Pharmaceutical composition comprising benzgalanthamine and application and preparation method thereof

Abstract

The present invention relates to a pharmaceutical composition comprising bengalanthamine, and uses and methods of preparation thereof. The present invention provides a pharmaceutical composition in the form of a tablet comprising a tablet core wherein the tablet core comprises benzgalanthamine (ALPHA-1062) or a salt thereof, and an enteric coating wherein the enteric coating is configured for dissolution at a pH of 5.5 and higher. The pharmaceutical composition can be used for treating brain diseases related to cognitive impairment and / or cholinergic insufficiency. The invention further provides a method for preparing the pharmaceutical composition.

Description

Field of the Invention

[0001] The present invention is in the field of pharmaceutical compositions comprising the active pharmaceutical ingredient bengalantamine (also known as galanthamine benzoate, GLN-1062, Memogain, ALPHA-1062).

[0002] The present invention relates to a pharmaceutical composition in the form of a tablet, the tablet comprising: a. a tablet core, wherein the tablet core comprises bengalantamine or a salt thereof, and b. an enteric coating, wherein the enteric coating is configured to dissolve at pH 5.5 and above. The present invention further relates to a composition configured to release bengalantamine in the small intestine of a subject at pH 5.5 and above after administration to the subject.

[0003] In addition, the present invention relates to a pharmaceutical composition for treating brain diseases associated with cognitive impairment and / or cholinergic insufficiency. The present invention further relates to a method for treating brain diseases associated with cognitive impairment and / or cholinergic insufficiency, comprising administering a pharmaceutical composition as described herein to a subject in need thereof.

[0004] The present invention further relates to a process for preparing a pharmaceutical composition in tablet form, wherein the composition is prepared by blending the components of a tablet core to form a blend, compressing the blend to form a tablet core, coating the tablet core with a film coating and coating the film coating with an enteric coating. Background Art

[0005] Galantamine, chemically known as (4aS,6R,8aS)-3-methoxy-11-methyl-4a,5,9,10,11,12-hexahydro-6H-benzofurano[3a,3,2-ef][2]benzazepine-6-ol (CAS 357-70-0), is a tertiary amide belonging to the phenanthrene chemical class, which occurs naturally in bulbous plants and can also be produced synthetically. Galantamine is an inhibitor of acetylcholinesterase (AChE) and further enhances cholinergic activity by non-competitive allosteric modulation of nicotinic acetylcholine receptors (nAChR), particularly the α7 subtype of nAChR. This slows down the degradation of acetylcholine (Ach) and increases the affinity of existing Ach for the receptor. This mechanism of action results in an improvement in cholinergic transmission (which is impaired, for example, in Alzheimer's disease).

[0006] Galantamine was introduced in 2000 as a drug for Alzheimer's disease and is currently approved in several countries around the world. Approved indications are generally mild to moderate Alzheimer's type dementia. It is currently available in immediate-release tablets, oral solutions, and extended-release capsules and tablets. It is marketed in the United States for ER sales, and elsewhere Sales. A number of generic equivalents have been approved by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) in several European countries. Development and ER extended-release capsules and tablets to reduce the dosage regimen to one capsule per day while maintaining bioequivalence to twice-daily immediate-release tablets.

[0007] Cholinergics such as galantamine, by their primary action, increase gastric acid secretion due to enhanced cholinergic activity. As with other cholinesterase inhibitors, the most common adverse reactions (≥5%) with galantamine, particularly when taken orally, occur in the gastrointestinal tract (GIT) and include nausea, vomiting, diarrhea, dizziness, headache, and decreased appetite. The most common adverse reactions associated with discontinuation of treatment (≥1%) in patients treated with galantamine in double-blind clinical trials were nausea (6.2%), vomiting (3.3%), decreased appetite (1.5%), and dizziness (1.3%).

[0008] Therefore, during oral treatment with galantamine, low doses are initially administered and subsequently increased over several months, adjusted for the level of side effects that the patient finds acceptable. Many patients never reach the most therapeutically effective dose or discontinue treatment altogether due to side effects. Most gastrointestinal-related adverse reactions occurred during dose escalation. Among those patients who experienced the most common adverse reaction (nausea), the median duration of nausea was 5-7 days.

[0009] Galantamine has been chemically modified to increase its lipophilicity, thereby allowing it to cross the blood-brain barrier (BBB) ​​and mucosal tissues. Galantamine derivatives and prodrugs are described in EP 1940817 Bl, WO 2009 / 127218A1 and US2009 / 0253654 A1.

[0010] The galantamine prodrug benzgalantamine, also known as galantamine benzoate or ALPHA-1062, has the chemical name ((4aS,6R,8aS)-4a,5,9,10,11,12-hexahydro-3-methoxy-11-methyl-6H-benzofurano[3a,3,2-ef][2]benzazepine-6-benzoate gluconate), and is a benzoate ester of galantamine that exhibits limited or no pharmacological activity at therapeutic doses until cleaved by esterase activity or under acidic conditions, resulting in the release of galantamine.

[0011] WO 2014 / 016430 discloses transmucosal administration of bengalantamine by intranasal, buccal or sublingual means, and also discloses various preparations and salts of bengalantamine, including, for example, lactate, gluconate, maleate and glucarate. In addition, the comparison between the nasal application of bengalantamine and the oral application of galantamine was evaluated in the study of Baakman et al (2016). Among them, compared with oral administration of galantamine, the incidence of gastrointestinal adverse reactions such as nausea and vomiting caused by nasal administration of bengalantamine is lower. In a multiple ascending dose study of bengalantamine administration by intranasal application, it was also observed that the side effects of bengalantamine were reduced compared with galantamine (Bakker et al., 2020). In terms of the daily dose of bengalantamine relative to oral galantamine, bengalantamine is well tolerated at a dose of up to 22 mg twice a day, and the incidence of GI side effects is reduced relative to a single 16 mg oral galantamine dose. No gastrointestinal adverse events were observed at a twice daily dose of 11 mg bengalantamine.

[0012] Drug solutions or emulsions are usually used for transmucosal administration of drugs, such as through the nasal cavity, and can also be administered by sublingual or buccal routes. Therefore, compared with solid dosage forms for oral application, the use of drug solutions has several disadvantages, including the need for highly soluble drugs to reach effective single dose levels, because the volume that can be applied to the nasal cavity or oral cavity in a single administration event is limited. In addition, drug solutions often have long-term stability problems, so it is necessary to, for example, directly redissolve before administration or add stabilizers and viscosity control agents in the solution. WO 2014 / 016430 discloses the stability problems of salts of benzogalanthamine and solutions thereof. High concentrations of benzogalanthamine gluconate solutions are metastable, and their salts are converted into stable salt forms with lower solubility during storage, requiring subsequent heating of the solution and taking precautions to avoid precipitation during storage.

[0013] Compared with pharmaceutical solutions or suspensions, solid dosage forms such as tablets for oral use provide high stability, and production is easier and more direct. However, the advantageous properties of prodrug bengalantamine relative to galanthamine, such as the gastrointestinal side effects reduced due to pharmacological inactivity before cracking, are usually difficult to obtain when administered orally in tablet form. This is because the prodrug bengalantamine is found to be an unstable ester in an acidic environment (such as present in the stomach), and is cleaved by enzymes in many tissues. The cracking of bengalantamine causes galanthamine to be present in the stomach, causing gastrointestinal adverse reactions. Generally, adverse reactions such as the occurrence of gastrointestinal adverse reactions can reduce the compliance of oral treatment. It is likely that compliance can be improved by reducing adverse reactions or alleviating the severity of adverse reactions.

[0014] It is known in the prior art that dosage forms for oral use such as tablets and capsules can be coated with acid-resistant enteric coatings to prevent dissolution of the tablets or capsules in an acidic environment, thereby preventing the drug from being released and decomposed in the stomach. WO 2014 / 016430 discloses the possibility of using enteric coated tablets including bengalantamine (ALPHA-1062). However, no detailed information is provided about the specific formulation, excipients, production method, pH value of expected release, or any effects or potential side effects reported.

[0015] Although various formulations of galantamine and bengalantamine and salts thereof are provided in the prior art, there is still a need to further develop improved, more effective oral formulations for delivering galantamine to subjects so that it is clinically effective and has reduced side effects. Summary of the invention

[0016] In view of the prior art, the technical problem underlying the present invention is to provide a pharmaceutical composition comprising benzogalantamine (ALPHA-1062) for oral administration which does not exhibit the disadvantages of the prior art.

[0017] It is an object of the present invention to provide improved or alternative pharmaceutical compositions comprising bengalantamine for oral delivery which show reduced adverse effects, in particular reduced gastrointestinal adverse effects, while showing high bioavailability.

[0018] Another object of the present invention is to provide an improved or alternative method for administration of galantamine which is clinically effective and shows reduced adverse effects, particularly gastrointestinal adverse effects, while showing high bioavailability. Considering that the active past form of bengalantamine is galantamine itself, it is an object of the present invention to provide galantamine therapy by oral delivery without or with reduced undesirable side effects.

[0019] Another problem underlying the present invention is to provide oral solid dosage forms and formulations comprising bengalantamine which show improved pharmacokinetic properties compared to dosage forms and formulations disclosed in the prior art, thereby providing effective treatment of diseases and / or symptoms associated with cognitive impairment and / or cholinergic insufficiency while showing reduced adverse effects.

[0020] Another problem underlying the present invention is to provide oral solid dosage forms and formulations comprising bengalantamine which exhibit improved pharmacokinetic properties compared to dosage forms and formulations disclosed in the prior art, independent of the food and drink intake of the subject.

[0021] These problems are solved by the features of the independent claims. Preferred embodiments of the invention are provided by the dependent claims.

[0022] In one aspect, the present invention relates to a pharmaceutical composition in the form of a tablet comprising:

[0023] a. a tablet core, wherein the core comprises bengalanthamine or a salt thereof, and

[0024] b. Enteric coating, wherein the enteric coating is configured to dissolve at pH 5.5 and above.

[0025] Unexpectedly, the composition of the present invention exhibits excellent pharmacokinetic properties and therapeutic effects while exhibiting a low incidence of adverse reactions in subjects.

[0026] Since bengalantamine is an ester, which is unstable in the acidic environment of the stomach and is cleaved by enzymes in many tissues, oral administration of bengalantamine often results in prodrug cleavage and induces gastrointestinal adverse reactions due to the action of galantamine in the stomach. Enteric coatings of solid dosage forms for oral administration prevent the release of bengalantamine in the stomach, thereby preventing acidic or enzymatic cleavage.

[0027] The compositions of the present invention include an enteric coating that dissolves at pH 5.5 and above and unexpectedly exhibit favorable pharmacokinetic profiles while demonstrating reduced gastrointestinal adverse events.

[0028] As shown in the following examples, the compositions of the present invention result in a maximum plasma concentration (c max ) was reduced while maintaining the area under the curve (AUC) of galantamine in plasma comparable to that of the immediate-release reference formulation of galantamine (without enteric coating).

[0029] Furthermore, the composition of the present invention results in a c max while maintaining AUC comparable to RAZADYNE extended-release capsules.

[0030] Thus, the compositions of the present invention provide benefits compared to compositions known in the prior art, since compared to immediate release formulations, the compositions of the present invention provide benefits due to the c max Lower, adverse reactions, especially gastrointestinal adverse events, and compared with RAZADYNE extended-release capsules, c max The AUC of the galantamine composition was increased and was similar to that of the oral galantamine compositions known in the prior art, thus maintaining the therapeutic effect.

[0031] Such beneficial effects of the compositions of the present invention, particularly those achieved by an enteric coating formulated to dissolve at pH 5.5 or higher, would not have been anticipated by those skilled in the art.

[0032] Due to the enteric coating of the composition of the present invention, bengalantamine is released in the intestine at a pH above 5.5, resulting in a lower c of galantamine compared to an immediate release composition that releases galantamine in the stomach. max The rise was slower and lower, and compared with the sustained-release composition c max The rate of increase in the plasma concentration of bengalantamine and the absolute concentration of bengalantamine in the plasma both affect the side effect profile and effect. Compared with the immediate release preparation, the composition of the present invention has a higher max The rise is slow and c max Lower, thus advantageously reducing side effects.

[0033] After the composition of the present invention releases bengalantamine in the intestine, the drug may be converted to galanthamine by esterase action in the following compartments: (a) in the intestinal lumen, (b) during transport across the intestinal wall (Ho et al. 2017, Xu et al. 2015), and (c) exposed to esterase activity in (portal vein) blood (Rudakova et al. 2010).

[0034] However, despite the complete or almost complete conversion of bengalantamine to galantamine, and the detection of only negligible (or below the limit of quantitation) amounts of bengalantamine in the bloodstream after administration to a subject (see Examples 2 and 3 below), the compositions of the present invention unexpectedly do not induce the side effect profile observed with the immediate release formulations known in the prior art. This led to the discovery that the compositions of the present invention unexpectedly do not result in free galantamine concentrations in the gastrointestinal tract and intestinal wall that induce the gastrointestinal side effects observed with the compositions of the prior art.

[0035] This represents an unexpected and beneficial effect, since it was originally expected that the conversion of bengalantamine in the compartment (ac) after release in the intestine might result in galantamine concentrations activating the enteric cholinergic nervous system, leading to gastrointestinal adverse events such as nausea, vomiting, diarrhea. Thus, the formulations of the present invention advantageously provide protection against gastrointestinal adverse events while achieving complete conversion of the prodrug to galantamine and having similar AUCs compared to the immediate-release and sustained-release reference formulations.

[0036] Furthermore, without being bound by theory, the results of the following examples indicate that the rate of drug presentation to the liver for first-pass metabolism does not exceed the metabolic capacity of the liver, thereby completely or almost completely converting bengalantamine to galanthamine. This improves the safety profile and tolerability of the compositions of the present invention compared to compositions known in the prior art.

[0037] Thus, the compositions of the present invention are capable of achieving a combination of beneficial features and characteristics that were not anticipated by the skilled person. Achieving a significant reduction in gastrointestinal adverse reactions while maintaining or potentially improving the therapeutic effect, and in addition improving the safety profile, represents an unexpectedly beneficial tablet formulation that exhibits unexpected advantages over the prior art formulations and / or expectations of those skilled in the art of pharmaceutical formulations. Thus, the enteric-coated compositions of the present invention configured to dissolve at pH 5.5 are advantageously capable of treating patients who previously discontinued treatment with AChE inhibitors due to intolerable gastrointestinal side effects associated with orally administered tablets.

[0038] In one aspect or embodiment, the present invention relates to a pharmaceutical composition in the form of a tablet comprising:

[0039] a. a tablet core, wherein the core comprises bengalanthamine or a salt thereof, and

[0040] b. an enteric coating comprising a copolymer of methacrylic acid and ethyl acrylate,

[0041] wherein the enteric coating is configured to dissolve at pH 5.5 and above,

[0042] wherein the tablet core is coated with a film coating, and

[0043] wherein the film coating is in direct contact with the tablet core and is coated by the enteric coating, and

[0044] Therein, in a dissolution test according to USP 711, the composition shows at most 10% dissolution of bengalantamine after 120 minutes in an acidic stage at pH 1.2, and at least 80% release of bengalantamine after 60 minutes in a buffered stage at pH 5.5 or 6.8.

[0045] In one aspect or embodiment, the present invention relates to a pharmaceutical composition in the form of a tablet comprising:

[0046] a. a tablet core, wherein the core comprises bengalanthamine or a salt thereof, and

[0047] b. Enteric coating, formulated to dissolve at pH 5.5 and above,

[0048] Therein, in a dissolution test according to USP 711, the composition shows at most 10% dissolution of bengalantamine after 120 minutes in an acidic stage at pH 1.2, and at least 80% release of bengalantamine after 60 minutes in a buffered stage at pH 5.5 or 6.8.

[0049] In one embodiment, the enteric coating is configured to dissolve at pH 5.5 and above, such as at pH 5.5, 5.6, 5.7, 5.8, 5.9, 6, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9 or 7, or at a value above 7. In one embodiment, the enteric coating is configured to dissolve within a pH range formed by any two values ​​disclosed herein. For example, in some embodiments, the enteric coating is configured to dissolve at pH 5.5 to 7, pH 5.5 to 6.5, or pH 5.5 to 6.

[0050] In one embodiment, the enteric coating is or includes a copolymer of methacrylic acid and ethyl acrylate.

[0051] In one embodiment, the copolymer includes a ratio of carboxylic acid groups of methacrylic acid to ester groups of ethyl acrylate of 2:1 to 1:2, or about 1:1, and the copolymer has an average molecular weight of about 250 kDa.

[0052] In one embodiment, the copolymer comprises a ratio of carboxylic acid groups of methacrylic acid to ester groups of ethyl acrylate of 2:1 to 1:2, such as 2:1, 1.8:1, 1.6:1, 1.5:1, 1.4:1, 1.2:1, 1:1, 1:1.2, 1:1.4, 1:1.5, 1:1.6, 1:1.8, and 1:2.

[0053] In one embodiment, the enteric coating is or includes Acryl-Eze II and / or Eudragit L100-55.

[0054] For example, Acryl-Eze II and / or Eudragit L 100-55 are considered the gold standard for extended release coatings for drug release in the mid-to-upper small intestine and reliably allow dissolution above pH 5.5. Eudragit products are generally available from Evonik Operations GmbH, Eudragit L 100-55 has a Cas number of 25212-88-8 and is a composition of methacrylic acid-ethyl acrylate copolymer (1:1). Acryl-EZE II is available in various pigmented formulations from Colorcon and uses Evonik's globally recognized enteric polymer, Eudragit L 100-55.

[0055] In one embodiment, the enteric coating is or includes methyl acrylate copolymer or a derivative thereof.

[0056] For example, SheffCoat TM Enteric film-coated products such as SheffCoatTM ENT, can be used to achieve pH-dependent release, i.e. dissolution at pH 5.5 and above. SheffCoat TM ENT is a functional delayed-release or enteric film coating that releases the API at a specific pH and / or region of the digestive tract. TM ENT provides consistent and reproducible delayed release performance by dissolving at pH 5.5 or higher. For example, the product SheffCoat TM ENT MA is a functional delayed-release or enteric film coating based on methyl acrylate copolymers that releases the API at a specific pH and / or region of the digestive tract.

[0057] In one embodiment, the enteric coating is or includes hydroxypropylmethylcellulose (HPMC) or hypromellose or a derivative thereof.

[0058] In one embodiment, the enteric coating is or includes hydroxypropylmethylcellulose phthalate (HPMC-P).

[0059] HPMC-P (also known as Hydroxypropyl Methylcellulose Phthalate) is often referred to as a modified form of HPMC and is a phthalic acid half ester. It is known to the technician that there are at least two types of HPMC-P with different solubility, such as HP-55 and HP-50, which show relevant pH release characteristics. HPMC-P is often used as an enteric coating material to prevent drug degradation in gastric acid.

[0060] The chemical structure of HPMCP is the monophthalate of hydroxypropyl methylcellulose. The critical pH for rapid disintegration of HPMCP can be controlled by varying the phthalate content. In addition, a special type of HP-55, HP-55S, is available, which features a higher molecular weight, greater film strength, and greater acid resistance. The appropriate grade of HPMCP can be selected for each formulation's specific application.

[0061] For example, SheffCoat TM ENT HPMC-P is a functional delayed-release or enteric film coating that releases the API at a specific pH and / or region of the digestive tract. SheffCoat TM ENT HPMC-P provides consistent and reproducible delayed-release performance by dissolving at pH 5.5 or higher.

[0062] In one embodiment, the enteric coating is or includes hypromellose acetate succinate (HPMCAS).

[0063] Hydroxypropyl methylcellulose acetate succinate (HPMCAS) is another enteric coating material that can be used in aqueous or organic media. Hydroxypropyl methylcellulose is a non-toxic material that has been used in the pharmaceutical, food and cosmetic industries for many years. Based on Hydroxypropyl methylcellulose, acetyl and succinyl groups are introduced on the hydroxyl groups of the main chain.

[0064] For example, products such as Shin-Etsu Hydroxypropyl methylcellulose acetate succinate (HPMCAS). There are nine grades with different particle sizes (fine, medium, coarse) and the degree of chemical substitution of acetyl and succinyl groups to obtain an open pH ranging from 5.5 to 6.5. Shin-Etsu also offers various products based on HPMC or HPMC-P for enteric coating.

[0065] In one embodiment, the enteric coating is or includes a phthalate polymer or a derivative thereof.

[0066] In one embodiment, the enteric coating is or includes polyvinyl acetate phthalate (PVAP).

[0067] Polyvinyl acetate phthalate (PVAP) is a phthalate polymer commonly used in the formulation of pharmaceuticals for enteric coating of tablets or capsules. It is a vinyl acetate polymer that has been partially hydrolyzed and then esterified with phthalates. For example, The product uses PVAP and is capable of pH-dependent release, making it suitable as an enteric coating.

[0068] As another example, Opadry Enteric is a family of enteric coating products that enable delayed release coating systems for solid oral dosage forms. These products can be made using organic or hydroalcoholic process technologies. Specific Opadry enteric coating formulations have been made by selecting enteric polymers whose solubility varies with the pH of the environment in the gastrointestinal tract. Opadry enteric products can be based on polyvinyl acetate phthalate (PVAP), hydroxypropyl methylcellulose phthalate (HPMC-P), or methacrylic acid copolymers (e.g., methacrylic acid-methyl methacrylate 1:1 copolymer).

[0069] In one embodiment, the enteric coating is or includes a cellulose ester or a derivative thereof.

[0070] In one embodiment, the enteric coating is or includes cellulose acetate phthalate (cellacefate).

[0071] Cellulose acetate phthalate is known by the CAS number [9004-38-0], or by the chemical name cellulose acetate 1,2-benzenedicarboxylate. Cellulose acetate phthalate (CAP), also known as cellulose acetate phthalate (INN), is a phthalate polymer that is often used to formulate enteric coatings for pharmaceuticals such as tablets or capsules and for controlled release preparations. It is a cellulose polymer in which approximately half of the hydroxyl groups are esterified with acetyl groups, one quarter are esterified with one or two carboxyl groups of phthalic acid, and the remainder are unchanged. For example, Eastman's products can be used, for example, Eastman CAP enteric coating material is a pH-sensitive cellulose derivative specifically designed for coating pharmaceutical tablets or granules. It can also be used as a matrix material in solid dosage forms. Eastman CAP enteric coating material withstands prolonged contact with acidic gastric fluids, but can be formulated to dissolve in the slightly acidic to neutral environment of the small intestine.

[0072] In an embodiment, the enteric coating is or includes one or more materials selected from the group consisting of methyl acrylate copolymer (methacrylic acid copolymer) or a derivative thereof (such as a copolymer of methacrylic acid and ethyl acrylate), hydroxypropyl methylcellulose (HPMC) or a derivative thereof (such as hydroxypropyl methylcellulose phthalate (HPMC-P) or hydroxypropyl methylcellulose acetate succinate (HPMCAS)), a phthalate polymer or a derivative thereof (such as polyvinyl acetate phthalate (PVAP)), and a cellulose ester or a derivative thereof (such as cellulose acetate phthalate (cellulose acetate)).

[0073] In one embodiment, the enteric coating is or includes shellac or a derivative thereof.

[0074] In one embodiment, the enteric coating is or includes a mixture of shellac and sodium alginate.

[0075] In one embodiment, the enteric coating is or includes a mixture of shellac and an additive, preferably a polymer such as polyvinyl alcohol (PVA), hydroxypropyl methylcellulose (HPMC) and / or a cross-linked polyacrylic acid polymer, or any other coating material or materials mentioned herein.

[0076] Shellac is a natural polymer used in various coating applications, such as in pharmaceutical compositions for film coating or to achieve enteric applications, controlled release properties, taste masking or seal coating. Shellac is a food additive approved in the United States and Europe and is also listed in the United States Pharmacopeia, the European Pharmacopoeia, and the Japanese Pharmacopoeia, Food Chemicals Codex. Shellac is a resin derived from the insect Kerria lacca species (family Coccidae), also known as lac. Shellac is usually produced from the resin secretions of the lac insect, which are produced when the lac insect attaches itself to the bark of a specific host tree and sucks the sap.

[0077] Shellac structurally includes esters of polyhydroxycarboxylic acids and other polar and non-polar components. For example, four common carboxylic acid components are: aleuritic (about 35%), jalaric (about 25%), shellolic (about 8%), and butolic (about 8%). In some enteric coatings, a combination of plasticizers and / or surfactants increases the flexibility of the shellac and adds to the adhesive structure strengthening properties of the coating. It has been demonstrated that shellac preparations (such as Protect TM , Sensient) are very successful in functional reproducibility and long-term product stability. In some coatings, after the addition of sodium alginate, enteric film coating systems provide gastric protection for granules, tablets and capsules, and have good film adhesion and flexibility. In an embodiment, the aqueous shellac preparation can be used in combination with one or more additives, such as polymer additives, such as polyvinyl alcohol (PVA), hydroxypropyl methylcellulose (HPMC) and / or cross-linked polyacrylic acid polymers (Carbomer 940). Examples are provided in Schad et al, Pharmaceutical Technology, Volume 2013, Supplement Issue 5 or U.S. Patent Publication 2007 / 0071821A, which are incorporated herein by reference. For example, Protect TM (from Sensient) is an effective two-component enteric coating system that combines aqueous shellac and sodium alginate. As another example, EP 1579771 A1 describes a water-based shellac dispersion comprising shellac, basic amino acids, basic phosphates and water. There are also aqueous ammoniated shellac dispersions available on the market, such as FC 300A. Esterification of shellac may occur when shellac forms salts with ammonia or protonated amino acids. According to US20110002986A1, shellac can be combined with non-ammonium base salts.

[0078] In embodiments, any coating material or derivative of an enteric coating material described herein maintains a desired dissolution rate at pH 5.5 and above, or can be formulated to maintain a desired dissolution rate at pH 5.5.

[0079] As can be seen from the above, the enteric coating of the present invention can be configured to dissolve at pH 5.5 and above. It is well known to the skilled person that various chemicals, polymers, etc. can be used to achieve such enteric coating.

[0080] In one embodiment, the tablet core comprises a water soluble filler.

[0081] In one embodiment, the water soluble filler is a sugar.

[0082] In one embodiment, the sugar is mannitol.

[0083] In one embodiment, the tablet core comprises a glidant.

[0084] In one embodiment, the glidant is colloidal silicon dioxide.

[0085] In one embodiment, the tablet core includes one or more lubricants.

[0086] In one embodiment, the lubricant is sodium stearyl fumarate and / or magnesium stearate.

[0087] In one embodiment, the tablet core comprises sodium stearyl fumarate and magnesium stearate.

[0088] In one embodiment, the tablet core is coated with a film coating comprising hydroxypropylmethylcellulose (HPMC), wherein the film coating is in direct contact with the tablet core and is coated with the enteric coating.

[0089] In one embodiment, the film coating comprises HPMC and polyethylene glycol, preferably wherein the film coating is or comprises Opadry YS-1-7006.

[0090] In one embodiment, bengalantamine is present in the form of a gluconate salt.

[0091] In one embodiment, bengalantamine gluconate is present in crystalline solid Form A (anhydrous form). Reference is made to WO 2022 / 150917 (US11795176B2), which is incorporated by reference in its entirety, which discloses a crystalline solid form of bengalantamine gluconate Form A.

[0092] As described therein, polymorph studies were performed on bengalanthamine (ALPHA-1062) using various solvents and crystallization conditions (Table 5 of WO 2022 / 150917) and subsequent XRPD analysis. Seven unique crystalline materials were observed and isolated and designated as Forms A, B, C, D and Materials E, F and G (Figure 6 of WO 2022 / 150917). Form A of bengalanthamine is an anhydrous crystalline material with melting / decomposition onset at around 117°C. Based on WO 2022 / 150917, anhydrous Form A, which is stored under appropriate temperature and humidity conditions to maintain its form and stability, appears to be most suitable for use in the formulation and production of various bengalanthamine forms of pharmaceutical products.

[0093] In one embodiment, the present invention relates to a composition comprising a crystalline solid form of bengalantamine gluconate (Form A), wherein the crystalline form has major peaks at 3.61, 10.98, 14.41 and 18.44 degrees 2-θ (± 0.2) in a powder X-ray diffraction pattern. Although enteric coated formulations have been previously hypothesized, none of the prior art formulations employ Form A. In some embodiments, the use of Form A of bengalantamine gluconate is advantageous because it has high stability during storage, can maintain high chemical stability, no, low or negligible amounts of chemical impurities, and can maintain the stability of Form A itself, thereby avoiding conversion to other forms or hydrates, and has high solubility, thereby also being able to achieve the advantageous effects described herein.

[0094] In one embodiment, in the powder X-ray diffraction pattern, Form A has one or more additional major peaks at 15.20, 17.31, 17.79, 22.77, 23.64, 24.88 and 34.31 degrees 2-θ (± 0.2). These peaks are selected from the list of major peaks provided in WO 2022 / 150917 and do not appear to overlap significantly with the major peaks in the XRPD pattern of Form BD or Material EG. In one embodiment, Form A has at least five major peaks in a powder X-ray diffraction pattern selected from the list consisting of 3.61, 10.98, 13.80, 14.41, 14.56, 15.08, 15.20, 17.02, 17.31, 17.79, 18.44, 19.24, 20.18, 20.91, 21.22, and 22.40 degrees 2-theta (±0.2).

[0095] The use of Form A of bengalantamine gluconate represents a preferred and advantageous embodiment of the present invention, since the stability of Form A can be maintained during storage after formulation. Form A also enables high drug solubility and effective therapeutic effects.

[0096] As demonstrated in the following example (Example 5), the composition of the present invention comprising bengalanthamine gluconate in crystalline solid form A (anhydrous form) has high chemical and crystal stability and favorable dissolution characteristics even under accelerated conditions for long-term storage. No impurities or decomposition products were detected, indicating that the API bengalanthamine in the composition of the present invention has high chemical stability. In addition, compared with the dissolution before storage, no changes in the dissolution in the acidic stage and the buffer stage were observed, indicating that the crystalline form did not change during storage.

[0097] In one embodiment, the tablet core comprises:

[0098] - bengalantamine or its salt in an amount (wt % of tablet core) of 5-20%,

[0099] - water-soluble fillers in an amount of 60-90%,

[0100] - a glidant in an amount of 0.1-5%, and

[0101] - One or more lubricants in an amount of 0.1-5%.

[0102] In one embodiment, the tablet core comprises:

[0103] - bengalantamine or its salt in an amount (wt % of tablet core) of 5-20%,

[0104] - mannitol in an amount of 60-90%,

[0105] - colloidal silicon dioxide in an amount of 0.1-5%,

[0106] - sodium stearyl fumarate in an amount of 0.1-5%, and

[0107] -Magnesium stearate in an amount of 0.1-5%.

[0108] In one embodiment, the tablet core comprises:

[0109] - bengalantamine or its salt in an amount (wt % of tablet core) of 10-15%,

[0110] - mannitol in an amount of 70-90%,

[0111] - colloidal silicon dioxide in an amount of 0.5-2%,

[0112] - sodium stearyl fumarate in an amount of 1-4%, and

[0113] -Magnesium stearate in an amount of 0.5-2%.

[0114] The above formulations and embodiments disclose preferred amounts of each component. Variations of these amounts, or combinations of different ranges of each component in different embodiments are contemplated.

[0115] In one embodiment, the enteric coating is present in an amount of 5-20%, preferably 7-15%, more preferably about 8%, about 10%, about 12% or about 14%, as determined by the % weight gain relative to the tablet core.

[0116] In one embodiment, the film coating is present in an amount of 2-10%, preferably about 3-7%, more preferably about 5%, as determined by the % weight gain relative to the tablet core.

[0117] In one embodiment,

[0118] a. Tablet core includes:

[0119] - bengalantamine or its salt in an amount (wt % of tablet core) of 10-15%,

[0120] - mannitol in an amount of 70-90%,

[0121] - colloidal silicon dioxide in an amount of 0.5-2%,

[0122] - sodium stearyl fumarate in an amount of 1-4%, and

[0123] - magnesium stearate in an amount of 0.5-2%, and

[0124] b. The enteric coating is present in an amount of 7-15%, the amount being determined by the % weight increase relative to the tablet core, and

[0125] c. The film coating is present in an amount of 3-7%, determined by the % weight gain relative to the tablet core, wherein the film coating is in direct contact with the tablet core and is covered by the enteric coating.

[0126] All values ​​provided herein, such as specific preferred values ​​for each component, can vary by + / -2wt%, or + / -1wt%. All values ​​for each tablet component provided herein can be used to characterize the present invention, independent of the presence or amount of any other component, or in combination with other components of the exemplary composition. The preferred range of each component disclosed below can be used to define the composition, independent of other components or in combination with other components. These embodiments are not limited by the total weight of the composition, but in some embodiments, are limited by the wt% value of each component, rather than by absolute weight.

[0127] Embodiments related to bengalantamine (ALPHA-1062) 5 mg, 10 mg or 15 mg tablets:

[0128]

[0129]

[0130] In one embodiment, the composition is configured to release bengalantamine in the small intestine of a subject at a pH of 5.5 and above following administration to the subject.

[0131] In one embodiment, the composition shows a dissolution of at most 10% of bengalantamine after 120 minutes in the acidic phase (pH 1.2) in a dissolution test according to USP 711, and a release of at least 80% of bengalantamine after 60 minutes in a buffered phase (pH 5.5 or 6.8) in a dissolution test according to USP 711.

[0132] In one embodiment, the composition shows a dissolution of at most 10% of bengalantamine after 120 minutes in the acidic phase (pH 1.2) in a dissolution test according to USP 711 and / or a release of at least 80% of bengalantamine after 60 minutes in a buffered phase (pH 5.5 or 6.8) in a dissolution test according to USP 711.

[0133] In one embodiment, the composition shows a dissolution of at most 5% of bengalantamine after 120 minutes in the acidic phase (pH 1.2) in a dissolution test according to USP 711, and a release of at least 80% of bengalantamine after 45 minutes in a buffered phase (pH 5.5 or 6.8) in a dissolution test according to USP 711.

[0134] In one embodiment, the composition shows a dissolution of at most 5% of bengalantamine after 120 minutes in the acidic phase (pH 1.2) in a dissolution test according to USP 711 and / or a release of at least 80% of bengalantamine after 45 minutes in a buffered phase (pH 5.5 or 6.8) in a dissolution test according to USP 711.

[0135] In one embodiment, the composition shows a dissolution of at most 10% of bengalantamine after 90 minutes in a dissolution test according to USP 711 in an acidic phase (pH 1.2) and in the presence of 20% (v / v) or less ethanol.

[0136] In one embodiment, the composition shows that at most 5% of bengalantamine is dissolved after 90 minutes in a dissolution test according to USP 711 in an acidic phase (pH 1.2) and in the presence of 20% (v / v) or less ethanol.

[0137] Even in the presence of up to 20% (v / v) ethanol, under acidic conditions, the composition of the present invention unexpectedly shows no dissolution or dissolution of negligible amounts. In addition, in the presence of up to 20% (v / v) ethanol, under buffered conditions, the composition shows no change in the release characteristics. These results indicate that the dissolution characteristics and release of bengalantamine from the composition of the present invention are advantageously not affected by the presence of alcohol, such as up to 20% (v / v) ethanol. Therefore, the composition of the present invention provides a high safety profile and favorable pharmacokinetic properties even in the presence of alcohol, i.e., when the composition is administered during alcohol intake by a subject.

[0138] In one embodiment, following administration of the composition to a subject, bengalantamine is present at negligible levels or below the limit of detection in the subject's plasma (indicating complete or nearly complete conversion of bengalantamine to galantamine).

[0139] This observation indicates that the present formulation achieves an unexpected and beneficial effect. Previous studies have observed that, for example, when nasal administration is used, a significant amount of bengalantamine (in some cases up to 10% of the administered compound) is not cleaved to release galantamine, and bengalantamine can be observed in the blood of subjects receiving the drug. As shown in the following report on clinical study participants, bengalantamine is (nearly) completely cleaved to galantamine, enabling rapid and complete release of the active agent, and is unexpectedly not associated with adverse reactions, as originally expected when observing the release of galantamine in the gastrointestinal tract.

[0140] In one embodiment, after administering the composition to a subject,

[0141] a. A lower maximum plasma concentration of galanthamine (c) was obtained compared to the immediate-release galanthamine reference composition max ),and

[0142] b. Obtaining a plasma area under the curve (AUC) of galanthamine of 80-125% of the AUC of the reference composition,

[0143] c. wherein preferably the immediate-release galanthamine reference composition is a tablet that does not include a coating, or includes a tablet that is configured to dissolve at a pH below 5.5, and the molar amount of galanthamine is higher than the molar amount of galanthamine in the bengalanthamine in the pharmaceutical composition.

[0144] In one embodiment, after repeated administration of the composition to a subject,

[0145] a. A greater maximum steady-state plasma concentration of galanthamine (c max,ss ),and

[0146] b. Obtaining a plasma area under the curve (AUC) of galanthamine of 80-125% of the AUC of the reference composition,

[0147] c. wherein preferably the sustained-release galanthamine reference composition (8 mg QD) is a solid dosage form configured for sustained-release galanthamine and comprises a molar amount of galanthamine greater than the molar amount of galanthamine in the bengalanthamine (5 mg BID) in the pharmaceutical composition.

[0148] In one embodiment, after administering the composition to a subject, the probability of the subject experiencing adverse events related to the gastrointestinal tract is equal to or less than 2%, such as 2%, 1.8%, 1.6%, 1.4%, 1.2%, 1%, 0.8%, 0.6%, 0.4%, 0.2% and 0%.

[0149] Unexpectedly, the composition of the present invention exhibits excellent pharmacokinetic properties, resulting in a low incidence of adverse reactions, particularly gastrointestinal adverse events, in subjects.

[0150] Therefore, compared with the immediate release formulation, c max Lower, so gastrointestinal adverse events are reduced, and because c max The AUC of galantamine is higher than that of RAZADYNE extended-release capsules, thus maintaining bioavailability, and is similar to oral galantamine compositions known in the prior art. Overall, the compositions of the present invention provide enhanced tolerability and maintained bioavailability, and thus can be considered more effective clinically.

[0151] After bengalantamine is released from the composition of the present invention at pH 5.5 or higher in the intestinal tract, the drug may be converted to galanthamine by the action of esterases in the intestinal tract during the transport process through the intestinal wall and in the (portal vein) blood. Therefore, it was originally expected that the conversion of bengalantamine after release in the intestinal tract would result in galanthamine concentrations activating the enteric cholinergic nervous system, leading to gastrointestinal adverse events such as nausea, vomiting, and diarrhea. However, although bengalantamine is completely or almost completely converted to galanthamine, and no or only negligible amounts of bengalantamine are detected in the bloodstream after administration to the subject, the composition of the present invention beneficially does not result in free galanthamine concentrations in the gastrointestinal tract that trigger the side effect characteristics observed for the immediate-release formulations known in the prior art.

[0152] In one aspect, the present invention relates to a pharmaceutical composition for treating a brain disease associated with cognitive impairment and / or cholinergic insufficiency.

[0153] In a related aspect, the present invention further relates to a method for treating a brain disease associated with cognitive impairment and / or cholinergic insufficiency, comprising administering to a subject in need thereof a pharmaceutical composition as described herein.

[0154] In one embodiment, the brain disease is selected from the group consisting of: a brain disease with cholinergic insufficiency, Alzheimer's disease, Parkinson's disease, dementia, schizophrenia, epilepsy, stroke, poliomyelitis, neuritis, myopathy, hypoxia, anoxia, asphyxia, brain hypoxia and malnutrition after cardiac arrest, chronic fatigue syndrome, poisoning, anesthesia, spinal cord disorders, central inflammatory disorders, Lewy body disease, multiple sclerosis, skeletal muscle pain, autism, Rett's syndrome, motor neuron disease such as amyotrophic lateral sclerosis, traumatic brain injury, post-traumatic stress disorder, postoperative delirium, neuropathic pain, alcohol and drug abuse, addictive alcohol and / or nicotine cravings, severe gastrointestinal (GIT) flatulence, constipation, hypotension, unstable heart rate, and the effects of radiation therapy.

[0155] In one aspect, the present invention relates to a process for preparing a pharmaceutical composition in tablet form according to any one of the preceding claims, wherein the composition is prepared by blending the components of a tablet core to form a blend, compressing the blend to form a tablet core, coating the tablet core with a film coating and coating the film coating with an enteric coating.

[0156] The process for preparing the compositions of the present invention employs direct mixing of excipients that mix well and exhibit good flow properties when blended, allowing for direct compression of the composition blend (also referred to herein as a "blend").

[0157] Surprisingly and beneficially, direct compression can be used to formulate tablets comprising large amounts of bengalantamine and its salts, such as bengalantamine gluconate, preferably Form A. Only a few active ingredients are suitable for direct compression, and usually require careful selection and large amounts of excipients to enable direct compression into tablets. The process of the present invention enables the formulation of bengalantamine tablets with high single dose levels for oral administration in a simple, economical, reliable and high throughput manner, which represents an improvement over other alternative production methods.

[0158] Features of the invention relate to compositions in tablet form as described herein including bengalantamine, and are related to and considered disclosed in combination with other aspects of the invention, such as methods for making the compositions and uses for treating diseases and / or symptoms associated with cognitive impairment and / or cholinergic insufficiency, and vice versa. For example, the composition, method of making, and use of the tablets are directly related to other aspects of the invention and can be used to appropriately characterize them, as will be understood by those skilled in the art. BRIEF DESCRIPTION OF THE DRAWINGS

[0159] The present invention is illustrated by the accompanying drawings disclosed herein. The accompanying drawings provide support for a detailed description of possible preferred non-limiting embodiments of the present invention.

[0160] Figure 1 : Mean plasma bengalantamine concentration versus time graph - linear scale. A clinical study evaluated the galanthamine benzoate (bengalantamine, ALPHA-1062) extended release 5 mg tablet (T) of the present invention versus the galanthamine hydrobromide 4 mg tablet (R).

[0161] Figure 2 : Mean plasma galanthamine concentration versus time graph - linear scale. A clinical study evaluated the bengalanthamine extended release tablets of the present invention, 5 mg tablets (T) versus galanthamine hydrobromide 4 mg tablets (R).

[0162] Figure 3 : Mean plasma galanthamine concentration versus time graph - linear scale. Clinical studies have evaluated the 5 mg bengalanthamine extended-release tablets of the present invention relative to ER (galantamine extended-release capsules) 8mg.

[0163] Figure 4 : Mean plasma bengalantamine concentration versus time graph - linear scale. Clinical studies have evaluated the bengalantamine extended-release tablets of the present invention 5 mg relative to ER (galantamine extended-release capsules) 8mg.

[0164] Figure 5 : Comparison of receiving the pharmaceutical composition of the present invention including bengalantamine or a single dose of galantamine composition ( The incidence of gastrointestinal adverse events in subjects treated with galantamine ER (galantamine extended-release capsules) 8 mg). 1 The data of bengalantamine were combined from different clinical studies, including the bioequivalence study of bengalantamine to IR (Example 2: bengalantamine extended-release tablets 5 mg tablets (T) to galanthamine hydrobromide (Yabao) 4 mg tablets (RT)) and the bioequivalence study of bengalantamine to ER (Example 3: bengalantamine extended-release tablets 5 mg to ER (galantamine extended-release capsules) 8 mg). 2 ISSD: Completed Phase 1 trial in healthy adults; J&J Reminyl NDA package submitted (Prior Art). 3 RAZADYNE Full Prescribing Information (Prior Art). DETAILED DESCRIPTION

[0165] Galantamine ((4aS,6R,8aS)-3-methoxy-11-methyl-4a,5,9,10,11,12-hexahydro-6H-benzofurano[3a,3,2-ef][2]benzazepan-6-ol (CAS 357-70-0)) is a reversible acetylcholinesterase inhibitor (AchEI), thus belonging to the class of reversible AchE inhibitors. It further enhances cholinergic activity through non-competitive allosteric modulation of nicotinic acetylcholine receptors (nAChRs).

[0166] It is approved as an immediate-release tablet and oral solution and as an extended-release capsule and tablet and is and ER (USA) and (elsewhere) for sale.

[0167] The chemical structure of galantamine is:

[0168]

[0169] according to and Full prescribing information for ER (US), its regulatory-approved indication is mild to moderate Alzheimer's type dementia. Based on REMINYL's initial approval in Sweden, followed by multiple approvals in other European countries, its indication is similar to the US approval for mild to moderate Alzheimer's type dementia. Tablets are available as 4 mg, 8 mg, and 12 mg galantamine tablets. ER capsules are available as 8 mg, 16 mg, and 24 mg extended-release capsules. The recommended initial dosing regimen for the 4 mg tablet is twice daily. This dose can be increased up to 12 mg twice daily. The recommended initial dose and dosage regimen for ER capsules is one 8 mg capsule daily, which can be increased to 24 mg once daily.

[0170] Galantamine is well absorbed, with an absolute oral bioavailability of ~90%, and is rapidly and completely absorbed. max When galantamine is administered with a meal, C max Reduced by 25%, and T max Delayed 1.5 hours. Under treatment conditions, the mean distribution volume of galantamine is 175L and the plasma protein binding rate is 18%. In whole blood, galantamine is mainly distributed in the cellular fraction (52.7%) ( 2020). Approximately 1 hour after a single oral dose of 8 mg of galantamine in healthy male subjects, maximum inhibition of acetylcholinesterase activity reached approximately 40% (IB 3rd edition, May 2020). Galantamine is metabolized by hepatic cytochrome P450 (CYP) enzymes, glucuronidated, and excreted unchanged in the urine. In vitro studies have shown that CYP2D6 and CYP3A4 are the main isoenzymes involved in the metabolism of galantamine, and inhibitors of both pathways slightly increase the oral BA of galantamine.

[0171] Bengalantamine, also known as ALPHA-1062 ((4aS,6R,8aS)-4a,5,9,10,11,12-hexahydro-3-methoxy-11-methyl-6H[1]benzofurano[3a,3,2-ef][2]benzazepine-6-benzoate gluconate) (CAS No. 224169-27-1, also known as galantamine benzoate, memogain or GLN-1062) is a galantamine prodrug that has no pharmacological effects on aChE activity or cholinergic activity. It is cleaved by carboxylesterases and in an acidic environment, releasing one galantamine molecule per molecule of the prodrug.

[0172] The chemical structure of bengalantamine is:

[0173]

[0174] Acetylcholine (ACh) is a neurotransmitter that acts on postsynaptic muscarinic acetylcholine (mAChR) or nicotinic acetylcholine receptors (nAChR). ACh is cleaved by acetylcholinesterase (aChE) present in the synaptic cleft, thereby inhibiting aChE and thus cleaving ACh, resulting in an increase in the concentration of ACh in the synaptic cleft. ACh is present in the central nervous system (CNS) and the peripheral nervous system (PNS). The PNS can be further subdivided into the somatic nervous system and the autonomic nervous system (parasympathetic nervous system, sympathetic nervous system, and enteric nervous system). In the somatic nervous system, ACh is a neurotransmitter at the neuromuscular end plate. In addition, ACh appears as a neurotransmitter in preganglionic sympathetic nerves and all parasympathetic nerves, mediating signal transmission from postganglionic parasympathetic neurons to end organs. The effects of ACh include mediating skeletal muscle contraction, regulating the autonomic nervous system, such as affecting blood pressure, heart rate, digestion and metabolism, and further regulating reward and cognitive functions in the CNS. ACh deficiency (cholinergic insufficiency) may lead to impaired function and action of ACh in the somatic and autonomic nervous systems and further in the CNS, resulting in impaired cognitive function (cognitive impairment), impaired learning and memory.

[0175] Diseases and / or symptoms associated with cognitive impairment and / or cholinergic insufficiency include, but are not limited to, brain diseases with cholinergic insufficiency, Alzheimer's disease, Parkinson's disease, dementia, schizophrenia, epilepsy, stroke, poliomyelitis, neuritis, myopathy, hypoxic brain hypoxia and malnutrition, hypoxia, asphyxia, cardiac arrest, chronic fatigue syndrome, poisoning, anesthesia, spinal cord disorders, central inflammatory disorders, Lewy body disease, multiple sclerosis, skeletal muscle pain, autism, Rett syndrome, motor neuron diseases such as amyotrophic lateral sclerosis, traumatic brain injury, post-traumatic stress disorder, postoperative delirium, neuropathic pain, alcohol and drug abuse, addictive alcohol and / or nicotine cravings, severe gastrointestinal (GIT) flatulence, constipation, hypotension, unstable heart rate, and the effects of radiation therapy. These medical indications represent preferred embodiments of the medical use of the present invention in the treatment of diseases and / or symptoms associated with cognitive impairment and / or cholinergic insufficiency.

[0176] "Administration" or "treatment", as it applies to an animal, a human, an experimental subject, a cell, a tissue, an organ, or a biological fluid, means contacting a drug, therapeutic agent, diagnostic agent, compound, or composition with an animal, a human, a subject, a cell, a tissue, an organ, or a biological fluid. "Administration" and "treatment" may refer to, for example, therapeutic agents, placebos, pharmacokinetics, diagnostics, research and experimental methods. The term "subject" includes human and veterinary subjects. "Treatment", as it applies to a human, veterinary, or research subject, refers to therapeutic treatment, preventative or prophylactic measures, research and diagnostic applications.

[0177] The present invention encompasses administering an effective amount of a chemical substance as described herein to a subject or patient in need thereof. An "effective amount" or "therapeutically effective amount" means an amount sufficient to cause a significant biological response, such as an improvement in symptoms or signs of a disease or physiological condition, when administered to a subject or patient. The effective amount for a particular patient or veterinary subject can vary according to factors such as the disease being treated and the patient's overall health and age. An effective amount can be the maximum dose or dosing regimen that avoids significant side effects or toxic effects. An "effective amount" also relates to an amount of a prodrug substance or a pharmaceutical composition thereof that is sufficient to allow or promote a significant biological response, such as an improvement in a disease, condition or pathological state and its symptoms or signs.

[0178] A prodrug is defined as an inactive or less active agent that is converted (also referred to as "metabolized") into an active agent (also referred to as a "metabolite") in an organism. In this case, a prodrug is an inactive or less active precursor of an active drug that is converted into the active form of the drug in a predictable manner in vivo by enzymatic cleavage or one or more non-enzymatic chemical processes. Prodrugs are developed to affect the physicochemical, sensory, pharmacokinetic and pharmacodynamic properties of active drugs. Typically, a prodrug is characterized by chemical coupling of the drug to a carrier molecule, which is cleaved in the organism (carrier-bound prodrug), resulting in conversion to an active drug. Common carrier-bound prodrugs include coupling carriers via covalent ester bonds (ester prodrugs). Other types of prodrugs include bioprecursors, which are not coupled to a carrier molecule, but are directly metabolized or conjugated in the organism to produce an active drug, as well as co-prodrugs (mutual prodrugs), which include two or more active drugs coupled to each other. The prodrug of the present invention, bengalantamine, comprises a covalent ester bond between the active drug galantamine and benzoic acid, which upon cleavage releases the active drug galantamine.

[0179] The present invention further relates to a salt of bengalantamine. In some embodiments, bengalantamine is present as a salt of bengalantamine, or as a crystalline form of bengalantamine, or as a polymorph or hydrate of bengalantamine. The term "salt" refers to salts prepared by conventional methods, meaning alkaline salts including inorganic and organic acids, including but not limited to acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, gluconate, gluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3-phenyl-propionate, picrate, pivalate, propionate, saccharate, succinate, tartrate, thiocyanate, toluenesulfonate and undecanoate. For therapeutic use, salts of the compound are those in which the counterion is a pharmaceutically acceptable salt. However, salts of acids and bases that are non-pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound.

[0180] In a preferred embodiment, the salt comprises a stoichiometric and / or non-stoichiometric salt and / or hydrate of bengalantamine, whereby the salt is preferably described as:

[0181] Bengalantamine·n HX·m H2O,

[0182] wherein n, m=0-5, and n and m may be the same or different, and HX=acid, preferably selected from acetic acid, citric acid, lactic acid, gluconic acid, maleic acid or saccharic acid.

[0183] Preferred are the quaternary nitrogen salts (also referred to herein as "quaternary ammonium salts") of bengalantamine with gluconic acid (gluconate), acetic acid (acetate), maleic acid (maleate), lactic acid (lactate), citric acid (citrate) and saccharic acid (glucarate).

[0184] The salts of bengalantamine disclosed in the prior art include maleate, lactate, glucarate and gluconate. In a preferred embodiment of the present invention, bengalantamine or its salt is bengalantamine gluconate.

[0185]

[0186] The chemical structure of bengalantamine (ALPHA-1062) gluconate is:

[0187] For example, the gluconate salt of bengalantamine can be created according to the following established general protocol:

[0188]

[0189] In one embodiment, the composition comprises a crystalline solid form of bengalantamine gluconate (Form A), wherein the crystalline form has major peaks at 3.61, 10.98, 14.41 and 18.44 degrees 2-θ (± 0.2) in a powder X-ray diffraction pattern. The use of Form A represents a preferred embodiment and can be combined with any one or more other embodiments or aspects of the present disclosure.

[0190] These 4 peaks are selected from the list of major peaks provided below and do not appear to overlap significantly with the major peaks in the XRPD patterns of Form BD or Material EG disclosed in WO 2022 / 150917. In one embodiment, therefore, when comparing the corresponding powder X-ray diffraction patterns, one or more major peaks (e.g., as described above) can be used to reliably distinguish Form A. In one embodiment, the presence of these peaks in a powder X-ray diffraction pattern can be used to identify Form A and / or distinguish Form A from solid forms previously described in the art (e.g., those described in WO2014 / 016430).

[0191] In one embodiment, in the powder X-ray diffraction pattern, Form A has one or more additional major peaks at 15.20, 17.31, 17.79, 22.77, 23.64, 24.88 and 34.31 degrees 2-θ (± 0.2). These peaks are selected from the main peak list and do not appear to overlap significantly with the major peaks in the XRPD pattern of Form BD or Material EG.

[0192] In one embodiment, Form A has at least five major peaks in a powder X-ray diffraction pattern selected from the list consisting of 3.61, 10.98, 13.80, 14.41, 14.56, 15.08, 15.20, 17.02, 17.31, 17.79, 18.44, 19.24, 20.18, 20.91, 21.22, and 22.40 degrees 2-theta (±0.2).

[0193] Generally, it is not necessary to detect all of the peaks in this list to determine the presence of Form A in any given formulation. According to the present invention, for example, in some embodiments, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more peaks (preferably those with relatively high signal intensities) can be used to determine any given crystalline form. For example, 4, 5, 6, 7, 8, 9 or 10 of the strongest peaks can be used to identify any given crystalline form. In one embodiment, when the presence of at least three or four major peaks can be determined based on XRPD comparison, a full identification of any given crystalline form such as Form A is achieved.

[0194] Typically, the major XRPD peak is the strongest low-angle, non-overlapping peak observed in the XRPD pattern. In some embodiments, in the powder X-ray diffraction pattern, the "major peak" preferably has ≥20% relative intensity, preferably ≥30% relative intensity, and more preferably ≥40% relative intensity. However, the value of relative intensity can vary depending on the device or analysis mode, and is not essentially limited to the solid forms described herein.

[0195] In one embodiment, in the powder X-ray diffraction pattern, Form A has peaks at 7.25 and / or 12.67 degrees 2-θ (± 0.2). The intensity of these peaks is relatively low compared to the peaks summarized above as major peaks. However, the peaks at 7.25 and / or 12.67 degrees 2-θ do not appear to be present in all other patterns of Form BD or Material EG.

[0196] In one embodiment, the peaks are determined using powder X-ray diffraction analysis in transmission mode.

[0197] In one embodiment, Form A has at least three peaks selected from the list consisting of 10.98, 14.41, 17.31, 18.44, and 22.40 degrees 2-theta (± 0.2) in a powder X-ray diffraction pattern. In one embodiment, the three peaks are within the five peaks with the highest relative intensity in a powder X-ray diffraction pattern obtained using analysis in transmission mode. In one embodiment, these five peaks are the highest intensity peaks in an XRPD pattern using transmission mode, as outlined in the Examples below.

[0198] In one embodiment, the peaks are determined using powder X-ray diffraction analysis in reflection mode.

[0199] In one embodiment, Form A has at least three peaks selected from the list consisting of 3.61, 7.25, 10.98, 14.56 and 22.40 degrees 2-theta (± 0.2) in a powder X-ray diffraction pattern. In one embodiment, the three peaks are preferably within the five peaks with the highest relative intensity in a powder X-ray diffraction pattern obtained using analysis in reflection mode. In one embodiment, these five peaks are the strongest peaks in an XRPD pattern using reflection mode, as outlined in the following examples.

[0200] In one embodiment, in the powder X-ray diffraction pattern, Form A has one or more peaks selected from the list consisting of 3.61, 7.25, 10.98, 14.56, 22.40 degrees 2-θ (± 0.2). These peaks can also be observed from the XRPD pattern using the reflection mode.

[0201] In one embodiment, in the powder X-ray diffraction pattern, Form A has one or more double peaks selected from the list consisting of 14.41 and 14.56, 15.08 and 15.20, and 24.88 and 25.09 degrees 2-θ (± 0.2). These double peaks can be used to identify Form A and, optionally, distinguish this form from other forms.

[0202] Provided below is a table of typical observed XRPD pattern peaks for Form A collected in transmission mode.

[0203] Peak List Form A: The peak list was determined from the powder X-ray diffraction pattern of Form A according to Figure 8 of WO 2022 / 150917. The precision of the 2-theta degrees is given to 2 decimal places and there may be some batch or device specific variation.

[0204]

[0205] *In some embodiments, a peak may be considered as the major peak observed in an XRPD pattern.

[0206] In one embodiment, Form A exhibits an onset of melting at a temperature of 116-120°C, preferably at about 117°C, when evaluated using differential scanning calorimetry (DSC).

[0207] In one embodiment, Form A exhibits a weight loss of <1%, preferably <0.5%, more preferably less than <0.3%, or <0.2% prior to onset of melting using DSC when evaluated using thermogravimetric analysis (TGA).

[0208] In other embodiments, the composition includes a crystalline solid form of bengalantamine gluconate, referred to as Form B, wherein the crystalline form has a main peak at 10.69, 17.17, 21.00, and 24.67 degrees 2-θ (± 0.2) in a powder X-ray diffraction pattern. In one embodiment, in a powder X-ray diffraction pattern, Form B may have one or more main peaks selected from a list consisting of 10.69, 12.92, 13.26, 14.56, 16.45, 17.17, and 21.00 degrees 2-θ (± 0.2). In one embodiment, when evaluated using thermogravimetric analysis (TGA), up to 114 ° C, Form B exhibits 3-4%, more preferably about 3.3% weight loss. In one embodiment, when evaluated using thermogravimetric analysis (TGA), up to 147 ° C, Form B exhibits 5-6%, more preferably about 5.2% weight loss. In one embodiment, Form B has good solubility in water and can be suitable for use in the present pharmaceutical formulations.

[0209] In other embodiments, the composition comprises a crystalline solid form of bengalantamine gluconate, referred to as Form C, wherein the crystalline form has a major peak at 3.90, 9.74, 10.35 and 21.43 (optionally also 15.66 and / or 23.90) degrees 2-θ (± 0.2) in a powder X-ray diffraction pattern. In one embodiment, Form C may have one or more major peaks selected from the list consisting of 3.90, 9.74, 10.35, 10.65, 13.35, 15.01, 15.66, 16.08, 16.46, 17.43, 19.77, 21.43 and 22.32 degrees 2-θ (± 0.2) in a powder X-ray diffraction pattern. In one embodiment, Form C exhibits an onset of melting at a temperature of 115-125° C., preferably at about 119° C., when evaluated using differential scanning calorimetry (DSC). In one embodiment, Form C exhibits a weight loss of 0.5-1.5%, preferably about 0.9%, up to 121° C., when evaluated using thermogravimetric analysis (TGA). In one embodiment, Form C has good solubility in water and may be suitable for use in the present pharmaceutical formulations.

[0210] In other embodiments, the composition comprises a crystalline solid form of bengalantamine gluconate, referred to as Form D, wherein the crystalline form has a major peak at 3.76, 10.16, 14.77 and 19.03 (optionally 17.96, 18.86 and / or 28.14) degrees 2-θ (± 0.2) in a powder X-ray diffraction pattern. In one embodiment, Form D may have one or more major peaks selected from the list consisting of 3.76, 10.16, 13.35, 13.75, 14.77, 16.27, 16.70, 17.24, 17.96, 18.86, 19.03, 19.87 and 20.15, 21.21 degrees 2-θ (± 0.2) in a powder X-ray diffraction pattern.

[0211] In other embodiments, the composition includes an amorphous solid form of bengalantamine gluconate.

[0212] Various solid forms of bengalantamine gluconate are described in WO2022 / 150917 and US11795176B2, which are incorporated herein by reference. Any one or more solid forms disclosed in WO2022 / 150917 and US11795176B2 can be used in the pharmaceutical composition of the present invention.

[0213] As used herein, crystalline preferably means a material having an ordered, long-range molecular structure.The degree of crystallinity of a crystalline form can be determined by a number of techniques including, for example, powder X-ray diffraction, water sorption, differential scanning calorimetry, solution calorimetry, and solubility characteristics.

[0214] Crystalline organic compounds are composed of a large number of atoms, which are arranged in a periodic array in three-dimensional space. Structural periodicity usually exhibits unique physical properties, such as sharp, clear spectral features of most spectroscopic probes (e.g., X-ray diffraction, infrared and solid-state NMR). X-ray diffraction (XRD) is considered to be one of the most sensitive methods for determining the crystallinity of solids. Crystals produce clear diffraction maxima, which appear at specific angles consistent with the lattice interplanar spacing, as predicted by Bragg's law. In contrast, amorphous materials do not have long-range order. They usually retain additional volume between molecules, such as in a liquid state. Due to the absence of long-range order of a repeating lattice, amorphous solids usually present featureless XRD patterns with extensive diffuse halos.

[0215] In many pharmaceutical applications, crystalline forms are preferred. Crystalline forms are usually more stable than amorphous forms of the same substance thermodynamically. This thermodynamic stability is preferably reflected in the improved physical stability of the crystalline form. The regular accumulation of molecules in crystalline solids preferably prevents the incorporation of chemical impurities. Therefore, crystalline materials usually have a higher chemical purity than their amorphous counterparts. The accumulation in crystalline solids usually limits molecules to clear lattice positions and reduces the molecular mobility that is a prerequisite for chemical reactions. Therefore, except for very few significant exceptions, crystalline solids are chemically more stable than amorphous solids of the same molecular composition. Preferably, the crystalline form of bengalanthamine gluconate disclosed in the present application has one or more of the favorable chemical and / or physical properties disclosed herein.

[0216] As used herein, the term stable can relate to chemical stability or polymorph stability. Polymorph stability refers to the likelihood that a polymorphic form will retain its specific crystalline state under appropriate storage conditions. For example, a stable polymorphic form will retain at least about 95% by weight, preferably at least about 98% by weight, and more preferably at least about 99% by weight or more of the crystalline form, in other words, the form remains unchanged after storage for a specified period of time under specified conditions. In the context of the present invention, Form A of bengalantamine gluconate appears to show good stability, for example, under storage conditions of room temperature and low water activity, such as at about 43% RH or less than 0.12a. w In some embodiments, Form A exhibits good chemical stability. In other words, after storage under appropriate conditions, bengalantamine gluconate in Form A exhibits low, negligible, or no conversion to a different chemical structure.

[0217] Powder X-ray diffraction (XRPD) measures the diffraction pattern of crystalline materials. Each active pharmaceutical ingredient (API) will produce a specific pattern based on the structure of its crystal lattice. Each polymorph, pseudopolymorph, polymorphic salt or co-crystal material will have its own specific pattern. Therefore, XRPD can be performed on the API under controlled conditions to assess the presence of crystalline material and any form conversion.

[0218] PXRD can also be used to determine whether any crystalline form changes occur in a drug product during, for example, storage or stability studies. Therefore, the identification of crystalline form depends on the presence of detectable diffraction peaks for any given crystalline form. In addition, if the composition is evaluated after formulation, the API peak must be distinguished from any crystalline excipient peak. PXRD can also be used for qualitative and sometimes quantitative assessments of pure API crystallinity. Technicians can evaluate PXRD patterns and identify the presence and / or absence of suitable peaks that can be used to characterize any given API crystalline form without excessive effort.

[0219] In some embodiments, the peaks determined by PXRD analysis are substantially the same as those presented in the following examples. The term "substantially the same" with respect to PXRD means that variations in peak position and peak relative intensity are taken into account. For example, the typical accuracy of 2-θ values ​​is within the range of ± 0.2 ° 2-θ.

[0220] As used herein, characteristic XRPD peaks are a subset of representative peaks of the XRPD pattern of a crystalline form of a material that can be statistically demonstrated to be distinguishable from other crystalline forms of the material. Not all crystalline polymorphs of a material necessarily have characteristic peaks.

[0221] As used herein, a major XRPD peak is generally the strongest low-angle, non-overlapping peak observed in an XRPD pattern. In some embodiments, in a powder X-ray diffraction pattern, a "major peak" preferably has ≥20% relative intensity, preferably ≥30% relative intensity, more preferably ≥40% relative intensity.

[0222] As used herein, representative XRPD peaks are peaks in an XRPD pattern of a crystalline form of a material that show statistically no bias from particle size / shape or preferred orientation over repeated sampling and measurement.

[0223] As used herein, preferred orientation is a phenomenon observed in XRPD analysis where it is very difficult or impossible to randomly orient particles of material during the collection process to achieve a pattern with statistically consistent intensity due to the size / shape of the particles and the pattern collection technique employed.

[0224] With regard to the relative intensities and major peaks of the above-mentioned powder X-ray diffraction patterns, the relative intensity values ​​provided are not intended to limit the identification of the major or characteristic peaks. As known to the skilled person, the relative peak intensities will show some instrument-to-instrument variability, batch-to-batch variability, and variability due to crystallinity, preferred orientation, sample preparation, and are therefore only an indication and qualitative measurement of the peak intensity in the powder X-ray diffraction pattern, rather than a restrictive definition.

[0225] Therefore, in the context of limiting the present invention, the term "main peak" is not limited to the respective relative intensities provided above, and any one or more of the respective peaks can be determined as the main peak of any given form of bengalanthamine gluconate. Preferably, at least 1, 2, 3 or 4 main peaks are used to characterize the crystalline form, and in other embodiments, at least 5, 6, 7, 8, 9 or 10 main peaks can be used. Therefore, the main peak is also not limited to the peak peculiar to any given crystal form, but the peak can be optionally combined with many other peaks in the PXRD diagram for identifying the crystal form. In the context of the present invention, crystal forms AD can share multiple main peaks, but can also show peaks different from each other, which can be used to distinguish any two forms. In some embodiments, the main peak mentioned in the embodiments of the present invention can also be a characteristic peak and / or a representative peak.

[0226] The term "active ingredient" or "API" herein refers to a pharmaceutically active molecule and a prodrug that is converted into a pharmaceutically active molecule in an organism (e.g., bengalantamine (ALPHA-1062)), and a pharmaceutically acceptable and / or therapeutically active salt thereof (e.g., bengalantamine (ALPHA-1062) gluconate). The term further refers to pharmaceutically acceptable and therapeutically active hydrates, esters, amides, metabolites, enantiomers, polymorphs, analogs, etc., which induce a desired pharmacological or physiological effect or induce a desired pharmacological or physiological effect after being converted into a pharmaceutically active molecule in an organism. Terms such as "active agent", "active pharmaceutical ingredient", "drug substance" can be used synonymously with "active ingredient". The term "pharmaceutically active molecule" herein refers to a molecule that induces a desired pharmacological or physiological effect in an organism and / or a subject. Terms such as "active drug", "active molecule", "therapeutically active molecule", "therapeutically active drug" can be used synonymously with "pharmaceutically active molecule".

[0227] As used herein, a "tablet" is considered to be a solid unit dosage form of a drug comprising one or more excipients.

[0228] The term "excipient" means a pharmacologically inactive component of a drug product, such as fillers, lubricants, binders, disintegrants, glidants, flavoring agents, sweeteners, colorants, film formers, gelling agents, acid regulators, preservatives, absorption promoters, stabilizers, etc. Excipients used to prepare pharmaceutical compositions are generally safe, non-toxic, and acceptable for veterinary as well as human pharmaceutical use. References to excipients include one excipient and more than one excipient.

[0229] In some embodiments, the excipients described herein are described in terms of "wt%" or "weight percent" or "% by weight." The %wt values ​​described herein preferably relate to the weight percentage of the material present in a pharmaceutical composition in tablet form.

[0230] According to the present invention, fillers can be used as fillers in tablets. Fillers for tablets include, but are not limited to, sugars and sugar alcohols such as lactose, sucrose, glucose, mannitol, sorbitol, xylitol, etc., oligosaccharides and polysaccharides such as corn starch, rice starch, potato starch, wheat starch, modified starch derivatives, cellulose, microcrystalline cellulose (MCC), etc., inorganic binders such as calcium phosphate, calcium hydrogen phosphate, calcium carbonate, and mixtures thereof.

[0231] According to an embodiment of the present invention, a preferred filler is mannitol. Mannitol (CAS No. 69-65-8) is a hexavalent sugar alcohol, the structure of which is derived from mannose and naturally present in plants, algae and lichens, etc. In the pharmaceutical industry, mannitol is used as a filler, a sweetener and a binder. In the context of the present invention, mannitol is defined as a filler, preferably a water-soluble filler.

[0232] Glidants improve the flow properties of a powder mixture by reducing interparticle friction, thereby allowing the powder to flow better from the filling slot into the die of the tablet press. Thus, flow regulators also improve dosing accuracy. In particular, highly dispersed silicon dioxide such as colloidal silicon dioxide is used as a glidant.

[0233] Silica is an oxide of silicon. It is a natural substance, for example found in crystalline form in quartz, granite and sand, and is used in the production of glass. In the pharmaceutical industry, various grades of silica are widely used as excipients. Therefore, in particular, highly dispersed silicas such as colloidal silica are used as glidants. The production of colloidal or highly dispersed silica is carried out by flame hydrolysis of SiCl4, resulting in submicroscopic amorphous spheres with a diameter of about 7-16 nm and a very large surface area of ​​about 200 m2 / g. Usually, the addition of a small amount of about 0.5% is sufficient to achieve significantly improved flow properties of the powder.

[0234] Lubricant is an excipient added to promote the tableting process. Lubricant can promote the fluidity of powder, make it easy to fill into the mold, can reduce the friction between the powder itself and the friction between the mold, punch, particles and powder, and can promote tablet compression and discharge from the mold. Therefore, lubricant can prevent tablet compounds and tablets from adhering to the tablet press punch and mold. Lubricants for preparing tablets include magnesium stearate, calcium behenate, glyceryl monostearate, stearic acid, sodium stearyl fumarate, talc, hydrated vegetable fats such as hydrogenated castor oil, hydrogenated cottonseed oil and mixtures thereof. According to the present invention, one or more lubricants are preferably selected from the group consisting of sodium stearyl fumarate and magnesium stearate.

[0235] Sodium stearyl fumarate (CAS No. 4070-80-8) is synthesized by reacting stearyl alcohol with maleic anhydride. The product of this reaction then undergoes an isomerization step and then forms a salt to produce sodium stearyl fumarate. Sodium stearyl fumarate is used as a lubricant in oral pharmaceutical preparations and is generally considered to be a non-toxic and non-irritating material.

[0236] Magnesium stearate (CAS No. 557-04-0) is the magnesium salt of stearic acid and belongs to the group of lime soaps. Magnesium stearate is a salt consisting of magnesium ions (Mg2+) and two stearate ions. Magnesium stearate is insoluble in water. It has a lamellar crystal structure, resulting in reduced internal friction, and a very small particle size of 3 to 15 μm. Therefore, magnesium stearate is very suitable for use as a lubricant because it adheres to the surfaces of other particles in a powder mixture, reducing inter-particle friction and friction with external surfaces.

[0237] In one embodiment, the composition of the present invention may optionally include additional excipients, such as binders, disintegrants and / or flavoring agents.

[0238] Binders bind the ingredients in the tablet together and increase the hardness and stability of the tablet. The use of binders in the granulation process and for direct compression of tablets ensures that tablets and granules with the required mechanical strength can be formed. Binders are preferably large molecular polar amorphous substances, which, due to their amorphous nature, show isotropic deformation behavior and provide optimal conditions for pouring into any available cavity during the compression process. Binders used in granulation act as processing aids during the granulation process. In the process of direct compression of tablets, binders are used to increase the cohesion of the powder particles during the compression process to obtain a pharmaceutical form with a specified hardness.

[0239] Binders can be classified into natural binders, semisynthetic polymer binders and synthetic polymer binders. In the context of the present invention, the expression "natural binder" refers to natural polymer binders or their salts or inorganic binders, including starch, processed or pretreated starch or starch salts, such as corn starch, potato starch, sodium starch, pregelatinized starch; alginic acid or its salts, such as sodium alginate; gelatin; guar gum; gum arabic; candelilla wax; carnauba wax, dextran, sugars and hexitols such as lactose, mannitol, sucrose and inorganic calcium compounds such as calcium hydrogen phosphate and tricalcium phosphate.

[0240] The expression "semi-synthetic polymer binder" refers to chemical derivatives of natural polymer binders, including chemical derivatives of cellulose or starch, preferably selected from the group consisting of hydrolyzed starches such as dextran and maltodextrin, hydroxypropyl cellulose (HPC, hydroxypropyl cellulose), hydroxypropyl methylcellulose (HPMC, hydroxypropyl methylcellulose), methylcellulose (MC), hydroxypropyl cellulose (HPC, hydroxypropyl cellulose), sodium carboxymethyl cellulose and hydroxypropyl starch, microcrystalline cellulose (MC).

[0241] The expression "polymer binder" refers to a completely chemically synthesized non-natural polymer or copolymer binder, preferably selected from the following group: polyvinyl alcohol, polyvinyl caprolactam-polyvinyl acetate, polyethylene glycol (PEG), polyethylene glycol graft copolymer, and polyethylene glycol-polyvinyl alcohol graft copolymer (PEG-PVA), povidone (PVP), copolyvidone (COP), and cross-polyvidone (XPVP).

[0242] Disintegrants are excipients used in tablets that cause tablet disintegration, dissolution, and release of the active ingredient when in contact with moisture. Disintegrants can be classified into substances that increase capillary action, absorb moisture and swell, compounds that burst with gas release when exposed to moisture, and substances that increase the wettability of the tablet (hydrophilic agents).

[0243] The material that increases capillarity includes soybean polysaccharide, alginic acid, cross-linked alginic acid, calcium alginate, sodium alginate, starch such as corn starch, pre-treated starch such as pre-gelatinized starch, sodium carboxymethylcellulose, cross-linked sodium carboxymethylcellulose, sodium carboxymethyl starch, cross-linked sodium carboxymethyl starch, sodium starch glycolate, polyvinyl pyrrolidone and cross-linked polyvinyl pyrrolidone. The influence of this group is significantly that the expansion pressure applied, the porosity and wettability of the tablet affect the penetration of water to the tablet, which is a prerequisite for the disintegration process. If these disintegrants have high expansion, high expansion pressure and form a pore system with sufficient wettability in the tablet, they are efficient.

[0244] Compared with other disintegrants, high-efficiency disintegrants are more effective at much lower concentrations, with higher disintegration efficiency and mechanical strength, and are called super disintegrants. Super disintegrants include soybean polysaccharides, cross-linked alginic acid, sodium carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch, cross-linked sodium carboxymethyl starch, sodium starch glycolate, polyvinyl pyrrolidone and cross-linked polyvinyl pyrrolidone. These water-insoluble substances have high swelling capacity and high capillary activity, and ensure spontaneous and complete disintegration without forming mucus.

[0245] Compounds that explode with the release of gas when exposed to moisture include sodium bicarbonate and combinations of bicarbonate with citric or tartaric acid. Tablets with this type of disintegrant disintegrate rapidly due to the release of carbon dioxide upon acidic reaction. These disintegrants are often used in oral tablets or effervescent tablets.

[0246] Hydrophilic agents include sodium lauryl sulfate, polysorbate, highly dispersed silicon dioxide and microcrystalline cellulose (MCC). Representatives of this group are not technically considered disintegrants per se. Rather, they enable disintegrants to become optimally effective. The tableting of lipophilic substances usually causes considerable difficulties, because the wettability of such tablets is low, so the incorporated disintegrants have no effect or only a very delayed effect. The addition of surfactants (hydrophilic agents) that hydrophilize the tablets ensures that water penetrates into the tablet and acts on the incorporated disintegrant.

[0247] In order to correct the taste, flavoring agents and sweeteners such as sugar, sugar substitutes and sugar substitutes can be optionally added to the composition of the present invention. The taste receptors of the tongue can distinguish the following tastes: sweet-sour-bitter-salty-fresh. The basic taste of the medicine can be coordinated by adding the flavoring agent or sweetener of the same or similar taste direction (for example, coordinating the sour taste with lemon), or the flavoring agent or sweetener of the opposite taste direction is covered (for example, covering the bitter taste with vanilla). Because sugar (sucrose) is unstable in hydrolysis under the presence of acidic active ingredients, and has the effect of promoting dental caries and providing heat, it is increasingly replaced by sweeteners such as fructose, sorbitol, mannitol, xylitol, sodium cyclamate, saccharin or aspartame as a sweetener.

[0248] The method for preparing tablets includes direct tableting (direct compression) and granulation (including wet and dry granulation) followed by compression. Tablet compression is carried out by a tablet press, which is a high-speed mechanical device. Two types of tablet presses are mainly used, including eccentric tablet presses and rotary tablet presses. Both have two movable punches (lower punch and upper punch), a die and a hopper per functional unit. These types of tablet presses and their uses are known to those skilled in the art. According to the present invention, direct compression is preferred.

[0249] In most cases, the active ingredient and excipients need to be granulated before tableting, i.e., to convert the powder into granules. This results in a product with a larger particle size, which has better flowability compared to powder granules. This ensures continuous and uniform filling of the tablet press die, resulting in a constant tablet quality and high dosing accuracy. Granules are asymmetric aggregates of powder particles, which usually do not have a harmonious geometry and have an uneven, jagged or rough surface, thus having good compressibility. Techniques for preparing granules include wet and dry granulation and are known to those skilled in the art.

[0250] Direct compression is the compression of a powdered active ingredient or a mixture of an active ingredient and an excipient. According to an embodiment of the present invention, a powder or a powder blend, also referred to herein as a "composition blend" or "blend", is compressed, which is a substantially dry solid, preferably consisting of a large number of fine particles that can flow when shaken or tilted.

[0251] Direct compression is characterized by a lower workload and is therefore more economical than granulation, which requires a previous granulation step before tablet compression. Direct compression is particularly advantageous for processing moisture- and heat-sensitive active ingredients, for which stability risks exist during the granulation operation.

[0252] However, not all active ingredients and excipients are suitable for direct compression, because the cohesive force between the blended particles may not be enough to form a tablet with sufficient hardness, or the powder flowability hinders the direct processing of the composition blend. By adding excipients such as binding agents, glidants, lubricants, powder blends suitable for direct compression can be obtained. In addition, good miscibility of excipients and active ingredients is a prerequisite for direct compression. Powder mixtures tend to separate, for example, due to different sizes and densities of excipient and active ingredient particles. The uniformity of the mixture must be ensured in all process steps.

[0253] Tablet coating is the process of applying a substantially dry outer layer of coating material to the surface of a dosage form such as a tablet. Typically, tablet coating involves applying a sugar or polymer coating to the tablet. The advantages of tablet coating can involve one or more of taste masking, odor masking, physical and chemical protection, or release characteristic control. There are two main methods of coating commonly applied to pharmaceutical dosage forms: roller coating and fluidized bed coating. Roller coating is commonly used to coat larger, non-fluidizable particles such as tablets and capsules. And roller coating can also be used to coat pills. Those skilled in the art can select a suitable coating method based on the dosage form and coating agent.

[0254] For quick-release tablets, film coating is applied, which will not significantly change the dissolution characteristics of the core tablet. Film coating is generally used to better visually distinguish different tablet strengths by color, to avoid medication errors, and to improve patient acceptance, such as easier to swallow. As disclosed in the U.S. FDA guide "Size, Shape, and Other Physical Attributes of Generic Tablets and Capsules" (June 18, 2015), the presence of coating can potentially affect the ease of swallowing tablets. Compared with coated tablets of the same size and shape, lack of film coating may also reduce or prevent tablet movement, and increase esophageal transit time. Coating can also affect other factors that contribute to patient acceptance, such as palatability and smell.

[0255] Film coating can also be used as the basis (also referred to as bottom coating) of applying one or more further coatings such as enteric coating and / or top coating on film coating. Bottom coating can prevent active ingredient from interacting with other coatings such as enteric coating. Material (" coating agent ") for film coating is known to technicians, and includes but is not limited to hydroxypropyl methylcellulose (HPMC, hydroxypropyl methylcellulose), polyethylene glycol (PEG, Macrogol), copolyvidone, polyvinyl alcohol and / or methacrylate polymer such as Eudragit E100. In addition to polymer, film coating can include further excipients, including but not limited to plasticizer, colorant and / or opacifier.

[0256] "Enteric coating" prevents tablets from dissolving or disintegrating in the acidic environment of the stomach. Enteric coating is generally used to protect drugs from degradation by enzymes present in acidic pH and stomach. Enteric coating can further prevent adverse reactions associated with drug dissolution in the stomach. In addition, enteric coating can be configured to dissolve at a certain pH to control the release of drugs from tablets in the gastrointestinal tract. In one embodiment, enteric coating is configured to dissolve at pH 5.5 or higher. In one embodiment, enteric coating is configured to release bengalantamine in the small intestine of a subject at pH 5.5 and higher. The material used for enteric coating is known to the technician, and includes but is not limited to copolymers of poly (meth) acrylate polymers such as methacrylic acid and ethyl acrylate, cellulose acetate phthalate (CAP), cellulose acetate succinate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate phthalate (PVAP), shellac, cellulose acetate trimellitate and / or sodium alginate.

[0257] Eudragit L-55 is an anionic copolymer of methacrylic acid and ethyl acrylate in an acid ester ratio of about 1: 1. The polymer is soluble at pH 5.5 or higher. The polymer is commercially available as Eudragit L 30D-55 (30% aqueous dispersion), Eudragit L 100-55 (powder), or Acryl-Eze II.

[0258] After administration to a subject, a drug undergoes a variety of actions and processes, known as the pharmacokinetics of the drug. The sum of all actions and processes that affect the active ingredient in an organism or subject is known as the LADME model, including release after administration, absorption (also referred to herein as "reabsorption"), distribution, metabolism, and excretion of the drug and its metabolites.

[0259] Release is the release of the active ingredient from the dosage form after administration, i.e., conversion into a resorbable dissolved form. The release of the drug is affected by the pharmaceutical composition and excipients used therein. Drug release from sublingual and buccal tablets for administration in the oral cavity usually occurs rapidly due to the short disintegration time of the tablets.

[0260] Absorption is that the drug is subsequently taken up by biomembrane such as gastrointestinal mucosa, muscle tissue and enters the blood or lymphatic system. The absorption of the drug depends on the size of the absorption site, the contact time and the blood perfusion of the application site, and the physicochemical properties of the further drug such as lipophilicity. Oral mucosal perfusion is good, usually causing the drug to take effect quickly and the blood level is high. However, it is necessary to find balance between the good dissolution of the drug (may hinder the good dissolution of the drug in the case of highly lipophilic drugs) and the good absorption of the lipophilic mucosa (the lipophilicity of the drug can promote the good absorption of the drug).

[0261] The distribution of a drug refers to the transport of a substance between different body fluids and tissues and depends on, for example, vascular permeability, tissue perfusion rate, tissue pH, the blood-brain barrier, and the plasma protein and tissue binding capacity of the drug and its lipophilicity.

[0262] The biochemical transformation and degradation of drugs in various parts of the body is called metabolism or biotransformation. Therefore, the first-pass effect describes the proportion of substances metabolized during the first pass through the intestine and liver.

[0263] Excretion of a drug or its metabolites from the bloodstream occurs primarily through the kidneys and urine (renal excretion). A small portion is excreted via bile into the small intestine and subsequently in the feces. Excretion via the skin (sweat) or mucous membranes (intestinal mucosa, enteric excretion) and via the lungs (pulmonary excretion) is of lesser importance.

[0264] Important parameters describing the pharmacokinetics of a drug include the time to maximum plasma concentration (t max ), half-life in plasma (t1 / 2 ), maximum plasma concentration (c max ), area under the curve (AUC), volume of distribution and clearance.

[0265] To characterize absorption and to assess bioequivalence of generic drugs, the maximum plasma concentration (c max ) and reach c max The time (t max ). max It is proportional to the rate of absorption and is independent of dose, providing information about the rate of drug absorption, allowing conclusions to be drawn about the expected time of onset of action. max It is directly proportional to the dose administered and provides information about the extent and rate of drug absorption. If there is a direct correlation between the plasma level of a drug and its effect, then c max The intensity of the effect can be indicated. In addition, it can be assessed whether the plasma concentration is within the therapeutically acceptable range.

[0266] The area under the curve (AUC) is the area under the concentration-time curve (usually the plasma level curve). It is a measure of the total amount of substance absorbed and thus describes the amount of drug available systemically. The elimination half-life (plasma half-life, t 1 / 2 ) is the time it takes for the plasma concentration to drop to half of its original value. Based on the half-life, drugs can be divided into short-acting, intermediate-acting and long-acting drugs. AUC can be calculated by a variety of methods, including the trapezoidal rule and compartmental data analysis. These calculation methods are known to those skilled in the art.

[0267] The bioavailability of a drug is defined as the rate and extent to which a drug or active ingredient is absorbed from a dosage form and is present in the systemic circulation and / or at the site of action. Absolute bioavailability thus describes the extent to which the active ingredient in a dosage form is available throughout the body compared to an intravenous solution of the active ingredient. Absolute bioavailability is determined by the physicochemical properties of the drug, the dosage form, and the physiological conditions at the site of absorption. Relative bioavailability describes the extent and rate to which the active ingredient in a dosage form is available throughout the body compared to a reference dosage form applied by the same route of administration. Relative bioavailability is usually determined by the dosage form.

[0268] Example

[0269] The present invention is illustrated by the examples disclosed herein. The examples provide technical support for detailed descriptions of possible preferred non-limiting embodiments of the present invention.

[0270] Example 1: Composition of the present invention

[0271] General procedure for preparing the compositions by direct compression process:

[0272] Step-1 (Blending):

[0273] I. API (Bengalantamine (ALPHA-1062) Gluconate Form A) was milled.

[0274] II. Blending the glidant and the first portion of filler with the API followed by de-agglomeration through a screen.

[0275] III. The second portion of filler is passed through a screen to de-agglomerate and blended with the mixture of step II.

[0276] IV. One or more lubricants are passed through a screen to de-agglomerate and blended with the mixture of step III.

[0277] Step-2 (Suppression):

[0278] The blend of step-IIIV is compressed into tablets by a compression machine using suitable machine parameters and suitable tooling.

[0279] Step-3 (Sub-coating):

[0280] I. Prepare a 7.5% suspension of the film former in purified water.

[0281] II. The tablets of step-2 were loaded in a coating pan and warmed until a bed temperature of 50°C was obtained.

[0282] III. Spray the suspension from step I. onto the tablets.

[0283] IV. Once the target weight of coating is reached, spraying is stopped and the tablets are allowed to cool until the bed temperature reaches <30°C.

[0284] Step-4 (Enteric Coating):

[0285] I. Prepare a 20% suspension of the enteric coating film-forming agent in purified water.

[0286] II. The sub-coated tablets of step-3 were charged in a coating pan and warmed until a bed temperature of 33°C was obtained.

[0287] III. Spray the suspension from step I. onto the tablets.

[0288] IV. Once the target weight of coating is reached, spraying is stopped and the tablets are allowed to cool until the bed temperature reaches <30°C.

[0289] Embodiments of the invention:

[0290] Table 1: Bengalantamine extended-release tablet preparations of the present invention (5 mg, 10 mg, 15 mg)

[0291]

[0292] Dissolution studies:

[0293] method:

[0294] ALPHA-1062 (bengalantamine) delayed-release tablets were tested by two-stage dissolution, first an acidic stage, followed by a buffered stage. Dissolution was performed according to USP <711> The method was carried out using Apparatus I with 1000 ml of dissolution medium of 0.01 N hydrochloric acid or phosphate buffer (pH 5.5 or 6.8) at a temperature of 37.0 ± 0.5° C. and a basket rotation speed of 50 RPM. The dissolution test duration was 2 hours for the acidic phase and 75 minutes for the buffered phase.

[0295] result:

[0296] Table 2a: Dissolution data of Bengalantamine (ALPHA-1062) extended release tablets 5 mg

[0297]

[0298] Table 2b: Dissolution data of Bengalantamine (ALPHA-1062) extended release tablets 10 mg

[0299]

[0300] Table 2c: Dissolution data of Bengalantamine (ALPHA-1062) extended release tablets 15 mg

[0301]

[0302] The composition of the present invention (including 5mg, 10mg or 15mg bengalantamine) shows that bengalantamine is not released under acidic conditions (pH 1.2). Under buffer conditions (pH 6.8), >80% of bengalantamine is released after 60 minutes. These results confirm that the formulation of the present invention does not release bengalantamine under acidic conditions (such as in the stomach), but releases bengalantamine at pH 5.5 and higher, such as at pH 6.8. This confirms that the composition of the present invention has favorable dissolution and release characteristics, thereby reducing the incidence of adverse reactions, particularly gastrointestinal adverse reactions, such as nausea and vomiting, and has favorable pharmacokinetic characteristics in subjects administered the composition.

[0303] Content Uniformity:

[0304] method:

[0305] According to USP <905> To determine content uniformity, each of the ten tablets was weighed individually, dissolved in an acidified buffer solution using mechanical shaking, followed by sonication with acetonitrile and water (50:50), and then filtered. An aliquot of the filtrate was diluted with water and analyzed by HPLC to determine the drug percentage.

[0306] result:

[0307] Table 3: Content uniformity in % of compositions of the invention.

[0308]

[0309]

[0310] The compositions of the invention (5 mg, 10 mg and 15 mg bengalantamine) showed content uniformity > 96%. These results show that the compositions of the invention can be produced in a reliable and reproducible manner, regardless of dosage strength.

[0311] Example 2: Clinical study (comparison of Bengalantamine (APLPHA-1062) extended release 5 mg tablets and Galantamine hydrobromide (Yabao) 4 mg tablets)

[0312] An open-label, balanced, randomized, single oral dose, two-treatment, two-period, two-way crossover study was conducted to evaluate the relative bioavailability (BA) of bengalantamine (ALPHA-1062) extended-release (DR) 5 mg tablets compared with galanthamine hydrobromide 4 mg tablets under fasting conditions in healthy adult subjects.

[0313] Test treatment (T): Bengalantamine (ALPHA-1062) tablets 5 mg according to the present invention.

[0314] Reference treatment (R): Galantamine hydrobromide 4 mg tablet.

[0315] Purpose:

[0316] main: The relative bioavailability (BA) of a single dose of 5 mg benzgalantamine (ALPHA-1062) tablet of the present invention (test) compared to 4 mg galantamine hydrobromide tablet (reference) under fasting conditions was evaluated.

[0317] secondary: The safety and tolerability of a single dose of the bengalantamine (ALPHA-1062) tablet of the present invention under fasting conditions was evaluated.

[0318] method:

[0319] Male and female study participants (in equal proportions) were enrolled in this study. A total of 54 normal healthy adult study participants were enrolled. All subjects received the test product (Test) or the reference product (Reference) in each period according to the randomization schedule after ensuring that the pre-dose restrictions (fasting in a sitting position for 10 hours before dosing, drinking 240±2mL of normal temperature drinking water) were maintained.

[0320] A 7-day washout period was observed between study cycles. Study restrictions on fluid intake and sitting were implemented during the restriction period in all cycles throughout the study. The total duration of participation for each subject was approximately 31 days, including the screening and washout periods.

[0321] Study participants were instructed not to break, cut, and chew the tablets (test or reference), but rather to swallow them whole and were asked to take them with the specified amount of water. No water was allowed from 1 hour before dosing until 1 hour after dosing, except at the time of dosing. After dosing, participants remained seated for the first two hours. On dosing days, meals were taken according to the following schedule. All study participants had the same meals during all cycles.

[0322] Table 4: Standard Meal Schedule

[0323] sky breakfast Lunch snack dinner D-1 - - - 11 hours before dosing Dosing day (D) - 4 hours after administration 8 hours after administration 12 hours after administration D+1 24 hours after administration 28 hours after administration 32 hours after administration 36 hours after administration

[0324] Post-dose meals were uniform across all clinical cycles and provided at the same time during each study cycle. Study participants who did not meet the 10-hour fasting requirement prior to dosing were ineligible for dosing and were withdrawn from the study. No meals were provided for at least 4 hours after dosing.

[0325] Study participants:

[0326] A total of 54 participants were enrolled, of whom 38 were eligible for the study. Healthy adult male and female participants between 18 and 70 years of age with a body mass index ≥18.0 kg / m at the screening visit were enrolled. 2 To ≤30.0kg / m 2 between.

[0327] Further research activities:

[0328] On the registration day, submit and obtain informed consent, perform urine drug screening (including alcohol), vital signs, physical examination, Columbia-Suicide Severity Rating Scale (C-SSRS) assessment, serum pregnancy test (only for female study participants), Covid rapid antigen test, body and baggage search, maintain pre-dose restrictions and provide uniform meals. Blood samples were collected only during the Cycle-I registration period for the evaluation of CYP2D6 genotype. Body weight (kg) was recorded at registration (only in Cycle-I) and after the study. Electrocardiogram (ECG) was measured within 24 hours before dosing in each cycle, that is, at registration, and at 3 hours and 36 hours (± 60 minutes) after dosing, and at the time of post-study evaluation.

[0329] The drug dispensing procedure was performed under yellow monochromatic light conditions.

[0330] Table 5: Study product, dose, administration route and batch / lot number:

[0331]

[0332] Pharmacokinetic Blood Sampling:

[0333] Blood sampling was collected at 20 time points in each cycle, including pre-dose (0 h) and post-dose samples. In each cycle, 2 pre-dose samples (5 mL each) were collected within 1 h before dosing to check for interference of contaminants or endogenous components on the retention time of the target peak and to analyze the lack of measurable drug concentration by adding internal standards (ISTD).

[0334] After administration, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 12, 16, 24, 36 and 48 hours were collected for the administration of samples. For the pharmacokinetics (PK) of bengalantamine (only for test product (test)), consider the administration of samples (each 5mL) collected at 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8 and 12 hours. For the PK of galanthamine (for testing and reference both), consider the administration of samples (each 5mL) collected at 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 12, 16, 24, 36 and 48 hours.

[0335] The total amount of blood collected from each study participant in this study did not exceed 255 mL (for males) and 259 mL (for females), including 9 mL for screening, 7-9 mL for post-clinical assessment of laboratory parameters, 18 mL for discarding saline-mixed blood samples resulting from the use of intravenous cannula for 24 hours, and an additional 2-9 mL that could be collected as needed for repeat / additional laboratory tests. Blood samples were collected by intravenous cannula until 24 hours after dosing, and the remaining blood samples were collected by direct sterile venipuncture using pre-labeled 5 mL K2EDTA vacutainers.

[0336] After collection, blood samples were placed in a wet ice bath maintained at approximately below 15°C. Once blood samples were obtained for all study participants at each time point, they were centrifuged at 3800 rpm for 10 minutes at 10°C ± 2°C to separate plasma. Centrifugation of all samples was completed within 45 minutes of each sample draw time point. All plasma samples were separated and divided into two aliquots, i.e., 1 mL in aliquot #1 and the remaining plasma in aliquot #2, placed in properly labeled polypropylene tubes and immediately stored at -20°C ± 4°C until analysis was completed. After analysis, plasma samples were retained for a period of 90 days from the date of report submission to the sponsor or as required by the sponsor. The time from sample collection to placement in the refrigerator did not exceed 120 minutes. Plasma samples were analyzed for bengalantamine (ALPHA-1062) and galantamine using LC-MS / MS analysis. All clinical activities were performed under yellow monochromatic light conditions.

[0337] Pharmacokinetic analysis:

[0338] use 8.0 or higher (Pharsight Corporation, USA) or 9.4 and Enterprise Guide 7.1 or later to calculate pharmacokinetic parameters of bengalantamine (ALPHA-1062) and galantamine in plasma.

[0339] Main parameters: C max , AUC 0-t and AUC 0-∞ .

[0340]

[0341] Secondary parameters: T max , k el , AUC 0-t / AUC 0-∞ 、AUC%extrap、t1 / 2 、T lag , Vz / F and Cl / F.

[0342]

[0343] For cases that do not show a terminal log-linear phase in the concentration versus time curve, k is not reported. el ,t 1 / 2 and AUC 0-∞ The actual post-dose collection time was used to calculate the above pharmacokinetic parameters. In all pharmacokinetic and statistical calculations, drug concentrations below the limit of quantification (BLQ) were considered “zero”.

[0344] Gastrointestinal Adverse Events:

[0345] Safety assessments performed during the study included monitoring of gastrointestinal adverse events. Adverse event (AE) monitoring was completed throughout the study by monitoring clinical examinations, vital sign checks, and observation of participant health status throughout the study.

[0346] Statistical Analysis and Descriptive Statistics:

[0347] Statistical analysis was performed on the pharmacokinetic data of samples for the determination and quantification of bengalantamine and galantamine in plasma. Statistical analysis of logarithmic (natural) transformed pharmacokinetic parameters was performed using SAS 9.4 and Enterprise Guide version 7.1 for Windows (SAS Institute Inc., Cary, NC, USA). Descriptive statistics (such as count (N), mean, median, minimum, maximum, standard deviation (SD), and coefficient of variation (CV)) were estimated for relevant pharmacokinetic parameters of the test and reference products. C max , AUC 0-t and AUC 0-∞ The geometric mean and coefficient of variation were obtained. In this study, the inferential statistical linear regression model was used.

[0348] Bioavailability Assessment:

[0349] Based on the Ln conversion of galantamine obtained after a single dose under fasting conditions, C max , AUC 0-t and AUC 0-∞ Bioavailability was assessed using 90% confidence intervals for the geometric least squares differences in treatment means. The acceptance criterion for bioavailability was the Ln-converted C max , AUC 0-t and AUC 0-∞The entire confidence interval for the difference in means should be between 80% and 125%.

[0350] Determination of sample size

[0351] A total of 36 normal healthy adult male or female study participants (equal ratio) were dosed in this study.

[0352] T / R ratio = 90% - 111%

[0353] Expected intra-subject CV (%) ~ 18%

[0354] Significance level = 5%

[0355] Confidence = 80%

[0356] Bioequivalence limit = 80-125%

[0357] Based on the above estimates, a sample size of 36 study participants was sufficient to establish bioequivalence between the two formulations with adequate power, taking into account a 10% dropout due to adverse events or noncompliance or for personal reasons.

[0358] result

[0359] Demographics and other baseline characteristics

[0360] Table 6: Demographic summary of all participants in the study (N=34).

[0361] parameter Age (years) Weight(kg) Height (cms) <![CDATA[BMI(kg / m 2 )]]> Mean (SD) 36.0(8.00) 66.9(8.80) 159.9(8.95) 26.1(2.51) Median 35.5 66.9 158.1 26.3 CV% 22.2 13.2 5.6 9.6 scope (24.0,57.0) (48.8,83.3) (145.0,175.0) (20.8,29.9)

[0362] Treatment compliance

[0363] All study participants took study medication; this was confirmed by direct observation of study medication administration and hand and mouth examinations and further confirmed by the presence of plasma bengalantamine (ALPHA-1062) and galantamine concentrations in individual blood samples after dosing.

[0364] Pharmacokinetic results:

[0365] Pharmacokinetic parameters were calculated by linear mixed effects models. Pharmacokinetic parameters were statistically analyzed to compare the C of the test and reference products. max , AUC 0-t and AUC 0–∞ .

[0366] Mean plasma concentrations of galantamine versus predetermined time plots (linear and log-linear scales) were obtained and Figure 2 and 3 Displayed in.

[0367] Table 7a: Arithmetic mean values ​​(SD) of pharmacokinetic parameters of galantamine. * For T max , showing median values ​​(Min, Max). NE: Not estimated.

[0368]

[0369] Table 7b: Arithmetic mean (SD) of pharmacokinetic parameters of bengalantamine (ALPHA-1062), * for T max , showing median values ​​(Min, Max). NE: Not estimated.

[0370]

[0371]

[0372] Table 8: Analysis of variance for galantamine (test (T) versus reference (R))

[0373]

[0374] Table 9: Statistical analysis results of the bioequivalence assessment of galantamine under fasting conditions.

[0375]

[0376] C of bengalantamine extended-release (DR) tablets 5 mg (test) and galanthamine hydrobromide 4 mg tablets (reference) max , AUC 0-t and AUC 0-∞ The geometric mean (GM) ratios of the estimated values ​​of galantamine with the 90% CI of the ratios were 75.76 (69.87, 82.14), 92.01 (88.90, 95.23), and 95.45 (88.60, 102.82), respectively (Table 9). max The 90% confidence interval (CI) for galantamine was not within the range of 80-125%. 0-t and AUC 0-∞ The 90% CI for β-catenin was in the range of 80-125% (Table 9).

[0377] The AUC of bengalantamine (ALPHA-1062) has not been estimated due to insufficiently measurable concentration curves (i.e., nearly all values ​​were always zero or below the limit of quantitation (BLQ)). 0-t and elimination of correlation parameters (AUC 0-∞ , AUC 外推 , K el and T 1 / 2 )(Table 7b). Therefore, the maximum observed concentration (Cmax point) is also zero. Therefore ln(0) is mathematically unpredictable, so statistical analysis is performed after applying the transformed logarithm.

[0378] Gastrointestinal adverse events

[0379] Adverse events monitoring in the form of clinical examinations, vital signs checks and health status of participants were monitored during the study. The reported results were normal, concluding that all treatments were well tolerated and proved to be safe.

[0380] Table 10: Incidence of gastrointestinal adverse events. N = Number of subjects experiencing adverse events (AEs). % = Percentage of adverse events calculated based on the total number of study subjects participating in the study.

[0381]

[0382] A total of 2 gastrointestinal adverse events (AEs) were reported. Of these 2 AEs, 1 AE (i.e., vomiting) was reported during Cycle-I and 1 AE (i.e., diarrhea) was reported during Cycle-II. No serious adverse events, major adverse events, or deaths occurred in this study.

[0383] Overall, subjects administered the compositions of the present invention showed a lower incidence of gastrointestinal adverse events compared to the bengalantamine 4 mg tablets (reference) (Table 10). This indicates that the compositions of the present invention comprising bengalantamine and an enteric coating configured for dissolution at pH 5.5 or higher show favorable dissolution and release characteristics and improved pharmacokinetic properties compared to the reference composition comprising bengalantamine but without such enteric coating, advantageously resulting in a reduced incidence of gastrointestinal adverse events.

[0384] in conclusion:

[0385] Overall, the composition of the present invention exhibits improved pharmacokinetic characteristics over the immediate release galanthamine hydrobromide 4 mg tablet (reference). max while maintaining the AUC of galantamine (AUC 0-t and AUC 0-∞ ) were comparable to the immediate-release reference formulation (90% CI for galantamine ranged from 80-125%) (Table 9).

[0386] Lower C max The side effects associated with galantamine, especially gastrointestinal side effects, are reduced because the side effects of the drug increase with the peak drug concentration present in the blood / target organs. Observing equivalent AUC means that overall, the amount of drug absorbed is the same (although at a slower rate), indicating that therapeutic effectiveness is maintained.

[0387] This results in most galantamine being absorbed in the stomach before reaching the intestine (t max =1h, substantially no Tlag], the release of bengalantamine occurs in the intestine at a pH above 5.5 due to the enteric coating of the composition of the present invention, causing galantamine to rise to C more slowly. max (For the composition (test) of the present invention, starting from the time when the drug first appears in the plasma (Tlag), T max The rate at which the plasma concentration of bengalantamine increases and the absolute concentration of bengalantamine in the plasma both affect the side effect profile. Therefore, the composition of the present invention rises to c more slowly. max And c max Lower beneficially reduces gastrointestinal side effects.

[0388] The negligible (or below the limit of quantitation) plasma bengalantamine concentrations observed following administration of the compositions of the present invention further indicate that bengalantamine is rapidly and completely or nearly completely converted to galanthamine following drug release in the small intestine, advantageously resulting in the production of only pharmacologically active galanthamine and the absence or presence of only negligible amounts of bengalantamine in the systemic circulation of the subject.

[0389] After the composition of the present invention releases bengalantamine in the intestine, the drug may be converted to galanthamine by esterase action in the following compartments: (a) in the intestinal lumen [esterases produced by microorganisms], (b) during transport across the intestinal wall (Ho et al. 2017, Xu et al. 2015), and (c) exposed to esterase activity in (portal vein) blood (Rudakova et al. 2010).

[0390] However, the results obtained in this study show that, although bengalantamine is converted to galantamine in any of compartments (a), (b) and / or (c), this conversion unexpectedly does not result in free galantamine concentrations in the gastrointestinal tract high enough to cause the side effect profile observed in immediate release formulations. This represents an unexpected effect, as it was expected that bengalantamine, after release in the intestine, would result in galantamine concentrations that activate the enteric cholinergic nervous system, leading to traditional gastrointestinal adverse events such as nausea, vomiting, and diarrhea through conversion in compartments (ac).

[0391] The formulations of the present invention include an enteric coating configured to release bengalantamine at pH 5.5 or higher, thereby unexpectedly and advantageously providing protection against gastrointestinal adverse events while achieving complete conversion of the prodrug to galanthamine and having similar AUC compared to the immediate release reference formulation.

[0392] Again, without being bound by theory, the results may be interpreted as the rate at which the drug is presented to the liver for first-pass metabolism (from T lag , T max About 1.5h) does not exceed the metabolic capacity of the liver to completely / almost completely convert bengalantamine to galanthamine. This demonstrates the dosage proportionality of the composition of the present invention and improves the safety profile and efficacy of the composition of the present invention.

[0393] Example 3: Clinical Study (Comparison of Bengalantamine (ALPHA-1062) Extended Release 5 mg Tablets and ER Galantamine HBr 8 mg Tablets)

[0394] Bengalantamine extended-release tablets 5 mg (BID) produced by Janssen Pharmaceuticals An open-label, balanced, randomized, multiple-dose, double-treatment, double-group, double-period, comparative steady-state study of ER (galanthamine extended-release capsules) 8 mg (QD) compared with .

[0395] Test treatment (T): Bengalantamine (ALPHA-1062) extended release tablets 5 mg according to the present invention.

[0396] Reference treatment (R): ER (galantamine extended-release capsules) 8mg.

[0397] Purpose and End Point:

[0398] main: Bengalantamine (ALPHA-1062) 5 mg extended-release tablets (BID, test) of the present invention were evaluated in healthy adult subjects compared with 8 mg Steady-state relative bioavailability (BA) compared with ER (galanthamine extended-release capsules) (QD, reference).

[0399] secondary: In healthy adult subjects, the efficacy of bengalantamine extended-release tablets was evaluated compared with Safety and tolerability compared with galantamine extended-release ER (galantamine extended-release capsules).

[0400] Primary endpoint: AUC on day 7 0-24 , C max,ss (Test and Reference)

[0401] Secondary endpoints: Other parameters include but are not limited to:

[0402] Day 4C 谷值 (equivalent to the morning trough value before dosing on the 5th day)

[0403] Day 5C谷值 (equivalent to the morning trough value before dosing on the 6th day)

[0404] Day 6C 谷值 (equivalent to the morning trough value before dosing on the 7th day)

[0405] Day 7C 谷值 (equivalent to the sample taken 24 hours after administration on the morning of day 7)

[0406] Day 7 Pharmacokinetics: AUC 0-12,ss 、T max (test and reference), C max1 (test only), C max2 (test only), T max1 (test only), T max2 (test only), C avg (AUC 0-24 / 24 ), C min (lowest concentration within 24 hours), T min (Time of minimum concentration within 24 hours), C 谷值 (The concentration at the end of the dosing interval, i.e., C 24h -same as above), C 12h (trough value of the test product for morning dosing), CL / F (apparent clearance [dose / AUC 0-24 ])、Flux(volatility[(C max -C min ) / C avg ]), swing [(C max -C min ) / C min ], K el 、T 1 / 2

[0407] method:

[0408] Male and female study participants (in equal proportions) were enrolled in this study. A total of 52 normal healthy adult study participants were enrolled. All subjects received the test product or reference product in each period according to the randomization schedule after ensuring that the pre-dose restrictions were maintained (sitting position, fasting, drinking 240 ± 2 mL of normal temperature drinking water before dosing).

[0409] A 6.5-day washout period was observed between study cycles. Study restrictions on fluid intake and sitting were implemented during the restriction period in all cycles throughout the study. The total duration of participation for each subject was approximately 51 days, including screening.

[0410] In each cycle, on dosing days (1-7), subjects were randomized in a crossover fashion to receive either 5 mg benzogalantamine extended-release tablets twice daily (test) or 8 mg once daily. ER (galantamine hydrobromide) extended-release capsules (reference).

[0411] Study participants were instructed not to break, cut, and chew the tablets or capsules, but to swallow them whole and were asked to take them with the specified amount of water. No water was allowed from 1 hour before dosing until 1 hour after dosing, except at the time of dosing. After dosing, participants remained seated for the first 2 hours after dosing. On dosing days, meals were taken according to the following schedule. All study participants had the same meals during all cycles.

[0412] Table 11: Standard Meal Schedule

[0413]

[0414]

[0415] Postdose meals were uniform across all clinical cycles and provided at the same time during each study cycle.

[0416] Dinner was provided to study participants to maintain the following standards:

[0417] In each cycle, dosing occurred on Days 1-7, inclusive.

[0418] - Dosing on the morning of Days 5 and 6: Subjects fasted for at least 8 hours before dosing on the morning of Days 5 and 6, and their C 谷值 Pharmacokinetic (PK) samples were taken on days 5 and 6 and then fasted for 2 hours after dosing in the morning.

[0419] - Dosing on the morning of Day 7: Starting from the evening of Day 6, subjects fasted for at least 10 hours before dosing on the morning of Day 7, and their C 谷值 PK samples were taken on the morning of Day 7 and then fasted for at least 5 hours after dosing.

[0420] - Evening dosing on Days 5 and 7: Subjects fasted for at least 2 hours before evening dosing and at least 2 hours after evening dosing.

[0421] - Day 6 Evening Dosing: Subjects fasted for at least 2 hours before evening dosing and at least 1 hour after evening dosing.

[0422] -Days 1-4: Study participants fasted for at least 10 hours prior to morning dosing.

[0423] The evening dosing of the test product was performed 12 hours after the morning dosing.

[0424] While restrained, standard meals and snacks were provided at appropriate times, except for situations requiring them to fast. Study participants fasted for at least 10 hours prior to dosing in the mornings of Days 1 to 4. While restrained in the Clinical Pharmacology Unit (CPU), study participants abstained from all food and beverages except water between meals and snacks.

[0425] Study participants:

[0426] A total of 52 study participants were enrolled, of which 47 participants were eligible for the study. Signed informed consent was obtained from each volunteer before they were enrolled in the study. Healthy adult male and female participants aged 18-70 years with a body mass index ≥18.0 kg / m at the screening visit were enrolled. 2 To ≤30.0kg / m 2 Forty study participants completed all study cycles and were included in the pharmacokinetic analysis, and 38 study participants were included in the statistical analysis.

[0427] Further research activities:

[0428] On the registration day, submit and obtain informed consent, urine drug screening (including alcohol), vital signs, physical examination, C-SSRS assessment, serum pregnancy test (only for female research participants), Covid rapid antigen test, 12-lead ECG, body and luggage search, maintenance of pre-dose restrictions and provide a unified diet. Blood samples are collected only during the cycle-I registration period for the evaluation of CYP2D6 genotype. Body weight (kg) is recorded at the registration and withdrawal of each cycle. ECG is measured at the registration of each cycle, 3 hours (± 60 minutes) after the morning administration of the 7th day, and the withdrawal starting 180 minutes before the withdrawal of each cycle. Pre-dose safety monitoring, administration, sample collection and processing, and safety monitoring, maintenance of post-dose restrictions and a unified diet are provided throughout their hospitalization.

[0429] Table 12: Study product, dose, administration route and batch / lot number.

[0430]

[0431] Pharmacokinetic Blood Sampling:

[0432] Blood sampling was collected at 38 time points per cycle for the test treatment, including pre-dose (0 hours) and post-dose samples for measuring galantamine and bengalantamine. Blood sampling was collected at 25 time points per cycle for the reference treatment, including pre-dose (0 hours) and post-dose samples for measuring galantamine. In each cycle, 2 samples (5 mL each) were collected before dosing on Day 1 (i.e., 0 hours before dosing) within 1 hour before dosing. Pre-dose samples on Days 5, 6, and 7, i.e., samples (5 mL each) at 0 hours before dosing, were collected within 0-10 minutes before dosing. Morning pre-dose samples were collected on Days 5, 6, and 7 for reference and test C 谷值 .

[0433] On Day 7 for Test - morning post-dose samples were collected at 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 12, 12.25, 12.5, 12.75, 13, 13.5, 14, 14.5, 15, 15.5, 16, 16.5, 17, 18, 20, 24, 28, 36, 48 and 60 hours. On Day 7 for Reference - morning post-dose samples were collected at 0.50, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 8, 12, 16, 24, 36, 48 and 60 hours.

[0434] The total amount of blood collected from each study participant in this study did not exceed 384 mL (for males) and 388 mL (for females), including 9 mL for screening, 7-9 mL for postclinical assessment of laboratory parameters, 26 mL for discarding the saline-mixed blood sample resulting from the use of intravenous cannulation for 24 hours on Day 7, and an additional 2-9 mL that could be collected as needed for repeat / additional laboratory testing. Blood samples were collected by direct venipuncture on Days 1, 5, and 6, and by intravenous cannulation using pre-labeled 5 mL K2EDTA vacutainers until 24 hours after dosing on the morning of Day 7.

[0435] After collection, blood samples were placed in a wet ice bath to maintain the temperature below 15°C. Once blood samples were obtained for all study participants at each time point, they were centrifuged at 3800 rpm for 10 minutes at 10°C ± 2°C to separate plasma. Centrifugation of all samples was completed within 45 minutes of each sample draw time point. All plasma samples were separated and divided into two aliquots, i.e., at least 1 mL in aliquot #1 and the remaining plasma in aliquot #2, into properly labeled polypropylene tubes and immediately stored at -20°C ± 4°C until analysis was completed. After analysis, plasma samples were retained for a period of 90 days from the date of report submission to the sponsor or as required by the sponsor. The time from sample collection to placement in the refrigerator was no more than 120 minutes. Plasma samples were analyzed for bengalantamine (ALPHA-1062) and galantamine using LC-MS / MS analysis. All clinical activities were performed under yellow monochromatic light conditions.

[0436] Pharmacokinetic analysis:

[0437] use 8.0 or higher (Pharsight Corporation, USA) or 9.4 and Enterprise Guide 7.1 or later calculate the following pharmacokinetic parameters for bengalantamine and galantamine in plasma.

[0438] Main parameters: AUC 0-24,ss and C max,ss

[0439] <![CDATA[AUC 0-24,ss ]]> The area under the daily steady-state concentration-time curve was calculated by the linear trapezoidal method. <![CDATA[C maxss ]]> Maximum observed concentration at steady state

[0440] Secondary parameters: Day 4C 谷值 Day 5C 谷值 Day 6C 谷值 Day 7C 谷值 , C 12h , AUC 0-12,ss 、T max,ss , C max1,ss , C max2,ss 、T max1,ss 、T max2,ss , C avg (AUC 0-24 / 24 ), C min (lowest concentration within 24 hours), T min (Minimum concentration time within 24 hours), K el ,t 1 / 2 , CL / F (apparent clearance [dose / AUC 0-24 ]), % FLUX (volatility [(C max -Cmin ) / C avg ]), swing [(C max -C min ) / C min ].

[0441]

[0442]

[0443] Gastrointestinal Adverse Events:

[0444] Safety assessments performed during the study included, but were not limited to, weight assessments, blood samples for organ function, adverse event monitoring, vital sign monitoring, and cardiology and physical assessments. Throughout the study, adverse event (AE) monitoring was performed through clinical examinations, vital sign checks, and observation of participant health status.

[0445] Statistical Analysis and Descriptive Statistics:

[0446] Statistical analysis of the pharmacokinetic data of samples for the determination and quantification of galantamine in plasma will be performed. System 9.4 or later and Enterprise Guide 7.1 or later for Windows ( Institute Inc.USA) used a linear mixed effects model to analyze the pharmacokinetic parameter AUC of galantamine in the ln transformation 0-24 and C max Statistical analysis was performed. Descriptive statistics (such as count (N), mean, median, minimum, maximum, standard deviation (SD), and coefficient of variation (CV)) of relevant pharmacokinetic parameters of the test and reference formulations were estimated. AUC 0-24 , C max , AUC 0-12 、T max , C max1 (test only), C max2 (test only), T max1 (test only), T max2 (test only), C avg (AUC 0-24 / 24 ), C min (lowest concentration within 24 hours), T min (Time of minimum concentration within 24 hours), C 谷值 (The concentration at the end of the dosing interval, i.e., C 24h ), C 12h (test product trough value for the morning dose), CL / F (apparent clearance [dose / AUC 0-24])、Flux(Volatility[(C max -C min ) / C avg ]), swing [(C max -C min ) / C min ], K el and T 1 / 2 The geometric mean and coefficient of variation were obtained. In this study, the inferential statistical linear regression model was used.

[0447] Bioavailability Assessment:

[0448] If the PK parameter of galantamine is AUC 0-24,ss and C max,ss If the 90% confidence interval for the ratio of the least square means of galantamine is within the reference range of 80% to 125%, a similar bioavailability can be concluded. max,ss If the entire 90% CI of the ratio of the least square means of max,ss ) is not less than the peak exposure of the reference product.

[0449] Determination of sample size

[0450] A total of 40 normal healthy adult male and female study participants were dosed in this study.

[0451] T / R ratio = 90% - 111%

[0452] Expected intra-subject CV (%) ~ 18%

[0453] Significance level = 5%

[0454] Confidence = 80%

[0455] Bioequivalence limit = 80-125%

[0456] Based on the above estimates, a calculated sample size of 40 study participants was sufficient to establish bioequivalence between the two formulations with adequate power, taking into account 10% withdrawals due to adverse events or noncompliance or due to personal reasons. 40 healthy adult male and female study participants were sufficient for the study.

[0457] result

[0458] Demographics and other baseline characteristics

[0459] Table 13: Demographic summary of all participants in the study (N=38).

[0460] parameter Age (years) Weight(kg) Height (cms) <![CDATA[BMI(kg / m 2 )]]> Mean (SD) 35.9(9.06) 66.1(9.68) 160.1(9.20) 25.7(2.49) Median 35.5 64.0 158.8 25.7 CV% 25.2 14.7 5.7 9.7 scope 21.0-56.0 50.0-90.9 143.5-179.0 20.0-29.9

[0461] Treatment compliance

[0462] All study participants took study medication; this was confirmed by direct observation of study medication administration and hand and mouth examinations and further confirmed by the presence of plasma bengalantamine and galantamine concentrations in individual blood samples after dosing.

[0463] Pharmacokinetic results:

[0464] Pharmacokinetic parameters were calculated by linear mixed effects models. Statistical analysis of pharmacokinetic parameters was performed to compare the C values ​​of the test and reference formulations. max,ss and AUC 0-24 .

[0465] Mean plasma concentrations of galantamine versus predetermined time plots (linear and log-linear scales) were obtained and Figure 3 The mean plasma concentrations of bengalantamine versus predetermined time plots (linear and log-linear scales) were obtained and plotted in Figure 4 Displayed in.

[0466] Table 14: Arithmetic mean values ​​(SD) of pharmacokinetic parameters of galantamine. * For T max,SS , showing the median value (Min, Max).

[0467]

[0468] Table 15: Galantamine Steady-State Study Bengalantamine Extended Release Tablets 5 mg (Form T) vs. Statistical results of the bioavailability evaluation of ER (galanthamine extended-release capsules) 8 mg (Form R).

[0469]

[0470] Table 16: Analysis of variance for Galantamine (Test (T) versus Reference (R))

[0471]

[0472]

[0473] Bengalantamine extended-release tablets 5 mg (test) and ER (Galantamine sustained-release capsules) 8mg (reference) C max,ss and AUC 0-24ssThe GM ratios of the estimated values ​​of galantamine and the 90% CI of the ratios were 126.88 (120.62, 133.47) and 107.19 (103.76, 110.73), respectively (Table 15). 0-24,ss The 90% CI for galantamine was in the range of 80-125% for galantamine (Table 15). The bioavailability of ER (galanthamine extended-release capsules) 8 mg (reference) under fasting conditions was similar.

[0474] Gastrointestinal adverse events

[0475] Table 17: Incidence of gastrointestinal adverse events. N = Number of subjects experiencing adverse events (AEs). % = Percentage of adverse events calculated based on the total number of study subjects participating in the study

[0476]

[0477] A total of 3 gastrointestinal adverse events (AEs) were reported. Of these 3 AEs, 2 AEs (i.e., nausea and vomiting) were reported during Cycle-I and 1 AE (i.e., diarrhea) was reported during Cycle-II. No serious adverse events, major adverse events, or deaths occurred in this study.

[0478] In general, Compared with galanthamine sustained release capsules 8 mg (reference), subjects administered the composition of the present invention showed a lower incidence of gastrointestinal adverse events (Table 17). This further indicates that the composition of the present invention comprising bengalanthamine and an enteric coating configured for dissolution at pH 5.5 or higher shows a favorable dissolution and release profile and improved pharmacokinetic properties compared to the reference composition comprising galanthamine, which advantageously leads to a reduced incidence of gastrointestinal adverse events.

[0479] in conclusion:

[0480] In general, the compositions of the present invention show ER (galanthamine sustained release capsules) 8 mg (reference) improved pharmacokinetic characteristics. Therefore, the composition of the present invention leads to a c max,ss Improve while maintaining the AUC of galantamine (AUC 0-24,ss ) were comparable to the extended-release reference formulation (90% CI for galantamine ranged from 80-125%) (Tables 14 and 15).

[0481] Higher C max A high level of effect was produced, while the equivalent AUC observed indicated that overall the same amount of drug was absorbed.

[0482] and ER (galanthamine sustained-release capsule) 8mg (reference) compared to the galanthamine C max,ss Higher, but same AUC, makes it more beneficial to patients and is desirable. ER (Galantamine Extended Release Capsules) 8 mg (reference) provides a constant slow release of galantamine, whereas the composition of the present invention provides a more rapid release of bengalantamine followed by conversion to galantamine after rupture of the pH-sensitive enteric coating in the intestine at pH 5.5 or higher.

[0483] The composition of the present invention produces max Higher than ER (galantamine extended-release capsules) 8 mg (reference), but c max Lower than immediate-release galanthamine 4mg tablets (reference example 3), and AUC is similar to two reference preparations, thus providing patients with benefits superior to two reference preparations, because adverse reactions, particularly gastrointestinal adverse events, are reduced while maintaining therapeutic effects. This beneficial effect of the composition of the present invention is unpredictable by those skilled in the art.

[0484] Example 4: Alcohol Dose Dumping Study of Bengalantamine Tablets of the Present Invention

[0485] The objective of this study was to evaluate the effect of alcohol on the release rate of bengalantamine (ALPHA-1062) from the bengalantamine extended-release tablets (5 mg and 15 mg) of the present invention.

[0486] Experimental methods

[0487] One batch of each strength of galanthamine benzoate extended-release tablets (5 mg and 15 mg) was subjected to dissolution testing (n=12) according to TP81939 using each dissolution medium described in the methods (0%, 5% and 20% ethanol). Bengalantamine (ALPHA-1062) extended-release tablets were tested by two-stage dissolution, first an acidic stage followed by a buffered stage. Dissolution was performed according to USP <711> The method was carried out using Apparatus I at a temperature of 37.0 ± 0.5°C and a basket speed of 50 RPM. The dissolution media were 5% and 20% ethanol in 1000 ml of 0.01 N hydrochloric acid or pH 6.8 phosphate buffer. The duration of the dissolution test was 2 hours in the acidic phase and 75 minutes in the buffered phase. The dissolution percentage results were calculated according to the method.

[0488] result

[0489] Table 18a: 0% Ethanol Medium Results - Acidic Phase (Bengalantamine (ALPHA-1062) Extended Release Tablets 5 mg)

[0490]

[0491] Table 18b: 0% Ethanol Medium Results - Buffer Phase (Bengalantamine (ALPHA-1062) Extended Release Tablets 5 mg)

[0492]

[0493]

[0494] Table 19a: 5% Ethanol Medium Results - Acidic Phase (Bengalantamine (ALPHA-1062) Extended Release Tablets 5 mg)

[0495]

[0496] Table 19b: 5% Ethanol Medium Results - Buffer Phase (Bengalantamine (ALPHA-1062) Extended Release Tablets 5 mg)

[0497]

[0498]

[0499] Table 20a: 20% Ethanol Medium Results - Acidic Phase (Bengalantamine (ALPHA-1062) Extended Release Tablets 5 mg)

[0500]

[0501] Table 20b: 20% Ethanol Medium Results - Buffer Phase (Bengalantamine (ALPHA-1062) Extended Release Tablets 5 mg)

[0502]

[0503]

[0504] Table 21a: 0% Ethanol Medium Results - Acidic Phase (Bengalantamine (ALPJHA-1062) Extended Release Tablets 15 mg)

[0505]

[0506] Table 21b: 0% Ethanol Medium Results - Buffer Phase (Bengalantamine (APLHA-1062) Extended Release Tablets 15 mg)

[0507]

[0508]

[0509] Table 22a: 5% Ethanol Medium Results - Acidic Phase (Bengalantamine (ALPHA-1062) Extended Release Tablets 15 mg)

[0510]

[0511] Table 22b: 5% Ethanol Medium Results - Buffer Phase (Bengalantamine (ALPHA-1062) Extended Release Tablets 15 mg)

[0512]

[0513]

[0514] Table 23a: 20% Ethanol Medium Results - Acidic Phase (Bengalantamine (ALPHA-1062) Extended Release Tablets 15 mg)

[0515]

[0516] Table 23b: 20% Ethanol Medium Results - Buffer Phase (Bengalantamine (ALPHA-1062) Extended Release Tablets 15 mg)

[0517]

[0518] Even in the presence of up to 20% (v / v) ethanol, the composition of the present invention (comprising 5 mg or 15 mg of bengalantamine) showed no dissolution or dissolution of negligible amounts under acidic conditions (acidic phase, pH 1.2). In addition, in the presence of up to 20% (v / v) ethanol, the composition showed no change in the release characteristics under buffered conditions (buffered phase, pH 6.8). These results indicate that the dissolution characteristics and release of bengalantamine from the composition of the present invention are not affected by the presence of alcohol, such as up to 20% (v / v) ethanol.

[0519] Example 5: Stability of the composition of the present invention

[0520] Table 24: Summary of stability results - Bengalantamine (ALPHA-1062) extended release tablets 5 mg. RH: room humidity; M: month.

[0521]

[0522]

[0523] Table 25: Summary of stability results - Bengalantamine (ALPHA-1062) extended release tablets 10 mg.

[0524] RH: indoor humidity; M: month

[0525]

[0526]

[0527] Table 26: Summary of stability results - Bengalantamine (ALPHA-1062) extended release tablets 15 mg.

[0528] RH: relative humidity; M: month

[0529]

[0530]

[0531] Compositions of the invention comprising bengalantamine (ALPHA-1062) gluconate (5 mg, 10 mg and 15 mg) in crystalline solid Form A (anhydrous form) were stability tested at 25°C / 75% RH for 12 months and at accelerated conditions of 40°C / 60% RH for 6 months.

[0532] When stored under the test conditions, the composition shows that the tablet formulation and API have high stability. No impurities or decomposition products were detected, indicating that the bengalantamine in the composition has high chemical stability. In addition, compared with the dissolution data shown in Example 1 (measured after preparing the composition), no dissolution changes were observed in the acidic stage and the buffer stage. Since the API solubility (dissolution) of the bengalantamine gluconate in different crystalline forms is different, the similar dissolution characteristics at the initial time point (after preparation) and after storage indicate that the crystalline form has not changed.

[0533] Thus, the composition comprising bengalantamine in crystalline solid Form A (anhydrous form) has high chemical and crystal stability and favorable dissolution properties even under long-term storage and accelerated conditions.

[0534] Example 6: Visual inspection of the bengalantamine tablets of the present invention

[0535] As described above, the tablet formulations were visually observed to understand the mechanism of the dissolution process. Interestingly, the dissolution process showed some unique features. Typically, under normal circumstances, the enteric coating dissolves at a specified pH, and then the tablet core disintegrates. Using the Bengalantamine delayed-release tablet formulation of the present invention of Table 1, in a standard dissolution test according to USP 711 and a buffer having a pH higher than pH 5.5, the enteric coating began to peel off from the edge, and the coating peeled off and dissolved within 10-25 minutes, resulting in a slight lag in the release of the core / API.

[0536] Once the enteric coating is dissolved, the tablet core is eroded, which means that the core remains intact in fact, and the dissolving liquid penetrates into the tablet core and dissolves the tablet core. The dissolution of the core is slower than expected. This is different from the expected tablet disintegration into multiple pieces, increasing the surface area and the mechanism of rapid release of the drug. Without being bound by theory, the observed erosion may cause the release of the drug to be slower than expected by disintegration. Possibly, as observed in PK studies, in addition to the pH 5.5 dissolution of the enteric coating, core erosion may also help to reduce Cmax (lower than IR preparations).

[0537] References

[0538] Baakman et al., First in human study with a prodrug of galantamine: Improved benefit-risk ratio? Alzheimers Dement(NY).2016Jan 20;2(1):13-22.

[0539] Ho MD,Ring N,Amaral K,Doshi U,Li AP.Human Enterocytes as an In VitroModel for the Evaluation of Intestinal Drug Metabolism:Characterization ofDrug-Metabolizing Enzyme Activities of Cryopreserved Human Enterocytes fromTwenty-Four Donors.Drug Metab Dispos.2017Jun;45(6):686-691.doi:10.1124 / dmd.116.074377.Epub 2017Apr 10.PMID:28396528.

[0540] Rudakova EV, Boltneva NP, Makhaeva GF. Comparative analysis of esteraseactivities of human, mouse, and rat blood. Bull Exp Biol Med. 2011 Nov; 152(1):73-5. English, Russian. doi: 10.1007 / s10517-011-1457-y. PMID: 22803044.

[0541] Bakker C,van der Aart J,Hart EP,Klaassen ES,Bergmann KR,van EsdonkMJ,Kay DG,Groeneveld GJ.Safety,pharmacokinetics,and pharmacodynamics of Gln-1062,a prodrug of galantamine.Alzheimers Dement(NY).2020Oct13;6(1):e12093.doi:10.1002 / trc2.12093.PMID:33083515;PMCID:PMC7551138。

Claims

1. A pharmaceutical composition in the form of a tablet, the tablet comprising: a. a tablet core, wherein the core comprises bengalanthamine or a salt thereof, and b. an enteric coating comprising a copolymer of methacrylic acid and ethyl acrylate, wherein the enteric coating is configured to dissolve at pH 5.5 and above, wherein the tablet core is coated with a film coating, and wherein the film coating is in direct contact with the tablet core and is coated by the enteric coating, and Therein, in a dissolution test according to USP 711, the composition shows at most 10% dissolution of bengalantamine after 120 minutes in an acidic stage at pH 1.2, and at least 80% release of bengalantamine after 60 minutes in a buffered stage at pH 5.5 or 6.

8.

2. The pharmaceutical composition according to claim 1, wherein The enteric coating is a copolymer of methacrylic acid and ethyl acrylate.

3. The pharmaceutical composition according to claim 1, wherein The tablet core includes a water-soluble filler.

4. The pharmaceutical composition according to claim 3, wherein The water-soluble filler is mannitol.

5. The pharmaceutical composition according to claim 1, wherein The tablet core comprises a glidant.

6. The pharmaceutical composition according to claim 5, wherein The glidant is colloidal silicon dioxide.

7. The pharmaceutical composition according to claim 1, wherein The tablet core includes one or more lubricants.

8. The pharmaceutical composition according to claim 7, wherein The lubricant is sodium stearyl fumarate and / or magnesium stearate.

9. The pharmaceutical composition according to claim 1, wherein The tablet core is coated with a film coating comprising hydroxypropylmethylcellulose (HPMC), wherein the film coating is in direct contact with the tablet core and is coated by the enteric coating.

10. The pharmaceutical composition according to claim 9, wherein The film coating includes HPMC and polyethylene glycol.

11. The pharmaceutical composition according to claim 1, wherein The bengalantamine is the gluconate salt of bengalantamine.

12. The pharmaceutical composition according to claim 11, wherein The bengalantamine gluconate is present in a crystalline solid Form A (anhydrous form), wherein the crystalline form has major peaks at 3.61, 10.98, 14.41 and 18.44 degrees 2-θ (±0.2) in a powder X-ray diffraction pattern.

13. The pharmaceutical composition according to claim 1, wherein The tablet core comprises: - bengalantamine or its salt in an amount of 5-20% based on the wt% of the tablet core, - water-soluble fillers in an amount of 60-90%, - a glidant in an amount of 0.1-5%, and - One or more lubricants in an amount of 0.1-5%.

14. The pharmaceutical composition according to claim 13, wherein The tablet core comprises: - bengalantamine or its salt in an amount of 10-15% based on the wt% of the tablet core, - mannitol in an amount of 70-90%, - colloidal silicon dioxide in an amount of 0.5-2%, - sodium stearyl fumarate in an amount of 1-4%, and -Magnesium stearate in an amount of 0.5-2%.

15. The pharmaceutical composition according to claim 1, wherein The enteric coating is present in an amount of 5-20%, the amount being determined by the % weight gain relative to the tablet core.

16. The pharmaceutical composition according to claim 9, wherein The film coating is present in an amount of 2-10%, the amount being determined by the % weight gain relative to the tablet core.

17. The pharmaceutical composition according to claim 1, wherein a. The tablet core comprises: - bengalantamine or its salt in an amount of 10-15% based on the wt% of the tablet core, - mannitol in an amount of 70-90%, - colloidal silicon dioxide in an amount of 0.5-2%, - sodium stearyl fumarate in an amount of 1-4%, and - magnesium stearate in an amount of 0.5-2%, and b. the enteric coating is present in an amount of 7-15%, the amount being determined by the % increase in weight relative to the tablet core, and c. The film coating is present in an amount of 3-7%, the amount being determined by the % weight increase relative to the tablet core, and wherein the film coating is in direct contact with the tablet core and is coated by the enteric coating.

18. The pharmaceutical composition according to claim 1, wherein The composition is configured to release bengalantamine in the small intestine of the subject at a pH of 5.5 and above following administration to the subject.

19. The pharmaceutical composition according to claim 1, wherein In the dissolution test according to USP 711, the composition showed that bengalantamine was dissolved by at most 10% after 90 minutes at an acidic stage of pH 1.2 and in the presence of 20% (v / v) or less ethanol.

20. A method for treating a brain disease associated with cognitive impairment and / or cholinergic insufficiency, comprising administering the pharmaceutical composition according to claim 1 to a subject in need thereof.

21. The method according to claim 20, wherein: The brain disease is selected from the group consisting of: brain diseases with cholinergic insufficiency, Alzheimer's disease, Parkinson's disease, dementia, schizophrenia, epilepsy, stroke, poliomyelitis, neuritis, myopathy, hypoxia, anoxia, asphyxia, brain hypoxia and malnutrition after cardiac arrest, chronic fatigue syndrome, poisoning, anesthesia, spinal cord disorders, central inflammatory disorders, Lewy body disease, multiple sclerosis, skeletal muscle pain, autism, Rett syndrome, motor neuron diseases such as amyotrophic lateral sclerosis, traumatic brain injury, post-traumatic stress disorder, postoperative delirium, neuropathic pain, alcohol and drug abuse, alcohol addiction and / or nicotine craving, severe gastrointestinal tract (GIT) flatulence, constipation, hypotension, heart rate instability and the effects of radiation therapy.

22. A method for preparing a pharmaceutical composition in tablet form according to claim 1, wherein: The composition is prepared by blending the components of the tablet core to form a blend, compressing the blend to form a tablet core, coating the tablet core with a film coating, and coating the film coating with an enteric coating.

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