Epinephrine malonate crystalline salt

Abstract

Described herein are adrenaline salts, particularly adrenaline malonate salts; adrenaline malonate salts in crystalline form; pharmaceutical compositions comprising adrenaline malonate; sublingual or buccal pharmaceutical compositions comprising adrenaline malonate in crystalline form; and a method for treating a patient comprising administering a pharmaceutical composition of adrenaline malonate in crystalline form.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to U.S. Provisional Application No. 62 / 711,936, filed on July 30, 2018, and U.S. Provisional Application No. 62 / 731,442, filed on September 14, 2018, the disclosures of which are incorporated herein by reference in their entireties. Technical Field

[0003] The present invention relates to a novel pharmaceutical salt in a crystalline form. More specifically, the present invention relates to a crystalline adrenaline malonate salt; a pharmaceutical composition comprising crystalline adrenaline malonate; and a method for treating a patient, the method comprising administering the pharmaceutical composition of crystalline adrenaline malonate to the patient. Background Art

[0004] Epinephrine has been used for decades to treat allergic reactions. In 1958, Bose and colleagues studied different epinephrine salts, such as epinephrine citrate, focusing on the pharmacological activity of epinephrine citrate salts. Bose et al., Observations on the pharmacological activity of different salts of adrenaline, morphine and strychnine, Indian J Med Res. 46 (2): 193-8 (March 1958). In 1972, John J. Sciarra and colleagues disclosed a method 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 the 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 40mg SublingualEpinephrine Tablet Formulations with Similar In Vitro Characteristics Have the Same Bioavailability? ,Biopharm.Drug Dispos.27,427–435(2006). Summary of the invention

[0005] The present invention relates to a novel crystalline adrenaline salt, adrenaline malonate, and a pharmaceutical composition comprising the adrenaline salt, a method for preparing the adrenaline salt, and a method for treating a patient, wherein the method comprises administering the adrenaline salt to the patient. In a preferred embodiment, the polymorphic crystalline adrenaline malonate has Figure 1 X-ray powder diffraction pattern identified in.

[0006] In certain embodiments, a pharmaceutical composition comprising adrenaline malonate salt is provided. The pharmaceutical composition may be suitable for oral, rectal, intragastric, local, intracranial, intranasal and parenteral administration. In a preferred embodiment, the pharmaceutical composition may be a sublingual tablet or a buccal tablet. The pharmaceutical preparation may include a pharmaceutically effective amount of adrenaline malonate salt and one or more pharmaceutically acceptable excipients, including, for example, fillers (e.g., microcrystalline cellulose) and disintegrants (e.g., cross-linked polyvinyl polypyrrolidine or low-substituted hydroxypropyl cellulose). In certain embodiments, the pharmaceutical composition may also include lubricants (e.g., magnesium stearate) and glidants (e.g., silicon dioxide). In certain embodiments, the pharmaceutical composition may also include diluents (e.g., mannitol) and / or pH regulators (e.g., citric acid). The pharmaceutical composition may include an amount of 0.3 to 10 mg of adrenaline malonate. The pharmaceutical composition may also include an amount of 20% to 30% by weight of filler and an amount of 5% to 15% by weight of disintegrant. In certain embodiments, the pharmaceutical composition can disintegrate in less than or equal to 30 seconds.

[0007] In certain embodiments, a method for preparing the malonate adrenaline salt is provided. The method may include adding malonic acid to a solution of adrenaline base in a solvent (e.g., ethanol). Malonic acid can be added to the solution at a ratio of at least 0.001:1, at least 0.01:1, at least 1:1, at least 2:1, at least 3:1, at least 5:1, at least 10:1, at least 25:1, at least 50:1, at least 100:1, at least 500:1 relative to adrenaline. Malonic acid can be added to the solution at a ratio of less than or equal to 100:1, less than or equal to 500:1, less than or equal to 100:1, less than or equal to 75:1, less than or equal to 5:1, less than or equal to 3:1, less than or equal to 2:1, less than or equal to 1:1. In certain embodiments, malonic acid can be added to the solution at a ratio between 0.01:1 and 3:1. In a preferred embodiment, malonic acid can be added to the solution at a 1:1 equivalent relative to adrenaline. The method may include stirring the solution and allowing the salt to precipitate from the solution. The method may also include filtering and drying the precipitate.

[0008] In certain embodiments, a method for treating a patient is provided. The method comprises administering a pharmaceutically effective amount of epinephrine malonate to a patient in need of such treatment, including, for example, a patient suffering from an allergic reaction. BRIEF DESCRIPTION OF THE DRAWINGS

[0009] The accompanying drawings, which are incorporated herein and form a part of this specification, illustrate various embodiments of the present disclosure and together with the description, further serve to explain the principles of the present disclosure and enable those skilled in the relevant art to practice and use the embodiments disclosed herein.

[0010] Figure 1 The proton nuclear magnetic resonance (H NMR) spectrum of adrenaline malonate salt is shown.

[0011] Figure 2 The x-ray powder diffraction (XRPD) spectrum of adrenaline malonate salt is shown.

[0012] Figure 3 The differential scanning calorimetry (DSC) spectrum of adrenaline malonate salt is shown.

[0013] Figure 4 Shown is the thermogravimetric analysis of the adrenaline malonate salt. DETAILED DESCRIPTION

[0014] The present invention generally relates to a novel crystalline adrenaline salt. It has been discovered that a novel adrenaline salt, adrenaline malonate, can be obtained in crystalline form having desirable properties for pharmaceutical compositions, including, for example, sublingual and buccal pharmaceutical compositions.

[0015] Before the present invention is described in detail below, it should be understood that the present invention is not limited to the specific methodology, scheme and reagent described herein, because these can change. It should also be understood that the terms used herein are only for the purpose of describing specific embodiments and are not intended to limit the scope of the present invention, which is limited only by the appended claims. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those generally understood by those of ordinary skill in the art to which the present invention belongs.

[0016] The term "about" when used in conjunction with a numerical value means encompassing the numerical value within a range having a lower limit that is less than 5% of the specified numerical value and an upper limit that is greater than 5% of the specified numerical value.

[0017] As used herein, "treat," "treating," or "treatment" of a disease or condition means accomplishing one or more of the following: (a) reducing the severity and / or duration of the condition; (b) limiting or preventing the development of symptoms characteristic of the condition or conditions being treated; (c) inhibiting the worsening of symptoms characteristic of the condition or conditions being treated; (d) limiting or preventing the recurrence of the condition or conditions in a patient who previously had the condition or conditions; and (e) limiting or preventing the recurrence of symptoms in a patient who previously had symptoms of the condition or conditions.

[0018] The "pharmaceutical composition" according to the present invention may be in the form of a composition in which different active ingredients and diluents and / or carriers are mixed with each other, or may take the form of a combined preparation in which the active ingredients are present in part or in a completely different form. An example of such a combination or combined preparation is a kit-of-parts.

[0019] A "therapeutic amount" or "therapeutically effective amount" is an amount of a therapeutic agent sufficient to achieve its intended purpose. The effective amount of a given therapeutic agent will vary with factors such as the nature of the agent, the route of administration, the size and species of the animal receiving the therapeutic agent, and the purpose of the administration. The effective amount in each individual case can be determined empirically by a skilled artisan according to methods established in the art.

[0020] As used herein, the term "patient" or "subject" most preferably refers to a human being. Also included are any mammals or birds that may benefit from the compounds described herein. Preferably, the "subject" or "patient" is selected from the group consisting of laboratory animals (e.g., mice or rats), livestock (including, e.g., guinea pigs, rabbits, chickens, turkeys, pigs, sheep, goats, camels, cattle, horses, donkeys, cats or dogs) or other primates (including chimpanzees).

[0021] "Pharmaceutically acceptable" generally means safe for administration to humans or animals. Preferably, a pharmaceutically acceptable component is one approved by a federal regulatory agency or a state government or listed in the U.S. Pharmacopeia published by the United States Pharmacopeial Convention, Inc., Rockville Md., or other generally recognized pharmacopeia for use in animals and more particularly in humans.

[0022] In one embodiment, the present invention provides adrenaline malonate in a crystalline form with the appearance of a white powder. The water solubility of the adrenaline malonate salt may be 1142.7 mg / mL; the pKa is 5.47; and the partition coefficient (logP) is -3.00. The water solubility of the crystalline form of the adrenaline malonate salt is surprisingly significantly higher than that of other adrenaline salts. The high water solubility makes the adrenaline malonate salt particularly suitable for transmucosal delivery of drugs. The high bioavailability and rapid delivery of drugs are particularly important for adrenaline, which is used to treat allergic reactions and is sometimes used in emergency situations. In addition, the adrenaline malonate salt is not hygroscopic and can exhibit a favorable stability distribution at 7, 14, 30, 60, 90, 120 or 150 days.

[0023] The adrenaline malonate salt may be substantially pure. For example, the adrenaline malonate salt may have a purity greater than or equal to 95%, 96%, 97%, 98%, 99%, 99.5%, 99.6%, 99.7%, 99.8% or 99.9%.

[0024] Adrenaline malonate salts may have Figure 1 Proton nuclear magnetic resonance (H NMR) spectrum shown.

[0025] Adrenaline malonate salts may have Figure 2 The X-ray powder diffraction (XRPD) spectrum shown. Figure 2 As shown, the adrenaline malonate salt can be a polymorph characterized by an x-ray powder spectrum having one or more peaks expressed as 2θ at about 12.1843, 13.4653, 14.2595, 14.6991, 15.8664, 17.3570, 17.9004, 19.5883, 20.4659, 21.5801, 22.3908, 22.9301, 23.8776, 24.6585, 25.3418, 26.0105, 26.4829, 25.3418, 26.0105, 26.4829, 27.2385, 27.8939, 29.4741, 33.2425, 34.2629, 34.8439.

[0026] like Figure 3 As shown, the melting temperature maximum value of the adrenaline malonate salt by differential scanning calorimetry may be from about 101°C to about 106°C, preferably from about 102°C to 104°C.

[0027] In another embodiment, the present invention provides a pharmaceutical composition comprising adrenaline malonate. The pharmaceutical composition may be suitable for oral, rectal, intragastric, local, intracranial, intranasal and parenteral administration. The pharmaceutical composition may be administered in any pharmaceutically acceptable dosage form, including solid, semisolid or liquid dosage forms, such as, for example, tablets, suppositories, pills, capsules, powders, liquids, suspensions, etc., preferably a unit dosage form suitable for single administration of precise doses, an immediate release dosage form, or a sustained release or controlled release dosage form for extending the administration of a compound at a predetermined rate. The pharmaceutical composition may include at least one of a conventional pharmaceutical carrier or excipient and a compound of the present invention, and in addition, may include other pharmaceutical agents, medicaments, carriers, adjuvants, etc. The pharmaceutical composition may contain 1% to 95% by weight of adrenaline 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 adrenaline malonate. Additionally, the pharmaceutical composition may exhibit a favorable stability profile over 7, 14, 30 days or longer.

[0028] In a preferred embodiment, the pharmaceutical composition is suitable for transmucosal administration in the form of a sublingual tablet or a buccal tablet. The pharmaceutical composition may include a pharmaceutically effective amount of adrenaline malonate salt. In certain embodiments, the pharmaceutical composition suitable for transmucosal administration in the form of a sublingual tablet or a buccal tablet includes an amount of 0.3 to 10 mg of adrenaline free alkali. The pharmaceutical composition may also include a filler (e.g., microcrystalline cellulose) and a disintegrant (e.g., low-substituted hydroxypropyl cellulose or cross-linked polyvinyl polypyrrolidone (cross-linked polyvinylpyrrolidone)). In certain embodiments, the pharmaceutical composition may also include a lubricant (e.g., magnesium stearate) and / or a glidant (e.g., silicon dioxide). In certain embodiments, the pharmaceutical composition may also include a diluent (e.g., mannitol). In certain embodiments, the pharmaceutical composition may also include a pH adjusting agent (e.g., citric acid).

[0029] In certain embodiments, the ratio of filler to disintegrant may be about 9:1, 9.5:0.5, 8:2, 7:3 and 6:4. The pharmaceutical composition can provide rapid and complete or substantially complete disintegration of buccal tablets or sublingual tablets, and can be adjusted to control the disintegration rate of the tablet. For example, the higher the disintegration rate, the slower the disintegration of the tablet, because the tablet has lower water permeability through capillary action. In certain embodiments, the buccal tablet or sublingual tablet can be substantially or completely disintegrated in less than or equal to 30 seconds. In certain embodiments, the pharmaceutical composition may include one or more fillers, one or more disintegrants, one or more lubricants and optionally other excipients known in the art. For example, as those of ordinary skill in the art have understood, the pharmaceutical composition may include one or more of a diluent, a binder, a glidant, a colorant, a flavoring agent, a pH adjuster, a coating material, etc.

[0030] In some embodiments of the invention, the pharmaceutical composition comprises a filler which is microcrystalline cellulose (e.g., -PH-301 or Ceolus KG 802). In other embodiments, the filler may be one or more of lactose, calcium carbonate, calcium bicarbonate, calcium phosphate, calcium hydrogen phosphate, calcium sulfate, calcium silicate, cellulose powder, dextrose, dextrate, dextran, starch, pregelatinized starch, sucrose, xylitol, lactitol, sorbitol, sodium bicarbonate, sodium chloride, polyethylene glycol, etc. In certain embodiments, the pharmaceutical composition comprises a filler in an amount of 15% to 35% by weight, more preferably 20% to 30% by weight or 22% to 27% by weight, or most preferably about 25% by weight.

[0031] In some embodiments of the invention, the pharmaceutical composition comprises a disintegrant which is a cross-linked polyvinylpolypyrrolidone (crospovidone) or a low-substituted hydroxypropylcellulose. In other embodiments, the disintegrant may be one or more of a cross-linked cellulose such as cross-linked sodium carboxymethylcellulose, cross-linked carboxymethylcellulose or cross-linked cross-linked carboxymethylcellulose, a cross-linked starch such as sodium starch glycolate (e.g., ), and other cross-linked polymers. In certain embodiments, the pharmaceutical composition comprises a disintegrant in an amount of 2 wt % to 20 wt %, more preferably 5 wt % to 15 wt % or 5 wt % to 10 wt %, or most preferably about 6 wt % to 8 wt %.

[0032] In some embodiments of the present invention, the pharmaceutical composition comprises a lubricant (which is magnesium stearate) and / or a glidant (which is silicon dioxide). A lubricant is a compound that prevents, reduces or inhibits adhesion or friction of a material. A glidant is a compound that improves the fluidity of a composition. In other embodiments, the lubricant and glidant 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 alkali metal and alkaline earth metal salts thereof (such as aluminum stearate, calcium stearate, magnesium stearate, zinc stearate, sodium stearate), glycerol, wax, 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 sulfate, silica gel, starch (such as corn starch), silicone oil. In certain embodiments, the pharmaceutical composition comprises a lubricant and / or a glidant in an amount of 0.1% to 5% by weight, more preferably 0.5% to 4% by weight, or most preferably about 1% to 3% by weight, respectively.

[0033] In some embodiments of the present invention, the pharmaceutical composition comprises a diluent, which is mannitol. In other embodiments, the diluent may be lactose, starch, sorbitol, dextrose, tricalcium phosphate, calcium phosphate; anhydrous lactose, spray-dried lactose, pregelatinized starch, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose acetate stearate, sucrose-based diluent, calcium hydrogen sulfate monohydrate, calcium sulfate dehydrate, calcium lactate trihydrate, dextran binder, cereal hydrolyzed solids, amylose, powdered cellulose, calcium carbonate, glycine, kaolin or sodium chloride. In certain embodiments, the pharmaceutical composition comprises a diluent in an amount of 25% to 75% by weight, more preferably 35% to 60% by weight, and most preferably 45% to 55% by weight.

[0034] In some embodiments of the invention, the pharmaceutical composition comprises a pH adjusting agent, which is citric acid. In other embodiments, the pH adjusting agent may be boric acid, lactic acid, malic acid, phosphoric acid, sodium dihydrogen phosphate or tartaric acid. In certain embodiments, the pharmaceutical composition comprises 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.

[0035] In certain embodiments, the pharmaceutical preparation can be prepared by using direct compression. As will be appreciated by those of ordinary skill in the art, the pharmaceutical preparation can be designed and prepared as described in Keith J. Simons et al., Fast-Disintegrating Sublingual Tablets: Effect of Epinephrine Load on Tablet Characteristics, AAP S Pharm Sci Tech 7 (2): E41 (February 2006), which is incorporated herein by reference.

[0036] In other embodiments, the present invention provides a method for manufacturing a malonate adrenaline salt. The method may include adding malonate to a solution comprising adrenaline and a solvent. Malonate may be added to the solution at a ratio of at least 0.001:1, at least 0.01:1, at least 1:1, at least 2:1, at least 3:1, at least 5:1, at least 10:1, at least 25:1, at least 50:1, at least 100:1, at least 500:1 relative to adrenaline. Malonate may be added to the solution at a ratio of less than or equal to 100:1, less than or equal to 500:1, less than or equal to 100:1, less than or equal to 75:1, less than or equal to 5:1, less than or equal to 3:1, less than or equal to 2:1, less than or equal to 1:1. In certain embodiments, malonate may be added to the solution at a ratio between 0.01:1 and 3:1. In a preferred embodiment, malonate may be added to the solution at a 1:1 equivalent relative to adrenaline. The method may further include stirring the solution. The method may further include adding an additional solvent to the solution. The method may further include stirring the solution. The method may further include precipitating the adrenaline salt from the solution. The method may further include filtering the precipitate. The method may further include drying the precipitate. In the method, the solvent may be an alcohol, a ketone or an ester. Exemplary solvents for use in the present invention include methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, tert-butanol, n-pentanol, 2-methylbutanol, 3-methylbutanol, hexanol, acetone, methyl ethyl ketone and ethyl acetate. In a preferred embodiment, the solvent is ethanol.

[0037] In other embodiments, the present invention provides a method for treating a patient. The patient may be a patient suffering from an allergic condition (e.g., anaphylaxis, asthma, or bronchial asthma). The method comprises administering a pharmaceutically effective amount of epinephrine malonate to a patient in need of such treatment (including, for example, a patient suffering from an allergic reaction). The method may comprise administering a buccal tablet or a sublingual tablet to a patient suffering from an allergic condition.

[0038] The following examples illustrate certain embodiments of the invention without limiting them.

[0039] Example

[0040] Although various embodiments have been described herein, it should be understood that the embodiments are presented by way of example only and are not limiting. Therefore, the breadth and scope of the present disclosure should not be limited by any of the exemplary embodiments described. In addition, unless otherwise indicated herein or clearly contradictory to the context, the present disclosure encompasses any combination of the elements in all possible variations thereof.

[0041] Example 1

[0042] Preparation of epinephrine malonate salt

[0043] The following method is used to form adrenaline malonate. Malonic acid 2.3g (1.0 equivalent) is added to a solution of adrenaline 4g (1.0 equivalent) in EtOH (8mL) at room temperature. The reaction mixture becomes a clear solution after vigorous stirring for 30 minutes. EtOH (10mL) is added, and a white solid product is precipitated. The mixture is further stirred for 10 hours, filtered and dried in a vacuum to obtain 5.7g adrenaline malonate (as a white powder).

[0044] Example 2

[0045] Physical and chemical properties of adrenaline malonate salt

[0046] The physical and chemical properties of the adrenaline malonate salt of Example 1 were evaluated and compared with other adrenaline salts.

[0047] A. Solubility

[0048] The solubility of adrenaline malonate salt was evaluated and compared with other adrenaline salts. The test was performed using a Sartorius balance (SQP model), a Thermo HPLC (UltiMate 3000 system, UV wavelength: 205 nm) and a Phenomenex Luna column (5 μm C18 (2), 4.6 x 250 mm). The column temperature was 40°C and the autosampler temperature was room temperature. The injection volume was 5 μL.

[0049] Mobile phase A was prepared by weighing 4.0 g of tetramethylammonium hydrogen sulfate (MERYER, batch number 77957139) and 1.11-heptyl sodium sulfonate (Admas-beta, batch number P1343755) and transferring the materials to a flask. 2 mL of 0.1 mol / L EDTA solution (brand: Sinopharm Chemical Reagent Co., Ltd., batch number 20150410) was added to the flask and the volume was adjusted to 950 mL with water. The solution was mixed and adjusted to pH 3.5 with 0.1 N sodium hydroxide solution (brand: Enox, batch number 20161201). Mobile phase B was prepared using ethanol. Isocratic elution was used with an A / B ratio of 85 / 15. The run time was 8 minutes.

[0050] A standard solution containing 10 mg of standard dissolved in 10 mL of water was used. Test solutions were prepared and water was added at 25°C ± 2°C. The solution was sonicated for 30 seconds every 5 minutes. Dissolution was observed within 30 minutes to ensure that the solution was saturated. The solution was filtered through a 0.45 um membrane and diluted for testing. Table 1 lists the results of the solubility study.

[0051] Table 1

[0052] Salt Solubility (mg / mL) Epinephrine Malonate 1142.7 Epinephrine bitartrate 827.0 Epinephrine Fumarate 38.9 Epinephrine hemisulfate 17.7 Epinephrine Maleate 82.7

[0053] B. pH

[0054] The pH of adrenaline malonate salt was evaluated and compared with other adrenaline salts. The test was performed using a Sartorius balance (SQP model) and a pH meter (brand: INESA, model PHS-3E). 20 mg of the sample was weighed and transferred to a 20 mL volumetric flask, with the remaining volume containing water. The solution was mixed. The pH meter was calibrated at 25°C with pH 4.0 and pH 6.8 standard buffer solutions. Table 2 lists the results of the analysis.

[0055] Table 2

[0056] Salt pH Epinephrine Malonate 4.34 Epinephrine bitartrate 3.75 Epinephrine Fumarate 3.77 Epinephrine hemisulfate 7.14 Epinephrine Maleate 4.48

[0057] C.pKa

[0058] The pKa of adrenaline malonate salt was evaluated and compared with other adrenaline salts. The test was performed using a Sartorius balance (SQP model) and a potentiometric titrator (brand: Methrom, model 905Titrando). 0.17 g of sample was weighed and transferred to a 50 mL volumetric flask, with the remaining volume containing deionized water. The solution was mixed. The solution was titrated with 0.1 mol / L NaOH solution, and the end point was indicated using a pH indicator. Table 3 lists the results of the analysis.

[0059] Table 3

[0060] Salt pKa Epinephrine Malonate 5.47 Epinephrine bitartrate 4.20 Epinephrine Fumarate 4.28 Epinephrine hemisulfate Undetermined Epinephrine Maleate 6.12

[0061] D. Partition coefficient

[0062] The distribution coefficient (logP) of adrenaline malonate was evaluated and compared with other adrenaline salts. The test was performed using a Sartorius balance (SQP model), a Thermo HPLC (UltiMate 3000 system, UV wavelength: 205nm) and a Phenomenex Luna column (5μm C18 (2), 4.6x250mm). The column temperature was 40°C and the autosampler temperature was room temperature. The injection volume was 5μL.

[0063] Mobile phase A was prepared by weighing 4.0 g of tetramethylammonium hydrogen sulfate (MERYER, batch number 77957139) and 1.11-heptyl sodium sulfonate (Admas-beta, batch number P1343755) and transferring the materials to a flask. 2 mL of 0.1 mol / L EDTA solution (brand: Sinopharm Chemical Reagent Co., Ltd., batch number 20150410) was added to the flask and the volume was adjusted to 950 mL with water. The solution was mixed and adjusted to pH 3.5 with 0.1 N sodium hydroxide solution (brand: Enox, batch number 20161201). Mobile phase B was prepared using ethanol. Isocratic elution was used with an A / B ratio of 85 / 15. The run time was 8 minutes.

[0064] Disodium hydrogen phosphate solution was prepared by weighing 7.1 g of disodium hydrogen phosphate (brand: Sinopharm Chemical Reagent Co., Ltd., batch number 20150910). Citric acid solution was prepared by weighing 5.25 g of hydrated citric acid (brand: General-Reagent, batch number 5949-29-1) and dissolving it in 1000 mL of water. pH 3.47 buffer solution was prepared by adjusting the pH of disodium hydrogen phosphate solution to 3.47 with citric acid solution. n-Octanol buffer solution was prepared by mixing 100 mL of n-octanol (brand: Chinasun Specialty Products Co., Ltd., batch number 20160601) and 100 mL of pH 3.47 buffer solution, vibrating it for 24 hours, and leaving it to stand for one hour to separate n-octanol phase and pH 3.47 buffer phase.

[0065] Dissolve 10 mg of sample in 10 mL of saturated n-octanol solution and mix thoroughly. Add 10 mL of saturated pH 3.47 buffer solution and vortex at 3000 r / min for 1 hour. After one hour, draw 1 mL of solution from the n-octanol and pH 3.47 phases. Prepare a standard solution containing 1 mg / mL of standard in the diluent. Prepare the LOQ solution from approximately 0.1% standard solution. Dilute the n-octanol phase solution with 1 mL of methanol for testing. Inject the pH 3.47 phase solution directly. Calculate the partition coefficient using the following formula: Where Co is the equilibrium concentration of the solute in the oil phase, and Cw is the equilibrium concentration of the solute in the water phase. Table 4 reports the results of the partition coefficient analysis.

[0066] Table 4

[0067] Salt LogP Epinephrine Malonate -3.00 Epinephrine bitartrate -2.95 Epinephrine Fumarate -3.00 Epinephrine hemisulfate not applicable Epinephrine Maleate -3.01

[0068] Example 3

[0069] Preparation of a pharmaceutical composition comprising adrenaline malonate salt

[0070] Pharmaceutical compositions comprising adrenaline malonate and other adrenaline salts were prepared. Sublingual tablets containing 10 mg of adrenaline (calculated from adrenaline base) were prepared. The composition also contained microcrystalline cellulose (PH-301) as a filler, low-substituted hydroxypropyl cellulose as a disintegrant, and magnesium stearate as a lubricant. Tablets were prepared by direct compression using a range of compression forces, wherein the tablet weight was about 80 mg.

[0071] Example 4

[0072] In vitro permeability of drug compositions

[0073] The in vitro permeability of the pharmaceutical composition of Example 3 was tested. The drug transdermal diffusion test instrument (brand Huanghai, model RJY-6B), Sartorius balance (SQP type), INESA pH meter (PHS-3E type), Thermo HPLC (UltiMate 3000 system, UV wavelength: 205nm) and Phenomenex Luna column (5μm C18 (2), 4.6x250mm) were used for testing. The column temperature was 40°C, and the autosampler temperature was room temperature. The injection volume was 5μL.

[0074] Mobile phase A was prepared by weighing 4.0 g of tetramethylammonium hydrogen sulfate (MERYER, batch number 77957139) and 1.11-heptyl sodium sulfonate (Admas-beta, batch number P1343755) and transferring the materials to a flask. 2 mL of 0.1 mol / L EDTA solution (brand: Sinopharm Chemical Reagent Co., Ltd., batch number 20150410) was added to the flask and the volume was adjusted to 950 mL with water. The solution was mixed and adjusted to pH 3.5 with 0.1 N sodium hydroxide solution (brand: Enox, batch number 20161201). Mobile phase B was prepared using methanol. Isocratic elution was used with an A / B ratio of 85 / 15. The run time was 10 minutes.

[0075] The in vitro diffusion of epinephrine salt was evaluated using Franz cells with an OD of 20 mm and a reservoir volume of 7 mL. Dialysis membranes (with a MWCO of 1000 Da) were used. The dialysis membrane simulates the sublingual mucosa in the in vitro permeability test. The measured content of the active ingredient is detected in the receiving cell. The receiving chamber with a magnetic stirrer is filled with a phosphate buffer solution (pH 7.4) as a diffusion medium. The water bath is set at 37°C and the water is circulated in the Franz cell.

[0076] Each tablet was placed in the center of the donor chamber on the membrane at T0, and 2 mL of artificial saliva (Brand: Biomart, Brand No. GL0305) was added to promote disintegration and dissolution of the tablet. 1 mL aliquots were drawn from the receptor chamber at 10, 30, 60, 90 and 120 min. The drawn volume was supplemented with fresh culture medium. The samples were transferred to HPLC vials for HPLC analysis. Table 5 reports the results of the in vitro permeability analysis.

[0077] Table 5

[0078] Epinephrine salts Diffusion content (%) 120min Adrenaline 10.5 Epinephrine Hydrochloride 44.0 Epinephrine bitartrate 67.8 Epinephrine Malonate 57.5 Epinephrine Fumarate 54.4 Epinephrine hemisulfate 42.7 Epinephrine Maleate 63.5

[0079] Example 5

[0080] Stability of pharmaceutical compositions

[0081] The stability of the pharmaceutical composition of Example 3 was tested. The stability study was conducted on the packaged adrenaline salt under 25°C / RH60% and 40°C / RH75% conditions, as well as the unpackaged samples exposed to light (4500Lux) for one month. The appearance, content and related substances were checked at 5, 7, 14 and 30 days.

[0082] The content was determined using a Sartorius balance (SQP model), INESA pH meter (PHS-3E model), Thermo HPLC (UltiMate 3000 system, UV wavelength: 205 nm) and a Phenomenex Luna column (5 μm C18 (2), 4.6 x 250 mm). The column temperature was 40°C and the autosampler temperature was room temperature. The injection volume was 5 μL.

[0083] Mobile phase A was prepared by weighing 4.0 g of tetramethylammonium hydrogen sulfate (MERYER, batch number 77957139) and 1.11-heptyl sodium sulfonate (Admas-beta, batch number P1343755) and transferring the materials to a flask. 2 mL of 0.1 mol / L EDTA solution (brand: Sinopharm Chemical Reagent Co., Ltd., batch number 20150410) was added to the flask and the volume was adjusted to 950 mL with water. The solution was mixed and adjusted to pH 3.5 with 0.1 N sodium hydroxide solution (brand: Enox, batch number 20161201). Mobile phase B was prepared using methanol. Isocratic elution was used with an A / B ratio of 85 / 15. The run time was 10 minutes.

[0084] The assay content was analyzed by dissolving 20 mg of each sample to be tested in 50 mL of mobile phase A (0.4 mg / mL) as the assay test solution. The samples were used and tested immediately after preparation and protected from light.

[0085] Purity was tested using a Sartorius balance (SQP model), INESA pH meter (PHS-3E model), Thermo HPLC (UltiMate 3000 system, UV wavelength: 205 nm) and a Phenomenex Synergi column (4 μm Polar-RP 80A 250x4.6 mm). The column temperature was 30°C and the autosampler temperature was room temperature. The injection volume was 5 μL.

[0086] Mobile phase A was prepared by weighing 1.136 g of potassium dihydrogen orthophosphate (brand: CNW, batch number A1040040) and 1.74 g of potassium dihydrogen orthophosphate (brand: Ourchem, batch number 20160219) and transferring them into 1000 mL of water. The pH was adjusted to 3.0 ± 0.05 with orthophosphoric acid (brand: Ourchem, batch number 4112K060). The solution was filtered through a 0.45 μm membrane and degassed. Mobile phase B was prepared using methanol. The run time was 50 minutes. The gradient listed in Table 6 was used.

[0087] Table 6

[0088]

[0089] Purity was analyzed by dissolving 10 mg of each sample to be tested in 25 mL of mobile phase A (0.4 mg / mL) as a purity and related substance test solution. The samples were used and tested immediately after preparation and protected from light. Tables 7 to 9 list the appearance, assay content, and related substances at 5, 7, 14, and 30 days under different conditions.

[0090] Table 7

[0091] Long-term stability study at 25℃±2℃ / 60%RH±5RH

[0092]

[0093]

[0094] Table 8

[0095] Accelerated stability study at 40℃±2℃ / 75%RH±5RH

[0096]

[0097] Table 9

[0098] Stability study in air with light (4500Lux)

[0099]

[0100] Example 6

[0101] Extended Stability Study of Epinephrine Malonate in the Absence of Humidity

[0102] The stability study of adrenaline malonate salt was conducted for five months at 30°C and 40°C without humidity. The adrenaline malonate salt was packaged to protect from light and moisture. The samples were prepared in brown glass bottles with an aluminum foil bag as the outer packaging and the samples were stored between layers of desiccant silica gel. Appearance, residual material, purity, TGA and DSC were analyzed every month. Table 10 lists the results of the 30°C stability test and Table 11 lists the results of the 40°C stability test.

[0103] Table 10

[0104] Results of stability studies at 30°C

[0105]

[0106] Table 11

[0107] Results of stability studies at 40°C

[0108]

[0109]

[0110] Example 7

[0111] Study on the Stability of Epinephrine Malonate in Water at 25℃

[0112] A 120-hour stability study of adrenaline malonate salt was conducted in water at 25°C. 20 mg of adrenaline malonate salt was weighed and placed in a 50 mL volumetric flask. The sample was dissolved and diluted to a certain volume with water and mixed thoroughly. The sample was placed in a 25°C oven and samples were collected at 0 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours and 120 hours. The diluent (mobile phase) used for the study was prepared by mixing approximately 1.36 g of potassium dihydrogen orthophosphate and 1.74 g of dipotassium hydrogen orthophosphate in a 1000 mL volumetric flask and adjusting the pH to 3.0 with orthophosphoric acid. The appearance and purity of the test samples were tested. Table 12 lists the results of the 25°C stability test in water.

[0113] Table 12

[0114]

[0115]

[0116] Example 8

[0117] Study on the Degradation of Epinephrine Malonate

[0118] Degradation studies were conducted on epinephrine malonate to evaluate the effects of acid degradation, alkaline degradation, oxidation and thermal degradation (solid and solution). The procedures for various conditions are listed below.

[0119] Standard: Weigh 20 mg of sample and dissolve it in a 50 mL volumetric flask, dilute to required volume with diluent, and mix thoroughly.

[0120] Acid degradation: Weigh 20 mg of sample and place it in a 50 mL volumetric flask. Add 2 mL of 2.0 mol / L HCl to the flask. Place the flask in a 40 °C water bath for 7 days.

[0121] Alkaline degradation: Weigh 20 mg of sample and place it in a 50 mL volumetric flask. Add 2 mL of 0.05 mol / L NaOH to the flask. Store the flask at room temperature for 24 hours.

[0122] Oxidation: Weigh 20 mg of sample and place it in a 50 mL volumetric flask. Add 2 mL of 10% H2O2 to the flask. Place the flask in a 40°C water bath for 44 hours.

[0123] Thermal degradation (solution, 80°C): Weigh 20 mg of sample and dissolve it in a 50 mL volumetric flask, dilute to the required volume with diluent, and mix thoroughly. Place the flask in a 80°C water bath for 46 hours.

[0124] Thermal degradation (solid, 80°C): 120 mg of sample was placed in an oven at 80°C for 7 days.

[0125] The samples were tested for appearance and purity. Table 13 lists the results of the degradation tests.

[0126] Table 13

[0127]

[0128]

[0129] Example 9

[0130] Sublingual pharmaceutical composition of epinephrine malonate

[0131] Epinephrine malonate sublingual tablets were prepared as follows. Table 14 lists the pharmaceutical composition.

[0132] Table 14

[0133]

[0134] *1 gram of adrenaline malonate corresponds to 0.638 g of adrenaline free base. Each tablet contains 20.0 mg of adrenaline free base.

[0135] Tablets were prepared as follows. Epinephrine malonate, microcrystalline cellulose, mannitol, and cross-linked polyvinyl polypyrrolidone were screened through a 425 micron screen. Citric acid was screened through an 850 micron screen. The screened material was transferred to a blending vessel of appropriate size and rotated for 500 revolutions. Silicon dioxide was screened through a 425 micron screen. Silicon dioxide was added to the blending vessel and rotated for 125 revolutions. Magnesium stearate was screened through a 425 micron screen. Magnesium stearate was added to the blending vessel and rotated for 125 revolutions. Tablets were blended by compressing a 200 mg dose with a force between 0.5 KN and 5 KN.

[0136] Example 10

[0137] Stability testing of sublingual pharmaceutical compositions

[0138] The stability of the epinephrine malonate sublingual tablets prepared in Example 9 was tested. The tablets were packaged into bottles of 20 tablets, each containing a single 1.0 gram silica desiccant and sufficient polyester coil to prevent the tablets from moving. The bottles were capped and sealed using child-resistant caps (CRC) with induction seal liners. The bottles were placed in 40°C and 25°C stability chambers. The stability of the samples was evaluated in the initial batch (t=0), after 1 week of storage (t=1), and after 4 weeks of storage (t=4). Table 15 lists the results of the stability study at 25°C, and Table 16 lists the results of the stability test at 40°C. n=10 determinations were performed at each time point.

[0139] Table 15

[0140] Results of stability studies at 25°C

[0141]

[0142] Table 16

[0143] Results of stability studies at 40°C

[0144]

[0145] As shown in Tables 15 and 16 herein, the pharmaceutical compositions yielded unexpected and surprising stability.

[0146] Embodiment 11

[0147] Dispersibility testing of sublingual pharmaceutical compositions

[0148] After sublingual administration, the dispersion rate of a placebo sublingual tablet similar to that described in Example 9 (i.e., the formulation of Example 9 without the drug product) was tested. The placebo tablet had the same composition as that described in Example 9, with the only difference being that the adrenaline malonate salt was replaced with an additional diluent (i.e., mannitol). Five human volunteers placed a diamond-shaped placebo tablet under the tongue without taking water or other liquids, and measured the time required for the tablet to be completely dispersed. The dispersion was determined by feeling and by visual confirmation. All five volunteers completed the dispersion within 20 to 25 seconds. As shown in this Example 11, the pharmaceutical composition produced an unexpected and surprising dispersion rate.

Claims

1. A crystalline form of an adrenaline malonate salt, wherein the crystalline form has an x-ray powder diffraction spectrum having one or more peaks expressed as 2θ at 12.1843, 13.4653, 14.2595, 14.6991, 15.8664, 17.3570, 17.9004, 19.5883, 20.4659, 21.5801, 22.3908, 22.9301, 23.8776, 24.6585, 25.3418, 26.0105, 26.4829, 25.3418, 26.0105, 26.4829, 27.2385, 27.8939, 29.4741, 33.2425, 34.2629, 34.8439 2. A pharmaceutical composition comprising the adrenaline malonate salt according to claim 1 and a pharmaceutically acceptable carrier.

3. The pharmaceutical composition of claim 2, wherein the pharmaceutical composition is suitable for oral, rectal, intragastric, topical, intracranial, intranasal and parenteral administration.

4. The pharmaceutical composition of claim 2, wherein the pharmaceutical composition is suitable for sublingual or buccal administration.

5. The pharmaceutical composition of claim 4, wherein the pharmaceutical composition comprises a filler and a disintegrant.

6. The pharmaceutical composition of claim 5, wherein the filler is microcrystalline cellulose and the disintegrant is cross-linked polyvinylpolypyrrolidone.

7. The pharmaceutical composition of claim 6, wherein the filler is present in an amount of 20 to 30 weight %, and the disintegrant is present in an amount of 5 to 15 weight %.

8. The pharmaceutical composition of claim 7, further comprising a lubricant and a glidant.

9. The pharmaceutical composition of claim 8, wherein the lubricant is magnesium stearate and the glidant is silicon dioxide.

10. The pharmaceutical composition of claim 9, further comprising a diluent.

11. The pharmaceutical composition of claim 10, wherein the diluent is mannitol.

12. The pharmaceutical composition of claim 11, further comprising citric acid.

13. The pharmaceutical composition of claim 4, wherein the pharmaceutical composition comprises adrenaline free base in an amount of 0.3 mg to 10 mg.

14. The pharmaceutical composition of claim 4, wherein the pharmaceutical composition disintegrates in less than or equal to 30 seconds.

15. A method for producing the adrenaline malonate salt according to claim 1, the method comprising: adding malonic acid to a solution comprising epinephrine and a solvent; stirring the solution; as well as The adrenaline malonate salt is allowed to precipitate from solution.

16. The method of claim 15, further comprising filtering the precipitate.

17. The method of claim 16, further comprising drying the precipitate.

18. The method of claim 15, wherein malonate is added at a ratio of 0.01:1 to 3:1 relative to epinephrine.

19. The method of claim 15, wherein the solvent is selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, tert-butanol, n-pentanol, 2-methylbutanol, 3-methylbutanol, and hexanol.

20. The method of claim 19, wherein the solvent is ethanol.

21. Use of the adrenaline malonate salt according to claim 1 or the pharmaceutical composition according to any one of claims 2 to 14 in the preparation of a medicament for treating a patient suffering from an allergic condition.

22. The use of claim 21, wherein the medicament is formulated for oral, rectal, intragastric, topical, intracranial, intranasal or parenteral administration.

23. The use according to claim 21, wherein the medicament is in the form of a buccal tablet or a sublingual tablet.

24. The use according to claim 21, wherein the allergic condition is selected from the group consisting of anaphylaxis, asthma or bronchial asthma.

25. The use according to claim 24, wherein the allergic condition is an anaphylactic reaction.

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