Salt forms of mesembrine

Abstract

The present application relates to benzene sulfonate salts, phosphate salts, tartrate salts, fumarate salts, and succinate salts of mesembrine, also known as 3a-(3, 4-dimethoxyphenyl)-octahydro-1-methyl-6H-indol-6-one. And the mesembrine has a chemical formula of C17H23NO3. The present application also relates to pharmaceutical compositions comprising such salts and their medical uses. In one embodiment, the salt is mesembrine benzene sulfonate in crystalline form. A general process for preparing mesembrine salts is also disclosed. # imgabs0 #

Description

[0001] This application relates to and claims the rights and interests of GB2204778.1 filed on April 1, 2022 (2022.04.01), the contents of which are hereby incorporated by reference in their entirety. Field of the Invention

[0002] The present invention relates to a novel crystalline salt form of mesembrine, also known as 3a-(3,4-dimethoxyphenyl)-octahydro-1-methyl-6H-indol-6-one. Mesembrine has the chemical formula C 17 H 23 NO3.

[0003] The present invention also relates to the preparation of a novel crystalline salt of mesembrine and the use of the mesembrine salt as a medicament. In one embodiment, the novel crystalline salt form of mesembrine is mesembrine benzenesulfonate. Background of the Invention

[0005] Mesembrine is an alkaloid naturally present in the South African native plant species Sceletium tortuosum. The genus Sceletium belongs to the Aizoaceae family and is native to the Western Cape, Eastern Cape and Northern Cape provinces of South Africa. In addition to mesembrine, other alkaloids have been found in extracts of Sceletium tortuosum. Other alkaloids include mesembrenol, Δ 7 Mesembryanthemum ketone (Δ 7 mesembrenone), mesembrenone, mesembranol, mesembranone, and epimesembranol.

[0006] The San and Khoikai people of South Africa have a long history of using extracts of Psoralea corylifolia in traditional medicine, where it is used as a chewable and thirst-quenching remedy, to combat fatigue, and for therapeutic, social, and spiritual purposes.

[0007] Recent studies have shown that extracts of the plant have many biological properties and that extracts of Mesembryanthemum contortus can be used to treat anxiety and depression, psychological and psychiatric disorders, improve mood, and promote relaxation and happiness.

[0008] In vivo studies in rats demonstrated positive effects of extracts of Mesembryanthemum contortus on restraint-induced anxiety (Smith, 2011), and a small series of case reports described preliminary evidence of antidepressant and anxiolytic activity in patients with major depression treated with tablets containing a standardized extract of ground Mesembryanthemum contortus raw material (Gericke, 2001). Dietary supplements containing such materials may be used as Available.

[0009] The mechanism of action on the central nervous system (CNS) was identified to result in blockade of the serotonin (5-HT) transporter and to achieve selective inhibition of the phosphodiesterase-4 (PDE4) enzyme (Harvey et al., 2011).

[0010] The various alkaloids present in P. contortus have also been studied, particularly the three major alkaloids, mesembrenol, mesembrenone and mesembrine. All three showed potent activity in 5-HT transporter binding assays and anti-PDE4B activity (Harvey et al., 2011).

[0011] Mesembryantone has been described as having dual activity on 5-HT uptake and PDE4 inhibition, as the IC 50 The concentration difference was x17, and for mesembryolinol, the IC 50 The concentration difference was x258, and for mesembrine, the IC 50 The difference in concentration was x5500. However, mesembrine had a greater selectivity for the 5-HT transporter relative to PDE4B.

[0012] The structure of mesembrine is described by Popelak et al., 1960 and PW Jeffs et al., 1969. Mesembrine occurs naturally as a (-)-isomer as (-)-mesembrine.

[0013] Mesembrine can be isolated from extracts of Mesembryanthemum contortum or can be chemically synthesized using the method described by Wang et al., 2016.

[0014] Mesembrine has a solubility of 10 mg / ml in chloroform and ethanol, but low solubility in water, which means that the use of mesembrine in the preparation of medicaments is limited, as such formation of a saline form of the compound is desirable.

[0015] In 1957, mesembrine base was successfully crystallized as its hydrochloride salt (Bodendorf and Krieger, 1957), however, the solubility of the HCl salt of mesembrine at higher concentrations was poor, which meant that only small doses of mesembrine could be prepared using the HCl salt.

[0016] The object of the present invention is to prepare salt forms of mesembryine having properties superior to those currently available.

[0017] It has now been found that the monobenzenesulfonate (also known as benzenesulfonate) salt form of mesembryanthemumine exhibits advantageous properties which make it particularly suitable for use as an active principle in medicaments.

[0018] In particular, the applicant has demonstrated that the benzenesulfonate form of mesembryine unexpectedly has superior properties compared to other salt forms. In particular, the benzenesulfonate salt of mesembryine of the present invention has improved solubility and stability, which is further improved relative to the hydrochloride or fumarate forms of the same compound.

[0019] The advantages associated with the besylate salt form of mesembryanthemumine compared to the free base form or to other saline forms such as the hydrochloride and fumarate salts are described with reference to physicochemical analysis and characterization.

[0020] Brief description of public content

[0021] According to a first aspect of the present invention, there is provided a mesembryine salt, wherein the salt is selected from the group consisting of mesembryine benzenesulfonate, mesembryine phosphate, mesembryine tartrate, mesembryine fumarate and mesembryine succinate.

[0022] Preferably, the mesembryine salt is mesembryine benzenesulfonate.

[0023] More preferably, the mesembrine salt is in solid form. More preferably, the salt is in crystalline form.

[0024] When the mesembryine salt of the present invention is mesembryine benzenesulfonate, the salt is preferably prepared according to Fig.18 The salt is characterized by an XRPD pattern comprising peaks at positions approximately as described in Table 3.10. Such a salt is defined as mesembryine benzenesulfonate pattern 1.

[0025] When the mesembryine salt of the present invention is mesembryine benzenesulfonate, the salt can be optionally prepared according to Fig. 20 The salt is characterized by an XRPD pattern comprising peaks at positions approximately as described in Table 3.13. Such a salt is defined as mesembryine benzenesulfonate pattern 2.

[0026] According to a second aspect of the present invention, there is provided a process for preparing mesembryine salt, the process comprising the following steps:

[0027] a) dissolving mesembryine in a solvent;

[0028] b) adding appropriate counter ions to the mesembryine solution under temperature cycling conditions; and

[0029] c) isolating the solid comprising the mesembrine salt.

[0030] In one embodiment, the counterion of step b) is a weak acid having a pKa greater than 0.5. Preferably, the counterion of step b) is benzenesulfonic acid.

[0031] According to a third aspect of the present invention, there is provided a pharmaceutical preparation comprising a mesembryine salt, wherein the salt is selected from the group consisting of mesembryine benzenesulfonate, mesembryine phosphate, mesembryine tartrate, mesembryine fumarate and mesembryine succinate.

[0032] Preferably, the salt is mesembryanthemumine benzenesulfonate.

[0033] According to a fourth aspect of the present invention, there is provided a mesembryine salt for use in treating a disease, wherein the salt is selected from the group consisting of mesembryine benzenesulfonate, mesembryine phosphate, mesembryine tartrate, mesembryine fumarate and mesembryine succinate.

[0034] Preferably, the mesembryine salt is mesembryine benzenesulfonate.

[0035] The mesembrine salts of the present invention may be used to treat impulse control in human or animal subjects. In particular, the treatment may be related to the field of sexual dysfunction, such as delaying ejaculation, delaying orgasm and / or preventing premature ejaculation during sexual activity in human males. In addition, the mesembrine salts of the present invention may be used to delay the ejaculation latency period in males.

[0036] The compositions provided herein include a therapeutically effective amount of one or more compounds provided herein and a vehicle, which can be used to prevent, treat or improve one or more symptoms of a disease or disorder described herein. Vehicles suitable for administering the compounds provided herein include any such carriers known to those skilled in the art to be suitable for a specific mode of administration.

[0037] Furthermore, the compound may be formulated as the sole active ingredient in the composition, or may be combined with other active ingredients.

[0038] Compositions include one or more compounds provided herein. In some embodiments, the compound is formulated into a suitable preparation, such as a solution, suspension, tablet, dispersible tablet, pill, capsule, powder, sustained release formulation or elixir, formulated for oral administration or formulated into a sterile solution or suspension for parenteral administration, and via a nebulizer, a pressurized metered dose inhaler (pressurized metered dose inhaler) and a dry powder inhaler for external use (topical administration), percutaneous administration, nasal inhalation and oral inhalation. In some embodiments, the compound described above is formulated into a composition using techniques and procedures well known in the art (see, for example, Ansel, Introduction to Pharmaceutical Dosage Forms, Seventh Edition (1999)).

[0039] In the composition, one or more compounds or derivatives thereof in effective concentrations are mixed with a suitable vehicle. Before preparation as described above, the compound can be derived into a corresponding salt, ester, enol ether or ester, acetal, ketal, orthoester, hemiacetal, hemiketal, acid, base, solvate, ion pair, hydrate or prodrug. The concentration of the compound in the composition effectively delivers the amount of treatment, causing prevention or improvement of one or more symptoms of the disease described herein or disorder after administration. In some embodiments, the composition is formulated for single dose administration. In order to prepare the composition, the compound of weight fraction is dissolved, suspended, dispersed or otherwise mixed in a selected vehicle with an effective concentration so that the treated condition is alleviated, prevented or one or more symptoms are improved.

[0040] The active compound is contained in a vehicle in an amount sufficient to exert a therapeutically useful effect without undesirable side effects on the treated patient. The therapeutically effective concentration can be predicted empirically by testing the compound in in vitro and in vivo systems familiar to those skilled in the art, and then extrapolating the dosage for humans from this. The human dosage is then usually fine-tuned in clinical trials and titrated according to the response.

[0041] The concentration of the active compound in the composition will depend on the absorption, inactivation and excretion rates of the active compound, the physicochemical properties of the compound, the dosing regimen and the amount administered, and other factors known to those skilled in the art. For example, the amount delivered is sufficient to ameliorate one or more symptoms of a disease or disorder as described herein.

[0042] In some embodiments, the therapeutically effective dose should produce a serum concentration of an active ingredient from about 0.001ng / ml to about 1.0ng / ml, 2ng / ml-10ng / ml, 11ng / ml to 50ng / ml, 51ng / ml-200ng / ml or about 200ng / ml to 1000ng / ml. In other embodiments, the composition should provide a dosage from about 0.0001mg compound / kg body weight / day to about 70mg compound / kg body weight / day. The dosage unit form is prepared to provide every dosage unit form from about 0.01mg, 0.1mg or 1mg to about 500mg or about 1000mg, and in some embodiments from about 10mg to about 500mg of the active ingredient or the combination of essential ingredients.

[0043] The active ingredient can be administered at once, or can be divided into a number of smaller doses to be administered at intervals. It should be understood that the precise dosage and duration of treatment vary with the disease being treated, and can be determined empirically using known test protocols or by extrapolating from in vivo or in vitro test data or subsequent clinical testing. It should be noted that concentrations and dosage values ​​can also vary with the severity of the condition to be alleviated. It should also be understood that for any particular subject, a specific dosage regimen should be adjusted over time according to individual needs and the professional judgment of the person administering the composition or supervising the administration of the composition, and the concentration ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed composition.

[0044] In cases where the compound exhibits insufficient solubility, methods for solubilizing the compound, such as the use of liposomes, prodrugs, complexation / chelation, nanoparticles or emulsions or tertiary templating, may be used. Such methods are known to those skilled in the art and include, but are not limited to, the use of cosolvents such as dimethyl sulfoxide (DMSO), the use of surfactants or surface modifiers such as Complexing agents such as cyclodextrins or dissolution by enhanced ionization (ie, dissolution in aqueous sodium bicarbonate). Derivatives of the compounds, such as prodrugs of the compounds, may also be used to formulate effective compositions.

[0045] After mixing or adding the compounds, the resulting mixture can be a solution, suspension, emulsion, or the like. The form of the resulting mixture depends on many factors, including the intended mode of administration and the solubility of the compound in the selected vehicle. The effective concentration is sufficient to ameliorate the symptoms of the disease, disorder, or condition being treated, and can be determined empirically.

[0046] Composition is provided for being applied to mankind and animals with the dosage form suitable for indication, and the dosage form is such as dry powder inhaler (DPI), pressurized metered dose inhaler (PMDI), nebulizer, tablet, capsule, pill, sublingual tape / bioerodible strip, tablet or capsule, powder, granule, lozenge, lotion, ointment, suppository, fast melt, transdermal patch or other transdermal application equipment / preparation, sterile parenteral solution or suspension and oral solution or suspension and the oil-water emulsion containing the compound or its derivative of suitable amount.In some embodiments, therapeutically active compound and its derivative are prepared and applied with unit dosage form or multiple dosage form.Unit dosage form as used herein refers to physically discrete unit suitable for human and animal subjects and individually packaged as known in the art.Each unit dose contains the therapeutically active compound and the required vehicle of predetermined amount enough to produce the desired therapeutic effect.The example of unit dosage form includes ampoule and syringe and individually packaged tablet or capsule.Unit dosage form can be applied with part or its multiple copies. A multiple dose form is more than one identical unit dosage form packaged in a single container to be administered in isolated unit dosage forms. Examples of multiple dose forms include vials, tablet bottles or capsule bottles or pint bottles or gallon bottles. Thus, a multiple dose form is a plurality of unit doses that are not separated in the packaging.

[0047] Liquid compositions can be prepared, for example, by dissolving, dispersing or otherwise mixing the active compound as defined above and optional adjuvants in a vehicle such as, for example, water, saline, aqueous dextrose, glycerol, glycols, ethanol and the like to form a solution or suspension, a colloidal dispersion, an emulsion or a liposomal formulation. If desired, the composition to be administered may also contain a small amount of non-toxic auxiliary substances, such as wetting agents, emulsifiers, solubilizers, pH buffers and the like, for example acetate, sodium citrate, cyclodextrin derivatives, sorbitan monolaurate, triethanolamine sodium acetate, triethanolamine oleate and other such agents.

[0048] Actual methods of preparing such dosage forms are known or will be apparent to those skilled in the art; for example, see Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa., 15th edition, 1975 or subsequent editions thereof.

[0049] Dosage forms or compositions containing active ingredients in the range of 0.005% to 100% and the balance consisting of vehicles or carriers can be prepared. Methods for preparing these compositions are known to those skilled in the art. The contemplated composition may contain 0.001%-100% active ingredients, in one embodiment 0.1%-95% active ingredients, and in another embodiment 0.4%-10% active ingredients.

[0050] In certain embodiments, the composition is a lactose-free composition comprising excipients that are well known in the art and are listed, for example, in the United States Pharmacopoeia (USP) 25-NF20 (2002). Typically, the lactose-free composition comprises an active ingredient, a binder / filler, and a lubricant in equal amounts. A specific lactose-free dosage form comprises an active ingredient, microcrystalline cellulose, pregelatinized starch, and magnesium stearate.

[0051] Anhydrous compositions and dosage forms comprising active ingredients are also provided, because water can promote the degradation of some compounds. For example, the addition of water (e.g., 5%) is widely accepted as a means of simulating long-term storage, so as to determine properties such as shelf life or the stability of the preparation over time. See, for example, Jens T.Carstensen, Drug Stability: Principles & Practice, Second Edition, Marcel Dekker, NY, NY, 1995, pages 379-380. In fact, water and heat accelerate the decomposition of some compounds. Therefore, the effect of water on the preparation can be extremely important, because moisture and / or humidity are usually encountered during the manufacture, operation, packaging, storage, transportation and use of the preparation.

[0052] Anhydrous compositions and dosage forms provided herein can be prepared using anhydrous ingredients or low moisture containing ingredients and low moisture or low humidity conditions.

[0053] Anhydrous compositions should be prepared and stored so that their anhydrous nature is maintained. Therefore, anhydrous compositions are typically packaged using materials known to prevent exposure to water so that they can be included in a suitable formulary kit. Examples of suitable packaging include, but are not limited to, hermetically sealed foils, plastics, unit dose containers (e.g., vials), blister packs, and strip packs.

[0054] Oral dosage forms are solid, gel or liquid. Solid dosage forms are tablets, capsules, granules and bulk powders. Types of oral tablets include compressed, chewable lozenges and tablets that can be enteric coated, sugar coated or film coated. Capsules can be hard gelatin capsules or soft gelatin capsules, while granules and powders can be provided in non-effervescent form or in effervescent form in combination with other ingredients known to those skilled in the art.

[0055] In certain embodiments, the preparation is a solid dosage form, such as, for example, a capsule or tablet. Tablets, pills, capsules, lozenges and the like may include one or more of the following ingredients or compounds of similar nature: binder; lubricant; diluent; glidant; disintegrant; colorant; sweetener; flavoring agent; wetting agent; enteric coating; film coating agent and modified release agent. Examples of binders include microcrystalline cellulose, methyl paraben, polyalkylene oxide, tragacanth, glucose solution, gum arabic mucus, gelatin solution, molasses, polyvinyl pyrrolidine, povidone, cross-linked polyvinylpyrrolidine, sucrose and starch and starch derivatives. Lubricants include talc, starch, magnesium stearate / calcium stearate, lycopodium and stearic acid. Diluents include, for example, lactose, sucrose, trehalose, lysine, leucine, lecithin, starch, kaolin, salt, mannitol and dicalcium phosphate. Flow aids include, but are not limited to, colloidal silicon dioxide. Disintegrants include cross-linked sodium carboxymethylcellulose, sodium starch glycolate, alginic acid, corn starch, potato starch, bentonite, methylcellulose, agar and carboxymethylcellulose. Colorants include, for example, any approved certified water-soluble FD and C dyes, mixtures thereof; and water-insoluble FD and C dyes suspended on alumina hydrates and advanced coloring or anti-counterfeiting coloring / milky additives known to those skilled in the art. Sweeteners include sucrose, lactose, mannitol and artificial sweeteners such as saccharin, and any number of spray-dried spices. Flavoring agents include natural spices extracted from plants such as fruits and synthetic blends of compounds that produce pleasant sensations or mask unpleasant tastes, such as, but not limited to, mint and methyl salicylate. Wetting agents include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate and polyoxyethylene lauryl ether. Enteric coatings include fatty acids, fats, waxes, shellac, ammoniated shellac and cellulose acetate phthalate. Film coatings include hydroxyethylcellulose, sodium carboxymethylcellulose, polyethylene glycol 4000 and cellulose acetate phthalate. Modified release agents include polymers such as the Eudragit° series and cellulose esters.

[0056] The compound or its derivative can be provided in a composition that protects it from the acidic environment of the stomach. For example, the composition can be formulated in an enteric coating that maintains its integrity in the stomach and releases the active compound in the intestine. The composition can also be formulated in combination with an antacid component or other such components.

[0057] When the dosage unit form is a capsule, in addition to the above type of material, the capsule can also include a liquid carrier such as a fatty oil. In addition, the dosage unit form can include a variety of other materials that change the physical form of the dosage unit, such as the coating of sugar and other enteric solvents. The compound can also be used as a component of an elixir, suspension, syrup, wafer, sprinkle, chewing gum or the like. In addition to the active compound, the syrup can include sucrose as a sweetener and some preservatives, dyes and coloring agents and spices.

[0058] The active material may also be mixed with other active materials that do not impair the desired effect, or with materials that supplement the desired effect. The active ingredient is a compound as described herein or a derivative thereof. A higher concentration of active ingredient up to about 98% by weight may be included.

[0059] In all embodiments, tablet and capsule formulations may be coated as known to those skilled in the art in order to modify or maintain the dissolution of the active ingredient. Thus, for example, they may be coated with conventional enteric digestible coatings such as phenyl salicylate, waxes and cellulose acetate phthalate.

[0060] Liquid oral dosage forms include aqueous solutions, emulsions, suspensions, solutions and / or suspensions reconstituted from non-effervescent granules, and effervescent preparations reconstituted from effervescent granules. Aqueous solutions include, for example, elixirs and syrups. Emulsions are oil-in-water or water-in-oil.

[0061] Elixirs are transparent, sweetened hydroalcoholic preparations. The vehicles used in elixirs include solvents. Syrups are concentrated aqueous solutions of sugars such as sucrose and may contain preservatives. Emulsions are two-phase systems in which one liquid is dispersed throughout another liquid in the form of globules. The carriers used in emulsions are non-aqueous liquids, emulsifiers, and preservatives. Suspensions use suspending agents and preservatives. Acceptable substances used in non-effervescent granules to be reconstituted into liquid oral dosage forms include diluents, sweeteners, and wetting agents. Acceptable substances used in effervescent granules to be reconstituted into liquid oral dosage forms include organic acids and carbon dioxide sources. Colorants and flavorings are used in all of the above dosage forms.

[0062] Solvents include glycerol, sorbitol, ethanol and syrup. Examples of preservatives include glycerol, methyl and propyl parabens, benzoic acid, sodium benzoate and alcohol. Examples of non-aqueous liquids used in emulsions include mineral oil and cottonseed oil. Examples of emulsifiers include gelatin, gum arabic, tragacanth, bentonite and surfactants such as polyoxyethylene sorbitan monooleate. Suspending agents include sodium carboxymethylcellulose, pectin, tragacanth, Veegum and gum arabic. Sweeteners include sucrose, syrup, glycerol and artificial sweeteners such as saccharin. Wetting agents include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate and polyoxyethylene lauryl ether. Organic acids include citric acid and tartaric acid. Carbon dioxide sources include sodium bicarbonate and sodium carbonate. Colorants include any approved certified water-soluble FD and C dyes and mixtures thereof. Flavoring agents include natural flavors extracted from plants such as fruits as well as synthetic blends of compounds that produce a pleasant taste.

[0063] For solid dosage forms, in some embodiments, solutions or suspensions in, for example, propylene carbonate, vegetable oils, or triglycerides are encapsulated in gelatin capsules. Such solutions and their preparation and encapsulation are disclosed in U.S. Pat. Nos. 4,328,245; 4,409,239; and 4,410,545. For liquid dosage forms, solutions such as, for example, in polyethylene glycol can be diluted with a sufficient amount of a liquid vehicle, such as water, to facilitate measurement for administration.

[0064] Alternatively, liquid or semisolid oral preparations can be prepared by dissolving or dispersing the active compound or salt in vegetable oils, glycols, triglycerides, propylene glycol esters (e.g., propylene carbonate) and other such carriers, and encapsulating these solutions or suspensions in hard or soft gelatin capsule shells. Other useful formulations include those described in U.S. Pat. Nos. RE 28,819 and 4,358,603. Briefly, such formulations include, but are not limited to, those comprising: a compound provided herein; a dialkylated monoalkylene glycol or a dialkylated polyalkylene glycol, including, but not limited to, 1,2-dimethoxyethane, diethylene glycol dimethyl ether, triethylene glycol dimethyl ether, tetraethylene glycol dimethyl ether, polyethylene glycol-350-dimethyl ether, polyethylene glycol-550-dimethyl ether, polyethylene glycol-750-dimethyl ether, wherein 350, 550, and 750 refer to the approximate average molecular weight of the polyethylene glycol; and one or more antioxidants, such as butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarins, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, thiodipropionic acid and its esters and dithiocarbamates.

[0065] Other preparations include, but are not limited to, alcohol aqueous solutions including acetals. The alcohol used in these preparations is any water miscible solvent with one or more hydroxyl groups, including but not limited to propylene glycol and ethanol. Acetals include, but are not limited to, di(lower alkyl) acetals of lower alkyl aldehydes, such as acetaldehyde diethyl acetal.

[0066] In some embodiments characterized by subcutaneous injection, intramuscular injection or intravenous injection, parenteral administration is also contemplated herein. Injection can be prepared in conventional form, as a liquid solution or suspension, suitable for solid forms dissolved or suspended in a liquid before injection, or as an emulsion. Injection, solution and emulsion also include one or more excipients. Suitable excipients are, for example, water, saline, dextrose, glycerol or ethanol. In addition, if necessary, the composition to be administered can also include a small amount of non-toxic auxiliary substances, such as wetting agents or emulsifiers, pH buffers, stabilizers, solubility enhancers and other such agents, such as, for example, sodium acetate, sorbitan monolaurate, triethanolamine oleate and cyclodextrin.

[0067] Implantation of a slow release system or sustained release system is also contemplated herein so that a constant dosage level is maintained (see, e.g., U.S. Pat. No. 3,710,795). Briefly, the compounds provided herein are dispersed in a solid inner matrix such as polymethyl methacrylate, polybutyl methacrylate, plasticized polyvinyl chloride or unplasticized polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene-vinyl acetate copolymers, silicone rubber, polydimethylsiloxane, silicone carbonate copolymers. The solid inner matrix is ​​composed of a hydrophilic polymer such as a hydrogel of an ester of acrylic acid and methacrylic acid, collagen, cross-linked polyvinyl alcohol and cross-linked partially hydrolyzed polyvinyl acetate, the solid inner matrix being surrounded by an outer polymer membrane that is insoluble in body fluids, such as polyethylene, polypropylene, ethylene / propylene copolymer, ethylene / ethyl acrylate copolymer, ethylene / vinyl acetate copolymer, silicone rubber, polydimethylsiloxane, chloroprene rubber, chlorinated polyethylene, polyvinyl chloride, copolymers of vinyl chloride with vinyl acetate, vinylidene chloride, ethylene and propylene, ionomer polyethylene terephthalate, butyl rubber, epichlorohydrin rubber, ethylene / vinyl alcohol copolymer, ethylene / vinyl acetate / vinyl alcohol terpolymer and ethylene / vinyloxyethanol copolymer. The compound diffuses through the outer polymer membrane in a release rate controlling step. The percentage of active compound contained in such a parenteral composition is highly dependent on its specific nature, as well as the activity of the compound and the needs of the subject.

[0068] Parenteral administration of the composition includes intravenous administration, subcutaneous administration and intramuscular administration. Preparations for parenteral administration include sterile solutions ready for injection, sterile dried soluble products such as lyophilized powders ready to be combined with solvents just before use, including subcutaneous tablets, sterile suspensions ready for injection, sterile dried insoluble products ready to be combined with vehicles just before use, and sterile emulsions. Solutions can be aqueous or non-aqueous.

[0069] If administered intravenously, suitable carriers include physiological saline or phosphate buffered saline (PBS), and solutions containing thickening and solubilizing agents, such as glucose, polyethylene glycol and polypropylene glycol, and mixtures thereof.

[0070] Vehicles used in parenteral formulations include aqueous vehicles, non-aqueous vehicles, antimicrobial agents, isotonic agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, emulsifiers, sequestering or chelating agents, and other substances.

[0071] Examples of aqueous vehicles include sodium chloride injection, Ringer's injection, isotonic dextrose injection, sterile water injection, dextrose and lactated Ringer's injection. Non-aqueous parenteral vehicles include fixed oils of plant origin, cottonseed oil, corn oil, sesame oil and peanut oil. Antimicrobial agents at bacteriostatic or fungistatic concentrations must be added to parenteral preparations packaged in multiple dose containers, including phenol or cresol, mercury, benzyl alcohol, chlorobutanol, methyl and propyl parabens, thimerosal, benzalkonium chloride and benzethonium chloride. Isotonic agents include sodium chloride and dextrose. Buffers include phosphates and citrates. Antioxidants include sodium bisulfate. Local anesthetics include procaine hydrochloride. Suspending and dispersing agents include sodium carboxymethylcellulose, hydroxypropyl methylcellulose and polyvinylpyrrolidone. Emulsifiers include polysorbate 80 Metal ion sequestrants or chelators include EDTA. Carriers also include ethanol, polyethylene glycol, and propylene glycol for water miscible vehicles, and sodium hydroxide, hydrochloric acid, citric acid, or lactic acid for pH adjustment.

[0072] The concentration of the compound is adjusted so that the injection provides an effective amount to produce the desired pharmacological effect. As known in the art, the exact dose depends on the age, weight, body surface area and condition of the patient or animal.

[0073] Unit dose parenteral preparations are packaged in ampoules, vials or syringes with needles. As known and practiced in the art, all preparations for parenteral administration must be sterile.

[0074] Illustratively, intravenous or intraarterial infusion of a sterile aqueous solution containing the active compound is an effective mode of administration.Another embodiment is a sterile aqueous or oily solution or suspension containing the active substance, which is injected as needed to produce the desired pharmacological effect.

[0075] Injections are designed for local and systemic administration. In some embodiments, a therapeutically effective dose is formulated to contain at least about 0.01% w / w up to about 90% w / w or higher concentrations of active compound to the treated tissue, in certain embodiments exceeding 0.1% w / w concentrations of active compound.

[0076] The compound may be suspended in micronized or other suitable form, or may be derivatized to produce a more soluble active product or to produce a prodrug. The form of the resulting mixture depends on many factors, including the intended mode of administration and the solubility of the compound in the selected carrier or vehicle. The effective concentration is sufficient to ameliorate the symptoms of the condition and can be determined empirically.

[0077] The active ingredients provided herein can be administered by controlled release means or by delivery devices well known to those of ordinary skill in the art. Examples include, but are not limited to, those described in the following U.S. Patent Nos.: 3,845,770; 3,916,899; 3,536,809; 3,598,123; 4,008,719; 5,674,533; 5,059,595; 5,591,767; 5,120,548; 5,073,543; 5,639,476; 5,354,556; 5,639,480; 5,733,566; 5,739,108; 5,8 Such dosage forms can be used to provide a slow or controlled release of one or more active ingredients using, for example, hydroxypropylmethylcellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres, or combinations thereof to provide the desired release profile in varying proportions. Suitable controlled release formulations known to those of ordinary skill in the art, including those described herein, can be readily selected for use with the active ingredients provided herein.

[0078] All controlled release products have a common goal, i.e., improved drug therapy relative to the drug therapy achieved by its non-controlled counterpart. Ideally, the controlled release formulations used in medical treatments are characterized by using a minimum of drug substances to cure or control conditions within a minimum amount of time. The advantages of controlled release formulations include prolonged drug activity, reduced dosing frequency and increased patient compliance. In addition, controlled release formulations can be used to affect the onset time or other characteristics, such as the blood level of the drug, and thereby can affect the generation of side effects (e.g., adverse effects).

[0079] Most controlled release formulations are designed to initially release a certain amount of drug (active ingredient) that rapidly produces the desired therapeutic effect, and gradually and continuously release other amounts of drug to maintain the therapeutic effect or preventive effect at that level over an extended period of time. In order to maintain this constant drug level in the body, the drug must be released from the dosage form at a certain rate, which will replace the drug that is metabolized and excreted from the body. The controlled release of the active ingredient can be stimulated by a variety of conditions, including but not limited to pH, temperature, enzymes, water or other physiological conditions or compounds.

[0080] In certain embodiments, the agent can be administered using intravenous infusion, implantable osmotic pumps, transdermal patches, liposomes, or other modes of administration. In some embodiments, a pump can be used (see, Sefton, CRC Crit. Ref. Biomed. Eng. 14: 201 (1987); Buchwald et al., Surgery 88: 507 (1980); Saudek et al., N Engl. J. Med. 321: 574 (1989)). In other embodiments, a polymer material can be used. In other embodiments, a controlled release system can be placed near the therapeutic target, i.e., so only a portion of the systemic dose is required (see, e.g., Goodson, Medical Applications of Controlled Release, Vol. 2, pp. 115-138 (1984)). In some embodiments, a controlled release device is introduced into an inappropriate immune activation site or tumor vicinity in a subject. Other controlled release systems are discussed in Langer's review (Science 249: 1527-1533 (1990)). The active ingredient can be dispersed in a solid internal matrix, such as polymethyl methacrylate, polybutyl methacrylate, plasticized polyvinyl chloride or unplasticized polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene-vinyl acetate copolymers, silicone rubber, polydimethylsiloxane, organosilicon carbonate copolymers, hydrophilic polymers such as hydrogels of esters of acrylic acid and methacrylic acid, collagen, cross-linked polyvinyl alcohol and cross-linked partially hydrolyzed polyvinyl acetate, solid internal matrix The parenteral composition is surrounded by an outer polymer film that is insoluble in body fluids, such as polyethylene, polypropylene, ethylene / propylene copolymer, ethylene / ethyl acrylate copolymer, ethylene / vinyl acetate copolymer, silicone rubber, polydimethylsiloxane, chloroprene rubber, chlorinated polyethylene, polyvinyl chloride, copolymers of vinyl chloride and vinyl acetate, vinylidene chloride, ethylene and propylene, ionomer polyethylene terephthalate, butyl rubber, epichlorohydrin rubber, ethylene / vinyl alcohol copolymer, ethylene / vinyl acetate / vinyl alcohol terpolymer and ethylene / ethyleneoxyethanol copolymer. The active ingredient then diffuses through the outer polymer film in a release rate controlling step. The percentage height of the active ingredient included in such a parenteral composition depends on its specific properties and the needs of the experimenter.

[0081] Also of interest herein are lyophilized powders, which can be reconstituted for administration as solutions, emulsions and other mixtures. They can also be reconstituted and formulated as solids or gels.

[0082] Sterile lyophilized powder is prepared by dissolving the compound provided herein or its derivative in a suitable solvent. The solvent may include an excipient, which improves the stability of the powder or the reconstituted solution prepared by the powder or other pharmacological components. The excipients that can be used include, but are not limited to, antioxidants, buffers, and fillers. In some embodiments, the excipient is selected from dextrose, sorbitol, fructose, corn syrup, xylitol, glycerol, glucose, sucrose, and other suitable agents. The solvent may be included in a buffer at about neutral pH, such as citrate, sodium phosphate or potassium phosphate or other such buffers known to those skilled in the art. Subsequent sterile filtration of the solution and then freeze drying under standard conditions known to those skilled in the art provide the desired formulation. In some embodiments, the resulting solution is distributed into vials for freeze drying. Each vial will contain a single dose or multiple doses of the compound. The lyophilized powder can be stored under appropriate conditions, such as at about 4 ° C to room temperature.

[0083] Reconstitution of the lyophilized powder with water for injection provides a formulation for parenteral administration. For reconstitution, the lyophilized powder is added to sterile water or other suitable carrier. The exact amount depends on the compound selected. Such an amount can be determined empirically.

[0084] Topical mixtures are prepared as described for topical and systemic administration. The resulting mixture may be a solution, suspension, emulsion, or the like, and formulated as a cream, gel, ointment, emulsion, solution, elixir, lotion, suspension, tincture, paste, foam, aerosol, rinse, spray, suppository, bandage, skin patch, or any other formulation suitable for topical administration.

[0085] The compound or its derivative can be formulated into an aerosol for topical administration, such as by inhalation (see, e.g., U.S. Pat. Nos. 4,044,126, 4,414,209, and 4,364,923, which describe aerosols for delivering steroids useful for treating inflammatory diseases, particularly asthma). These preparations for administration to the respiratory tract can be in the form of an aerosol or solution for a nebulizer, or as a fine powder for insufflation, either alone or in combination with an inert carrier such as lactose. In such cases, in some embodiments, the particles of the preparation will have a mass median geometric diameter of less than 5 microns, and in other embodiments, a mass median geometric diameter of less than 10 microns.

[0086] Oral inhalation preparations suitable for the compound or derivative of inhalation include metered dose inhalers, dry powder inhalers and liquid preparations for use from a nebulizer or a metered dose liquid dispensing system. For both metered dose inhalers and dry powder inhalers, the crystalline form of the compound or derivative is the preferred physical form of the drug to confer longer product stability.

[0087] In addition to particle size reduction methods known to those skilled in the art, the crystalline particles of a compound or derivative can be produced using supercritical fluid processing, which provides significant advantages in producing such particles for inhalation delivery by producing respirable particles of desired size in a single step. (e.g., International Publication No. WO2005 / 025506). The controlled particle size of microcrystals can be selected to ensure that a considerable portion of a compound or derivative is deposited in the lungs. In some embodiments, these particles have a mass median aerodynamic diameter of about 0.1 micron to about 10 microns, have a mass median aerodynamic diameter of about 1 micron to about 5 microns in other embodiments, and have a mass median aerodynamic diameter of about 1.2 microns to about 3 microns in other embodiments.

[0088] Inert and non-flammable HFA propellants are selected from HFA 134a (1,1,1,2-tetrafluoroethane) and HFA 227e (1,1,1,2,3,3,3-heptafluoropropane), and are provided alone or in a ratio that matches the density of the crystal particles of the compound or derivative. The ratio is also selected to ensure that the product suspension avoids harmful sedimentation or cream (which can precipitate irreversible agglomerates) and instead promotes a loosely flocculated system that is easily dispersed when shaken. The loosely flocculated system is well considered to provide the best stability for the pMDI canister. Due to the nature of the formulation, the formulation does not contain ethanol and surfactant / stabilizer.

[0089] The compounds can be formulated for topical or external administration in the form of gels, creams and lotions, such as for external application to the skin and mucous membranes such as in the eye, and for application to the eye or for intracisternal or intraspinal administration. External administration is contemplated for transdermal delivery and also for application to the eye or mucous membranes, or for inhalation therapy. Nasal solutions of the active compound alone in combination with other excipients may also be administered.

[0090] For nasal administration, the formulation may comprise the esterified phosphonate compound dissolved or suspended in a liquid carrier, particularly an aqueous carrier, for aerosol administration. The carrier may comprise a solubilizing or suspending agent such as propylene glycol, a surfactant, an absorption enhancer such as lecithin or cyclodextrin, or a preservative.

[0091] Solutions, particularly those intended for ophthalmic use, can be formulated with appropriate salts as 0.01%-10% isotonic solutions, pH about 5-7.4.

[0092] Other routes of administration, such as transdermal patches, including iontophoretic and electrophoretic devices, and rectal administration are also contemplated herein.

[0093] Transdermal patches, including iontophoresis devices and electrophoresis devices, are well known to those skilled in the art. For example, such patches are disclosed in U.S. Pat. Nos. 6,267,983, 6,261,595, 6,256,533, 6,167,301, 6,024,975, 6,010715, 5,985,317, 5,983,134, 5,948,433 and 5,860,957.

[0094] For example, the dosage form for rectal administration is a rectal suppository, capsule and tablet for systemic effect. Rectal suppository used herein means a solid for insertion into the rectum, which melts or softens at body temperature, releasing one or more pharmacologically active ingredients or therapeutically active ingredients. The material used in the rectal suppository is a base or vehicle and an agent that improves the melting point. Examples of bases include a suitable mixture of monoglycerides, diglycerides and triglycerides of the monoglycerides, diglycerides and triglycerides of the monoglycerides, diglycerides and triglycerides of the monoglycerides, diglycerides and triglycerides of the monoglycerides, diglycerides and triglycerides of the monoglycerides, diglycerides and triglycerides of di ...

[0095] Compounds or derivatives thereof provided herein can also be formulated into specific tissues, receptors or other areas of the body of a subject to be treated. Many such targeting methods are well known to those skilled in the art. It is contemplated herein that all such targeting methods are used for compositions of the present invention. For non-limiting examples of targeting methods, see, for example, U.S. Patent Nos. 6,316,652, 6,274,552, 6,271,359, 6,253,872, 6,139,865, 6,131,570, 6,120,751, 6,071,495, 6,060,082, 6,048,736, 6,039,975, 6,004,534, 5,985,307, 5,972,366, 5,900,252, 5,840,674, 5,759,542 and 5,709,874.

[0096] In some embodiments, liposome suspensions, including liposomes targeting tissues, such as liposomes targeting tumors, may also be suitable as carriers. These can be prepared according to methods known to those skilled in the art. For example, liposome preparations can be prepared as described in U.S. Patent No. 4,522,811. In short, liposomes such as multilamellar vesicles (MLV) can be formed by drying phosphatidylcholine and phosphatidylserine (7:3 molar ratio) inside a flask. Add a solution of the compound provided herein in phosphate buffered saline (PBS) lacking divalent cations, and shake the flask until the lipid film is dispersed. Wash the resulting vesicles to remove unencapsulated compounds, granulate by centrifugation, and then resuspend in PBS.

[0097] The compound or derivative can be packaged as an article of manufacture comprising packaging material, a compound or derivative thereof provided herein that is effective for treating, preventing, or ameliorating one or more symptoms of the above-mentioned diseases or disorders within the packaging material, and a label indicating that the compound or composition or derivative thereof is used to treat, prevent, or ameliorate one or more symptoms of the above-mentioned diseases or disorders.

[0098] Articles provided herein include packaging materials. Packaging materials for packaging products are well known to those skilled in the art. See, for example, U.S. Patent Nos. 5,323,907, 5,052,558 and 5,033,252. Examples of packaging materials include, but are not limited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, bottles and any packaging materials suitable for selected formulations and intended modes of administration and treatment. The wide range of formulations of the compounds and compositions provided herein are expected to be used for a variety of treatments for any disease or disorder described herein.

[0099] In human therapeutics, the doctor will determine the most suitable dosage regimen according to preventive treatment or therapeutic treatment and according to the age, body weight, disease stage and other factors unique to the subject to be treated. In other embodiments, the composition should provide a dosage of from about 0.0001mg compound / kg body weight / day to about 70mg compound / kg body weight / day. The dosage unit form is prepared to provide a combination of active ingredients or essential ingredients from about 0.01mg, 0.1mg or 1mg to about 500mg or about 1000mg per dosage unit form, and in some embodiments from about 10mg to about 500mg of active ingredients or a combination of essential ingredients.

[0100] The amount of active ingredient in the formulations provided herein that will be effective in preventing or treating a disorder or one or more symptoms thereof will vary with the nature and severity of the disease or condition and the route of administration of the active ingredient. The frequency and dosage will also vary according to factors unique to each subject, depending on the specific therapy (e.g., therapeutic or prophylactic agent) being administered, the severity of the disorder, disease or condition, the route of administration, and the age, weight, response, and previous medical history of the subject.

[0101] Exemplary dosages of the formulations include milligram or microgram amounts of active compound per kilogram of subject (e.g., from about 1 microgram / kg to about 50 mg / kg, from about 10 microgram / kg to about 30 mg / kg, from about 100 microgram / kg to about 10 mg / kg, or from about 100 microgram / kg to about 5 mg / kg).

[0102] In some cases, it may be necessary to use dosages of the active ingredient outside the ranges disclosed herein, as will be apparent to one of ordinary skill in the art. In addition, it should be noted that the clinician or treating physician will know how and when to interrupt, adjust or terminate therapy in conjunction with the subject's response.

[0103] Different therapeutically effective amounts can be applicable to different diseases and conditions, which will be readily known by those of ordinary skill in the art. Similarly, the amount sufficient to prevent, manage, treat or improve such a disorder but not sufficient to cause the adverse reactions associated with the compositions provided herein or the amount sufficient to reduce the adverse reactions associated with the compositions provided herein is also covered by the dosage and administration frequency scheme described above. In addition, when a subject is administered multiple doses of the compositions provided herein, not all doses need to be the same. For example, the dose administered to the subject can be increased to improve the preventive effect or therapeutic effect of the composition, or the dose can be reduced to reduce one or more side effects that a particular subject is experiencing.

[0104] In certain embodiments, administration of the same formulation provided herein can be repeated, and administrations can be separated by at least 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days, 3 months, or 6 months. BRIEF DESCRIPTION OF THE DRAWINGS

[0106] Embodiments of the present invention are further described below with reference to the accompanying drawings, in which:

[0107] Figure 1 HPLC analysis of mesembrine is shown;

[0108] Figure 2 The 1 H NMR spectrum;

[0109] Figure 3 The 1 H / 13 C HSQC NMR spectrum;

[0110] Figure 4 The IR spectrum of mesembrine is shown;

[0111] Figure 5 XRPD of solids from hydrochloric acid wet (A), dry (B) and after 40°C / 75%RH (C) are shown;

[0112] Figure 6 TG / DSC analysis of the solid of hydrochloride salt mode 1 is shown;

[0113] Figure 7 The solid of hydrochloride salt model 1 in d6-DMSO is shown. 1 H NMR spectrum;

[0114] Figure 8 An exemplary HPLC chromatogram of solids in ethanol from experiments using hydrochloric acid is shown;

[0115] Fig. 9 Shown are XRPDs of solids from benzenesulfonic acid wet (A), dry (B), and after 40°C / 75%RH (C);

[0116] Fig.10 TG / DSC analysis of the solid of benzenesulfonate mode 1 is shown;

[0117] Fig.11 The solid of benzenesulfonate salt model 1 in d6-DMSO is shown. 1 H NMR spectrum;

[0118] Fig.12 An exemplary HPLC chromatogram of a solid from the benzenesulfonate salt pattern 1 of MEK is shown;

[0119] Fig.13 Shown are XRPDs of solids from fumaric acid wet (A), dry (B), and after 40°C / 75%RH (C);

[0120] Fig.14 TG / DSC analysis of the solids of fumarate mode 1 (A), fumarate mode 2 (B), and fumarate mode 3 (C) are shown;

[0121] Fig.15 Solids of fumarate pattern 1 (A), fumarate pattern 2 (B) and fumarate pattern 3 (C) in d6-DMSO are shown. 1 H NMR spectrum;

[0122] Fig.16 Exemplary HPLC chromatograms of solids of fumarate pattern 1 (A), fumarate pattern 2 (B), fumarate pattern 3 (C) from THF are shown;

[0123] Fig.17 Polarized light microscopy of hydrochloride salt mode 1 (A), benzenesulfonate salt mode 1 (B), and fumarate salt mode 1 and fumarate salt mode 4 (C) are shown;

[0124] Fig.18 XRPD of the solid (A) and the enlarged dried solid (B) from the besylate salt pattern 1 are shown;

[0125] Fig.19 XRPD of the lyophilized besylate salt is shown;

[0126] Fig. 20 XRPD of benzenesulfonate salt pattern 2 is shown;

[0127] Fig.21 A comparison of the two crystalline besylate salt forms is shown;

[0128] Fig. 22 Shown are the mean total concentrations of mesembryanthemum benzyl salt following IP administration at 10.0 mg / kg to male C57B1 / 6J mice; and

[0129] Fig.23 Shown are the mean total free base concentrations following IP administration at 10.0 mg / kg to male C57Bl / 6J mice.

[0130] definition

[0131] Various definitions are made throughout this document. Most words have the meanings that a person skilled in the art would attribute to these words. Words specifically defined below or elsewhere in this document have the meanings provided as a whole in the context of the present invention and as generally understood by a person skilled in the art.

[0132] The term "substantially crystalline" means at least about 50% crystalline and ranges up to about 100% crystalline. The invention provides salts in at least about 50% crystalline, at least about 60% crystalline, at least about 70% crystalline, at least about 80% crystalline, at least about 90% crystalline, at least about 95% crystalline, at least about 98% crystalline, or at least about 100% crystalline form.

[0133] The degree of crystallinity or percentage of crystallinity can be determined by a skilled person using X-ray powder diffraction (XRPD). Other techniques such as solid-state nuclear magnetic resonance (NMR), FT-IR, Raman spectroscopy, differential scanning calorimetry (DSC) and microcalorimetry can also be used.

[0134] The crystalline form of the salt of the present invention may be in the form of a solvate, including but not limited to a hydrate (eg, a monohydrate) or other forms (eg, in the form of an anhydrous compound).

[0135] "Subject", "individual" or "patient" are used interchangeably herein and refer to a vertebrate, preferably a mammal. Mammals include, but are not limited to, murines, rodents, great apes, humans, farm animals, sport animals, and pets.

[0136] In some embodiments, "treating" or "treatment" of any disease or disorder refers to improving the disease or disorder (i.e., preventing or reducing the development of the disease or at least one of its clinical symptoms). Treatment may also be considered to include preemptive or prophylactic administration to improve, prevent or prevent the development of the disease or at least one clinical symptom. Treatment may also refer to reducing the severity and / or duration of one or more symptoms of a disease or disorder. In additional features, the treatment provided has a lower likelihood of long-term side effects over many years. In other embodiments, "treatment" or "treatment" refers to improving at least one physical parameter that the patient may not be able to discern. In yet another embodiment, "treatment" or "treatment" refers to physically suppressing a disease or disorder (e.g., stabilization of identifiable symptoms), physiologically suppressing a disease or disorder (e.g., stabilization of physical parameters), or both. In yet other embodiments, "treatment" or "treatment" refers to delaying the onset of a disease or disorder.

[0137] "Therapeutically effective amount" means the amount of a compound that, when administered to a patient for treating a disease, is sufficient to effect such treatment of the disease. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity, and the age, weight, absorption, distribution, metabolism and excretion, etc., of the patient to be treated.

[0138] "Vehicle" refers to a diluent, excipient, or carrier with which a compound is administered to a subject. In some embodiments, the vehicle is pharmaceutically acceptable.

[0139] "Active ingredient" or "active pharmaceutical ingredient" or "API" refers to the novel mesembrine salt of the present invention.

[0140] Mesembrine is a chiral alkaloid having the CAS name: (3aS-cis)-3a-(3,4-dimethoxyphenyl)octahydro-1-methyl-6H-indol-6-one. It exists naturally as a cis isomer, but can also be synthesized as a trans isomer or as a racemate. The following structure represents the structural configuration of mesembrine. The mesembrine of the present invention can exist as a cis isomer, a trans isomer, or a racemate of both.

[0141] DETAILED DESCRIPTION OF THE INVENTION

[0143] The following examples describe the development stages of the highly soluble and characterized mesembrine salts of the present invention. Applicants have determined that the solubility of mesembrine in aqueous systems is poor, and therefore means that the use of this compound as an active pharmaceutical ingredient in pharmaceutical presentations is limited by its lack of solubility. A new salt form has been produced that is both soluble and stable, and therefore can be used in the preparation of medicaments and supplements.

[0144] Mesembrine can be isolated from extracts of Mesembryanthemum contortum or can be chemically synthesized using the method described by Wang et al., 2016.

[0145] Example 1: Characterization of mesembryrine

[0146] Materials and methods

[0147] The mesembrine used in the following series of experiments was isolated from an extract of Mesembryanthemum contortum and the compound was characterized by several different methods in order to determine the purity of the starting material and compare it to the subsequently formed salt.

[0148] HPLC analysis was performed to determine the chemical purity of mesembrine and provide information on any impurities. The following conditions were used:

[0149] Column: Waters Acquity BEH C18 1.7μm 150mm×2.1mm

[0150] Column temperature: 33°C

[0151] Autosampler temperature: 25°C

[0152] UV wavelength: 280nm

[0153] Injection volume: 5 μL

[0154] Flow rate: 0.29mL / min

[0155] Mobile phase A: 0.1% NH4 in H2O

[0156] Mobile phase B: methanol: water 20% v / v: 80% v / v

[0157] Gradient Program:

[0158] Time (minutes) Mobile phase A[%] Mobile phase B[%] 0.00 80 20 2.0 80 20 4.0 60 40 6.0 50 50 9.0 50 50 14.0 10 90 17.0 10 90 17.1 80 20 23.0 80 20

[0159] conduct 1 H NMR and 1 H / 13 C NMR analysis was performed to determine the chemical structure of the mesembrine used. NMR experiments were performed on a Bruker AVIIIHD spectrometer equipped with a DCH cryoprobe operating at 500.12 MHz for protons. Experiments were performed in deuterated DMSO and each sample was prepared to a concentration of approximately 10 mM.

[0160] Infrared (IR) spectra were also recorded to obtain a baseline of the starting mesembrine material. The following conditions were used. IR spectroscopy was performed on a Bruker ALPHA P spectrometer. Sufficient material was placed onto the center of the spectrometer plate and the spectrum was obtained using the following parameters:

[0161] Resolution: 4cm -1

[0162] Background scan time: 16 scans

[0163] Sample scanning time: 16 scans

[0164] Data collection: 4000cm -1 Up to 400cm -1

[0165] Result spectrum: Transmittance

[0166] Software: OPUS Version 6

[0167] Finally, Karl Fischer (KF) analysis was performed in order to determine the water content of the mesembrine samples used. The following conditions were used. The solids were analyzed using the evaporator method or using the external dissolution method:

[0168] Evaporator Method: Approximately 10 mg of material was weighed into a 10 mL glass vial and sealed tightly with a screw cap. The samples were analyzed for water content using an InMotion KFoven autosampler at 150 °C. The samples were run in duplicate and the average moisture content was reported.

[0169]

[0170] External dissolution method: A known mass of the sample to be analyzed is dissolved in a known mass of methanol. Before analysis, a solvent blank measurement is performed. Approximately 1 mL of methanol is injected into the titration cell of a Mettler Toledo C30 Compact Titrator and the syringe is reweighed to determine the weight of methanol added.

[0171] For sample analysis, approximately 1 mL of solution is injected into the titration cell, the syringe is reweighed, and the weight of the added solution is entered on the instrument. Once complete dissolution is observed, the titration is started and the water content is automatically calculated by the instrument. The measurement is performed in duplicate and the average water content is reported.

[0172] result

[0173] Figure 1 HPLC analysis of the mesembrine starting material and impurity peaks found in the sample are shown. The purity of mesembrine was determined to be 91.17% by HPLC with an HPLC impurity area of ​​8.83%.

[0174] Figure 2 Detailed 1 H NMR spectrum confirmed that the spectrum was consistent with the chemical structure of mesembrine. There was a residual content of 5.0 wt% DCM, which was equivalent to 0.2 equivalents of DCM. No residual methanol was observed.

[0175] Figure 3 Detailed 1 H / 13 C HSQC NMR spectrum analysis showed that the sample was consistent with mesembrine.

[0176] Figure 4 The IR spectrum of the mesembrine used is detailed and KF analysis determined the water content of the received material to be 1.1% (w / w).

[0177] in conclusion

[0178] Characterization of Mesembrine It was determined that the samples used for salt formation evaluation were of acceptable purity, matched the expected chemical structure of mesembrine, and contained acceptable levels of water.

[0179] Therefore, the mesembrine samples were suitable for additional experiments to evaluate the salt forming ability.

[0180] Example 2: Solubility of Mesembrine

[0181] Materials and methods

[0182] About 360 mg of mesembrine was weighed and dissolved in 5 mL of dichloromethane (DCM). After dissolution, 278 μL of the solution was aliquoted into pre-peeled vials and the solvent was allowed to evaporate at ambient conditions for 1 h. The vials were then dried at 20 °C under vacuum for about 22 h. After drying, the vials were reweighed to determine the mass of mesembrine in each vial.

[0183] Miscibility studies were performed by adding aliquots of the desired solvent system to each vial. The following aliquot sizes were used: Aliquot No. 1-10—20 μL; 11-16—50 μL; 17-19—200 μL; 20—750 μL.

[0184] Between additions, the experiment was heated to 40°C for approximately 5 minutes to promote miscibility / solubility. Additions were continued until miscibility was observed, or approximately 100 volumes (2 mL) had been added.

[0185] result

[0186] Table 2.1 below details the approximate solvent miscibility / solubility of mesembrine in 18 different solvents tested.

[0187] Table 2.1 Solubility of mesembrine in various solvents

[0188]

[0189]

[0190] As can be seen from Table 2.1, the solubility of mesembrine in heptane and water is very poor, while it has reasonable solubility in ethanol and other organic solvents.

[0191] in conclusion

[0192] Many organic solvents are classified as toxic or carcinogenic and are therefore unsuitable for use as diluents in pharmaceutical compositions.

[0193] The low solubility of mesembrine in water means that the compound would be difficult to formulate into a pharmaceutical composition since only a small amount of the compound can be dissolved in water.

[0194] In determining In the study of toxicity, is an extract of Mesembryanthemum contortum containing approximately 20% mesembrine, and the no observed adverse effect level (NOAEL) was determined to be 420 mg, which was extrapolated to a 70 kg human (Murbach et al., 2014).

[0195] Thus, a dose of about 84 mg mesembrine (20% of 420 mg) would require about 10 ml of water to form a miscible solution, an amount far greater than the standard 00 capsule size used for drug delivery, which has a fill volume of 0.9 ml.

[0196] Example 3: Primary Salt Formation Assessment

[0197] Materials and methods

[0198] Primary salt formation was evaluated using reactions with 12 counterions in six solvent systems. Multiple counterions were selected based on their pKa and as a result of their molecular weight, toxicity, and diversity. The counterions and solvents used for the primary salt formation evaluation are detailed in Table 3.1 below.

[0199] Table 3.1 Counterion and solvent details

[0200]

[0201] Prepare a 200 mg / mL stock solution of mesembrine in the desired solvent system. Separately, dispense (weigh or measure using an automated pipette) 1.1 equivalents of the counterion into a 72 x 2 mL vial and add a stir bar.

[0202] To each vial, add 100 μL of the appropriate solvent system to dissolve / suspend the counterion. At the specified upper temperature limit, add 100 μL of the mesembryrine stock solution in the correct solvent system to each vial.

[0203] The experiment was then temperature cycled at 0.1°C / min between the upper temperature limit (specified in Table 3.1) and 5°C, with a hold at the upper temperature limit for 1 h and a hold at 5°C for approximately 72 h.

[0204] After temperature cycling, the solids were isolated from the experiment at 5°C and analyzed by XRPD. Any experiment that did not contain solids was performed with the addition of antisolvent and temperature cycling continued as described above for an additional approximately 24 h.

[0205] The solid was dried at 40°C under vacuum for about 24 h and then re-analyzed by XRPD.

[0206] The solid was then stored at 40°C / 75% RH for approximately 24 h and then reanalyzed by XRPD.

[0207] Potential salt forms were also analyzed by TGA / DSC.

[0208] Additional experiments were performed for selected counterions (numbers 2, 3, 4 and 6 from Table 3.1), but no solids of potential salts of mesembrine base were produced from the initial set of salt formations. The upper temperature limit was lowered from 40°C to 25°C because degradation was observed in these during the initial experiments, as detailed below and in Table 3.2.

[0209] Prepare a 200 mg / mL stock solution of mesembrine in MEK. Separately, dispense (weigh or measure using an automated pipette) 1.1 equivalents of the counterion into 4 x 2 mL vials and add a stir bar.

[0210] To each vial, 100 μL of MEK was added to dissolve / suspend the counterions. To each vial, 100 μL of mesembryrine stock solution was added at 25°C.

[0211] The experiment was then temperature cycled between 25°C and 5°C at 0.1°C / min with a 1 h hold at 25°C and a 72 h hold at 5°C. After temperature cycling, antisolvent additions were made at 5°C in 100 μL aliquots until a visual change was observed or 1 mL of heptane had been added.

[0212] The experiment was temperature cycled as described above for an additional approximately 24 h.

[0213] Table 3.2 Counterions and solvent details used for additional salt formation evaluations

[0214]

[0215] result

[0216] A primary salt formation evaluation from reactions with 12 counterions in six different solvent systems was determined. The results of the primary salt screening are summarized in Tables 3.3 to 3.5 below.

[0217] Table 3.3 Summary of wet XRPD analysis from primary formation assessment

[0218]

[0219]

[0220]

[0221] Table 3.4 Summary of dry XRPD analysis from primary formation assessment

[0222]

[0223]

[0224] Table 3.5 Summary of 40°C / 75%RH XRPD analysis from primary formation evaluation

[0225]

[0226]

[0227] Apart from Figures 5 to 16 In addition, the properties of the hydrochloride, benzenesulfonate and fumarate salts are summarized and reported in Table 3.6 below.

[0228] Table 3.6 Summary of salt properties

[0229]

[0230]

[0231]

[0232] As can be seen from the table above, no solids were isolated for the following counterions: sulfuric acid, p-toluenesulfonic acid, methanesulfonic acid, maleic acid, and benzoic acid. Additional experiments were performed for these counterions as described in the methodology section, however, no solids were observed after temperature cycling and addition of antisolvent.

[0233] The results from the reactions with each acid that formed solids are summarized in more detail below.

[0234] hydrochloric acid:

[0235] When hydrochloric acid was used, the following results and observations were obtained.

[0236] Solids of potential hydrochloride salt pattern 1 were isolated from five solvent systems: THF, ethyl acetate, ethanol, MEK, and acetonitrile. XRPD analysis showed that hydrochloride salt pattern 1 was still present after drying at 40°C under vacuum and after storage at 40°C / 75%RH, as shown in Figure 2. Figure 5 shown.

[0237] TG / DSC analysis of the solid of the hydrochloride salt Mode 1 isolated from ethyl acetate showed a weight loss of 2.1 wt% between 20°C and 191°C. An endothermic event was observed with an onset temperature of 194°C and a peak temperature of 208°C, as shown in FIG. Figure 6 shown.

[0238] Separation of the hydrochloride salt of Model 1 solid from ethanol 1 The H NMR spectrum is consistent with the chemical structure of mesembrine, with an additional signal at 11.39 ppm, consistent with salt formation. The residual ethanol content is 0.5% wt, as Figure 7 shown.

[0239] HPLC analysis of the dried solid from ethanol showed a chemical purity of 92.2% area (reference: input purity was 91.2% area), as Figure 8 shown.

[0240] HPLC analysis of the filtered mother liquor from the experiment in ethyl acetate indicated a chemical purity of 40.3% area.

[0241] Benzenesulfonic acid:

[0242] The results of experiments using benzenesulfonic acid are summarized below.

[0243] Solids of potential benzenesulfonate salt pattern 1 were isolated from five solvent systems: THF, ethyl acetate, ethanol, MEK and acetonitrile. After drying at 40°C under vacuum and after storage at 40°C / 75%RH, the XRPD pattern remained, as shown in Figure 2. Fig. 9 shown.

[0244] TG / DSC analysis of the dried solid of benzenesulfonate salt model 1 isolated from ethyl acetate showed a weight loss of 1.1 wt% between 20°C and 196°C. In the DSC thermogram, an endothermic event was observed with an onset temperature of 138°C and a peak temperature of 149°C, as shown in FIG. Fig.10 shown.

[0245] Separation of solid benzenesulfonate model 1 from ethanol 1 The H NMR spectrum was consistent with the structure of mesembrine, with an additional signal at 9.92 ppm, indicating salt formation. Benzenesulfonic acid was also observed in the NMR spectrum and was present in an amount equal to 1.3 equivalents. A residual ethanol content of 0.37 wt% was observed, as shown in Fig.11 shown.

[0246] HPLC analysis of the dried solids from the experiments in MEK indicated a chemical purity of 91.46% area (reference: input purity was 91.2% area), as Fig.12 shown.

[0247] HPLC analysis of the mother liquor from the experiment in ethyl acetate indicated a chemical purity of 44.21% area.

[0248] Phosphoric acid:

[0249] The results of experiments using phosphoric acid are summarized below.

[0250] The solids isolated from THF and MEK were poorly crystalline and were labeled as potential phosphate mode 1. After drying at 40°C under vacuum, the poorly crystalline phosphate mode 1 solids remained. After storage at 40°C / 75%RH, the solids isolated from MEK had deliquesced but resolidified at high humidity. For both materials, a conversion to phosphate mode 3 was observed.

[0251] The solid isolated from the experiment in ethyl acetate was amorphous and remained amorphous after drying.After 24 h at 40°C / 75%RH, conversion to phosphate mode 3 was observed.

[0252] The solid isolated from ethanol was poorly crystalline and was labeled as potential phosphate mode 2. After drying at 40°C under vacuum, the poorly crystalline phosphate mode 2 solid remained, and after storage at 40°C / 75%RH, conversion to phosphate mode 3 was observed.

[0253] HPLC analysis of the dried solid of Pattern 1, the phosphate salt from THF, showed a chemical purity of 93.4% area.HPLC analysis of the dried solid of Pattern 2, the phosphate salt from ethanol, showed a chemical purity of 92.67% area.

[0254] The purity of the mother liquor from the experiment in MEK was 65.31% area.

[0255] TG / DSC analysis of the solid of Phosphate Mode 1 from THF showed a weight loss of 10.5 wt% between 20° C. and 211° C. In the DSC thermogram, one endothermic event was observed with an onset temperature of 82° C. and a peak temperature of 113° C.

[0256] Separation of phosphate pattern 1 from THF 1 The H NMR spectrum was consistent with the structure of mesembrine. A residual THF content of 2.3 wt% was observed. 31 P NMR analysis indicated the presence of phosphate groups within the material.

[0257] TG / DSC analysis of the solid of Mode 2, the phosphate salt from ethanol, showed a weight loss of 9.0 wt% between 20° C. and 201° C. In the DSC thermogram, no endothermic events were observed.

[0258] Separation of Phosphate from Ethanol Model 2 1 The H NMR spectrum was consistent with the structure of mesembrine. A residual ethanol content of 1.6 wt% was observed. The 31 P NMR spectrum was consistent with the presence of phosphate groups in the material.

[0259] TG / DSC analysis of the solid of Phosphate Mode 3 obtained from THF after storage at 40° C. / 75% RH showed a weight loss of 1.7 wt% between 20° C. and 119° C., followed by a second weight loss of 5.3 wt% between 119° C. and 199° C., with a final weight loss of 7.5 wt% observed between 199° C. and 300° C. In the DSC thermogram, there was one endothermic event with an onset temperature of 103° C. and a peak temperature of 113° C. In the DSC thermogram, there were also two exothermic events with onset temperatures of 167° C. and 218° C., and peak temperatures of 171° C. and 230° C.

[0260] Phosphate Mode 3 isolated from MEK after storage at 40°C / 75%RH 1 The H NMR spectrum was consistent with the structure of mesembrine. No residual solvent was detected. The 31P NMR spectrum indicated the presence of phosphate groups within the material.

[0261] (+)-L-Tartaric acid:

[0262] The results of experiments using (+)-L-tartaric acid are summarized below.

[0263] Solids of potential tartrate mode 1 were isolated from ethanol and MEK, but were poorly crystalline and isolated from acetonitrile. After drying under vacuum, solids of tartrate mode 1 remained in the solids from ethanol, MEK and acetonitrile. After exposure to 40°C / 75%RH, the solids from ethanol and MEK deliquesced and resolidified when removed from the humidity chamber. These solids were amorphous. The solids from acetonitrile remained as tartrate mode 1, but the crystallinity was reduced.

[0264] Tartrate salt Pattern 1 solids were also observed in the solids isolated from THF after drying under vacuum at 40 °C.

[0265] The solid of tartrate salt Model 1 isolated from THF had a chemical purity of 91.70% area by HPLC (reference: input purity was 91.2% area).

[0266] The mother liquor used for the experiments in acetonitrile had a chemical purity of 34.80% area.

[0267] TG / DSC analysis of the solid of the tartrate salt Mode 1 from ethanol showed a weight loss of 2.3 wt% between 20° C. and 164° C., followed by a second weight loss of 35.9 wt% between 164° C. and 301° C. Two endothermic events were observed in the DSC thermogram with onset temperatures at 126° C. and 171° C., and peak temperatures at 141° C. and 192° C.

[0268] Isolation of the solid tartrate salt of Model 1 from acetonitrile 1 The H NMR spectrum was consistent with the structure of mesembrine. Tartaric acid was observed with a content equal to 1.1 equivalents. No residual acetonitrile was observed.

[0269] Fumaric Acid:

[0270] The results of experiments using fumaric acid are summarized below.

[0271] The solid isolated from THF was poorly crystalline and was labeled as a potential fumarate salt, Mode 1. After drying at 40°C under vacuum, this poorly crystalline Mode 1 material still existed. After storage at 40°C / 75%RH, an increase in crystallinity was observed and the material remained Mode 1.

[0272] The solid isolated from ethyl acetate was crystalline and was labeled as potential fumarate pattern 2. After drying under vacuum at 40°C, a mixture of fumarate pattern 1 and fumarate pattern 2 was observed by XRPD. After storage at 40°C / 75%RH, conversion to fumarate pattern 1 was observed.

[0273] Fumarate Mode 2 solids were also observed from ethanol which remained after drying.After exposure to 40°C / 75%RH, a conversion to fumarate Mode 1 was observed with an additional peak.

[0274] A poorly crystalline solid of fumarate mode 1 was observed from MEK and held after drying under vacuum at 40° C. Exposure to 40° C. / 75% RH resulted in conversion to a mixture of fumarate mode 1 and fumarate mode 4.

[0275] The solid isolated from acetonitrile was crystalline and labeled as fumarate mode 3 and persisted after drying under vacuum at 40° C. Exposure to 40° C. / 75% RH resulted in conversion to a mixture of fumarate mode 1 and fumarate mode 4.

[0276] The XRPD of salt pattern 1, salt pattern 2 and salt pattern 3 are shown in Fig.13 middle.

[0277] TG / DSC analysis showed that the solid of fumarate salt mode 1 isolated from THF showed a weight loss of 4.3 wt% between 20° C. and 168° C., followed by a second weight loss of 31.2 wt% between 168° C. and 336° C. An endothermic event was observed in the DSC thermogram with an onset temperature of 143° C. and a peak temperature of 153° C.

[0278] Isolation of fumarate pattern 1 from THF 1The H NMR spectrum is consistent with the structure of mesembrine. The fumaric acid content is equal to 1.5 equivalents (30.7 wt%). The residual THF content is 1.7 wt%.

[0279] TG / DSC analysis showed that the solid of fumarate salt mode 2 isolated from ethanol showed a weight loss of 5.7 wt% between 72° C. and 159° C., and a second weight loss of 31.1 wt% between 159° C. and 330° C. There were two endothermic events in the DSC thermogram with onset temperatures of 141° C. and 200° C., and peak temperatures of 152° C. and 205° C.

[0280] Separation of fumarate from ethanol Model 2 1 The H NMR spectrum is consistent with the structure of mesembrine. The fumaric acid content is equal to 1.3 equivalents (27.6 wt%). The residual ethanol content is 2.9 wt%.

[0281] TG / DSC analysis of the solid of fumarate salt pattern 3 isolated from acetonitrile showed a weight loss of 2.9 wt% between 112° C. and 175° C., followed by a second weight loss of 39.1 wt% between 175° C. and 304° C. Two endothermic events were observed with onset temperatures of 139° C. and 186° C., and peak temperatures of 147° C. and 207° C.

[0282] Separation of fumarate mode 3 from acetonitrile 1 The H NMR spectrum was consistent with the structure of mesembrine. The fumaric acid content was equal to 1.4 equivalents. No residual acetonitrile was observed.

[0283] TG / DSC analysis of the solid of the mixture of fumarate mode 1 and fumarate mode 4 isolated from acetonitrile after storage at 40° C. / 75% RH showed a weight loss of 7.7 wt % between 20° C. and 170° C., and a second weight loss of 30.6 wt % between 170° C. and 303° C. In the DSC thermogram, an endothermic event was observed with an onset temperature of 137° C. and a peak temperature of 148° C.

[0284] Mixture of Fumarate Mode 1 + Fumarate Mode 4 isolated from MEK after exposure to 40°C / 75%RH 1 The H NMR spectrum was consistent with the chemical structure of mesembrine. The fumaric acid content was equal to 1.2 equivalents. No residual MEK was observed.

[0285] TG / DSC of salt mode 1 to salt mode 3 is shown in Fig.14 and salt mode 1-salt mode 3 1 H NMR spectrum is shown in Fig.15 middle.

[0286] HPLC analysis showed a chemical purity of 90.36% area for the solid of fumarate pattern 1 isolated from THF. A chemical purity of 94.35% area for the solid of fumarate pattern 2 isolated from ethanol. A chemical purity of 96.47% area for the solid of fumarate pattern 3 isolated from acetonitrile. A chemical purity of 93.1% area for the solid of a mixture of fumarate pattern 1 and fumarate pattern 4 isolated from MEK after exposure to 40°C / 75%RH (reference: input purity was 91.2% area), as shown in Figure 5. Fig.16 shown.

[0287] Succinic acid

[0288] The results of the experiments using succinic acid are summarized below.

[0289] The solid isolated from MEK was crystalline and was labeled as potential succinate pattern 1. This pattern persisted after drying at 40°C under vacuum, however after exposure to 40°C / 75% RH, a transformation to an amorphous material was observed.

[0290] The solid of potential succinate mode 1 had a chemical purity of 89.2% by area.

[0291] TG / DSC analysis of potential succinate mode 1 showed a weight loss of 2.5 wt% between 20° C. and 127° C., followed by a second weight loss of 56.0 wt% between 127° C. and 316° C. In the DSC thermogram, two endothermic events were observed with onset (and peak) temperatures of 74° C. (83° C.) and 152° C. (161° C.).

[0292] Potential succinate model 1 1 H NMR analysis was consistent with the chemical structure of mesembrine. A succinic acid content of 35.9 wt% (1.9 eq.) was observed. No residual solvent was detected.

[0293] in conclusion

[0294] The data detailed above demonstrate that the salts formed using the counterions hydrochloric acid, benzenesulfonic acid, and fumaric acid are crystalline anhydrous solids with high potential melting temperatures and are capable of exhibiting physical stability.

[0295] Therefore, these counterions were selected for secondary salt formation evaluation.

[0296] Table 3.1 details the pKa of various counterions tested in the salt formation evaluation. It is generally believed that proton transfer requires a difference of at least 2 pKa units between acid and base, and therefore the stronger the acid (lower pKa), the more likely it is to form a salt. Therefore, it is surprising that, in addition to hydrochloric acid, stronger acids such as sulfuric acid, p-toluenesulfonic acid, and methanesulfonic acid were unable to form salts with mesembrine.

[0297] Example 4: Secondary Salt Formation Evaluation

[0298] Materials and methods

[0299] Hydrochloride Mode 1:

[0300] The following procedure was used for scale-up of hydrochloride salt model 1. About 0.5 g of mesembrine was dissolved in 2.5 mL of ethanol. 1.1 equivalents of HCl (0.156 mL) was dissolved in 2.5 mL of ethanol and added to the mesembrine solution at 25°C (initial concentration: 100 mg / mL).

[0301] The experiment was stirred for about 1 h and then cooled at 0.1 °C / min to 5 °C. After about 18 h at 5 °C, 200 μL was sub-sampled and centrifuged, and the solids were analyzed by XRPD.

[0302] The solid was mainly amorphous, so the experiment was heated to 25°C over 10 minutes and 15 mL of heptane was added over 30 minutes. The experiment was then cooled to 5°C at 0.1°C / min and held at 5°C. After about 2 hours at 5°C, 200 μL was subsampled and centrifuged, and the solid was analyzed by XRPD. The mother liquor was biphasic.

[0303] The solid was poorly crystalline, so the experiment was temperature cycled at 0.1°C / min between 25°C and 5°C, with a hold at 25°C for 1 h and a hold at 5°C for about 18 h. At 5°C, the solid was isolated by Buchner filtration and analyzed by XRPD. The solid was dried at 40°C under vacuum for about 72 h and then further characterized.

[0304] Benzenesulfonate mode 1:

[0305] The following procedure was used for scale-up of besylate model 1.

[0306] About 0.5 g of mesembrine was dissolved in 2.5 mL of MEK. 1.1 equivalents of benzenesulfonic acid (306.78 mg) was dissolved in 2.5 mL of MEK and added to the mesembrine solution at 25° C. (concentration: 100 mg / mL).

[0307] The experiment was stirred for about 1.5 h. The experiment was then cooled to 5°C at 0.1°C / min and held at 5°C for about 18 h. A subsample (200 μL) was taken and centrifuged, and the solid analyzed by XRPD.

[0308] The solid was isolated by Buchner filtration and dried under vacuum at 40 °C for about 18 h before being further characterized.

[0309] Fumarate Mode 1 + Fumarate Mode 4 (mixture):

[0310] The following procedure was used for the scale-up of fumarate mode 4.

[0311] About 0.5 g of mesembrine was dissolved in 2.5 mL of MEK. 1.1 equivalents of fumaric acid (222 mg) was dissolved in 2.5 mL of MEK, and the solution of mesembrine (concentration: 100 mg / mL) was added dropwise to the fumaric acid at 25°C.

[0312] The experiment was stirred at 25°C for about 1 h. The experiment was then cooled to 5°C at 0.1°C / min and held at 5°C for about 18 h. A subsample (200 μL) was taken and centrifuged, and the solid analyzed by XRPD.

[0313] The slurry was very thick, so an additional 2 mL of MEK was added to improve slurry fluidity, and stirring was continued for about 30 min. The solid was isolated by Buchner filtration and dried under vacuum at 40° C. for about 18 h. The solid was analyzed by XRPD and then transferred to 40° C. / 75% RH.

[0314] After 5 days at 40°C / 75%RH, the solids were removed and further characterized.

[0315] The solids were subsampled after 1, 2 and 5 days for XRPD analysis.

[0316] Re-preparation of fumarate salt model 4:

[0317] The following general procedure was used for the re-preparation of the fumarate salt model 4.

[0318] About 103 mg of mesembrine was weighed into a vial and dissolved in 0.52 mL of MEK at 25° C. 1.1 equivalents of fumaric acid were suspended in 0.52 mL of MEK. The mesembrine solution was added to the fumaric acid at 25° C. and stirred.

[0319] The experiment was stirred at 25°C for 1.5 h and then cooled to 5°C at 0.1°C / min and held at 5°C for about 18 h before separation. The solid was separated by centrifugation. The solid was separated and dried under vacuum at 40°C for about 24 h.

[0320] result

[0321] Hydrochloride Mode 1:

[0322] The solid of hydrochloride salt pattern 1 was isolated in 48% yield with a chemical purity of 90.5% area. KF indicated a water content of 0.4% w / w. CAD indicated a chloride content of 0.9 equivalents, indicating that the material was the monohydrochloride salt.

[0323] The solid is light beige (BE10) relative to the Sigma Aldrich color chart.

[0324] TG / DSC analysis showed a weight loss of 1.7 wt% between 20° C. and 160° C., followed by a weight loss of 21.7 wt% between 162° C. and 273° C. An endothermic event was observed with an onset temperature of 188° C. and a peak temperature of 200° C.

[0325] DSC analysis showed an endothermic event with an onset temperature of 182°C and a peak temperature of 197°C.

[0326] VT-XRPD analysis showed that solids for the hydrochloride salt, Pattern 1, were still present between 25°C and 160°C. At 188°C and above (to 205°C), the material was amorphous and remained amorphous after cooling. The solids appeared to have melted.

[0327] Polarized light microscopy (PLM) showed that the material had no obvious morphology and no obvious birefringence, see Fig.17 A.

[0328] IR spectra were recorded for reference.

[0329] 1 The H NMR spectrum was consistent with the formation of a salt of mesembrine.A residual ethanol content of 0.98 wt% and a residual heptane content of 0.64 wt% were observed.

[0330] DVS analysis showed a water absorption of 5.4 wt% at 80% RH and 25°C, indicating that the material is hygroscopic. At 90% RH, the water absorption was 20.3 wt%, indicating significant hygroscopicity above 80% RH. The solid of hydrochloride salt mode 1 was recovered from the DVS analysis.

[0331] VH-XRPD analysis showed that even after 12 h at 90% RH, the solid was still consistent with the hydrochloride salt pattern 1. No change in crystallinity was observed.

[0332] Benzenesulfonate mode 1 :

[0333] The solid of besylate pattern 1 was isolated in 69% yield with a chemical purity of 98.1% area. KF indicated a water content of 0.3% w / w.

[0334] The solid is light beige (BE10) relative to the Sigma Aldrich color chart.

[0335] TG / DSC analysis showed a weight loss of 0.3 wt% before decomposition.In the DSC thermogram, two endothermic events were observed with onset (and peak) temperatures of 131°C (141°C) and 151°C (158°C).

[0336] In the DSC, at a heating rate of 10°C / min, two overlapping endothermic events were observed in the first heat with onset (and peak) temperatures of 132°C (141°C) and 150°C (158°C). In the first cool, a glass transition was observed with a midpoint half height of 59°C, and in the second heat, a glass transition was observed with a midpoint half height of 65°C. The DSC was repeated at a heating rate of 1°C / min, which successfully resolved the endothermic events in the first heat, which were observed to have onset (and peak) temperatures of 129°C (135°C) and 151°C (156°C).

[0337] VT-XRPD analysis showed that solids of the besylate salt, Pattern 1, were still present between 25° C. and 150° C. At temperatures between 157° C. and 160° C., and after returning to 25° C., the material was amorphous and appeared to have melted.

[0338] PLM shows that the material has no obvious morphology and has some birefringence, see Fig.17 B.

[0339] IR spectra were recorded for reference.

[0340] 1 The H NMR spectrum was consistent with the formation of a salt of mesembryrine. The benzenesulfonic acid content was 1.1 equivalents, indicating that the material was a monobenzenesulfonate salt.

[0341] DVS analysis showed that benzenesulfonate mode 1 had a water absorption of 2.3 wt% at 80% RH and 25°C, indicating that the material is hygroscopic. At 90% RH, the water absorption was 13 wt%, indicating significant hygroscopicity above 80% RH. The solid isolated at the end of the DVS analysis was consistent with benzenesulfonate mode 1.

[0342] VH-XRPD analysis showed that even after 17 h at 90% RH, solids were still present for the besylate salt pattern 1. There was no change in crystallinity during this analysis.

[0343] Fumarate Mode 1 + Fumarate Mode 4 (mixture):

[0344] The solid of a mixture of fumarate pattern 1 and fumarate pattern 4 was isolated in 55% yield with a chemical purity of 96.6% area. KF analysis indicated a water content of 4.0% w / w (approximately 1 equivalent of water).

[0345] The solid is light beige (BE10) relative to the Sigma Aldrich color chart.

[0346] TG / DSC analysis showed a weight loss of 3.4 wt% between 20° C. and 95° C., followed by a second weight loss of 1.8 wt% between 95° C. and 162° C. In the DSC thermogram, two endothermic events were observed with onset (and peak) temperatures of 67° C. (80° C.) and 131° C. (154° C.).

[0347] In the DSC thermogram, two endothermic events were observed with onset (and peak) temperatures at 61°C (75°C) and 136°C (152°C).

[0348] VT-XRPD showed that between 25°C and 90°C, a mixture of fumarate mode 1 and fumarate mode 4 was still present. At 130°C, the diffraction pattern was consistent with fumarate mode 4. At 154°C and to 170°C, and after returning to ambient temperature, the material was amorphous.

[0349] PLM displays materials with no distinct morphology and limited birefringence, see Fig.17 C.

[0350] IR spectra were recorded for reference.

[0351] 1 The H NMR spectrum was consistent with salt formation of mesembrine. The fumaric acid content was equal to 1.3 equivalents, indicating that the material was a monofumarate salt. A residual MEK content of 0.74 wt% was observed.

[0352] DVS analysis showed a water absorption of 0.7 wt% at 80% RH and 25°C, indicating that the material is slightly hygroscopic. Between 0% RH-20% RH, a water absorption of 2.1 wt% was observed, indicating that at ambient humidity, the material may be hydrated. The solid isolated at the end of the analysis was consistent with a mixture of fumarate mode 1 and fumarate mode 4.

[0353] VH-XRPD showed that between 40% RH and 10% RH, the solid was consistent with a mixture of fumarate mode 1 and fumarate mode 4. At 0% RH, a new diffraction pattern, labeled fumarate mode 5, was observed.

[0354] Re-preparation of fumarate salt model 4:

[0355] XRPD showed the presence of Mode 4 and the absence of Mode 1. DVS analysis of the fumarate salt Mode 4 showed a water absorption of 0.5 wt% at 80% RH, 25°C, indicating that the material is slightly hygroscopic. HPLC showed a chemical purity of 95.88% area.

[0356] in conclusion

[0357] Salts were successfully formed from all three counterions and analyzed accordingly. These three salts exhibited properties consistent with improved attributes consistent with the ability to produce enhanced pharmaceutical formulations.

[0358] Example 5: Salt hydration study

[0359] Materials and methods

[0360] About 20 mg of the hydrochloride (HCl), benzenesulfonate, and fumarate salts were weighed into 3 x 2 mL push-top vials. To each vial was added 0.05 mL - 0.1 mL of the relevant solvent system at 25 °C.

[0361] Using known water activities (respectively a w 0.2, 0.5 and 0.8) of methanol / water solvent system (99:1, 75:25, 33:67). The experiment was stirred for about 24 hours. After 24 hours, any slurry was centrifuged and the solid was analyzed by XRPD.

[0362] For the HCl and benzenesulfonate salts, additional hydration studies were required due to dissolution in the first set of experiments in order to repeat the salt hydration studies:

[0363] For each salt, approximately 10 mg was weighed into 4 x 2 mL vials and a stir bar was added. 10 μL of each solvent system was added at 25° C. The experiment was stirred for 24 h and any solids recovered were then analyzed by XRPD.

[0364] result

[0365] The results of the hydration studies are summarized in Table 3.7 below.

[0366] Clear solutions were obtained for the experiments using the hydrochloride salt model 1 and the benzenesulfonate salt model 1.

[0367] Additional experiments using hydrochloride mode 1 resulted in slurries at a w 0.5 and 0.8 were still present. The isolated solid was consistent with Pattern 1, the hydrochloride salt.

[0368] Clear solutions were obtained from additional experiments using the besylate salt mode 1, indicating a solubility >1000 mg / mL.

[0369] For the fumarate salt, the slurry was maintained. The isolated solid was consistent with fumarate pattern 4.

[0370] Table 3.7 Summary of results from hydration studies

[0371]

[0372]

[0373] in conclusion

[0374] The besylate salt is highly soluble, resulting in greater than 1000 mg / ml at all water activity levels, providing evidence that this salt is highly suitable for development of pharmaceutical compositions.

[0375] The hydrochloride salt was insoluble at higher concentrations and higher water activity levels. The fumarate salt did not produce a clear solution at any concentration or water activity level tested.

[0376] Example 6: pH Solubility Study

[0377] Materials and methods

[0378] About 20 mg of each salt was weighed into 3×2 mL push-top vials. At 25° C., 0.1 mL of buffer (chloride pH 1.2; acetate pH 4.5; phosphate pH 6.8) was added to each vial. The experiment was stirred for about 24 h. After 2 h, the pH was measured and adjusted as needed. After 24 h, the final pH measurement was obtained. Any slurry was centrifuged and the solids were analyzed by XRPD. The clear solution / mother liquor was analyzed by HPLC.

[0379] result

[0380] The results from the pH solubility studies are summarized in Table 3.8:

[0381] High solubility (>96.75 mg / mL relative to mesembrine) was observed for both hydrochloride salt mode 1 and benzenesulfonate salt mode 1 in all pH ranges (1.2, 4.5, 6.8).

[0382] At pH 1.2, the solubility of the fumarate salt mode 1 was 29.44 mg / mL. The solid isolated from this experiment was consistent with fumaric acid.

[0383] Oiling was observed in the fumarate mode 1 experiment at pH 6.8.

[0384] Table 3.8 Summary of results from pH studies

[0385]

[0386]

[0387] in conclusion

[0388] The besylate and hydrochloride salts are highly soluble over all pH ranges, providing evidence that these salts would be suitable for development of pharmaceutical compositions.

[0389] The fumarate salt was only able to produce a clear solution at pH 4.5.

[0390] Example 7: Stability Study

[0391] Materials and methods

[0392] The stability study of hydrochloride mode 1, benzenesulfonate mode 1, fumarate mode 1 + fumarate mode 4, and fumarate mode 4 was conducted for 1 week.

[0393] About 5 mg of salt was weighed into 3 x 2 mL push-top vials. The 2 mL vials were then each placed inside a 20 mL vial with the lid open or closed as needed. The solids were placed under the desired stability conditions for 1 week under the following three conditions: 40°C / 75% RH (open); 80°C (closed); ambient light, ambient temperature, and ambient humidity (open).

[0394] After 1 week, visual observations were recorded and the solids were then analyzed by XRPD and HPLC.

[0395] result

[0396] The results from the 1-week stability study are summarized in Table 3.9.

[0397] A slight increase in chemical purity was observed from all stability conditions for the hydrochloride salt Mode 1. Solids of the hydrochloride salt Mode 1 were isolated from all stability conditions.

[0398] For besylate salt Model 1, no decrease in chemical purity was observed after 1 week at 40°C / 75%RH or ambient conditions. A slight decrease in chemical purity was observed after 1 week at 80°C. Solids of besylate salt Model 1 were isolated from all conditions.

[0399] For Fumarate Pattern 1 + Fumarate Pattern 4, a slight decrease in chemical purity was observed after 1 week at 40°C / 75%RH, and the solid was consistent with a mixture of Fumarate Pattern 1 and Fumarate Pattern 4. A decrease in chemical purity was observed after 1 week at 80°C, converting to a new Fumarate Pattern 6. No significant decrease in chemical purity was observed after 1 week at ambient conditions, and the solid had an XRPD diffraction pattern consistent with a mixture of Fumarate Pattern 1 and Fumarate Pattern 4.

[0400] Solids of fumarate salt pattern 4 were recovered from all stability conditions for fumarate salt pattern 4. There was a slight increase in chemical purity after 1 week at all stability conditions.

[0401] Table 3.9 Summary of results from the 1-week stability study

[0402]

[0403]

[0404] in conclusion

[0405] The besylate, hydrochloride and fumarate salts of Model 4 were stable under all storage conditions, providing evidence that these salts would be suitable for development of pharmaceutical compositions.

[0406] Fumarate Mode 1 and Fumarate Mode 4, which produced new salt types upon storage at 80°C, could only produce clear solutions at pH 4.5.

[0407] Example 8: Scale-up of benzenesulfonate mode 1

[0408] Materials and methods

[0409] A scale-up of the besylate salt model 1 was performed in order to fully characterize this form of the salt and perform polymorph screening. The anti-solvent addition step was performed to maximize the yield:

[0410] About 4.5 g of mesembrine was weighed out and dissolved in 27.7 mL of MEK, and transferred to a 100 mL container at 25° C. Next, 1.1 equivalents (2.79 g) of benzenesulfonic acid was weighed out and dissolved in 17.7 mL of MEK.

[0411] The stock solution of benzenesulfonic acid was added dropwise to the vessel and the experiment was stirred at 25 °C for 1 h.

[0412] The experiment was cooled to 5° C. at 0.1° C. / min. At 5° C., 15 mL of heptane was added over 3.3 h. The final solvent system was: MEK:heptane 75% v / v:25% v / v.

[0413] The experiment was then continued for about 12 h with stirring at 5° C. Crusting was observed on the walls of the container and was reintroduced into the slurry by hand.

[0414] The solid was isolated by Buchner filtration and washed with 5 mL of MEK:heptane 75% v / v:25% v / v.

[0415] Prior to separation, a subsample of the solid was taken by centrifugation for XRPD analysis.The solid was dried at 40°C under vacuum for approximately 29 h and used for further analysis and polymorph screening.

[0416] The besylate salt was then lyophilized to produce the amorphous material using the following procedure.

[0417] About 50 mg of benzenesulfonate salt mode 1 was weighed into a 2 mL push-top vial. The solid was dissolved in 0.5 mL of water and then frozen at -20°C. Once frozen, the material was lyophilized. The isolated solid was then analyzed by XRPD, TGA / DSC and HPLC.

[0418] result

[0419] like Fig.18 XRPD of solids from scaled-up experiments were prepared as detailed in . Details of the peaks are found in Table 3.10 below.

[0420] Table 3.10 XRPD peaks of benzenesulfonate pattern 1

[0421]

[0422]

[0423] The solid was isolated in 80% yield. The isolated solid had a chemical purity of 96.4% by area by HPLC.

[0424] The theoretical yield was 99% based on the loss of the mother liquor and the washing liquid. The concentration of the mother liquor and the washing liquid was 0.3 mg / mL.

[0425] Fig.19 The lyophilized material appeared to be predominantly amorphous, with one peak present at 24.7° 2θ in the isolated material, consistent with benzenesulfonate mode 1.

[0426] in conclusion

[0427] Mesembrine benzenesulfonate salt pattern 1 was fully characterized by XRPD analysis, demonstrating a new mesembrine salt form with excellent properties that can be lyophilized to produce an amorphous material suitable for the preparation of pharmaceutical compositions.

[0428] Example 9: Solubility screening of mesembryanthemum benzoate

[0429] Materials and methods

[0430] The amorphous benzenesulfonate prepared in Example 8 was used for the following solubility screening:

[0431] Aliquots of known volumes of the solvent system were added to each vial, heating at 40°C for approximately 5 minutes between each addition. Solvent additions continued until dissolution was observed, or until 100 volumes (approximately 1 mL) were added.

[0432] After the solvent addition was complete, the experiment was stirred at 40°C for about 16 h. The slurry was stirred at 40°C and the clear solution was left to evaporate at 40°C at ambient pressure for about 24 h. The solid was isolated by centrifugal filtration and analyzed by XRPD.

[0433] The clear solution was left to evaporate under vacuum at 40°C for about 72 h. Any isolated solid was analyzed by XRPD.

[0434] result

[0435] The results of the solubility screen are summarized in Table 3.11 below.

[0436] Table 3.11 Solubility screening of amorphous benzenesulfonate

[0437]

[0438]

[0439]

[0440] Solubility screening indicated that in addition to besylate salt pattern 1, an additional salt pattern 2 was formed in DMA.

[0441] in conclusion

[0442] The amorphous material is soluble in many solvent systems and is capable of forming an additional polymorph described as Mode 2 besylate.

[0443] Example 10: Screening of polymorphs of mesembryanthemum benzoate

[0444] Materials and methods

[0445] The amorphous benzenesulfonate salt prepared in Example 8 was used as input for this set of experiments.

[0446] About 1.25 g of the benzenesulfonate salt was weighed and dissolved in 17.5 mL of water. The solution was divided into 25×2 mL vials and frozen. The frozen material was lyophilized for about 24 h. The isolated solid was dried at 20° C. under vacuum for about 24 h. The dried solid was analyzed by XRPD.

[0447] To each vial, add solvent to obtain a slurry. If dissolution is observed, add more amorphous material to try and create a slurry.

[0448] The experiment was temperature cycled at 0.1°C / min between 30°C and 5°C, with a hold at 30°C for 1 h and a hold at 5°C for 48 h. After 48 h, the solids were separated from the slurry by centrifugal filtration at 30°C and analyzed by XRPD. The solids were then dried under vacuum at 40°C for 18 h. The clear solution was cooled to 5°C over 10 minutes and held for 30 minutes in an attempt to induce precipitation.

[0449] result

[0450] The results of the solubility screen are summarized in Table 3.12 below.

[0451] Table 3.12 Polymorph screening of amorphous benzenesulfonate

[0452]

[0453]

[0454] As shown, many solvent systems were able to produce polymorph besylate mode 1 or besylate mode 2. In addition, some systems produced a mixture of the two salt modes.

[0455] The new polymorph benzenesulfonate salt pattern 2 was further characterized by XRPD, as Fig. 20 As shown, where the peak positions and heights are specified in Table 3.13 below. Fig.21 A comparison of the two crystalline forms, Mode 1 and Mode 2, is additionally shown in FIG.

[0456] Table 3.13 XRPD peaks of benzenesulfonate mode 2

[0457]

[0458]

[0459] in conclusion

[0460] The amorphous material is able to form two distinct forms; characterized as besylate mode 1 and besylate mode 2. Example 11: Pharmacokinetic Analysis of Mesembrine Benzenesulfonate

[0461] Materials and methods

[0462] In this example, in addition to mesembrine free base, the amorphous benzenesulfonate prepared in Example 8 was also used to determine the pharmacokinetic (PK) characteristics of both.

[0463] Groups of 18 male C57Bl / 6J mice (body weight between 20 and 30 g) received a single administration of test compound (10 mg / kg; ip) at a nominal concentration of 1.0 ng / mL in methylcellulose (0.5% w / v).

[0464] At 0.25 h, 0.50 h, 1.00 h, 1.50 h, 2.00 h, and 4.00 h after dosing, three mice from each dose group underwent cardiac puncture under general anesthesia and plasma samples were generated for application of standard LC-MS / MS bioanalytical methods.

[0465] Quantification of compound concentrations was derived from reference calibration data. Pharmacokinetic data were derived from serial plasma concentrations.

[0466] result

[0467] Table 4 details the PK parameters measured using mesembryanthine besylate or mesembryanthine free base.

[0468] Fig. 22 and Fig.23 The average total concentrations of mesembryine benzenesulfonate and mesembryine free base are detailed separately.

[0469] Table 4. Summary of PK parameters

[0470]

[0471]

[0472] Both mesembryine benzenesulfonate and mesembryine free base exhibited a short T at only 15 minutes. max , however, the besylate half-life of the besylate salt form of mesembrine is significantly longer than the free base. Here it can be seen that the besylate salt has a half-life of 36.9 minutes, while the free base is 27.2 minutes, a difference of nearly 10 minutes.

[0473] Different C max and AUC. max Both AUC and AUC were greater in mesembryine benzenesulfonate than in the free base. Regarding AUC, mesembryine benzenesulfonate produced an AUC that was more than 100 ng.h / mL greater than that produced by mesembryine free base.

[0474] Table 5 below details the blood:plasma and blood:brain ratios observed for both mesembryanthemum benzenesulfonate and free base in a separate cohort of satellite animals dosed in the same manner but sacrificed at t=0.25h to obtain brain samples.

[0475] Table 5. Summary of average ratios

[0476]

[0477] As detailed above, the plasma concentrations of the besylate salt were greater than those observed with the free base, which is consistent with the observations described in Table 4. In addition, higher brain exposure was observed in animals dosed with the besylate salt when compared to the free base. Mesembryanthemum besylate resulted in a higher mean blood-to-plasma ratio than the free base. Such differences infer that the salt form is able to enter the plasma at greater concentrations than the free base.

[0478] in conclusion:

[0479] The ability of mesembryine benzenesulfonate to preferentially improve the PK properties of mesembryine free salt demonstrates the importance of using a salt form of mesembryine in pharmaceutical formulations.

[0480] The improvements in PK properties demonstrated by the besylate form of mesembryanthemumine will allow more of the active substance to be absorbed and therefore smaller doses of the drug to be given. Advantages include lower costs for the active ingredient due to smaller amounts required to achieve the same effect, and potentially fewer side effects for the patient due to lower doses of the drug required.

[0481] Conclusion

[0482] Examples 1 to 10 presented above demonstrate that alternative salt forms of mesembrine can be formed using a variety of counterions. The HCl salt is known in the art, however, this salt form presents significant problems because it can only dissolve at relatively low mesembrine concentrations to form a clear solution. This physicochemical property makes the hydrochloride salt unsuitable for drug development because only low doses of mesembrine can be delivered.

[0483] However, the besylate salt was found to be highly soluble, resulting in solubility greater than 1000 mg / ml, providing evidence that this salt is highly suitable for development of pharmaceutical compositions.

[0484] Such a finding is surprising, as salts formed from benzenesulfonic acid are rarely found to be used in active pharmaceutical ingredients. The hydrochloride salt is the most common pharmaceutical salt and is present in about 15.5% of all approved pharmaceutical compounds. The sodium salt and sulfate salt are also present in 9% and 4% of all pharmaceutical compounds, respectively.

[0485] The finding that the benzenesulfonate salt is the most soluble and stable salt compared to the hydrochloride and fumarate salts is additionally surprising given the relatively high pKa of benzenesulfonic acid, especially compared to hydrochloric acid. As described in Example 3, weak acids are unlikely to form suitable salts due to the inability to complete proton transfer.

[0486] In the formulation of pharmaceutical compositions, it is important that the active pharmaceutical ingredient (API) is in a form in which it can be conveniently handled and processed. This is important not only from the perspective of obtaining a commercially viable manufacturing process, but also from the perspective of the subsequent manufacture of pharmaceutical formulations (e.g., oral dosage forms such as tablets) containing the active pharmaceutical ingredient.

[0487] In the manufacture of oral pharmaceutical compositions, it is important to provide a reliable, reproducible and constant plasma concentration profile of the active pharmaceutical ingredient following administration to a patient.

[0488] The chemical stability, solid state stability and shelf life of the active pharmaceutical ingredient are also very important factors when considering the form used to prepare the drug.

[0489] Amorphous materials, such as mesembrine, are generally more difficult to handle and formulate, and are often unstable. Thus, mesembrine benzenesulfonate provides a form that can be used to prepare commercially viable and pharmaceutically acceptable drug compositions, as it has been shown to occur as a highly soluble substantially crystalline and stable form.

[0490] Furthermore, the data presented in Example 11 demonstrate that the besylate salt of the present invention is able to produce superior pharmacokinetic properties compared to mesembrine free base.

Claims

1. A mesembryine salt, wherein the salt is selected from the group consisting of mesembryine benzenesulfonate; mesembryine phosphate; mesembryine tartrate; mesembryine fumarate and mesembryine succinate.

2. The mesembrine salt according to claim 1, wherein the salt is mesembrine benzenesulfonate.

3. The mesembrine salt according to claim 1 or claim 2, wherein the salt is in solid form.

4. The mesembrine salt according to any one of the preceding claims, wherein the salt is in crystalline form.

5. The mesembrine salt according to claim 2, characterized by the XRPD pattern of Figure 18.

6. The mesembrine salt of claim 5, characterized by an XRPD pattern comprising peaks at positions approximately as described in Table 3.

10.

7. The mesembrine salt according to claim 2, characterized by the XRPD pattern of Figure 20.

8. The mesembrine salt of claim 7, characterized by an XRPD pattern comprising peaks at positions approximately as described in Table 3.

13.

9. A process for preparing mesembryine salt, comprising the following steps: a) dissolving mesembryine in a solvent; b) adding appropriate counter ions to the mesembryine solution under temperature cycling conditions; and c) isolating a solid comprising the mesembryine salt.

10. The process of claim 9, wherein the counterion of step b) is benzenesulfonic acid.

11. A pharmaceutical formulation comprising a mesembryine salt, wherein the salt is selected from the group consisting of mesembryine benzenesulfonate, mesembryine phosphate, mesembryine tartrate, mesembryine fumarate and mesembryine succinate.

12. The pharmaceutical formulation according to claim 11, wherein the salt is mesembryanthemum benzylsulfonate.

13. A pharmaceutical formulation according to claim 11 or claim 12, wherein the formulation produces elevated blood levels of mesembrine of between 80% and 125% compared to blood levels obtained with a pharmaceutical formulation not comprising mesembrine in salt form.

14. A mesembryine salt for use in treating a disease, wherein the salt is selected from the group consisting of mesembryine benzenesulfonate; mesembryine phosphate; mesembryine tartrate; mesembryine fumarate and mesembryine succinate.

15. The mesembrine salt for use according to claim 14, wherein the salt is mesembrine benzenesulfonate.

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