Ladostigil formulation and use thereof

Abstract

The present invention is directed to a formulation including a therapeutically effective amount of a Ladostigil salt and a pharmaceutically acceptable excipient including one or more fatty acid glycerides, wherein a concentration of the Ladostigil salt within the formulation is at least 1% w / w; and wherein the one or more fatty acid glycerides is a fatty acid triglyceride including C5-C10 fatty acid residues. Further provided are an oral delivery capsule including the formulation of the invention, and use of same, such as for delivering Ladostigil or a salt thereof to a colon of a subject in need thereof.

Description

LADOSTIGIL FORMULATION AND USE THEREOF CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority of IL Patent Application No. 318332, entitled “LADOSTIGIL FORMULATION AND USE THEREOF”, filed January 12, 2025, the contents of which are incorporated herein by reference in their entirety.FIELD OF THE INVENTION

[0002] The present invention relates to oral Ladostigil formulations and use thereof.BACKGROUND

[0003] Ladostigil (Formula 1) 6-(N-ethyl, N-methyl, carb amyl oxy )-N propargyl- 1(R)-aminoindan is a drug with antioxidant and anti-inflammatory activity.Formula 1

[0004] It has been shown to slow cognitive decline in aging rats and humans with mild cognitive impairment, the prodromal stage of Alzheimer’s disease.

[0005] Ladostigil is well absorbed from the small intestine after oral administration. Peak concentrations in the blood are reached within 15 minutes in rodents and 30 minutes in humans. However, the inter subject variability in drug exposure (AUC) and in blood levels at peak times after administration is very high, with coefficients of variation of more than 100% irrespective of the dose administered. This is undesirable and could exacerbate any variability in the response to treatment by Ladostigil of potential patients.

[0006] There is therefore a need for a novel method of delivery of Ladostigil that will reduce the wide inter individual variation in blood levels after oral dosing.SUMMARY

[0007] In one aspect, there is provided a formulation comprising a therapeutically effective amount of a Ladostigil salt and a pharmaceutically acceptable excipient comprising one or more fatty acid glycerides, wherein a concentration of the Ladostigil salt within the formulation is at least 1% w / w; and wherein the one or more fatty acid glycerides is a fatty acid triglyceride comprising C5-C10 fatty acid residues.

[0008] In one embodiment, the Ladostigil salt is represented by Formula 2:, wherein X is a pharmaceutically acceptable carboxylate anion and n is between 1 and 3, as allowed by valency.

[0009] In one embodiment, the formulation further comprising a mineral particle and an antioxidant.

[0010] In one embodiment, the antioxidant is butylated hydroxytoluene (BHT) and the mineral particle comprise silica nanoparticles.[Oil] In one embodiment, a concentration of the mineral particle within the formulation is between 0.1 and 5% w / w; and wherein a concentration of the antioxidant within the formulation is between about 0.01 and about 0.5% w / w.

[0012] In one embodiment, the pharmaceutically acceptable carboxylate anion is tartrate, and wherein n is 1 or 2.

[0013] In one embodiment, the therapeutically effective amount comprises a concentration of the Ladostigil salt within the formulation ranging between 1 and 10% w / w.

[0014] In one embodiment, the Ladostigil salt is [Ladostigil] itartrate; and wherein a concentration of the one or more fatty acid glycerides in the formulation is between 90 and 98%; and wherein the fatty acid triglyceride consists of C6-C8 fatty acid residues.

[0015] In one embodiment, a concentration of the Ladostigil salt within the formulation is about 4%w / w; wherein the concentration of the one or more fatty acid glycerides in the formulation is between 93 and 96%; and wherein the formulation is a suspension and is characterized by at least one of (i) viscosity at 20°C of between 100 and 500 cP; and (ii) density between 0.9 and 1 g / ml.

[0016] In one embodiment, wherein a weight ratio between the one or more fatty acid glycerides and the Ladostigil salt within the formulation is between about 9:1 and about 24:1.

[0017] In one embodiment, the formulation consists or consists essentially of [Ladostigil] itartrate in an amount of between 1 and 10% w / w; the one or more fatty acid glycerides in an amount of 90 and 99%w / w, and optionally of BHT and silica nanoparticles.

[0018] In one embodiment, the fatty acid triglyceride is selected from the group consisting of: capric acid triglyceride and caprylic acid triglyceride, including any homo-triglyceride and mixed triglyceride, and any combination thereof.

[0019] In another aspect, there is provided an oral delivery capsule comprising a therapeutically effective amount of the formulation of the invention, and wherein the oral delivery capsule is coated with an enteric coating.

[0020] In one embodiment, the therapeutically effective amount comprises an amount of the Ladostigil salt corresponding to an amount of Ladostigil free base of between 5 and 12 mg; and wherein the oral delivery capsule is configured to release the Ladostigil salt in a colon of a subject.

[0021] In one embodiment, the Ladostigil salt is Ladostigil tartrate; and wherein the therapeutically effective amount corresponds to between about 6 and about 9 mg Ladostigil free base.

[0022] In one embodiment, the oral delivery capsule comprises a water-soluble material selected from the group consisting of: a water-soluble poly saccharide / oligosaccharide, a protein, a water-soluble synthetic polymer, and any combination thereof.

[0023] In one embodiment, the water-soluble material comprises gelatin, a cellulose derivative (Hydroxypropyl Methylcellulose (HPMC)), PVA, a modified starch, a gel-forming polysaccharide / oligosaccharide (pullulan, alginate, hyaluronate, agar, ulvan, pectin, chitosan, dextran, a gum), or any combination or co-polymer thereof.

[0024] In one embodiment, the enteric coating is configured to undergo dissolution at a pH of about 7.

[0025] In one embodiment, the enteric coating comprises any one of: acrylate-based polymer, hydroxypropyl methylcellulose phthalate (HPMCP), Cellulose acetate phthalate (CAP), Polyvinyl acetate phthalate (PVAP), Carboxymethyl ethyl cellulose (CMEC) and Hydroxypropyl methylcellulose acetate succinate (HPMCAS).

[0026] In one embodiment, the acrylate-based polymer comprises a first methyl acrylate co-polymer and a second methyl acrylate co-polymer; each independently comprising poly (methacrylic acid) and one or more additional acrylate polymer selected from poly (methyl acrylate), poly (ethyl acrylate), poly(methyl-methacrylate), and poly(ethyl-methacrylate).

[0027] In one embodiment, the oral delivery capsule of the invention is a unit dosage form for use in colonic delivery of the Ladostigil salt in a subject in need thereof.

[0028] In another aspect, there is a method for delivering Ladostigil or a salt thereof to a colon of a subject in need thereof, the method comprising administering to the subject the oral delivery capsule of the invention.

[0029] In one embodiment, the subject is afflicted with a neurodegenerative disease or disorder.

[0030] In one embodiment, the method is for treating the neurodegenerative disease or disorder in the subject.

[0031] In one embodiment, the delivering is with reduced individual variation in blood levels of the Ladostigil or salt thereof, in the subject after being orally administered therewith.

[0032] In one embodiment, the treating comprises reducing individual variation in blood levels of the Ladostigil or salt thereof, in the subject after being orally administered therewith.

[0033] Unless otherwise defined, all technical and / or scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the invention pertains. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of embodiments of the invention, exemplary methods and / or materials are described below. In case of conflict, the patent specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and are not intended to be necessarily limiting.

[0034] Further embodiments and the full scope of applicability of the present invention will become apparent from the detailed description given hereinafter. However, it should be understood that the detailed description and specific examples, while indicating preferred embodiments of the invention, are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description.BRIEF DESCRIPTION OF THE DRAWINGS

[0035] Fig. 1 includes a graph showing comparison of concentration-time curve of the two forms of capsules for oral and colonic delivery. Shown are mean concentrations of ladostigil in men and women after oral and colonic delivery. Dotted line indicates concentration necessary to inhibit cytokine release from microglia.DETAILED DESCRIPTION

[0036] The present invention in some embodiments thereof is based on a surprising finding that a specific excipient (Miglyol 812N, a medium chain fatty acid triglyceride containing a mixture of capric acid triglyceride and caprylic acid triglyceride) out of a long list of species was found to be a suitable carrier for Ladostigil tartrate. In contrast numerous excipients including a structurally similar Capryol 90 (Propylene Glycol Monocaprylate, i.e. a glycol ester of caprylic acid) and PEG were not suitable for the formulation disclosed herein due to insufficient stability, insufficient solubility in simulated colonic medium and / or incompatibility with Ladostigil.

[0037] Furthermore, an exemplary oral delivery capsule containing a formulation of Ladostigil tartrate and coated with an enteric coating showed an optimum release of the API at pH 7, mimicking the pH of the colon. Accordingly, the current invention provides a dosage form (oral delivery capsule) suitable for a targeted colonic delivery of Ladostigil.Formulation

[0038] In one aspect of the invention, there is provided a formulation comprising a Ladostigil salt and a pharmaceutically acceptable excipient comprising one or more fatty acid glycerides, wherein a concentration of the Ladostigil salt within the formulation is at least l%w / w. The term "pharmaceutically acceptable" can mean approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.

[0039] In another aspect of the invention, there is provided a formulation comprising a therapeutically effective amount of the Ladostigil salt and a pharmaceutically acceptable excipient comprising one or more fatty acid glycerides, wherein a concentration of the Ladostigil salt within the formulation is at least l%w / w.

[0040] In some embodiments, the pharmaceutically acceptable excipient is a liquid at an atmospheric pressure of about 1 atm and at a temperature between 0 and 50°C, between 5and 45°C including any range between and. In some embodiments, the liquid is a free flowable liquid. A "free flowable liquid" refers to a liquid that can move or flow easily without significant resistance. This characteristic is essential for ensuring that the liquid can be handled, processed, or administered efficiently in various applications, such as in pharmaceutical formulations. In some embodiments, the pharmaceutically acceptable excipient being a free flowable liquid is characterized by a viscosity of between 1 and 100 cP at 25°C.

[0041] In some embodiments, the Ladostigil salt has a solubility in the pharmaceutically acceptable excipient of at least 0.1%, at least 0.5% or at least 0.8%w / w, including any range between.

[0042] In some embodiments, the Ladostigil salt is characterized by a dispersibility in the in the pharmaceutically acceptable excipient at least about 4%w / w or between about 4 and about 10%w / w relative to a combined weight the Ladostigil salt and the pharmaceutically acceptable excipient. The term "dispersibility" refers to the ability of a substance, such as a powder, to distribute uniformly throughout a liquid medium without forming clumps or settling. In the context of pharmaceutical formulations, dispersibility is characterized by the absence of visible sedimentation at a temperature between 20 and 30°C for a time period of 1 h. Sedimentation can be determined visually using the sedimentation test disclosed herein.

[0043] In some embodiments, the pharmaceutically acceptable excipient comprises a single fatty acid glyceride or a plurality and / or a combination (e.g., 2, 3, or 4) of chemically distinct fatty acid glyceride species. In some embodiments, the pharmaceutically acceptable excipient consists essentially of one or more fatty acid glyceride.

[0044] In some embodiments, the excipient in the formulation disclosed herein consists essentially of one or more fatty acid glycerides, wherein the term “consists essentially of’ encompasses that at least 80%, at least 90% or between 80 and 100%, between 85 and 100%, between 90 and 100%, between 95 and 100%, between 80 and 90%, between 80 and 95%, between 90 and 99%, between 90 and 97%, between 90 and 95%, between 90 and 98%, between 90 and 96% by weight of the excipient consist of the one or more fatty acid glyceride.

[0045] In some embodiments, the pharmaceutically acceptable excipient is the sole liquid in the formulation. In some embodiments, at least 80%, at least 90% or between 80 and 100%, between 85 and 100%, between 90 and 100%, between 95 and 100%, between 80and 90%, between 80 and 95%, between 90 and 99%, between 90 and 97%, between 90 and 95%, between 90 and 98%, between 90 and 96% w / w of the liquid phase in the formulation consists of the one or more fatty acid glyceride.

[0046] In some embodiments, the pharmaceutically acceptable excipient is the sole liquid in the formulation. In some embodiments, at least 80%, at least 90% or between about 80 and about 96%, between 85 and about 90%, between 85 and about 93%, between 85 and about 96%, between 85 and about 95%, between 90 and about 96%, between 90 and 95%, between 90 and 94%, between 90 and 93%w / w of the formulation consists of the one or more fatty acid glyceride.

[0047] In some embodiments, the pharmaceutically acceptable excipient is a synthetic or a semi-synthetic compound. In some embodiments, the pharmaceutically acceptable excipient is a natural compound or is derived (i.e., extracted) from a natural product. In some embodiments, the pharmaceutically acceptable excipient derived from a natural product is a fractionated coconut oil.

[0048] In some embodiments, the pharmaceutically acceptable excipient is a natural extract. In some embodiments, the natural extract characterized by chemical purity (with respect to the one or more fatty acid glyceride, e.g., determined via HPLC or LC-MS) of at least 70%, at least 80%, at least 90% or between 90 and 99%, between 95 and 99%, between 80 and 90%, between 80 and 95%, between 90 and 99%, between 90 and 97%, between 90 and 95%, between 90 and 98%, between 90 and 96%w / w, including any range between. In some embodiments, the pharmaceutically acceptable excipient is a pharmaceutical grade compound.

[0049] In some embodiments, the one or more fatty acid glyceride is or comprises any one of: a monoglyceride, a di glyceride or a triglyceride. In some embodiments, the one or more fatty acid glyceride is / are fatty acid triglyceride(s).

[0050] In some embodiments, the pharmaceutically acceptable excipient consists essentially of fatty acid triglyceride(s), wherein the term “consists essentially of’ is as described above. In some embodiments, the fatty acid triglyceride(s) are medium chain triglyceride(s).

[0051] In some embodiments, the one or more fatty acid glyceride / triglyceride comprises or consists of medium chain fatty acid residues. In some embodiments, the medium chain triglyceride consists of medium chain fatty acid residues. In some embodiments, themedium chain fatty acid residue is derived from a corresponding fatty acid upon esterification thereof with glycerol. The term “fatty acid residue” encompasses the following structure: -C(=O)-R, wherein R is an alkyl or an alkenyl. In some embodiments, the medium chain fatty acid residues have an R being between 4 and 11, between 5 and 11, between 5 and 10, between 5 and 7, or any one of: 4, 5, 6, 7, 8, 9, 10 or 11 carbon atoms long, including any range between. In some embodiments, the one or more fatty acid glyceride / triglyceride comprises or consists of medium chain fatty acid residues being between 5 and 12, between 6 and 12, between 6 and 10, between 6 and 8 or any one of: 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms long.

[0052] Non-limiting examples of medium chain fatty acids include Caproic acid (C6:0), caprylic acid (C8:0), capric acid (C10:0), and lauric acid (C12:0) are examples of.

[0053] In some embodiments, each of the fatty acid triglyceride(s) is a homo-triglyceride (i.e., having the same chemical structure of the entire fatty acid residues) or a mixed-triglyceride (i.e., including 1, 2 or 3 fatty acid residues with different chemical structure). The term “chemical structure” refers to the chemical composition of R (i.e., number of C-atoms, degree of unsaturation and position of the unsaturated bond), relative position of (chemically distinct) fatty acid residues in the triglyceride and / or conformation of R (i.e., Z / E).

[0054] In some embodiments, the pharmaceutically acceptable excipient consists essentially of fatty acid triglyceride(s), wherein the fatty acid triglyceride(s) is selected from capric acid triglyceride and caprylic acid triglyceride, including a mixture thereof. In some embodiments, the pharmaceutically acceptable excipient consists essentially of fatty acid triglyceride(s) consisting of capric acid and / or caprylic acid residues. In some embodiments, the pharmaceutically acceptable excipient consists essentially of capric acid triglyceride, caprylic acid triglyceride, or a mixture thereof.

[0055] In some embodiments, the pharmaceutically acceptable excipient consists essentially of capric acid triglyceride and caprylic acid triglyceride, wherein a ratio between capric acid residues (i) and caprylic acid residues (ii) is between about 1 :4 and about 1 : 1 or between about 1:3 and about 1:1, including any range between. In some embodiments, a free acid content (e.g., a combined concentration of non-esterified fatty acids such as caproic, lauric and myristic acid) in the pharmaceutically acceptable is below 10%, below 8% or below 6%w / w. The chemical composition of the pharmaceutically acceptableexcipient can be determined as disclosed in Ph. Eur Monograph 0868, Ph. Eur 2.4.22 (Method C).

[0056] In some embodiments, the formulation is a liquid. In some embodiments, the formulation is a free flowable liquid. In some embodiments, the formulation is a suspension or dispersion. In some embodiments, the formulation comprises the Ladostigil salt dispersed in the pharmaceutically acceptable excipient. In some embodiments, the formulation is a homogenous dispersion or suspension. In some embodiments, the dispersion or suspension is stable at a temperature between 20 and 30°C for a time period of Ih; wherein stability is determined by sedimentation test disclosed herein.

[0057] In some embodiments, the formulation is characterized by density between 0.8 and 0.99, between 0.8 and 0.99, between 0.8 and 0.99, between 0.8 and 1, between 0.8 and 0.99, between 0.85 and 1, between 0.9 and 0.99, between 0.95 and 0.99, or about 0.98 g / ml, including any range between.

[0058] In some embodiments, the formulation is characterized by viscosity between 100 and 500 cP, between 200 and 500 cP, between 300 and 500 cP, between 350 and 500 cP, between 350 and 450 cP, or between about 400 and about 450 cP, including any range between; wherein the viscosity is measured at 20°C. Optionally, viscosity can be assessed according to the viscosity measurement method disclosed herein.

[0059] In some embodiments, a w / w concentration of the pharmaceutically acceptable excipient in the formulation is between 80 and 96%, between 90 and 95%, between 85 and 96%, between 90 and 96%, between 92 and 96%, between 93 and 96%, between 94 and 96% or about 96%w / w, including any range between.

[0060] In some embodiments, a w / w concentration of the medium chain fatty acid triglyceride(s) in the formulation is between 80 and 96%, between 80 and 92%, between 90 and 95%, between 85 and 96%, between 85 and 92%, between 85 and 90%, between 80 and 90%, between 93 and 96%, between 94 and 96%, about 92%w / w or about 96%w / w, including any range between.

[0061] In some embodiments, a w / w water content in the formulation is below 5%, below 3%, below 2% or below 1%. In some embodiments, the pharmaceutically acceptable excipient is the sole liquid in the formulation. In some embodiments, the pharmaceutically acceptable excipient constitutes at least 95%, at least 96%, at least 97%, at least 98%, at least 99% by weight of the entire liquids in the formulation.

[0062] In some embodiments, the Ladostigil salt is a pharmaceutically active ingredient in the formulation disclosed herein. In some embodiments, the Ladostigil salt is the sole pharmaceutically active ingredient in the formulation. In some embodiments, the formulation is devoid of additional pharmaceutically active ingredient(s) other than Ladostigil or the Ladostigil salt. In some embodiments, the pharmaceutically active ingredient consists essentially of the Ladostigil salt, i.e., at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% by weight the pharmaceutically active ingredient consists of the Ladostigil salt.

[0063] In some embodiments, a concentration of the Ladostigil salt within the formulation is between about 1 and about 10%w / w, between about 1 and about 8%w / w, between about 1 and about 7%w / w, between about 1 and about 6%w / w, between about 1 and about 5%w / w, between about 2 and about 8%w / w, between about 2 and about 6%w / w, between about 3 and about 10%w / w, between about 3 and about 8%w / w, between about 3 and about 5%w / w, between 3.3 and 5%w / w, between 3.3 and 4.5%w / w, between 3.5 and 4.5%w / w, between 3.8 and 4.5%w / w, between 3.8 and 4.2%w / w, between 3.9 and 4.2%w / w, between 3.9 and 4.1%w / w relative to the total weight of the formulation, including any range between.

[0064] In some embodiments, a concentration of the Ladostigil salt corresponds to between about 6 and about 9 mg, at least 7 mg, at least 7.8 mg, at least 8 mg or between 7.5 and 9, between 7.5 and 8 mg Ladostigil free base in the unit dosage form.

[0065] In some embodiments, the Ladostigil salt is a pharmaceutically acceptable salt. In some embodiments, the Ladostigil salt comprises a stoichiometric ratio of Ladostigil cation and a pharmaceutically acceptable counter anion. In some embodiments, the Ladostigil salt is represented by Formula 2:, wherein X is the pharmaceutically acceptable anion (also used herein as “counter anion”) and wherein n is 1, 2 or 3 to meet the stoichiometric ratio between X and Ladostigil cation.

[0066] As used herein, the terms "pharmaceutically acceptable salt" or “pharmaceutically acceptable anion" refers to any non-toxic salt / counter anion of Ladostigil that. For example, the term "pharmaceutically acceptable" can mean approved by a regulatory agency of theFederal or a state government or listed in the U. S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.

[0067] Exemplary pharmaceutically acceptable anions may include tartrate, halide, hydroxide, carboxylate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphor sulfonate, cyclopentane propionate, digluconate, dodecyl sulfate, ethane sulfonate, formate, fumarate, glucoheptonate, glycerophosphate, glycolate, gluconate, heptanoate, hexanoate, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methane sulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, palmoate, pectinate, persulfate, 3- phenylpropionate, picrate, pivalate, propionate, salicylate, stearate, succinate, sulfate, thiocyanate, p-toluene sulfonate, undecanoate, valerate, and the like.

[0068] In some embodiments, the Ladostigil salt is represented by Formula 2, wherein X is tartrate and wherein n is 1 or 2. In some embodiments, the Ladostigil salt is represented by Formula 2, wherein X is tartrate and wherein n is 2.

[0069] In some embodiments, the formulation further comprises a viscosity enhancer. In some embodiments, the viscosity enhancer is in a form of solid particles and is dispersed or suspended in the pharmaceutically acceptable excipient. In some embodiments, the viscosity enhancer is or comprises a mineral particle. In some embodiments, a w / w concentration of the viscosity enhancer in the formulation is below 5%, below 3%, below 2%, below 1.5% or between 0.5 and 5%, between 0.5 and 4%, between 0.5 and 3%, between 0.5 and 2%, between 0.5 and 1.5%, or about 1% w / w, including any range between.

[0070] In some embodiments, a w / w concentration of the mineral particle in the formulation is below 5%, below 3%, below 2%, below 1.5% or between 0.5 and 5%, between 0.5 and 4%, between 0.5 and 3%, between 0.5 and 2%, between 0.5 and 1.5%, or about 1% w / w, including any range between.

[0071] In some embodiments, the mineral particle is characterized by an average particle size between 10 nm and 100 pm, between 10 and 500 nm, between 50 and 500 nm, between 1 and 10 pm, including any range between.

[0072] In some embodiments, the mineral particle is an inorganic particle comprising or being selected from a metal (or metalloid) oxide particle and a clay particle. In some embodiments, the metal (or metalloid) oxide particle is or comprises any one of: silica, TiCh, AI2O3, Fe2O3, ZnO, and ZrO particle, or any combination thereof.

[0073] The term “silica” as used here refers to a structure containing at least the following elements: silicon and oxygen. Silica may have the fundamental formula of SiCh or it may have another structure including SixOy(where x and y can each independently be about 1 to 10). Additional elements including, but not limited to, carbon, nitrogen, sulfur, phosphorus, or ruthenium may also be used. Silica may be porous fumed silica (e.g., microporous silica), mesoporous silica or microporous silica. The porous silica may have an average specific surface area ranging between 100 and 400 m2 / g, between 100 and 350 m2 / g, between 200 and 400 m2 / g, or between 250 and 350 m2 / g or about 200 m2 / g.

[0074] Exemplary clay particles include but are not limited to talc, mica, bentonite, sepiolite, illite, zeolite, palygorskite, attapulgite, smectite, montmorillonite, hectorite, kaolinite, halloysite, or vermiculite, including any combination thereof. In some embodiments, the mineral particle is or consist essentially of silica.

[0075] In some embodiments, the formulation further comprises an antioxidant. In some embodiments, the antioxidant is configured to induce a radical scavenging effect in a solution. In some embodiments, the antioxidant comprises or is selected from: alkyl phenol (such as tert-butyl ated phenol or tert-butyl ated hydroquinone, alkylated phenol, alkoxylated phenol), a vitamin (Vitamin C, Vitamin E, or additional tocopherols), a carotenoid (e.g., beta-carotene, lycopene), and a thiol (e.g., glutathione). In some embodiments, the antioxidant is a phenol -based antioxidant (e.g., Quercetin, Catechins, Curcumin or Resveratrol). In some embodiments, the antioxidant is an alkylphenol-based antioxidant. In some embodiments, the alkyl phenol is a tert-butylated alkylphenol. In some embodiments, the tert-butylated alkyl phenol is or comprises any one of: butylated hydroxytoluene (BHT), hydroxytoluene, butylated hydroxyanisole, propyl gallate, tert-butylhydroquinone and ethoxyquin, including any combination thereof.

[0076] In some embodiments, a w / w concentration of the antioxidant in the formulation is below 1%, below 0.5%, below 0.1% or between 0.01 and 0.5%, between 0.05 and 0.1%, between 0.05 and 0.5%, or about 0.05% w / w, including any range between.

[0077] In some embodiments, the antioxidant is BHT.

[0078] In some embodiments, the formulation consists essentially of the fatty acid glyceride excipient (e.g., medium chain fatty acid triglyceride(s)), Ladostigil tartrate salt, silica and the antioxidant.

[0079] In some embodiments, the formulation consists essentially of the fatty acid glyceride excipient (e.g., medium chain fatty acid triglyceride(s)), Ladostigil tartrate salt at a concentration between about 3 and about 6%w / w, silica at a concentration between about 0.5 and about 2%w / w and the antioxidant at a concentration between about 0.01 and about 0.5%w / w. In some embodiments, the formulation consists essentially of between 90 and 95% w / w of the medium chain fatty acid triglyceride(s)), between about 3 and about 5% Ladostigil tartrate salt, between about 0.5 and about 2%w / w silica and below 0.1%w / w BHT.

[0080] In some embodiments, the formulation further comprises one or more pharmaceutically acceptable additive. In some embodiments, a w / w concentration of the pharmaceutically acceptable additive in the formulation is below 10%, below 5%, between 0.01 and 5%, including any range between.

[0081] An "additive" in the context of pharmaceutical formulations refers to any substance added to the formulation to enhance its organoleptic properties, spoilage stability, or usability. Examples of pharmaceutical additives include:

[0082] Coloring Agents: Used to provide a distinctive appearance to the formulation, making it easily identifiable. Examples include FD&C Red No. 40 and FD&C Blue No. 1.

[0083] Flavoring Agents: Added to improve the taste of oral medications, making them more palatable. Examples include natural flavors like vanilla or synthetic flavors like ethyl vanillin.

[0084] Preservatives: Used to prevent microbial growth and extend the shelf life of the formulation. Examples include benzalkonium chloride and sodium benzoate.

[0085] Sweeteners: Improve the taste of the formulation. Examples include sucrose, aspartame, and sucralose.

[0086] In some embodiments, the Ladostigil salt described herein can exist in a non solvated form as well as in solvated form, including a hydrated form.

[0087] In some embodiments, the Ladostigil salt is in form of a single enantiomer with enantiomeric purity of more than 70%, more than 80%, more than 90%, more than 95% or more than 99% or between 80 and 99%, between 90 and 99% or between 95 and 99%, including any range between. Enantiomeric purity of Ladostigil salt can be determined by HPLC using a suitable chiral chromatographic column.Capsule

[0088] In another aspect, there is provided an oral delivery capsule comprising a therapeutically effective amount of the formulation of the invention; and wherein the oral delivery capsule is coated with an enteric coating. In some embodiments, the oral delivery capsule is a pharmaceutical unit dosage form. In some embodiments, the oral delivery capsule is a pharmaceutical dosage form for colonic release.

[0089] In some embodiments, the oral delivery capsule is configured to facilitate colonic delivery of Ladostigil, Ladostigil salt or both. In some embodiments, the oral delivery capsule is configured to release the Ladostigil salt in a colon of a subject. In some embodiments, the oral delivery capsule is configured to undergo disintegration in an aqueous medium (i.e., any aqueous solution containing water as the sole solvent and optionally comprising salts, enzymes or any biomolecules) at a pH ranging between 6.6 and 8, between 6.8 and 7.5, between 6.8 and 7.3, between 6.9 and 7.1, at a temperature between 30 and 40°C. In some embodiments, the oral delivery capsule is configured to undergo disintegration in the aqueous medium under pH and temperature conditions disclosed above, wherein a complete disintegration of the capsule occurs 1 min., 5 min., 10 min., 30 min., 1 h, 2 h, 4 h after introducing the capsule into the aqueous medium, including any range between. In some embodiments, the oral delivery capsule is pharmaceutical unit dosage form for oral administration for colonic delivery of Ladostigil, Ladostigil salt or both.

[0090] The oral delivery capsule is configured to maintain its stability in the lumen of the small intestine (i.e., the ability to pass, intact, until arriving at the ileo-cecal junction), and to undergo erosion in the lumen of the colon to release the entrapped Ladostigil salt. The oral delivery capsule is configured to undergo disintegration to release the Ladostigil salt around the ileocecal junction. The release time (corresponding to release of about 80-90% of the initial amount of Ladostigil salt in the capsule) is between 2 and 5 h, between 2 and 4 h, between 3 and 5 h, including any rage between.

[0091] In some embodiments, the therapeutically effective amount of the formulation is equivalent to an amount of Ladostigil free base (unit dose) in each capsule of between 5 and 15 mg, between 5 and 15 mg, between 5 and 12 mg, between 5 and 10 mg, between 5 and 9 mg, between 5 and 8 mg, between 6 and 9 mg, between 6 and 8 mg, between 8 and 15 mg, between 8 and 12 mg, between 9 and 12 mg, between 9 and 11 mg, about 7 or about 10 mg, including any range between. In some embodiments, the therapeutically effectiveamount of the formulation is equivalent to an amount of Ladostigil free base (unit dose) in each capsule of between 7 and 9, between 7.5 and 9, between 7.8 and 8, between 7.8 and 8.5, between 7.8 and 8 mg, including any range between.

[0092] In some embodiments, the therapeutically effective amount of the formulation is equivalent to an amount of the Ladostigil salt (unit dose) in each capsule of between 8 and 20 mg, between 8 and 15 mg, between 8 and 12 mg, between 8 and 10 mg, between 8 and 13 mg, between 9 and 12 mg, between 9 and 13 mg, between 9 and 11 mg, about 13 mg or about 10 mg, including any range between.

[0093] In some embodiments, the oral delivery capsule comprises or consists essentially of a capsule body comprising, filled with and / or encapsulating the formulation of the invention, and wherein the capsule body is in contact with the enteric coating. In some embodiments, the capsule body is in direct contact with the enteric coating.

[0094] In some embodiments, the capsule body comprises or consists of a water-soluble material suitable for use in a pharmaceutical capsule. In some embodiments, the water-soluble material is a gel-forming material. In some embodiments, the water-soluble material is selected from a water-soluble polysaccharide, a water-soluble oligosaccharide, a protein, and a water-soluble synthetic polymer.

[0095] In some embodiments, the water-soluble material is selected from gelatin, cellulose derivative (e.g., a hydroxy alkylated cellulose such as Hydroxypropyl Methylcellulose (HPMC), carboxylated cellulose or carboxylated alkyl cellulose), PVA, starch, a modified starch, a gel-forming polysaccharide / oligosaccharide (pullulan, alginate, hyaluronate, agar, ulvan pectin, chitosan, dextran, a gum), or any combination or copolymer thereof.

[0096] In some embodiments, the water-soluble material is selected from gelatin and HPMC.

[0097] In some embodiments, the enteric coating is configured to undergo dissolution at a pH of about 7, or above 6.5, above 6.7, above, 6.8, above 6.6, above 6.9 or between 6.6 and 9, between 6.9 and 8, between 6.8 and 7.5, including any range between.

[0098] In some embodiments, the enteric coating is stable at a pH below 6, or below 6.5.

[0099] In some embodiments, the enteric coating comprises or consists essentially of any one of: acrylate-based polymer, hydroxypropyl methylcellulose phthalate (HPMCP),Cellulose acetate phthalate (CAP), Polyvinyl acetate phthalate (PVAP), Carboxymethyl ethyl cellulose (CMEC) and Hydroxypropyl methylcellulose acetate succinate (HPMCAS).

[0100] In some embodiments, the enteric coating comprises or consists essentially of one or more acrylate-based polymer. In some embodiments, the enteric coating comprises or consists essentially of a first acrylate-based polymer and a second acrylate-based polymer.

[0101] In some embodiments, each of the first acrylate-based polymer and the second acrylate-based polymer is a co-polymer independently comprising poly(methacrylic acid) and one or more additional acrylate polymer selected from poly(methyl acrylate), poly(ethyl acrylate), poly(methyl-methacrylate), and poly(ethyl-methacrylate).

[0102] In some embodiments, the first acrylate-based polymer is poly(methacrylic acid)-co-poly(ethyl-acrylate) (such as EUDRAGIT® L 30 D-55) and the second acrylate-based polymer is poly(methacrylic acid)-co-poly(methyl-methacrylate)-co- poly(methyl acrylate) (such as EUDRAGIT® FS 30 D).

[0103] In some embodiments, a w / w ratio between the first acrylate-based polymer and the second acrylate-based polymer in the coating is between about 6:1 and 1:6, between about 6:1 and 1:1, between about 5:1 and 1:1, between about 4:1 and 1:1, between about 4:1 and 2:1, between about 6:1 and 1:2, between about 5:1 and 1:2, between about 4:1 and 1:2, including any range between.Methods of Treatment

[0104] According to some embodiments, the present invention provides a method for delivering Ladostigil and / or a salt thereof to a colon of a subject in need thereof, the method comprising administering to the subject the oral delivery capsule of the invention. According to some embodiments, the present invention provides a method for delivering Ladostigil and / or a salt thereof specifically or predominantly to a colon of a subject in need thereof, the method comprising administering to the subject the oral delivery capsule of the invention.

[0105] In some embodiments, specifically or predominantly refers to at least 85%, 90%, 95%, 97%, 99%, or any value and range therebetween of Ladostigil and / or a salt thereof of the oral delivery capsule of the invention being absorbed in the colon. Each possibility represents a separate embodiment of the invention.

[0106] In some embodiments, specifically or predominantly refers to the amount of Ladostigil and / or a salt being absorbed in any site of the gastrointestinal tract excluding thecolon, such as oral cavity, esophagus, stomach, and small intestine, or any combination thereof, being negligible. In some embodiments, negligible refers to at most 10%, 8%, 7%, 5%, 3%, 2%, 1%, or any value and range therebetween of Ladostigil and / or a salt thereof of the oral delivery capsule of the invention being absorbed in any site of the gastrointestinal tract excluding the colon, such as oral cavity, esophagus, stomach, small intestine, or any combination thereof.

[0107] In some embodiments, the subject is afflicted with a neurodegenerative disease or disorder. In some embodiments, the subject is afflicted with a fibrosis-related disease. In some embodiments, the subject is afflicted with fibrosis, sclerosis, or both. In some embodiments, the subject is afflicted with a disease or disorder selected from: Parkinson’s disease, ulcerative colitis, diabetes, idiopathic lung disease, diabetes. In some embodiments, the method is for administering to the subject the unit dose of Ladostigil.

[0108] In some embodiments, the method is for prolonging Ladostigil release in the subject, compared to a control. In some embodiments, the method is for extending the release time of Ladostigil in the subject, compared to a control. In some embodiments, the method is for increasing Ladostigil absorption time in the subject, compared to a control.

[0109] In some embodiments, the method is for prolonging exposure of the subject to an effective plasma concentration of Ladostigil of at least 2 ng / ml, compared to a control. In some embodiments, the method is for delivering Ladostigil for specific or predominant absorption in the colon of a subject. In some embodiments, treating is with reduced individual variation in ladostigil blood levels.

[0110] In some embodiments, an increasing / prolonging or extending is by at least 50%, at least 100%, at least 200%, at least 300%, including any range between, compared to the control.

[0111] In some embodiments, the control refers to the above-mentioned parameters (Ladostigil release, absorption time, exposure) after oral delivery of the same amount of Ladostigil salt to the subject.

[0112] In some embodiments, the method comprises administering the oral delivery capsule of the invention at least 1 time, at least 2 times, 1-3 times per day, 1-4 times per day. Each possibility represents a separate embodiment of the invention.

[0113] In some embodiments, the oral delivery capsule of the present invention is administered in a therapeutically safe and effective amount. As used herein, the term “safeand effective amount” refers to the quantity of a component which is sufficient to yield a desired therapeutic response without undue adverse side effects, including but not limited to toxicity, such as calcemic toxicity, irritation, or allergic response, commensurate with a reasonable benefit / risk ratio when used in the presently described manner. The actual amount administered, and the rate and time-course of administration, will depend on the nature and severity of the condition being treated. Prescription of treatment, e.g., decisions on dosage, timing, etc., is within the responsibility of general practitioners or specialists, and typically takes account of the disorder to be treated, the condition of the individual patient, the site of delivery, the method of administration and other factors known to practitioners. Examples of techniques and protocols can be found in Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott Williams & Wilkins, Philadelphia, Pa., (2005).

[0114] In one embodiment, the subject is afflicted with and / or at risk of being afflicted with a neurodegenerative disease, idiopathic lung disease and / or ulcerative colitis.

[0115] In some embodiments, the oral delivery capsule is for use in the prevention or treatment of a disease or disorder in the subject. In some embodiments, the disease or disorder is selected from a neurodegenerative disease, idiopathic lung disease, diabetes, and ulcerative colitis. In some embodiments, a neurodegenerative disease is selected from: cognitive disorder, prodromal Alzheimer’s disease, multiple sclerosis, dementia, Parkinson’s disease, and any combination thereof. Non-limiting examples of neurodegenerative diseases include cognitive disorder, Alzheimer’s disease, multiple sclerosis, dementia, Parkinson’s disease, Huntington’s disease, Down syndrome, Amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Dystonia and prion disease or any combination thereof.

[0116] The term "subject" as used herein refers to an animal, more particularly to nonhuman mammals and human organism. Non-human animal subjects may also include prenatal forms of animals, such as, e.g., embryos or fetuses. Non-limiting examples of non-human animals include: horse, cow, camel, goat, sheep, dog, cat, non-human primate, mouse, rat, rabbit, hamster, guinea pig, and pig. In some embodiments, the subject is a mammal. In one embodiment, the subject is a human. Human subjects may also include fetuses.

[0117] In some embodiments delivering is with reduced individual variation in blood levels of Ladostigil or salt thereof, in a subject after being administered therewith. In some embodiments, treating comprises reducing individual variation in blood levels of Ladostigil or salt thereof, in a subject after being administered therewith. In some embodiments, administered comprises or is orally administered.

[0118] In some embodiments, reducing comprises at least 3%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 97%, or 99% reduction, and any value and range therebetween. In some embodiments, reducing comprises 3-100%, 5-100%, 10-100%, 20-100%, 30-100%, 40-100%, 50-100%, 60-100%, 70-100%, 80-100%, 90-100%, 95-100%, 97-100%, or 99-100% reduction. Each possibility represents a separate embodiment of the invention.

[0119] In some embodiments, reducing is compared to a control. In some embodiments, a control comprises a non-treated subject. In some embodiments, a control comprises a subject not treated with the formulation of the invention, the oral delivery capsule of the invention, or both. In some embodiments, a control comprises a subject treated with Ladostigil or a salt thereof, which is not formulated within the formulation of the invention, the oral delivery capsule of the invention, or both. In some embodiments, a control comprises a subject treated with a “naked” Ladostigil or a salt thereof.

[0120] As used herein, the term “naked” in the context of Ladostigil or a salt thereof, refers the compound being provided or administered to a subject per se and / or not as a part of a formulation and / or an oral delivery capsule such as disclosed herein.

[0121] In some embodiments, treating comprises preventing and / or treating.

[0122] As used herein, the terms “treatment” or “treating” of a disease, disorder, or condition encompasses alleviation of at least one symptom thereof, a reduction in the severity thereof, or inhibition of the progression thereof. Treatment need not mean that the disease, disorder, or condition is totally cured. To be an effective treatment, a useful composition herein needs only to reduce the severity of a disease, disorder, or condition, reduce the severity of symptoms associated therewith, or provide improvement to a patient or subject’s quality of life.

[0123] As used herein, the term “prevention” of a disease, disorder, or condition encompasses the delay, prevention, suppression, or inhibition of the onset of a disease, disorder, or condition.

[0124] The term "suppression" is used to describe a condition wherein the disease / disorder process has already begun but obvious symptoms of the condition have yet to be realized. Thus, the cells of an individual may have the disease / disorder, but no outside signs of the disease / disorder have yet been clinically recognized. In either case, the term prophylaxis can be applied to encompass both prevention and suppression. Conversely, the term "treatment" refers to the clinical application of active agents to combat an already existing condition whose clinical presentation has already been realized in a patient.

[0125] As used herein, the term "condition" includes anatomic and physiological deviations from the normal that constitute an impairment of the normal state of the living animal or one of its parts, that interrupts or modifies the performance of the bodily functions.Chemical Definitions

[0126] Compounds are described using standard nomenclature. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this invention belongs.

[0127] A dashthat is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, -(C=O) NH2 is attached through the carbon of the keto (C=O) group.

[0128] The term “substituted”, as used herein, means that any one or more hydrogens on the designated atom or group is replaced with a moiety selected from the indicated group, provided that the designated atom’s normal valence is not exceeded, and the resulting compound is stable. For example, when the substituent is oxo (i.e., =0) then two hydrogens on the atom are replaced. For example, a pyridyl group substituted by oxo is a pyridine. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds or useful synthetic intermediates. A stable active compound refers to a compound that can be isolated and can be formulated into a dosage form with a shelf life of at least one month. A stable manufacturing intermediate or precursor to an active compound is stable if it does not degrade within the period needed for reaction or other use. A stable moiety or substituent group is one that does not degrade, react or fall apart within the period necessary for use. Non-limiting examples of unstable moieties are those that combine heteroatoms in an unstable arrangement, as typically known and identifiable to those of skill in the art.

[0129] Any suitable group may be present on a “substituted” or “optionally substituted” position that forms a stable molecule and meets the desired purpose of the invention and includes, but is not limited to: alkyl, haloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocycle, aldehyde, amino, carboxylic acid, ester, ether, halo, hydroxy, keto, nitro, cyano, azido, oxo, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, sulfonylamino, or thiol.

[0130] As used herein, the term "alkyl" describes an aliphatic hydrocarbon including straight chain and branched chain groups. The term "alkyl", as used herein, also encompasses saturated or unsaturated hydrocarbon, hence this term further encompasses alkenyl and alkynyl.

[0131] The term "alkenyl" describes an unsaturated alkyl, as defined herein, having at least two carbon atoms and at least one carbon-carbon double bond. The alkenyl may be substituted or unsubstituted by one or more substituents, as described hereinabove.

[0132] The term "alkynyl", as defined herein, is an unsaturated alkyl having at least two carbon atoms and at least one carbon-carbon triple bond. The alkynyl may be substituted or unsubstituted by one or more substituents, as described hereinabove.

[0133] The term "cycloalkyl" describes an all-carbon monocyclic or fused ring (i.e., rings which share an adjacent pair of carbon atoms) group where one or more of the rings does not have a completely conjugated pi-electron system. The cycloalkyl group may be substituted or unsubstituted, as indicated herein.

[0134] The term "aryl" describes an all-carbon monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of carbon atoms) groups having a completely conjugated pi-electron system. The aryl group may be substituted or unsubstituted, as indicated herein.

[0135] The term "alkoxy" describes both an O-alkyl and an -O-cycloalkyl group, as defined herein. The term "aryloxy" describes an -O-aryl, as defined herein.

[0136] Each of the alkyl, cycloalkyl and aryl groups in the general formulas herein may be substituted by one or more substituents, whereby each substituent group can independently be, for example, halide, alkyl, alkoxy, cycloalkyl, nitro, amino, hydroxyl, thiol, thioalkoxy, carboxy, amide, aryl and aryloxy, depending on the substituted group and its position in the molecule. Additional substituents are also contemplated.

[0137] The term "halide", "halogen" or “halo” describes fluorine, chlorine, bromine or iodine. The term “haloalkyl” describes an alkyl group as defined herein, further substitutedby one or more halide(s). The term “haloalkoxy” describes an alkoxy group as defined herein, further substituted by one or more halide(s). The term “hydroxyl” or "hydroxy" describes a -OH group. The term "mercapto" or “thiol” describes a -SH group. The term "thioalkoxy" describes both an -S-alkyl group, and a -S-cycloalkyl group, as defined herein. The term "thioaryloxy" describes both an -S-aryl and a -S-heteroaryl group, as defined herein. The term “amino” describes a -NR’R” group, or a salt thereof, with R’ and R” as described herein.

[0138] The term "heterocyclyl" describes a monocyclic or fused ring group having in the ring(s) one or more atoms such as nitrogen, oxygen and sulfur. The rings may also have one or more double bonds. However, the rings do not have a completely conjugated pi-electron system. Representative examples are piperidine, piperazine, tetrahydrofuran, tetrahydropyran, morpholino and the like.

[0139] The term "carboxy" describes a -C(O)OR' group, or a carboxylate salt thereof, where R' is hydrogen, alkyl, cycloalkyl, alkenyl, aryl, heteroaryl (bonded through a ring carbon) or heterocyclyl (bonded through a ring carbon) as defined herein, or "carboxylate"

[0140] The term “carbonyl” describes a -C(O)R' group, where R' is as defined hereinabove. The above-terms also encompass thio-derivatives thereof (thiocarboxy and thiocarbonyl).

[0141] The term “thiocarbonyl” describes a -C(S)R' group, where R' is as defined hereinabove. A "thiocarboxy" group describes a -C(S)OR' group, where R' is as defined herein. A "sulfinyl" group describes an -S(O)R' group, where R' is as defined herein. A "sulfonyl" or “sulfonate” group describes an -S(O)2R' group, where R' is as defined herein.

[0142] A "carbamyl" or “carbamate” group describes an -OC(O)NR'R" group, where R' is as defined herein and R" is as defined for R'. A "nitro" group refers to a -NO2 group. The term "amide" as used herein encompasses C-amide and N-amide. The term "C-amide" describes a -C(O)NR'R" end group or a -C(O)NR' -linking group, as these phrases are defined hereinabove, where R' and R" are as defined herein. The term "N-amide" describes a -NR"C(O)R' end group or a -NR'C(O)- linking group, as these phrases are defined hereinabove, where R' and R" are as defined herein.

[0143] A "cyano" or "nitrile" group refers to a -CN group. The term "azo" or "diazo" describes an -N=NR' end group or an -N=N- linking group, as these phrases are defined hereinabove, with R' as defined hereinabove. The term "guanidine" describes a -R'NC(N)NR"R"' end group or a -R'NC(N) NR"- linking group, as these phrases are defined hereinabove, where R', R" and R'" are as defined herein. As used herein, the term “azide” refers to a -N3 group. The term “sulfonamide” refers to a -S(0)2NR'R" group, with R' and R" as defined herein.

[0144] The term “phosphonyl” or “phosphonate” describes an -OP(O)-(OR')2 group, with R' as defined hereinabove. The term “phosphinyl” describes a -PR'R" group, with R' and R" as defined hereinabove. The term “alkylaryl” describes an alkyl, as defined herein, which substituted by an aryl, as described herein. An exemplary alkylaryl is benzyl.

[0145] The term "heteroaryl" describes a monocyclic or fused ring (i.e., rings which share an adjacent pair of atoms) group having in the ring(s) one or more atoms, such as, for example, nitrogen, oxygen and sulfur and, in addition, having a completely conjugated pi-electron system. As used herein, the term “heteroaryl” refers to an aromatic ring in which at least one atom forming the aromatic ring is a heteroatom. Heteroaryl rings can be foamed by three, four, five, six, seven, eight, nine and more than nine atoms. Heteroaryl groups can be optionally substituted. Examples of heteroaryl groups include, but are not limited to, aromatic C3-8 heterocyclic groups containing one oxygen or sulfur atom, or two oxygen atoms, or two sulfur atoms or up to four nitrogen atoms, or a combination of one oxygen or sulfur atom and up to two nitrogen atoms, and their substituted as well as benzo- and pyrido-fused derivatives, for example, connected via one of the ring-forming carbon atoms. In certain embodiments, heteroaryl is selected from among oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, pyridinyl, pyridazinyl, pyrimidinal, pyrazinyl, indolyl, benzimidazolyl, quinolinyl, isoquinolinyl, quinazolinyl or quinoxalinyl.

[0146] In some embodiments, a heteroaryl group is selected from among pyrrolyl, furanyl (furyl), thiophenyl (thienyl), imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,3-oxazolyl (oxazolyl), 1,2-oxazolyl (isoxazolyl), oxadiazolyl, 1,3-thiazolyl (thiazolyl), 1,2-thiazolyl (isothiazolyl), tetrazolyl, pyridinyl (pyridyl)pyridazinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1,2,4,5-tetrazinyl, indazolyl, indolyl, benzothiophenyl, benzofuranyl, benzothiazolyl, benzimidazolyl, benzodi oxolyl, acridinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, thi enothiophenyl, 1,8-naphthyridinyl, other naphthyridinyls, pteridinyl or phenothiazinyl. Where the heteroaryl group includes more than one ring, each additional ring is the saturated form (perhydro form) or the partially unsaturated form (e.g., the dihydro form or tetrahydro form) or themaximally unsaturated (nonaromatic) form. The term heteroaryl thus includes bicyclic radicals in which the two rings are aromatic and bicyclic radicals in which only one ring is aromatic. Such examples of heteroaryl are include 3H-indolinyl, 2(lH)-quinolinonyl, 4-oxo-l,4-dihydroquinolinyl, 2H-1 -oxoisoquinolyl, 1,2-dihydroquinolinyl, (2H)quinolinyl N-oxide, 3,4-dihydroquinolinyl, 1,2-dihydroisoquinolinyl, 3,4-dihydro-isoquinolinyl, chromonyl, 3,4-dihydroiso-quinoxalinyl, 4-(3H)quinazolinonyl, 4H-chromenyl, 4-chromanonyl, oxindolyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydro-quinolinyl, lH-2,3-dihydroisoindolyl, 2,3-dihydrobenzo[f]isoindolyl, 1,2,3,4-tetrahydrobenzo-[g]isoquinolinyl, l,2,3,4-tetrahydro-benzo[g]isoquinolinyl, chromanyl, isochromanonyl, 2,3-dihydrochromonyl, 1,4-benzo-dioxanyl, 1,2,3,4-tetrahydro-quinoxalinyl, 5,6-dihydro-quinolyl, 5,6-dihydroiso-quinolyl, 5,6-dihydroquinoxalinyl, 5,6-dihydroquinazolinyl, 4,5-dihydro-lH-benzimidazolyl, 4,5-dihydro-benzoxazolyl, 1,4-naphthoquinolyl, 5, 6,7,8-tetrahydro-quinolinyl, 5,6,7,8-tetrahydro-isoquinolyl, 5,6,7,8-tetrahydroquinoxalinyl, 5,6,7,8-tetrahydroquinazolyl, 4,5,6,7-tetrahydro-lH-benzimidazolyl, 4,5,6,7-tetrahydro-benzoxazolyl, lH-4-oxa-l,5-diaza-naphthalen-2-onyl, l,3-dihydroimidizolo-[4,5]-pyridin-2-onyl, 2,3-dihydro-l,4-dinaphtho-quinonyl, 2,3-dihydro-lH-pyrrol[3,4-b]quinolinyl, 1.2.3.4-tetrahydrobenzo[b]-[ 1 ,7]naphthyridinyl, 1 ,2,3 ,4-tetra-hydrobenz[b] [1,6]-naphthyridinyl, l,2,3,4-tetrahydro-9H-pyrido[3,4-b]indolyl, l,2,3,4-tetrahydro-9H-pyrido[4,3-b]indolyl, 2,3-dihydro-lH-pyrrolo-[3,4-b]indolyl, 1 H-2, 3,4,5 -tetrahydro-azepino[3,4-b]indolyl, lH-2,3,4,5-tetrahydroazepino-[4,3-b]indolyl, lH-2,3,4,5-tetrahydro-azepino[4,5-b]indolyl, 5,6,7,8-tetrahydro[l,7]napthyridinyl, 1,2,3,4-tetrahydro-[2,7]-naphthyridyl, 2,3-dihydro[l,4]dioxino[2,3-b]pyridyl, 2,3-dihydro[l,4]-dioxino[2,3-b]pryidyl, 3,4-dihydro-2H-l-oxa[4,6]diazanaphthalenyl, 4,5,6,7-tetrahydro-3H-imidazo-[4,5-c]pyridyl, 6,7-dihydro[5,8]diazanaphthalenyl, l,2,3,4-tetrahydro[l,5]-napthyridinyl, 1.2.3.4-tetrahydro[ 1 ,6]napthyridinyl, 1 ,2,3 ,4-tetrahydro[ 1 ,7]napthyridinyl, 1 ,2,3 ,4-tetrahydro-[l,8]napthyridinyl or l,2,3,4-tetrahydro[2,6]napthyridinyl. In some embodiments, heteroaryl groups are optionally substituted. In one embodiment, the one or more substituents are each independently selected from among halo, hydroxy, amino, cyano, nitro, alkylamido, acyl, Ci-6-alkyl, Ci-6-haloalkyl, Ci-6-hydroxyalkyl, Ci-6-aminoalkyl, Ci-6-alkylamino, alkylsulfenyl, alkylsulfinyl, alkylsulfonyl, sulfamoyl, or tri fluorom ethyl.

[0147] Examples of heteroaryl groups include, but are not limited to, unsubstituted and mono- or di-substituted derivatives of furan, benzofuran, thiophene, benzothiophene, pyrrole, pyridine, indole, oxazole, benzoxazole, isoxazole, benzisoxazole, thiazole, benzothiazole, isothiazole, imidazole, benzimidazole, pyrazole, indazole, tetrazole, quinoline, isoquinoline, pyridazine, pyrimidine, purine and pyrazine, furazan, 1,2,3-oxadiazole, 1,2, 3 -thiadiazole, 1,2,4-thiadiazole, triazole, benzotri azole, pteridine, phenoxazole, oxadiazole, benzopyrazole, quinolizine, cinnoline, phthalazine, quinazoline and quinoxaline. In some embodiments, the substituents are halo, hydroxy, cyano, O — Ci- 6-alkyl, Ci-6-alkyl, hydroxy-Ci-6-alkyl and amino-Ci-6-alkyl.

[0148] As used herein, the terms "halo" and "halide", which are referred to herein interchangeably, describe an atom of a halogen, that is fluorine, chlorine, bromine or iodine, also referred to herein as fluoride, chloride, bromide and iodide.General

[0149] As used herein the term “about” refers to ± 10 %.

[0150] The terms "comprises", "comprising", "includes", "including", “having” and their conjugates mean "including but not limited to".

[0151] The term “consisting of means “including and limited to”.

[0152] The term “comprising” encompasses “consisting”, “consisting essentially of’, or both.

[0153] The term "consisting essentially of means that the composition, method or structure may include additional ingredients, steps and / or parts, but only if the additional ingredients, steps and / or parts do not materially alter the basic and novel characteristics of the claimed composition, method or structure.

[0154] The word “exemplary” is used herein to mean “serving as an example, instance or illustration”. Any embodiment described as “exemplary” is not necessarily to be construed as preferred or advantageous over other embodiments and / or to exclude the incorporation of features from other embodiments.

[0155] The word “optionally” is used herein to mean “is provided in some embodiments and not provided in other embodiments”. Any particular embodiment of the invention may include a plurality of “optional” features unless such features conflict.

[0156] As used herein, the singular form "a", "an" and "the" include plural references unless the context clearly dictates otherwise. For example, the term "a compound" or "at least one compound" may include a plurality of compounds, including mixtures thereof.

[0157] Throughout this application, various embodiments of this invention may be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 3, 4, 5, and 6. This applies regardless of the breadth of the range.

[0158] Whenever a numerical range is indicated herein, it is meant to include any cited numeral (fractional or integral) within the indicated range. The phrases “ranging / ranges between” a first indicate number and a second indicate number and “ranging / ranges from” a first indicate number “to” a second indicate number are used herein interchangeably and are meant to include the first and second indicated numbers and all the fractional and integral numerals therebetween.

[0159] As used herein the term "method" refers to manners, means, techniques and procedures for accomplishing a given task including, but not limited to, those manners, means, techniques and procedures either known to, or readily developed from known manners, means, techniques and procedures by practitioners of the chemical, pharmacological, biological, biochemical and medical arts.

[0160] As used herein, the term “treating” includes abrogating, substantially inhibiting, slowing or reversing the progression of a condition, substantially ameliorating clinical or aesthetical symptoms of a condition or substantially preventing the appearance of clinical or aesthetical symptoms of a condition.

[0161] It is appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable sub-combination or as suitable in any other described embodiment of the invention.Certain features described in the context of various embodiments are not to be considered essential features of those embodiments, unless the embodiment is inoperative without those elements.

[0162] Various embodiments and aspects of the present invention as delineated hereinabove and as claimed in the claims section below find experimental support in the following examples.EXAMPLES

[0163] Reference is now made to the following examples, which together with the above descriptions illustrate some embodiments of the invention in a non-limiting fashion.Material and Methods

[0164] The excipients listed in Table 1 below were used in the formulation development.Table 1:API Solubility Method

[0165] The API (i.e., Ladostigil tartrate mono-salt) solubility assessment was carried out by weighing 1 g of the selected excipient into a scintillation vial (thermo-softening excipients were melted prior to dispensing). An initial 10 mg of API was dispensed into 1 g of excipient in each vial. The API and excipient mix was then stirred with a spatula and any initial visual solubility of the mix was noted. If the API appeared to dissolve visuallyat this point (no particles of API could be seen visually) then the mix was observed microscopically and compared with a corresponding placebo sample of just excipient. For thermo-softening excipients, the hot stage attached to the microscope was set to the temperature used during mixing (50 °C or 80 °C) and microscopy was used to confirm complete dissolution of the API. For the hot stage, 50 °C was used for semi-solid excipients with a melting point less than or equal to 45 °C and 80 °C was used for excipients with a melting point above 45 °C. For excipients with a melting point less than 25 °C, microscopy was performed at room temperature. For samples where solubilization was achieved at this point, an ultrasonic bath was used at the solubilization temperature for 15 minutes, for a maximum of four cycles (15, 30, 45 and 60 minutes). At the end of each 15- minute cycle, the samples’ solubility was again visually assessed. If the API appeared visually dissolved then the sample was observed using microscopy, at the appropriate temperature to confirm complete dissolution of the API.API / Excipient Compatibility Study Method

[0166] All of the excipients detailed in Table 1 with the exception of kolliphor RH40, which was only used in the API solubility study, were then progressed to the API / excipient compatibility study. The API / excipient compatibility study was performed at a target API concentration of 4%, by weighing 9.6 g of the selected excipient (detailed in Table 1) and 0.4 g of API into 15 ml amber glass jars. Thermo-softening excipients were melted prior to dispense into amber jars. The API / excipient mix was initially mixed with a spatula, to ensure the API was wetted by excipient. Following this, the mix was high shear mixed to ensure a homogenous mix was produced. High shear mixing was done for 2.5 minutes for each sample, and temperatures were recorded before and after high shear mixing. For each excipient mix, 2 g of the homogenized API / excipient mix was transferred to a 15 ml amber jar, and this was analyzed by HPLC for assay and related substances, to provide the t=0 stability. Further samples of 2 g of the homogenized API / excipient mixes were transferred to 15 ml amber jars and stored in a stability cabinet set to 40 °C / 75% RH (accelerated conditions), for 4 weeks before analysis by HPLC for assay and related substances.

[0167] The HPLC analysis was performed using a Waters X Terra RP18, 4.6 x 250 mm column with injection volume 30 pL, flow rate of 1.0 ml / minute and column temperature of 50 °C. The detection wavelength was 272 nm, with mobile phase A consisting of pH 2.5 buffer and mobile phase B consisting of acetonitrile. To analyze the variety of excipientschosen three gradient methods were selected and these are detailed in Tables 2-4. The remaining homogenized API / excipient mix was put down on stability at the same conditions as ‘spare’ samples. Additionally, 5 g placebo samples of each excipient (detailed in Table 1) were also set down on stability at the same conditions, to assess any co-eluting peaks in the excipient sample or excipient related changes under accelerated conditions, to aid in API peak and related substances identification.Table 2 - HPLC Gradient Method 1 used for Capryol 90Table 3 - HPLC Gradient Method 2 used for for Lauroglycol 90, Labrasol ALF, Gelucire 48 / 16, Gelucire 44 / 14, Miglyol 812N, KolliphorHS 15, KollisolvP124 andKolliphorP407Table 4 - HPLC Gradient Method 3 used for Vitamin E TPGS, Tween 80, Peceol, Maisine CC, Kolliphor EL and Labrafac Lipophile WL1349Preparation Of Prototype Formulations For Use In Dispersion And Density Assessments

[0168] The prototype formulations were prepared by weighing out the quantities of excipients (detailed in Table 5) into labelled amber glass jars (the thermos-softening excipients were melted prior to further processing). For each prototype form, the appropriate amount of Ladostigil tartrate was dispensed to each separate glass jar and mixed with a spatula to wet. Themixeswere high shear mixed for 2.5 minutes, and the temperature was recorded before and after high shear mixing. The bulk mixes were not placed under vacuum to remove residual air, asthis wasn't required due to the small scale of the mixes. Matching placebo formulations were prepared for each prototype formulation. Initially prototype formulations 1-5 were prepared, and following dispersion, formulations 6-10 were then designed and prepared, based on the dispersion results for formulations 1-5.Table 5 - Prototype Formulations Initial DesignDispersion Assessment Of Prototype Formulations

[0169] The formulations prepared in section 3.3. were used for dispersion assessments in both water and colonic media. Initially the prototypes were assessed alongside the placebo formulations in water using the following method. The formulations were preheated to at least 5°C above the melting point of the highest melting point excipient, to ensure the formulations were molten and stirred to ensure homogeneity. To a glass beaker, 1 g of formulation was added, and a stirrer bar was placed into the beaker. The beaker was then transferred into a water bath at 37°C.

[0170] Initially, 10 ml of water was added to the beaker, maintained at 37 °C, and dispersion characteristics recorded after visual assessment. The volume of water was increased sequentially to 25, 75 and 100 ml. After each addition of water, the dispersion characteristics were determined visually. After the final addition to 100 ml water the mixture continually stirred and visually assessed, with the dispersion characteristics recorded after 1 hour and then after approximately five hours. On completion of the final time point, the beaker was removed from the water bath and left to stand on the bench at room temperature for approximately 24 hours. The mixture was visually assessedand the dispersion stability recorded.

[0171] The colonic media used for the dispersion assessment was simulated colonic fluid 2 (SCoF2) (Dissolution Technologies, August 2011,15-28). The composition of thecolonic media was 170mM acetic acid and - 157 mM sodium hydroxide, with a target pH of 5.8. The prototype formulations were assessed alongside the placebo formulations in colonic media, using the following method. The formulations were preheated to at least 5 °C above the melting point of the highest melting point excipient, to ensure the formulations were molten and stirred to ensure homogeneity. For all prototype formulations, 1 g of formulation was dispensed into aglass beaker. The beaker containing 1 g of formulation and a stirrer bar, was then placed into a water bath at 37°C. Initially, 10 ml of colonic media was added to the beaker at 37 °C and dispersion characteristics recorded after visual assessment. The volume of colonic media was increased sequentially to 25, 75 and 100 ml. After each addition of water, the dispersion characteristics were recorded after visual assessment. After the addition to 100 ml colonic media, the mixture was continually stirred and visually assessed, with the dispersion characteristics recorded after 1 hour and then after approximately five hours. On completion of the final time point, the beaker was removed from the water bath and left to stand on the bench at room temperature for approximately 24 hours. The mixture was visually assessed and the dispersion stability recorded.Short-Term suspension sedimentation study

[0172] A sedimentation study was performed to assess the propensity of the API to sediment from the excipients over time. For each formulation, 8 ml was transferred to 10 ml measuring cylinders. The measuring cylinders were pre-heated in an oven at 60 °C for the thermo-softening formulations. The measuring cylinders were stored at suitable conditions, 60 DC for formulations 6, 7 and 10 and room temperature for formulation 1. Sedimentation of the formulations were observed over a period of 180 minutes with images being taken after approximately 10, 30, 60, 120 and 180 minutes. The measuring cylinders were left at these conditions overnight and observations on any sedimentation occurring with the formulation were made along with images being taken.Viscosity assessment of Prototype formulations

[0173] Viscosity of the lead formulations were assessed using a Brookfield DV-III Ultra Programmable Rheometer. The CP-40spindle was used and the rheometer was calibrated using Viscosity Standard 100 cP prior to use. Intervals of 30 seconds and a 30 second hold prior to each measurement were used throughout.EXAMPLE 1Formulation developmentAPI / excipient compatibility study results

[0174] All excipients used in the solubility assessment were progressed to an API and excipient compatibility study. Preparation of the API / Excipient compatibility samples was performed under yellow light, using high shear mixing for 2.5 minutes and all samples were stored in amber jars. The t=0 samples were then stored in a refrigerator for 2 weeks while awaiting analysis, and the t=4 samples were stored at 40 °C / 75% RH for 4 weeks.

[0175] There were several challenges in both preparation and chromatography, leading to difficulties in analysis for some excipients. Oily excipients were difficult to dissolve in diluent prior to HPLC analysis, which required additional sample method development, excipients Lauroglycol 90 and Maisine CC for example displayed this type of problem.

[0176] An additional problem that was encountered was the formation of oily emulsions during HPLC sample preparation, and this was especially a problem for excipients Gelucire 44 / 14 and Gelucire 48 / 16. Also, in many cases it was difficult to achieve chromatographic separation of impurities, which lead to challenges in identifying peaks of the API and related substances. Gelucire 48 / 16 was particularly challenging in this way.

[0177] For Capryol 90, Maisine CC, Peceol, Labrasol ALF and Vitamin E TPGS degradation was observed after accelerated stability test and higher levels of degradation occurred in binary mixes with Kolliphor EL, Tween 80, Kolliphor HS-15 and Gelucire 48 / 16. Finally, very high levels of degradation were seen for Kolliphor P407 and Gelucire 44 / 14 and based on the results both excipients are not recommended for use in future formulations.

[0178] Based on the results of APVexcipient compatibility study 10 Formulations (Table 5) were prepared for further studies.Dispersion Assessments & Sedimentation study

[0179] Formulation prepared as disclosed herein (listed in Table 5) were subjected to colonic medium dispersion test.

[0180] Formulation 1 showed positive dispersion characteristics, with fast solubilization in the simulated colonic medium. Based on both sedimentation and dispersion studies,Formulation 1 [Aerosil 200 (1.00%), Miglyol 812N (95.50%), BHT (0.5%) Ladostigil Tartrate (4.00%)] was found superior over the additional formulations listed in Table 5.Enteric coating

[0181] Gelatin capsule containing formulation 1 was further subjected to a coating process. Coating suspensions with varying ratios of EUDRAGIT® L 30 D-55 and EUDRAGIT® FS 30 D were used to change the dissolution pH of the coated capsules to target release at the ileocecal junction.

[0182] The dissolution study was performed first in acidic media (which mimics the pH of the stomach and to which the coating of the capsules should be resistant) then in pH 6.4 buffer to represent the pH in the lower small intestine and finally at pH 7 to mimic that of the colon, where full release is expected.

[0183] Although various EUDRAGIT® L 30 D-55 (L) and / or EUDRAGIT® F S 30D (S) based coatings may be suitable for use as enteric coatings of the present pharmaceutical capsule, it was found that formulation 1 showed the optimum release at pH 7, when coated with coating suspension (L / S 80:20), using a 60 mg (±6.0 mg) coat. This formulation was progressed to a lab scale technical batch and the amount of BHT was reduced from the proof-of-concept concentration 0.5% to 0.05%, based on acceptable levels, according to the FDA database of inactive ingredients. In addition, capsule content uniformity was investigated to assess the filling performance, at the start, middle and end of filling, by HPLC.

[0184] Based on the above, an exemplary oral delivery capsule of the invention has been prepared based on a gelatine capsule body coated with a coating suspension (L / S 80:20) and filled with formulation 1 in an amount equivalent to 10 mg of Ladostigil tartrate (monosalt).EXAMPLE 2Comparative pharmacokinetics of Ladostigil capsules designed for oral and colonic delivery

[0185] The study was conducted in eight men and women, aged 23-55 years weighing 60.5-100 kg, with aBMI of 21.5-27.8 kg / m2. Two capsules containing 10 mg of Ladostigil tartrate for oral delivery were administered to each subject at 7:00 hours after an overnightfast of 10 hours. Blood samples of 2 ml were collected via an intravenous catheter 1 hour before, and 0.17, 0.33, 0.5, 0.75, 1, 1.5, 2 and 2.5 hours after dose administration. Ten days later, the same subjects received two 10 mg capsules of the formulation designed for colonic delivery. A blood sample was taken 1 hour before dosing (0 reading). To allow for time for the capsule contents to reach the colon, 10 blood samples were collected one hour before doing after 2.5, 3.0, 3.5,4.17, 4.50, 5.0, 5.33, 6.0, 6.5, 7.0 hours. Two women and one man were excluded from the final calculations because of incomplete data.

[0186] The concentration in plasma of aging rats that had received Ladostigil (0.8 mg / kg base) in the drinking fluid and in which it had prevented the decline in memory was 2.39 ± 1.08 ng / ml. The dotted line in Fig. 1 indicates the concentration that was compatible with that which was effective in the rats. It was also found that the peak reduction of 57 ± 8% in the release of IL-ip by Ladostigil from primary cultures of mouse microglia activated by LPS was achieved by a concentration of 2.73 ng / ml (Reichert et al, 2024). AUCt [ng * h * L'1] for Ladostigil delivered by oral formulation was 8.14 ± 8.08 and for colonic delivery, 14.03 ± 9.72, p=0.01 (paired t test). Inter-subject variability was also smaller for the colonic delivery capsules for similar plasma concentrations. An additional advantage was that peak concentrations achieved by this formulation were lower than with the oral delivery capsules. This should reduce the likelihood of adverse effects.

[0187] Although the invention has been described in conjunction with specific embodiments thereof, it is evident that many alternatives, modifications and variations will be apparent to those skilled in the art. Accordingly, it is intended to embrace all such alternatives, modifications and variations that fall within the spirit and broad scope of the appended claims.

[0188] All publications, patents and patent applications mentioned in this specification are herein incorporated in their entirety by reference into the specification, to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated herein by reference. In addition, citation or identification of any reference in this application shall not be construed as an admission that such reference is available as prior art to the present invention. To the extent that section headings are used, they should not be construed as necessarily limiting.

Claims

CLAIMSWhat is claimed is:

1. A formulation comprising a therapeutically effective amount of a Ladostigil salt and a pharmaceutically acceptable excipient comprising one or more fatty acid glycerides, wherein a concentration of said Ladostigil salt within said formulation is at least 1% w / w; and wherein the one or more fatty acid glycerides is a fatty acid triglyceride comprising C5-C10 fatty acid residues.

2. The formulation of claim 1, wherein said Ladostigil salt is represented by Formula, wherein X is a pharmaceutically acceptable carboxylate anion and n is between 1 and 3, as allowed by valency.

3. The formulation of claim 1 or 2, further comprising a mineral particle and an antioxidant.

4. The formulation of claim 3, wherein the antioxidant is butylated hydroxytoluene (BHT) and the mineral particle comprise silica nanoparticles.

5. The formulation of claim 3 or 4, wherein a concentration of the mineral particle within the formulation is between 0.1 and 5% w / w; and wherein a concentration of the antioxidant within the formulation is between about 0.01 and about 0.5% w / w.

6. The formulation of any one of claims 2 to 5, wherein the pharmaceutically acceptable carboxylate anion is tartrate, and wherein n is 1 or 2.

7. The formulation of any one of claims 1 to 6, wherein the therapeutically effective amount comprises a concentration of said Ladostigil salt within the formulation ranging between 1 and 10% w / w.

8. The formulation of any one of claims 1 to 7, wherein said Ladostigil salt is [Ladostigil] itartrate; and wherein a concentration of the one or more fatty acid glycerides in the formulation is between 90 and 98%; and wherein the fatty acid triglyceride consists of C6-C8 fatty acid residues.

9. The formulation of claim 8, wherein a concentration of said Ladostigil salt within said formulation is about 4%w / w; wherein the concentration of the one or more fatty acid glycerides in the formulation is between 93 and 96%; and wherein said formulation is asuspension and is characterized by at least one of (i) viscosity at 20°C of between 100 and 500 cP; and (ii) density between 0.9 and 1 g / ml.

10. The formulation of any one of claims 1 to 9, wherein a weight ratio between the one or more fatty acid glycerides and said Ladostigil salt within said formulation is between about 9:1 and about 24:1.

11. The formulation of claim 10, consisting or consisting essentially of [Ladostigil] itartrate in an amount of between 1 and 10% w / w; said one or more fatty acid glycerides in an amount of 90 and 99%w / w, and optionally of BHT and silica nanoparticles.

12. The formulation of any one of claims 1 to 11, wherein said one or more fatty acid glycerides comprises at least one of capric acid triglyceride and caprylic acid triglyceride, including any homo-triglyceride and mixed triglyceride, and any combination thereof.

13. The formulation of claim 12, wherein said one or more fatty acid glycerides is selected from (i) capric acid triglyceride and caprylic acid triglyceride, and (ii) a mixed capric acid / caprylic acid triglyceride.

14. The formulation of any one of claims 1 to 13, wherein a concentration of the one or more fatty acid glycerides in the formulation is between about 94 and about 95%w / w; wherein said Ladostigil salt is [Ladostigil] itartrate and is present in the formulation at a concentration of about 4%w / w; and wherein said formulation further comprises about l%w / w silica nanoparticles and about 0.5%w / w BHT.

15. An oral delivery capsule comprising a therapeutically effective amount of the formulation of any one of claims 1 to 14, and wherein the oral delivery capsule is coated with an enteric coating.

16. The oral delivery capsule of claim 15, wherein the therapeutically effective amount comprises an amount of said Ladostigil salt corresponding to an amount of Ladostigil free base of between 5 and 12 mg; and wherein the oral delivery capsule is configured to release said Ladostigil salt in a colon of a subject.

17. The oral delivery capsule of claim 15 or 16, wherein said Ladostigil salt is Ladostigil tartrate; and wherein the therapeutically effective amount corresponds to between about 6 and about 9 mg Ladostigil free base.

18. The oral delivery capsule of any one of claims 15 to 17, wherein the oral delivery capsule comprises a water-soluble material selected from the group consisting of: a water-soluble poly saccharide / oligosaccharide, a protein, a water-soluble synthetic polymer, and any combination thereof.

19. The oral delivery capsule of claim 18, wherein said water-soluble material comprises gelatin, a cellulose derivative (Hydroxypropyl Methylcellulose (HPMC)), PVA, a modified starch, a gel-forming polysaccharide / oligosaccharide (pullulan, alginate, hyaluronate, agar, ulvan, pectin, chitosan, dextran, a gum), or any combination or co-polymer thereof.

20. The oral delivery capsule of any one of claims 15 and 19, wherein said enteric coating is configured to undergo dissolution at a pH of about 7.

21. The oral delivery capsule of any one of claims 15 to 20, wherein said enteric coating comprises any one of acrylate-based polymer, hydroxypropyl methylcellulose phthalate (HPMCP), Cellulose acetate phthalate (CAP), Polyvinyl acetate phthalate (PVAP), Carboxymethyl ethyl cellulose (CMEC) and Hydroxypropyl methylcellulose acetate succinate (HPMC AS).

22. The oral delivery capsule of claim 21, wherein said acrylate-based polymer comprises a first methyl acrylate co-polymer and a second methyl acrylate co-polymer; each independently comprising poly(methacrylic acid) and one or more additional acrylate polymer selected from poly(methyl acrylate), poly(ethyl acrylate), polymethylmethacrylate), and poly(ethyl-methacrylate).

23. The oral delivery capsule of any one of claims 15 to 22, wherein said wherein said enteric coating comprises (i) methacrylic acid and ethyl acrylate copolymer and (ii) methyl acrylate, methyl methacrylate and methacrylic acid copolymer.

24. The oral delivery capsule of any one of claims 15 to 23, being a unit dosage form for use in colonic delivery of said Ladostigil salt in a subject in need thereof.

25. A method for delivering Ladostigil or a salt thereof to a colon of a subject in need thereof, the method comprising administering to said subject the oral delivery capsule of any one of claims 15 to 24.

26. The method of claim 22, wherein the subject is afflicted with a neurodegenerative disease or disorder.

27. The method of claim 23, wherein the method is for treating the neurodegenerative disease or disorder in said subject.

28. The method of any one of claims 25 to 27, wherein said delivering is with reduced individual variation in blood levels of said Ladostigil or salt thereof, in said subject after being orally administered therewith.

29. The method of claim 27 or 28, wherein said treating comprises reducing individual variation in blood levels of said Ladostigil or salt thereof, in said subject after being orally administered therewith.

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