alimazine or a pharmaceutically acceptable salt thereof includes an initial dose between 2.5 mg and approximately 5.0 mg.

16. The method of claim 15, further comprising, if treatment of pain associated with trigeminal neuralgia is not achieved, administering an additional therapeutically effective amount of alimazine or a pharmaceutically acceptable salt thereof approximately every 12 hours after the initial dose.

17. The method according to claim 16, wherein, The additional therapeutically effective amount of alimazine or its pharmaceutically acceptable salt is increased approximately every 30 minutes to 5 hours until treatment of pain associated with trigeminal neuralgia is achieved.

18. The method according to claim 17, wherein, Once treatment for pain associated with trigeminal neuralgia is achieved, an additional therapeutically effective amount of alimazine or a pharmaceutically acceptable salt thereof is maintained as the minimum effective level for treating pain associated with trigeminal neuralgia.

19. The method according to claim 18, wherein, Administer the minimum effective level of therapeutically effective amount of alimazine or a pharmaceutically acceptable salt thereof until treatment of pain associated with trigeminal neuralgia is no longer achieved. Thereafter, the minimum effective level of therapeutically effective amount of alimazine or a pharmaceutically acceptable salt thereof may be further increased until treatment of pain associated with trigeminal neuralgia is achieved again.

20. The method of claim 16, wherein, At least every 3 months, the therapeutically effective amount of alimazine or a pharmaceutically acceptable salt thereof should be reduced to the minimum effective level of alimazine or a pharmaceutically acceptable salt thereof.

21. The method according to claim 16, wherein, Discontinue the administration of a therapeutically effective amount of alimazine or a pharmaceutically acceptable salt thereof at least every 3 months.

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