Polymorphs of epinephrine malonate

Abstract

A polymorph of crystalline epinephrine malonate, comprising forms A, B, and C of crystalline epinephrine malonate. Also described are a pharmaceutical composition comprising one or more of the polymorphs, and a method of treating a patient, comprising administering to the patient a pharmaceutical composition comprising one of the polymorphs of crystalline epinephrine malonate.

Description

TECHNICAL FIELD

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 63 / 535,184 filed on August 29, 2023 and U.S. Provisional Application No. 63 / 573,095 filed on April 2, 2024, the disclosures of which are incorporated herein by reference in their entireties.

[0002] The present invention relates to polymorphic forms of epinephrine malonate. More specifically, the present invention relates to polymorphic forms of crystalline epinephrine malonate, pharmaceutical compositions comprising the polymorphic forms of crystalline epinephrine malonate, and methods of treating a patient comprising administering to the patient a pharmaceutical composition comprising the polymorphic forms of crystalline epinephrine malonate. BACKGROUND ART

[0003] Epinephrine has been used to treat anaphylaxis for decades. In 1958, Bose and his collaborators focused on the pharmacological activity of epinephrine cyanide and studied different epinephrine salts, including epinephrine cyanide. (Bose, et al., Observations on the pharmacological activity of different salts of adrenaline, morphine and strychnine, Indian J Med Res. 46(2):193-8 (Mar. 1958)). In 1972, John J. Sciarra and his collaborators disclosed methods for preparing epinephrine maleate, epinephrine malate, and epinephrine fumarate. John J. Sciarra, et al., Synthesis and Formulation of Several Epinephrine Salts as an Aerosol Dosage Form, Journal of Pharmaceutical Sciences, 61(2), 219-223 (1972). Other salts studied in this literature include epinephrine hydrochloride and epinephrine bitartrate.TE Peddicord, et al., Stability of high-concentration dopamine hydrochloride, norepinephrine bitartrate, epinephrine hydrochloride, and nitroglycerin in 5% dextrose injection, Am J Health-Syst Pharm. 54, 1417-1419 (1997); MM Rawas-Qalaji, et al., Epinephrine for the Treatment of Anaphylaxis: Do All 40 mg Sublingual Epinephrine Tablet Formulations with Similar In Vitro Characteristics Have the Same Bioavailability?, Biopharm. Drug Dispos. 27, 427-435 (2006).

[0004] Polymorphism is often defined as the ability of a substance to exist in two or more crystalline forms with different molecular arrangements and / or conformations within the crystal lattice. Bernstein, “Polymorphism in Molecular Crystals,” IUCR Monographs on Crystallography 14, Oxford Science Publications, pp. 1-28, 240-256 (2002). The influence of polymorphism on the quality and performance of pharmaceuticals is widely recognized. The arrangement of molecules within a crystal determines physical properties such as dissolution rate, solubility, bioavailability, crystal habit, and mechanical strength. Datta et al., Nature Reviews-Drug Discovery, 2004, 3:42-57.

[0005] Epinephrine malonate has been described in the Art as one salt form of epinephrine having improved physicochemical properties. Epinephrine malonate is disclosed in U.S. Patent No. 10,995,059, and the entire disclosure is incorporated herein by reference, except for definitions, disclaimers, denials, and inconsistencies. [Overview of the project]

[0006] The present invention relates to polymorphs of crystalline epinephrine malonate, a pharmaceutical composition comprising one or more of the polymorphs, a method for producing the polymorphs, and a method for treating a patient, comprising administering the polymorphs to the patient.

[0007] In one embodiment, epinephrine malonate is form B. In a particular embodiment, epinephrine malonate form B may have one or more peaks in the powder X-ray diffraction spectrum (copper, Kα1), represented as 2-theta, as shown in Table 1 and / or Figure 4. In a particular embodiment, epinephrine malonate may be form B with a purity of 95%. In a particular embodiment, epinephrine malonate may be form B with a purity of 99%.

[0008] In certain embodiments, a pharmaceutical composition is provided comprising epinephrine malonate of form B and a pharmaceutically acceptable carrier. In certain embodiments, the pharmaceutical composition may be suitable for sublingual or buccal administration.

[0009] In a particular embodiment, a method is provided for treating a patient suffering from an allergic disease. The method comprises administering a pharmaceutically effective amount of epinephrine malonate in form B to the patient.

[0010] In one embodiment, epinephrine malonate is form C. In certain embodiments, epinephrine malonate may have one or more peaks in the powder X-ray diffraction spectrum (copper, Kα1), represented as 2-theta, as shown in Table 2 and / or Figure 5. In certain embodiments, epinephrine malonate may be form C with a purity of 95%. In certain embodiments, epinephrine malonate may be form C with a purity of 99%.

[0011] In certain embodiments, a pharmaceutical composition is provided comprising epinephrine malonate of form C and a pharmaceutically acceptable carrier. In certain embodiments, the pharmaceutical composition may be suitable for sublingual or buccal administration.

[0012] In a particular embodiment, a method is provided for treating a patient suffering from an allergic disease. The method comprises administering a pharmaceutically effective amount of epinephrine malonate in form C to the patient.

[0013] In one embodiment, epinephrine malonate is form A. In a particular embodiment, epinephrine malonate form A may have one or more peaks in the powder X-ray diffraction spectrum (copper, Kα1), represented as 2-theta, as shown in Table 3 and / or Figure 6.

[0014] In another embodiment, epinephrine malonate may be form A with a purity of 95%. In a particular embodiment, epinephrine malonate may be form A with a purity of 99%.

[0015] In a particular embodiment, a pharmaceutical composition is provided comprising 95% pure form A epinephrine malonate and a pharmaceutically acceptable carrier. The pharmaceutical composition may be suitable for sublingual or buccal administration.

[0016] In a particular embodiment, a method is provided for treating a patient suffering from an allergic disease. The method comprises administering a pharmaceutically effective amount of epinephrine malonate in form A to the patient.

[0017] In certain embodiments, a method is provided for producing one of the aforementioned polymorphs of epinephrine malonate. In certain embodiments, a method is provided for producing substantially pure form A. The method comprises dissolving a certain amount of epinephrine in a suitable solvent. Once the solute is dissolved, a suitable amount of malonic acid is added. In certain embodiments, polymorph A is better formed than polymorph C by minimizing solid precipitation before programmed cooling. In certain embodiments, the solution may be filtered after the stirring step following the addition of malonic acid to prevent the formation of polymorph C when polymorph A is desired. In certain embodiments, the filtrate may be reheated and stirred at a temperature of about 35°C to about 40°C for at least 1 hour (e.g., 1.5 hours, 2 hours, 2.5 hours, etc.) to form a homogeneous solution. In certain embodiments, the solution may be cooled. In certain embodiments, a seed crystal of form A may be added and stirred for at least 1 hour (e.g., 1.5 hours, 2 hours, 2.5 hours, etc.) to form crystals of epinephrine malonate. In some embodiments, the resulting crystals can be filtered to remove the solvent. [Brief explanation of the drawing]

[0018] The accompanying drawings incorporated herein and forming part thereof serve to illustrate and describe various embodiments of the present disclosure, and further to illustrate the principles of the present disclosure and to enable those skilled in the art to implement and use the embodiments disclosed herein.

[0019] [Figure 1] Figure 1 shows an example of a polarized light microscope (PLM) image of epinephrine malonate as morphology B. [Figure 2] Figure 2 shows an example of a PLM photograph of epinephrine malonate as morphology C. [Figure 3] Figure 3 shows an example of a PLM image of epinephrine malonate as morphology A. [Figure 4]Figure 4 shows a powder X-ray diffraction (XRPD) spectrum of epinephrine malonate as Form B. [Figure 5] Figure 5 shows an XRPD spectrum of epinephrine malonate as Form C. [Figure 6] Figure 6 shows an XRPD spectrum of epinephrine malonate as Form A. [Figure 7] Figure 7 shows an overlay of XRPD spectra of Forms A, B, and C of crystalline epinephrine malonate. [Figure 8] Figure 8 shows moisture absorption of epinephrine malonate measured by dynamic vapor sorption (DVS). [Figure 9] Figure 9 shows an overlay of XRPD spectrum patterns of the product of Example 6 (bottom), Form A (middle), and Form C (top). DESCRIPTION OF EMBODIMENTS

[0020] The present invention relates to polymorphic forms of epinephrine malonate, and includes pharmaceutical compositions comprising a polymorphic form of crystalline epinephrine malonate, and methods of treating a patient comprising administering to a patient said pharmaceutical composition comprising a polymorphic form of crystalline epinephrine malonate.

[0021] Before describing the present invention in detail hereinafter, it should be understood that the present invention is not limited to the specific methods, protocols, and reagents described herein, as these may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the present invention, which is limited solely by the appended claims. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the present invention belongs.

[0022] The term "about" when used in connection with a numerical value is meant to encompass numerical values within a range having a lower limit that is 5% less than the stated numerical value and an upper limit that is 5% greater than the stated numerical value.

[0023] As used herein, “to treat,” “to treat,” or “to treat” a disease or disorder means achieving one or more of the following: (a) reducing the severity and / or duration of the disorder; (b) limiting or preventing the appearance of symptoms characteristic of the disorder(s) being treated; (c) suppressing the exacerbation of symptoms characteristic of the disorder(s) being treated; (d) limiting or preventing recurrence of the disorder(s) in a patient with a history of the disorder(s); and (e) limiting or preventing recurrence of symptoms in a patient who has previously shown symptoms of the disorder(s).

[0024] The "pharmaceutical composition" of the present invention may exist in the form of a composition in which different active ingredients and diluents and / or carriers are mixed with each other, or in the form of a combination formulation in which the active ingredients exist in partially or completely different forms. An example of such a combination or combination formulation is a kit of parts.

[0025] The "therapeutic dose" or "therapeutic effective dose" is the amount of therapeutic agent sufficient to achieve the intended purpose. The effective dose of a given therapeutic agent varies depending on factors such as the properties of the agent, the route of administration, the size and species of the animal receiving the agent, and the purpose of administration. The effective dose in each case can be determined empirically by a person skilled in the art according to methods established in the art.

[0026] As used herein, the terms “patient” or “subject” most preferably refer to human beings. Likewise included are any mammals or birds that may benefit from the compounds described herein. Preferably, “subject” or “patient” is selected from the group consisting of laboratory animals (e.g., mice or rats), livestock (e.g., guinea pigs, rabbits, chickens, turkeys, pigs, sheep, goats, camels, cattle, horses, donkeys, cats, or dogs, etc.), or other primates such as chimpanzees.

[0027] "Medically acceptable" means generally safe for administration to humans or animals. Preferably, medicamentally acceptable ingredients are those approved by federal or state regulatory agencies, or listed in the United States Pharmacopeia issued by the United States Pharmacopeial Convention, Inc., Rockville Md., or other drugs generally accepted for use in animals, more specifically in humans.

[0028] The present invention relates to polymorphs of epinephrine malonate and includes a pharmaceutical composition comprising polymorphs of crystalline epinephrine malonate and a method of treating a patient comprising administering the pharmaceutical composition of the polymorphs of crystalline epinephrine malonate to the patient. Epinephrine is effective in treating symptoms of severe allergic reactions, for example, by opening the airways to alleviate dyspnea, and by constricting blood vessels to counteract blood pressure and relieve fainting. Epinephrine as a free base is a highly insoluble and easily oxidized catecholamine derivative, with low stability and low bioavailability. However, previous attempts to improve stability by limiting the reactivity of the basic nitrogen atom using epinephrine salts have been limited or unsuccessful, for example, due to insufficient solubility (e.g., hydrochloride) or limited cellular transport due to excessive reactivity or polar hydroxyl groups (e.g., tartrate).

[0029] Epinephrine malonate is a salt of epinephrine that can be obtained in crystalline form having the appearance of a white powder. Epinephrine malonate form A may have a water solubility of at least 1142.7 mg / mL and a pKa of 5.47. The water solubility of crystalline epinephrine malonate is significantly higher than that of other epinephrine salts (e.g., maleate, fumarate, hemisulfate, tartrate, or hydrochloride), making epinephrine malonate particularly suitable for mucosal drug delivery. Furthermore, epinephrine malonate can exhibit a favorable stability profile at 7, 14, 30, 60, 90, 120, or 150 days.

[0030] 1. In certain embodiments, epinephrine malonate is provided as polymorph B. Polymorph B of epinephrine malonate may have one or more peaks in the powder X-ray diffraction spectrum (copper, Kα1) represented as a 2-theta, as shown in Figure 4. In certain embodiments, polymorph B of epinephrine malonate may have one or more peaks in the powder X-ray diffraction spectrum (copper, Kα1) represented as a 2-theta, as shown in Table 1. In certain embodiments, polymorph B of epinephrine malonate may have one or more peaks in the powder X-ray diffraction spectrum (copper, Kα1), represented as 2-theta, at approximately 9.8, 13.0, 14.2, 15.1, 16.9, 17.2, 20.0, 20.6, 22.9, 24.9, 25.9, 26.4, 27.4, 28.7, or 31.3.

[0031] Form B may be a crystalline monohydrate of epinephrine malonate monosalt. Solid form B can transition from form A at 40% RH or higher, and once formed, it may be kinetically stable at 0-80% RH. TIFF2026530440000002.tif39170

[0032] In certain embodiments, epinephrine malonate is polymorph C. Polymorph C of epinephrine malonate may have one or more peaks in the powder X-ray diffraction spectrum (copper, Kα1) represented as a 2-theta, as shown in Figure 5. In certain embodiments, polymorph C of epinephrine malonate may have one or more peaks in the powder X-ray diffraction spectrum (copper, Kα1) represented as a 2-theta, as shown in Table 2. In certain embodiments, polymorph C of epinephrine malonate may have one or more peaks in the powder X-ray diffraction spectrum (copper, Kα1), represented as 2-theta, at approximately 12.2, 13.5, 14.3, 14.7, 15.9, 17.4, 17.9, 19.6, 20.5, 21.6, 22.4, 22.9, 23.9, 24.7, 25.3, 26.0, 26.5, 25.3, 26.0, 26.5, 27.2, 27.9, 29.5, 33.2, 34.3, or 34.8. TIFF2026530440000003.tif37170

[0033] In certain embodiments, epinephrine malonate is polymorph A. Polymorph A of epinephrine malonate may have one or more peaks in the powder X-ray diffraction spectrum (copper, Kα1) represented as a 2-theta, as shown in Figure 6. In certain embodiments, polymorph A of epinephrine malonate may have one or more peaks in the powder X-ray diffraction spectrum (copper, Kα1) represented as a 2-theta, as shown in Table 3. In certain embodiments, polymorph A of epinephrine malonate may have one or more peaks in a powder X-ray diffraction spectrum (copper, Kα1), represented as 2-theta, at approximately 12.2, 13.5, 14.3, 14.7, 15.9, 17.4, 17.9, 19.6, 20.5, 21.6, 22.4, 22.9, 23.9, 24.7, 25.3, 26.0, 26.5, 25.3, 26.0, 26.5, 27.2, 27.9, 29.5, 33.2, 34.3, or 34.8. TIFF2026530440000004.tif47170

[0034] Polymorphs A, B, and C of epinephrine malonate can be isolated and substantially pure. In certain embodiments, the polymorphs of epinephrine malonate substantially do not contain other polymorphs of epinephrine malonate. For example, polymorphs A, B, and C of epinephrine malonate may have purities of 95%, 96%, 97%, 98%, 99%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9% or higher.

[0035] Polymorphs A, B, and C of epinephrine malonate may have crystal sizes of 50 μm or less. For example, polymorphs of epinephrine malonate may have crystal sizes of 5 μm, 10 μm, 15 μm, 20 μm, 25 μm, 30 μm, 35 μm, 40 μm, 45 μm, or 50 μm or less.

[0036] Polymorphs A, B, and C of epinephrine malonate may be stable at room temperature and below 40% RH for periods of 5, 10, 15, 20, 30, 60, 90, 120 days or longer.

[0037] Pharmaceutical composition In certain embodiments, pharmaceutical compositions of epinephrine malonate in the form of epinephrine malonate or its prodrug are provided, in forms A, B, or C. The pharmaceutical composition may contain finely powdered epinephrine malonate, for example, D, which is about 5 μm to 600 μm. 90 This is an epinephrine malonate having a particle size characterized by a certain value. In a particular embodiment, the epinephrine malonate has a particle size of approximately 200 μm to 600 μm. 90 The pharmaceutical composition may contain epinephrine malonate having a particle size characterized by a specific value. The pharmaceutical composition may contain 1 to 95% by weight of epinephrine malonate, or more preferably 2 to 50% by weight, 5 to 20% by weight, 10 to 20% by weight, or 5 to 15% by weight of epinephrine malonate.

[0038] In certain embodiments, the pharmaceutical composition may be suitable for oral, rectal, gastric, topical, intracranial, intranasal, intramuscular, and parenteral administration. The pharmaceutical composition may be administered via any pharmaceutically acceptable dosage form, including solid, semi-solid, or liquid dosage forms such as tablets, suppositories, pills, capsules, powders, liquids, and suspensions, preferably as a unit dosage form suitable for a single dose of a precise amount, or as a rapid-acting dosage form, or as a sustained-release or controlled-release dosage form for long-term administration of the compound at a predetermined rate. The pharmaceutical composition may comprise a conventional pharmaceutical carrier or excipient and at least one of the compounds of the present invention, and may also comprise other pharmaceuticals, agents, carriers, and adjuvants.

[0039] In certain embodiments, the pharmaceutical composition is in the form of a powder comprising or essentially comprising epinephrine malonate of form A, form B, or form C. The powder may be contained in a sachet, stick pack, sprinkle capsule, or other suitable means of delivery.

[0040] Sublingual or buccal tablets In certain embodiments, the pharmaceutical composition is suitable for transmucosal administration in the form of sublingual or buccal tablets. The pharmaceutical composition may contain a pharmaceutically effective amount of polymorphic epinephrine malonate. In certain embodiments, the pharmaceutical composition suitable for transmucosal administration in the form of sublingual or buccal tablets contains an amount of epinephrine malonate in the form of about 0.5 to 5% by weight, more preferably about 1 to 4% by weight, even more preferably about 1.5 to 3% by weight, or most preferably about 2% by weight.

[0041] In certain embodiments, the pharmaceutical composition includes a filler. For example, the filler may include one or more selected from the group consisting of microcrystalline cellulose (e.g., Ceolus®-PH-301 or Ceolus KG 802), lactose, calcium carbonate, calcium bicarbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium silicate, cellulose powder, dextrose, dextrate, dextran, starch, pregelatinized starch, sucrose, xylitol, lactitol, sorbitol, sodium bicarbonate, sodium chloride, polyethylene glycol, and the like. In preferred embodiments, the filler is microcrystalline cellulose. In certain embodiments, the pharmaceutical composition includes a filler in an amount of about 15-35% by weight, about 20-30% by weight, about 22-27% by weight, or about 25% by weight.

[0042] In certain embodiments, the pharmaceutical composition includes a disintegrant. For example, the disintegrant may include one or more selected from the group consisting of cross-linked polyvinylpolypyrrolidone (crospovidone), cross-linked cellulose such as cross-linked polyvinylpolypyrrolidone (crospovidone), cross-linked sodium carboxymethylcellulose, cross-linked carboxymethylcellulose, or cross-linked starch such as cross-linked croscarmellose, sodium starch glycolate (e.g., Explotab®), sodium croscarmellose (e.g., Solutab®), and other cross-linked polymers. In preferred embodiments, the disintegrant is crospovidone or low-substituted hydroxypropylcellulose. In certain embodiments, the pharmaceutical composition contains a disintegrant in an amount of about 2 to 20% by weight, about 5 to 15% by weight, or 5 to 10% by weight, or about 6 to 8% by weight.

[0043] In certain embodiments, the pharmaceutical composition includes a lubricant or a flow enhancer. In certain embodiments, the lubricant may be magnesium stearate and / or the flow enhancer may be silicon dioxide. A lubricant is a compound that prevents, reduces, or inhibits adhesion or friction of materials. A flow enhancer is a compound that improves the fluidity of the composition. In other embodiments, the lubricant and flow promoter may be one or more of the following: stearic acid, calcium hydroxide, talc, sodium stearyl fumarate, hydrocarbons such as mineral oil, or hydrogenated vegetable oils such as hydrogenated soybean oil, higher fatty acids and their alkali metal salts and alkaline earth metal salts, such as aluminum, calcium, magnesium, zinc, sodium stearate, glycerol, wax, Stearowet®, boric acid, sodium benzoate, sodium acetate, sodium chloride, leucine, polyethylene glycol (e.g., PEG-4000) or methoxypolyethylene glycol, sodium oleate, sodium benzoate, glyceryl behenate, polyethylene glycol, magnesium lauryl sulfate or sodium lauryl sulfate, colloidal silica, starch such as corn starch, or silicone oil. In preferred embodiments, the lubricant is magnesium stearate and the flow promoter is silicon dioxide. In certain embodiments, the pharmaceutical composition contains about 0.1 to 5% by weight, about 0.5 to 4% by weight, or about 1 to 3% by weight, respectively, of the lubricant and / or flow promoter.

[0044] In certain embodiments, the pharmaceutical composition includes a diluent. For example, the diluent may be selected from one or more of the group consisting of mannitol, lactose, starch, sorbitol, dextrose, tricalcium phosphate, calcium phosphate, anhydrous lactose, spray-dried lactose, pregelatinized starch, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose acetate stearate, sucrose-based diluents, monobasic calcium sulfate monohydrate, calcium sulfate dihydrate, calcium lactate trihydrate, dextrose, hydrolyzed cereal solids, amylose, powdered cellulose, calcium carbonate, glycine, kaolin, or sodium chloride. In preferred embodiments, the diluent is mannitol. In certain embodiments, the pharmaceutical composition includes a diluent in an amount of about 25-75% by weight, about 35-60% by weight, or about 45-55% by weight.

[0045] In certain embodiments, the pharmaceutical composition includes a pH adjuster. In certain embodiments, the pH adjuster may be citric acid, boric acid, lactic acid, malic acid, phosphoric acid, monosodium phosphate, or tartaric acid. In certain embodiments, the pharmaceutical composition includes a diluent in an amount of 0.1 to 3% by weight, more preferably 0.1 to 2% by weight, or most preferably about 0.1 to 1% by weight.

[0046] In certain embodiments, the pharmaceutical composition includes a flavoring agent and / or a sweetener. For example, the flavoring agent and / or sweetener may include one or more selected from the group consisting of almond oil, benzaldehyde, ethyl acetate, ethyl vanillin, menthol (mint), methyl salicylate, peppermint oil, peppermint spirit, sucralose, and vanillin. In certain embodiments, the flavoring agent may be mint, raspberry, licorice, orange, lemon, grapefruit, caramel, vanilla, cherry, or grape flavor. In certain embodiments, the sweetener may be sucralose micronized NF, aspartame, acesulfame K, or thaumatin. In certain embodiments, the pharmaceutical composition contains a flavoring agent in an amount of about 0-0.02% by weight, about 0.002-0.018% by weight, about 0.004-0.016% by weight, about 0.006-0.014% by weight, about 0.008-0.012% by weight, or about 0.01% by weight. In certain embodiments, the pharmaceutical composition contains a sweetener in an amount of about 0.1-0.5% by weight, about 0.1-0.4% by weight, about 0.2-0.3% by weight, or about 0.25% by weight.

[0047] In certain embodiments, the pharmaceutical composition includes a coloring agent. For example, the coloring agent may include one or more selected from a list consisting of red, black, and yellow iron oxides, as well as FD&C dyes such as FD&C Blue 2 and FD&C Red 40 available from Ellis & Everard.

[0048] In certain embodiments, the pharmaceutical composition includes a flavoring agent (taste masking agent). For example, the flavoring agent may include sodium bicarbonate, ion exchange resin, cyclodextrin inclusion compound, adsorbent, or microencapsulated active substance.

[0049] In certain embodiments, the pharmaceutical composition includes antioxidants. For example, antioxidants include alpha-tocopherol, arachidonic acid, ascorbic acid, ascorbyl palmitate, benzethonium chloride, benzethonium bromide, benzalkonium chloride, butylhydroxyanisole (BHA), dibutylhydroxytoluene (BHT), capric acid, caproic acid, carbon dioxide, cetylpyridinium chloride, chelating agents, chitosan derivatives, citric acid monohydrate, dodecyldimethylaminopropionate, enanthic acid, erythorbic acid, ethyl oleate, fumaric acid, glycerol oleate, glyceryl monostearate, lauric acid, limonene, linolenic acid, lysine, malic acid, menthol, methionine, monothioglycerol, and mi The pharmaceutical formulation may contain one or more selected from the group consisting of ristic acid, oleic acid, palmitic acid, pelargonic acid, peppermint oil, phosphoric acid, polysorbate, potassium pyrosulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium caprate, sodium deoxycholate, sodium deoxyglycolate, sodium formaldehyde sulfoxylate, sodium glycocholate, sodium hydroxybenzoylaminocaprylate, sodium lauryl sulfate, sodium pyrosulfite, sodium sulfite, sodium taurocholate, sodium thiosulfate, stearic acid, sulfur dioxide, and combinations thereof. In certain embodiments, the pharmaceutical formulation further comprises a synergistic agent with an antioxidant selected from citric acid monohydrate, tartaric acid, thymol, tocopherol (alpha-tocopherol), tocoferazole, vitamin E, and vitamin E polyethylene glycol succinate, and combinations thereof. In preferred embodiments, the antioxidant is L-methionine. In certain embodiments, the pharmaceutical composition contains an antioxidant in an amount of about 0.1 to 5% by weight, about 1 to 3% by weight, or about 2% by weight.

[0050] In certain embodiments, the pH of the pharmaceutical composition may be between approximately 6.5 and approximately 9.0, or between approximately 6.5 and approximately 8.5, or between approximately 7.0 and approximately 8.5, or between approximately 7.0 and approximately 8.4, or between approximately 7.5 and approximately 8.4, or between approximately 7.5 and approximately 8.2, or between approximately 7.8 and approximately 8.4, or between approximately 7.8 and approximately 8.2. In certain embodiments, the pH of the pharmaceutical composition may be about 6.5, about 6.6, about 6.7, about 6.8, about 6.9, about 7.0, about 7.1, about 7.2, about 7.3, about 7.4, about 7.5, about 7.6, about 7.7, about 7.8, about 7.9, about 8.0, about 8.1, about 8.2, about 8.3, about 8.4, about 8.5, about 8.6, about 8.7, about 8.8, about 8.9, or about 9.0.

[0051] The pH of a pharmaceutical composition can be adjusted using a pH adjuster. In some embodiments, the pharmaceutical composition includes a pH adjuster. The pH adjuster may include an acid, a base, a buffer, or a combination thereof. For example, the pH adjuster is one or more selected from adipic acid, ammonium chloride, boric acid, citric acid, acetic acid, hydrochloric acid, lactic acid, malic acid, meglumine, phosphoric acid, propionic acid, sulfuric acid, tartaric acid, monosodium phosphate, sodium hydroxide, sodium citrate, sodium bicarbonate, sodium carbonate, phosphate buffer, acetate buffer, or citrate buffer. In certain embodiments, the pH adjuster is meglumine or sodium carbonate.

[0052] In certain embodiments, the pharmaceutical composition includes a permeability enhancer. The presence of a permeability enhancer in the formulation can improve the in vivo breakdown and pharmacokinetic properties of the drug. Permeability enhancers can also help overcome the mucosal barrier and improve the permeability of a particular drug or pharmaceutically active ingredient by reversibly regulating the permeability of the barrier layer to favor drug absorption and facilitating the transport of molecules through the epithelium. In certain embodiments, the permeability enhancer may be an adrenergic receptor interacting substance. The adrenergic receptor interacting substance may be an adrenergic receptor blocker. In certain embodiments, the adrenergic receptor interacting substance may be a terpenoid, terpene, or C3-C 22 Alcohol or acid, preferably C7-C 18The substance is one or more selected from the group consisting of alcohols or acids, sesquiterpenes, farnesol, linoleic acid, arachidonic acid, docosahexaenoic acid, eicosapentaenoic acid, or docosapentaenoic acid. The acid may be a carboxylic acid, phosphoric acid, sulfuric acid, hydroxamic acid, or a derivative thereof. The derivative may be an ester or amide. For example, the adrenergic receptor interacting substance may be a fatty acid or a fatty alcohol. In certain embodiments, the permeation enhancer may be a plant extract or a phenylpropanoid. In certain embodiments, the plant extract may be, for example, an essential oil extract of a plant material (e.g., leaves, flower buds, or stems of a clove plant), or a synthetic analog of a compound extracted from a plant material. In certain embodiments, the phenylpropanoid may be at least one of eugenol, eugenol acetate, cinnamic acid, cinnamic acid ester, cinnamaldehyde, hydrocinnamic acid, chavicol, or safrole. In further embodiments, the permeation enhancer may include natural or synthetic bile salts such as sodium fusidate; glycocholates or deoxycholates and their salts; fatty acids and derivatives such as sodium laurate, oleic acid, oleyl alcohol, monoolein, and palmitoylcarnitine; chelating agents, sodium citrate and sodium lauryl sulfate, azon, sodium cholate, sodium 5-methoxysalicylate, sorbitan laurate, glyceryl monolaurate, octoxynonyl-9, laureth-9, polysorbate, sterols, chitosan, or glycerides such as caprylocaproyl polyoxylglycerides, e.g., Labrasol. The permeation enhancer may also include plant extract derivatives and / or monolignols. The permeation enhancer may also be a fungal extract. In certain embodiments, the permeation enhancer is selected from the group consisting of sodium dodecyl sulfate, dodecyl-β-D-maltopyranoside, and sodium cholate.

[0053] Sublingual or buccal film In certain embodiments, the pharmaceutical composition is suitable for transmucosal administration in the form of sublingual or buccal film. In certain embodiments, the pharmaceutical composition may be bioequivalent to, or provide comparable exposure to, an intramuscular epinephrine composition marketed under the trade name EpiPen®.

[0054] The pharmaceutical composition may contain a pharmaceutically effective amount of epinephrine malonate. In certain embodiments, a pharmaceutical composition suitable for transmucosal administration in the form of sublingual or buccal film contains polymorphic forms of epinephrine malonate in amounts of about 0.5–5% by weight, about 1–4% by weight, about 1.5–3% by weight, or about 2% by weight.

[0055] In certain embodiments, the pharmaceutical composition may further comprise a water-soluble polymer. For example, the water-soluble polymer may comprise one or more selected from the group consisting of hydroxypropyl methylcellulose, methylcellulose, pullulan, carboxymethylcellulose, polyvinylpyrrolidone, pectin, gelatin, sodium, alginate, hydroxypropylcellulose, polyvinyl alcohol, or maltodextrin.

[0056] In certain embodiments, the pharmaceutical composition may further include a plasticizer. For example, the plasticizer may include one or more selected from the group consisting of glycerol, dibutyl phthalate, or polyethylene glycol.

[0057] In certain embodiments, the pharmaceutical composition may further include a surfactant. For example, the surfactant may include one or more selected from the group consisting of sodium lauryl sulfate, benzalkonium chloride, or Tween.

[0058] In certain embodiments, the pharmaceutical composition may further comprise one or more agents selected from sweeteners, saliva secretion promoters, flavoring agents, colorants, stabilizers and thickeners, and super-disintegrants.

[0059] In certain embodiments, the pharmaceutical composition further comprises a permeability enhancer. The permeability enhancer may help overcome the mucosal barrier and improve the permeability of a particular drug or pharmaceutically active ingredient by reversibly regulating the permeability of the barrier layer to favor drug absorption and facilitating the transport of molecules through the epithelium. In certain embodiments, the permeability enhancer may be an adrenergic receptor interacting substance. The adrenergic receptor interacting substance may be an adrenergic receptor blocker. In certain embodiments, the adrenergic receptor interacting substance may be a terpenoid, terpene, or C3-C 22 Alcohol or acid, preferably C7-C 18 The adrenergic receptor interacting substance is one or more selected from the group consisting of alcohols or acids, sesquiterpenes, farnesol, linoleic acid, arachidonic acid, docosahexaenoic acid, eicosapentaenoic acid, or docosapentaenoic acid. The acid may be a carboxylic acid, phosphoric acid, sulfuric acid, hydroxamic acid, or a derivative thereof. The derivative may be an ester or an amide. For example, the adrenergic receptor interacting substance may be a fatty acid or a fatty alcohol.

[0060] In certain embodiments, the permeation enhancer may be a plant extract or a phenylpropanoid. In certain embodiments, the plant extract may be, for example, an essential oil extract of a plant material (e.g., leaves, flower buds, or stems of a clove plant) or a synthetic analog of a compound extracted from a plant material. In certain embodiments, the phenylpropanoid may be at least one of eugenol, eugenol acetate, cinnamic acid, cinnamic acid ester, cinnamaldehyde, hydrocinnamic acid, chavicol, or safrole.

[0061] In further embodiments, the permeation enhancer may include natural or synthetic bile salts such as sodium fusidate; glycocholates or deoxycholates and their salts; fatty acids and derivatives such as sodium laurate, oleic acid, oleyl alcohol, monoolein, and palmitoylcarnitine; chelating agents, sodium citrate and sodium lauryl sulfate, azon, sodium cholate, sodium 5-methoxysalicylate, sorbitan laurate, glyceryl monolaurate, octoxynonyl-9, laureth-9, polysorbate, sterol, or glycerides such as caprylocaproyl polyoxylglycerides, e.g., Labrasol. The permeation enhancer may also include plant extract derivatives and / or monolignols. The permeation enhancer may also be a fungal extract.

[0062] Nasal spray In certain embodiments, the pharmaceutical composition is suitable for transmucosal administration in the form of a nasal spray. In certain embodiments, the pharmaceutical composition may be bioequivalent to, or provide comparable exposure to, an intramuscular epinephrine composition marketed under the trade name EpiPen®.

[0063] The nasal spray pharmaceutical composition may contain a pharmaceutically effective amount of epinephrine malonate. In certain embodiments, the nasal spray pharmaceutical composition contains polymorphs of epinephrine malonate in amounts of about 0.4 to 2.4 mg, about 0.4 to 2.0 mg, or about 0.4 to 1.8 mg per single dose of the nasal spray pharmaceutical composition. In some embodiments, the nasal spray pharmaceutical composition contains about 0.5 to 2.0 mg, about 0.5 to 1.5 mg, or about 0.5 to 0.7 mg of epinephrine malonate per single dose of the nasal spray pharmaceutical composition. In some embodiments, the nasal spray pharmaceutical composition contains about 1.0 mg, or about 1.3 to 1.5 mg of epinephrine malonate per single dose of the nasal spray pharmaceutical composition.

[0064] In certain embodiments, a nasal spray pharmaceutical composition in a dose of about 100 μL may contain about 1 to 40 mg / mL of epinephrine malonate, more preferably 1 to 20 mg / mL. In some embodiments, a nasal spray pharmaceutical composition in a dose of about 100 μL may contain 3 mg / mL, 3.5 mg / mL, 4 mg / mL, 4.5 mg / mL, 5 mg / mL, 6 mg / mL, 6.5 mg / mL, 7 mg / mL, 7.5 mg / mL, 8 mg / mL, 8.5 mg / mL, 9 mg / mL, 9.5 mg / mL, 10 mg / mL, 10.5 mg / mL, 11 mg / mL, 11.5 mg / mL, 12 mg / mL, 12.5 mg / mL, 13 mg / mL, 13.5 mg / mL, 14 mg / mL, 14.5 mg / mL, or 15 mg / mL of epinephrine malonate.

[0065] In certain embodiments, the nasal spray pharmaceutical composition is an aqueous solution, an aqueous suspension, an aqueous emulsion, a non-aqueous solution, a non-aqueous suspension, a non-aqueous emulsion, or a dry powder.

[0066] In certain embodiments, the nasal spray pharmaceutical composition may comprise one or more absorption enhancers. In certain embodiments, the one or more absorption enhancers are selected from dodecyl maltoside, benzalkonium chloride, oleic acid or its salts, polysorbate 20, polysorbate 80, and sodium lauryl sulfate. In further embodiments, one or more absorption enhancers include alcohol, aprotinin, benzalkonium chloride, benzyl alcohol, capric acid, ceramide, cetylpyridinium chloride, chitosan, cyclodextrin, deoxycholic acid, decanoyl, dimethyl sulfoxide, glyceryl monooleate, glycoflor, glycoflor, glycosylated sphingosine, glycyrrhetinic acid, 2-hydroxypropyl-β-cyclodextrin, laureth-9, lauric acid, lauroyl carnitine, lysophosphatidylcholine, menthol, poloxamer 407 or F68, poly-L-arginine, polyoxyethylene-9-lauryl ether, isopropyl myristate, isopropyl palmitate, lano Phosphorus, light mineral oil, linoleic acid, menthol, myristic acid, myristyl alcohol, oleic acid or its salts, oleyl alcohol, palmitic acid, polysorbate 20, polysorbate 80, propylene glycol, polyoxyethylene alkyl ether, polyoxylglyceride, pyrrolidone, quillaja saponin, salicylic acid, sodium salt, β-sitosterol β-D-glucoside, sodium lauryl sulfate, sucrose cocoate, taurocholic acid, taurodeoxycholic acid, taurodihydrofusidic acid, thymol, tricaprylin, triolein, alkyl saccharides or alkyl glycosides, medium-chain and long-chain fatty acids or their salts, saturated and unsaturated fatty acids or their salts, alcohol glycerin, or PEG 300 / 400 may be selected.

[0067] In certain embodiments, the nasal spray pharmaceutical composition may further contain one or more agents selected from isotonic agents, stabilizers, preservatives, flavoring agents, viscosity modifiers, antioxidants, buffering agents, and pH adjusters. In certain embodiments, one or more isotonic agents are dextrose, glycerin, mannitol, potassium chloride, or sodium chloride. In some embodiments, the preservative is benzalkonium chloride.

[0068] In certain embodiments, antioxidants include alpha-tocopherol, arachidonic acid, ascorbic acid, ascorbyl palmitate, benzethonium chloride, benzethonium bromide, benzalkonium chloride, butylhydroxyanisole (BHA), dibutylhydroxytoluene (BHT), capric acid, caproic acid, carbon dioxide, cetylpyridinium chloride, chelating agents, chitosan derivatives, citric acid monohydrate, dodecyldimethylaminopropionate, enanthic acid, erythorbic acid, ethyl oleate, fumaric acid, glycerol oleate, glyceryl monostearate, lauric acid, limonene, linolenic acid, lysine, malic acid, menthol, methionine, and monostearate. Thioglycerol, myristic acid, oleic acid, palmitic acid, pelargonic acid, peppermint oil, phosphoric acid, polysorbate, potassium pyrosulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium caprate, sodium deoxycholate, sodium deoxyglycolate, sodium formaldehyde sulfoxylate, sodium glycocholate, sodium hydroxybenzoylaminocaprylate, sodium lauryl sulfate, sodium metabisulfite, sodium sulfite, sodium taurocholate, sodium thiosulfate, stearic acid, sulfur dioxide, and combinations thereof are selected. In certain embodiments, the nasal spray pharmaceutical formulation further comprises a synergistic agent with an antioxidant selected from citric acid monohydrate, tartaric acid, thymol, tocopherol (alpha-tocopherol), tocoferazole, vitamin E, and vitamin E polyethylene glycol succinate, and combinations thereof.

[0069] In certain embodiments, the pH adjuster may be an acid, a base, a buffer, or a combination thereof. In certain embodiments, the acid may be adipic acid, ammonium chloride, citric acid, acetic acid, hydrochloric acid, lactic acid, phosphoric acid, propionic acid, sulfuric acid, or tartaric acid; the base may be sodium hydroxide, sodium citrate, sodium bicarbonate, or sodium carbonate; and the buffer may be phosphate buffer, acetate buffer, or citrate buffer.

[0070] In some embodiments, the nasal spray pharmaceutical composition includes a buffering agent. In certain embodiments, the buffering agent may be, but is not limited to, adipic acid, boric acid, calcium carbonate, calcium hydroxide, calcium lactate, calcium phosphate, tribasic acid, citric acid monohydrate, sodium hydrogen phosphate, diethanolamine, glycine, maleic acid, malic acid, methionine, sodium dihydrogen phosphate, monoethanolamine, sodium glutamate, phosphoric acid, potassium citrate, sodium acetate, sodium bicarbonate, sodium borate, sodium carbonate, sodium citrate dihydrate, sodium hydroxide, sodium lactate, and triethanolamine.

[0071] Method of administration In other embodiments, methods for treating a patient are provided. The patient may be a patient suffering from an allergic disease, such as anaphylaxis, asthma, or bronchial asthma. The patient may be a patient suffering from other allergic reactions such as hives, itching, flushing, itching and swelling of mucous membranes, itching and pressure of the throat, dysphonia and hoarseness, difficulty breathing, chest tightness, wheezing or bronchospasm, anxiety, throbbing headache, dizziness, confusion, tunnel vision, chest pain, hypotension, tachycardia, weak pulse, syncope, nausea, convulsions, abdominal pain, vomiting, or diarrhea.

[0072] The method involves administering a pharmaceutically effective amount of epinephrine malonate in form A, form B, or form C to a patient in need of such treatment, such as a patient suffering from anaphylaxis. Epinephrine malonate can be administered in any form of the above-described pharmaceutical composition. For example, epinephrine malonate can be administered in a transmucosal form, such as sublingual or buccal tablet or sublingual or buccal film, or in the form of a nasal spray or nasal medication. In certain embodiments, epinephrine malonate is administered in the form of a sublingual or buccal tablet.

[0073] Administration of the aforementioned composition may be bioequivalent to, or provide comparable exposure to, an intramuscular epinephrine composition marketed under the trade name EpiPen® (with a dose concentration of 0.3 mg per 0.3 mL (1 mg / mL)).

[0074] Manufacturing method In one embodiment, the present invention provides a method for producing a substantially pure amount of one of the aforementioned polymorphic forms of epinephrine malonate.

[0075] In certain embodiments, a method is provided for preparing substantially pure form A. The method involves dissolving a certain amount of epinephrine in a suitable solvent, such as water, an organic solvent, or a mixture thereof. In certain embodiments, the organic solvent is methanol, ethanol, propanol, isopropyl acetate, methyl t-butyl ether, dimethyl sulfoxide, ethyl acetate, 2-methyltetrahydrofuran, methyl ethyl ketone, and methyl isobutyl ketone, hexane, or heptane. In non-limiting examples, epinephrine can be dissolved by heating the solvent to a temperature above room temperature (e.g., up to 25°C, 30°C, 35°C, 40°C, 45°C, 50°C, etc.), by agitating (e.g., shaking or stirring) the solvent / solute mixture, and by a combination of heating and stirring.

[0076] In certain embodiments, the solvent / solute mixture may be degassed before dissolution. In certain other embodiments, degassing during or after dissolution may be useful. Degassing can be achieved by various means known in the art, such as by a freeze-pump-thaw cycle or by sparging with an inert gas (e.g., nitrogen or argon).

[0077] Once the solute has dissolved, the solution can be maintained at a temperature of approximately 35°C to 40°C while adding an appropriate amount of malonic acid. The amount of epinephrine in the solution may slightly exceed the amount of malonic acid, for example, between approximately 2 parts epinephrine to 1 part malonic acid and approximately 3 parts epinephrine to 1 part malonic acid (for example, 3 parts epinephrine to 2 parts malonic acid). When adding malonic acid, the solution must be agitated (e.g., stirred). After adding malonic acid, stirring at a temperature of approximately 35°C to 40°C must be continued for at least 1 hour, for example, 1.5 hours, 2 hours, 2.5 hours, or 3 hours or more.

[0078] In certain embodiments, the formation of polymorph A outweighs the formation of polymorph C by minimizing solid precipitation before programmed cooling. For example, to prevent the formation of polymorph C when polymorph A is desired, the solution may be filtered after the stirring step following the addition of malonic acid. In certain embodiments, the filtrate may be reheated and stirred for at least 1 hour (e.g., 1.5 hours, 2 hours, 2.5 hours, etc.) at a temperature of about 35°C to about 40°C to form a homogeneous solution.

[0079] At this stage of the process, the solution can be cooled to a temperature of approximately 25°C to 30°C. Seed crystals of form A can be added, and stirring at a temperature of approximately 25°C to 30°C can be applied for at least 1 hour (e.g., 1.5 hours, 2 hours, 2.5 hours, etc.). The temperature can be gradually lowered to approximately 10°C to 15°C over at least 1 hour (e.g., 1.5 hours, 2 hours, 2.5 hours, etc.) and stirred for at least 10 hours (e.g., at least 12 hours, at least 14 hours, at least 15 hours, at least 16 hours, etc.). The temperature can then be gradually lowered again to approximately 5°C over at least 1 hour (e.g., 1.5 hours, 2 hours, 2.5 hours, etc.) and stirred for at least another hour (e.g., 1.5 hours, 2 hours, 2.5 hours, 3 hours, etc.).

[0080] At this point, crystals of epinephrine malonate will have formed. In some embodiments, the obtained crystals can be filtered to remove the solvent. In some embodiments, the filter cake can be rinsed with a cold solvent (e.g., ethanol) (e.g., 5±5°C). If a rinsing step is employed, it may also be desirable to dry the sample (e.g., under vacuum). In some embodiments, the obtained crystals can be crushed and / or milled to obtain finer particles of epinephrine malonate.

[0081] The following examples illustrate specific embodiments of the present invention without limitation. [Examples]

[0082] While various embodiments have been described above, it should be understood that these are merely examples and not limiting. Therefore, the breadth and scope of this disclosure should not be limited by any of the exemplary embodiments described above. Furthermore, unless otherwise indicated herein, or unless clearly contradicted by the context, any combination of all possible variations of the elements described above is incorporated herein.

[0083] Example 1 Polymorphic screening procedure Polymorphisms were generated during the initial screening tests. Epinephrine malonate (40-100 mg) was weighed into a 2 mL vial containing a tumble stirring disc. Solvent (500-1000 μL) was dispensed, and the sample was stirred at room temperature for 1 hour. The sample was heated to 40°C and stirred for 1 hour, then cooled to room temperature and stirred for 5 minutes. Additional epinephrine malonate (60 mg) was added to the solution or dilute suspension. The sample was stirred for a total of 48 hours, cycling the temperature between 5 and 40°C.

[0084] After 48 hours, the samples were equilibrated at room temperature for approximately 2 hours. The suspension was separated by filtration. The solid was air-dried at room temperature for 4 hours. The filtrate was transferred to 2 mL vials for cooling and evaporation experiments. The cooled samples were capped and stored at 5°C for 1–7 days. The evaporated samples were covered with tissue and evaporated under ambient conditions for 1–7 days. Polymorphic screening experiments produced three crystalline forms: form A (anhydrous form), form B (monohydrate), and form C (possibly anhydrous). PLM images of the polymorphs are provided in Figures 1–3. Figure 1 shows an example of a PLM image of epinephrine malonate as form B. Figure 2 shows an example of a PLM image of epinephrine malonate as form C. Figure 3 shows an example of a PLM image of epinephrine malonate as form A.

[0085] Table 4 below outlines the characteristics of forms A, B, and C. TIFF2026530440000005.tif80170

[0086] Relative thermodynamic stability tests were conducted in EtOH (crystallization process solvent), EtOH / water, and IPA / water. The results showed that at room temperature, morphology A was most stable at aw ≤ 0.4, morphology B was most stable at aw ≥ 0.55, and morphology C was more stable at 40°C and aw = 0. The critical water activity for morphology A / B interconversion is between aw = 0.4 and 0.55 (40-55% RH). The transition temperature (Tt) of the intermodally related morphology A / C is between RT (room temperature) and 40°C. In the solid state, morphology B forms relatively rapidly (several hours) at >55% RH and, once formed, is kinetically stable at 0-80% RH. Morphology C is kinetically stable (several days) in the solid state at <40% RH.

[0087] Example 2 Preparation for reproducing polymorphic forms Morphologies B and C, obtained during the polymorphic screening described in Example 1, were reproduced.

[0088] The preparation of Form B was as follows: Form A (500 mg) was manually weighed into a 20 mL vial containing a PTFE magnetic stirring bar. Ethyl acetate saturated with water (5.0 mL, 10 vol) was added to the vial, and a sticky solid mass was formed. Form B (approximately 2 mg) was added as a seed crystal to the sample. The solid was dispersed with a spatula. The sample was stirred at room temperature for 3 days. The solid was isolated by vacuum filtration at room temperature using a Whatman filter (Grade 1) and air-dried for 1 hour. The yield was determined to be 95% (475 mg).

[0089] The preparation of morphology C was as follows: Morphology A (100 mg) was manually weighed into a 2 mL vial containing a tumble stirring disc. Ethyl alcohol:water (97:3, 0.5 mL) was added to the vial and heated at 40°C for 1 hour to obtain a solution. Additional API (60 mg) was added to the solution at 40°C to obtain a viscous, dilute slurry. The obtained slurry was temperature-cycled between 40 and 5°C for 24 hours and stirred at 5°C for 2 hours. Aliquots were isolated at 5°C and determined to be phase-pure morphology C. The remaining solid was isolated by vacuum filtration at room temperature using a nylon membrane filter and dried under nitrogen for 1 hour, revealing morphology C with a small amount of morphology A.

[0090] Example 3 XRPD analysis of three polymorphic forms of crystalline epinephrine malonate The products obtained during the polymorphic screening described in Examples 1 and 2 were subjected to XRPD. The tests were conducted using a Bruker D8 Advance equipped with a LynxEye-2 detector and a copper X-ray tube. The scan was performed using TIFF2026530440000006.tif6170. The scan range was 3° to 40° 2-theta, and the number of scans was 4000. For morphology A, the obtained XRPD graph is shown in Figure 7, and the obtained XRPD peaks are shown in Table 1. For morphology B, the obtained XRPD graph is shown in Figure 5, and the obtained XRPD peaks are shown in Table 2. For morphology A, the obtained XRPD graph is shown in Figure 6, and the obtained XRPD peaks are shown in Table 3.

[0091] Example 4 DVS isotherm plot Form A was subjected to DVS. DVS is a gravimetric analysis technique that measures how quickly and how much solvent is absorbed by a sample, such as when a dry powder absorbs water. The test was performed using Surface Measurement Systems DVS Intrinsic Plus at a temperature of 25°C with nitrogen as the carrier gas. The relative humidity range was 0-95%, and the maximum equilibration time was 240 minutes. The relative humidity steps included 40-50-60-70-75-70-60-50-40-30-20-10-0-10-20-30-40-50-60-70-75-80-90-95-90-80-75-70-60-50-40-30-20-10-0%.

[0092] Morphology A was subjected to increasing relative humidity until a mass change occurred. Once a mass change occurred, the relative humidity was lowered to determine the stability of the resulting mass. Then, the relative humidity was raised again until another mass change occurred. Once a mass change occurred, the relative humidity was lowered again to determine the stability of the resulting mass. Two mass changes occurred during the DVS of morphology A. The resulting masses are morphology B and morphology C. The resulting DVS graph is shown in Figure 8.

[0093] Example 5 Solubility test Form A The kinetic solubility of epinephrine malonate and tartarate (form A) was determined using the procedure described herein. The solid active pharmaceutical ingredients were equilibrated from 5°C to ambient temperature for 1 hour. The solids (0.76 g of malonate and 0.20 g of tartarate) were weighed into a 4 mL vial containing a magnetic polytetrafluoroethylene (PTFE) stirring bar. Water (0.5 mL) was added, and the sample was stirred at 20°C. Additional API was gradually added in small amounts over 30 minutes until trace amounts of residual solid remained. At 30 minutes, the contents of the nearly dissolved sample were transferred to a volumetric flask (VF), diluted, and subjected to HPLC analysis to adjust for the initial volume of water used.

[0094] HPLC analysis was performed using an Agilent 1100 with a 100 × 4.6 mm, 3.0 μm Phenomenx Gemini C18 column. The column temperature was 50°C, the wavelength was 210 nm, and the flow rate was 1.2 mL / min. Mobile phase A was 5:95 MeCN:buffer, and mobile phase B was 45:55 MeCN:buffer.

[0095] The HPLC data is summarized in Table 5. The results showed that 912 mg of malonate form A and 259 mg of tartrate were almost completely dissolved in 0.5 mL of added water within 30 minutes. Therefore, the solubility of malonate form A was approximately 1.82 g / mL, and the solubility of tartrate was approximately 0.52 g / mL. TIFF2026530440000007.tif56170

[0096] Form B The kinetic solubility of form B was determined using the procedure described herein. Solid form B was equilibrated from storage temperature (5°C) to ambient temperature for 1 hour. The solid (0.025 g of form B) was weighed into a 4 mL vial containing a magnetic PTFE stirring bar. Water (0.5 mL) was added, and the sample was stirred at 20°C. Additional API was gradually added in small amounts over 30 minutes until trace amounts of residual solid remained. At 30 minutes, the contents of the nearly dissolved sample were transferred to a volumetric flask (VF), diluted, and subjected to HPLC analysis to adjust for the initial volume of water used.

[0097] HPLC analysis was performed using an Agilent 1100 with a 100 × 4.6 mm, 3.0 μm Phenomenx Gemini C18 column. The column temperature was 50°C, the wavelength was 210 nm, and the flow rate was 1.2 mL / min. Mobile phase A was 5:95 MeCN:buffer, and mobile phase B was 45:55 MeCN:buffer.

[0098] The HPLC data is summarized in Table 6. The results showed that 511 mg of form B was almost completely dissolved in 0.5 mL of added water in 30 minutes. Therefore, the solubility of malonate form B (hydrate) is 1.0 g / mL. TIFF2026530440000008.tif40170

[0099] Example 6 Preparation of morphology A on a kilogram scale One kilogram of epinephrine was added to 3.16 kg of ethanol and stirred. The mixture was degassed with nitrogen and heated to 35°C. The mixture was kept at a temperature of 35°C to 40°C while stirring, and 624.8 g of malonic acid was added. Once all the solids had dissolved, the mixture was stirred for 2 hours while maintaining a temperature of 35°C to 40°C.

[0100] To minimize the formation of morphology C at this stage, it was determined that it was important that no solids were present in the solution before adding the seed crystal. The solution was filtered to remove solids, and the solution was stirred at a temperature of 35°C to 40°C for 2 hours to form a homogeneous solution and ensure that all solids were dissolved.

[0101] Next, the solution was cooled to a temperature of 25°C to 30°C while continuously stirring. Seed crystals of form A were added, and the mixture was stirred at 25°C to 30°C for 2 hours. The temperature was gradually lowered to 15°C over 2 hours, and then stirred at 15°C for a further 16 hours. The temperature was again gradually lowered to 5°C over 2 hours, and stirred for a further 3 hours.

[0102] The resulting mixture was filtered to remove ethanol. The filter cake was rinsed with cold (5±5°C) ethanol and dried under vacuum at 30°C for 16 hours. The product was ground and milled until the particle size distribution was Dv(10) = 2.47 μm, Dv(50) = 11.4 μm, and Dv(90) = 43.8 μm. The analytical results of the product are shown in Table 7 below. TIFF2026530440000009.tif93170

[0103] The product samples were assayed by XRPD using a Bruker D8 Advance. The instrument parameters are shown in Table 8 below. The superimposed XRPD spectra (Figure 9) showed that the material was phase-pure morph A and morph C was not detected. Figure 9 shows the superimposed XRPD spectral patterns of the product (bottom), morph A (middle), and morph C (top) from Example 6. TIFF2026530440000010.tif81170

[0104] The above description is provided for illustrative and explanatory purposes only. This description is not intended to limit the invention to the exact form disclosed. Those skilled in the art will understand that modifications and substitutions to the basic description of the invention may be made.

Claims

1. Epinephrine malonate as form B.

2. The epinephrine malonate according to claim 1, wherein the epinephrine malonate has one or more peaks in a powder X-ray diffraction spectrum (copper, Kα1), represented as 2-theta, at approximately 9.8, 13.0, 14.2, 15.1, 16.9, 17.2, 20.0, 20.6, 22.9, 24.9, 25.9, 26.4, 27.4, 28.7, or 31.

3.

3. The epinephrine malonate according to claim 2, wherein the epinephrine malonate is form B with a purity of 95%.

4. The epinephrine malonate according to claim 3, wherein the epinephrine malonate is form B with a purity of 99%.

5. A pharmaceutical composition comprising epinephrine malonate as described in claim 1 and a pharmaceutically acceptable carrier.

6. The pharmaceutical composition according to claim 4, wherein the pharmaceutical composition is suitable for sublingual or buccal administration.

7. A method for treating a patient suffering from an allergic disease, comprising administering to the patient a pharmaceutically effective amount of epinephrine malonate according to claim 1.

8. Epinephrine malonate as form C.

9. The epinephrine malonate according to claim 8, wherein the epinephrine malonate has one or more peaks in a powder X-ray diffraction spectrum (copper, Kα1), represented as 2-theta, at approximately 10.3, 10.7, 13.4, 16.7, 18.1, 18.5, 19.7, 19.9, 21.0, 21.5, 24.2, 24.7, 25.3, or 25.

8.

10. The epinephrine malonate according to claim 9, wherein the epinephrine malonate is form C with a purity of 95%.

11. The epinephrine malonate according to claim 10, wherein the epinephrine malonate is form C with a purity of 99%.

12. A pharmaceutical composition comprising epinephrine malonate as described in claim 8 and a pharmaceutically acceptable carrier.

13. The pharmaceutical composition according to claim 11, wherein the pharmaceutical composition is suitable for sublingual or buccal administration.

14. A method for treating a patient suffering from an allergic disease, comprising administering to the patient a pharmaceutically effective amount of epinephrine malonate according to claim 8.

15. Epinephrine malonate in form A, with a purity of 95%.

16. The epinephrine malonate according to claim 15, wherein the epinephrine malonate has one or more peaks in a powder X-ray diffraction spectrum (copper, Kα1), represented as 2-theta, at approximately 12.2, 13.5, 14.3, 14.7, 15.9, 17.4, 17.9, 19.6, 20.5, 21.6, 22.4, 22.9, 23.9, 24.7, 25.3, 26.0, 26.5, 25.3, 26.0, 26.5, 27.2, 27.9, 29.5, 33.2, 34.3, or 34.

8.

17. The epinephrine malonate according to claim 15, wherein the epinephrine malonate is form A with a purity of 99%.

18. A pharmaceutical composition comprising the epinephrine malonate described in claim 15 and a pharmaceutically acceptable carrier.

19. The pharmaceutical composition according to claim 17, wherein the pharmaceutical composition is suitable for sublingual or buccal administration.

20. A method for treating a patient suffering from an allergic disease, comprising administering to the patient a pharmaceutically effective amount of epinephrine malonate according to claim 15.

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