Solid oral formulation of mono-amine re-uptake inhibitor

Abstract

The present invention relates to solid formulations of a mono-amine re-uptake inhibitor compound as disclosed herein or a pharmaceutically acceptable salt thereof.

Description

[0001] Solid oral formulation of mono-amine re-uptake inhibitor

[0002] Technical field

[0003] The present invention relates to solid formulations of a mono-amine re-uptake inhibitor compound as disclosed herein or a pharmaceutically acceptable salt thereof.

[0004] Background

[0005] The compound exo-7-(8-aza-bicyclo[3.2.1]oct-3-yloxy)-chromen-2-one (also known as IP2018) is a mono-amine re-uptake inhibitor under clinical development. The compound’s effect on the nervous system is to increase the level of neurotransmitters, which has utility in treatment of central nervous system disorders.

[0006] Given the compound’s effect on the central nervous system, it is necessary that oral formulations are able to accommodate the prescribed therapeutically effective dosage in a precise and reproducible manner. For some applications, it is highly desirable that a complete release of the compound is achieved as fast as possible, in order to attain the therapeutic effect as soon as possible.

[0007] The compound displays low solubility and the effective dosages are small. This poses a challenge in the development of solid formulations that contain the therapeutically effective dosages in a precise and reproducible manner; while ensuring a fast and complete release upon oral administration.

[0008] Until now, no known solid formulations of the compound have shown to produce an effective release of the compound. Accordingly, there is a strong un-met need for solid forms that can ensure a robust and fast administration of IP2018.

[0009] Summary

[0010] The inventors have surprisingly found that solid formulations of IP2018 of the invention provide immediate release of the compound, despite the compound’s low solubility and difficulty in achieving acceptable API distribution within solid formulations. The formulations according to the present disclosure provide complete release of the compound in under 30 mins. This is highly advantageous in the clinical application of IP2018, since it allows a safe and robust administration of the compound with a fast release and on-set of the therapeutic effect. An improved uniformity of I P2018 distribution across the formulation is achieved using the compositions according to the present disclosure.

[0011] In one aspect, the present disclosure provides for a pharmaceutical composition comprising pellets, said pellets comprising; a. a pellet core; b. a drug layer comprising a compound of formula (I); formula (I), or a pharmaceutically acceptable salt thereof, said drug layer covering the pellet core.

[0012] In one aspect, the present disclosure provides a pharmaceutical dosage form or a unit dosage form comprising the pharmaceutical compositions described herein.

[0013] In one aspect, the present disclosure provides for a method of preparing a composition comprising pellets, the method comprising: a) providing a pellet core, b) providing a drug layer solution comprising a compound of formula (I) formula (I), or a pharmaceutically acceptable salt thereof and at least one film-forming agent(s), and c) coating the drug layer solution onto the pellet core.

[0014] In one aspect, the present disclosure provides for a method of preparing a tablet, the method comprising: a) a composition comprising pellets, said pellets comprising a pellet core and a drug layer as described herein, b) mixing the composition in step a) with at least one filler material, to obtain a blend, c) compressing the blend in b) to obtain a tablet. Description of Drawings

[0015] Figure 1 : Release of IP2018 from IR capsules I described in Example 3.

[0016] Release was tested in an USP 2 apparatus with paddles; rotation speed was 50 rpm and using 500 ml purified water as dissolution medium. Samples were analysed by UV spectrometry at 325 nm. After 20 mins, 95% of IP2018 is released.

[0017] Detailed description

[0018] Definitions

[0019] As used herein, the singular forms “a,” “an” and “the” include plural referents unless the content clearly dictates otherwise.

[0020] The term, “compound,” as used herein is meant to include all stereoisomers, geometric isomers, tautomers, and isotopes of the structures depicted, unless otherwise specified.

[0021] As used herein, “pellets” refers to approximately spherical particulates of substances widely used in the pharmaceutical industry. As used herein, the terms “pellet core”, “inert core” refer to a pharmaceutically acceptable pellet that does not contain a drug substance for use in pharmaceutical formulations. Techniques and materials to produce pellets are well-known in the pharmaceutical industry and a wide range of commercial brand names (Suglets™, Vivapur™, Cellets™) and vendors of pellets made from specific materials and with specific size ranges exist. Exemplary materials in pellets for pharmaceutical applications include but are not limited to sucrose, lactose, silica, starch, calcium carbonate, tartaric acid, or microcrystalline cellulose (MCC).

[0022] For a perfect sphere, the sphericity ratio as determined by equation (I) is 1 .0.

[0023] Sphericity = 4nA / P2wherein A is the area of a P is the perimeter of a two-dimensional cross-section of an imaged sphere. Pellets have preferably a high degree of sphericity, meaning sphericity close to 1.0, preferably above 0.9. The sphericity of pellets may be determined by analysis of particle population using microscopy and image analysis techniques, such as using dynamic image analysis. As used herein, "pharmaceutically acceptable" refers to that which is useful in preparing a pharmaceutical composition that is generally safe, non-toxic, and neither biologically nor otherwise undesirable and includes that which is acceptable for veterinary as well as human pharmaceutical use.

[0024] As used herein, “IP2018” or “compound I” is meant the compound of formula I. The compound of formula I is:

[0025] As used herein, hypromellose (hydroxypropyl methyl cellulose or HMPC) refers to a partially O-methylated and C>-(2-hydroxypropylated) cellulose ether. HMPC is widely used as a film-forming agent in pharmaceutical formulations.

[0026] As used herein, the term “pharmaceutically acceptable salt” of a compound refers to a salt that is pharmaceutically acceptable, as defined herein, and preferably possesses the desired pharmacological activity of the parent compound. Pharmaceutically acceptable salts include acid addition salts formed with inorganic acids; or formed with organic acids; or salts formed when an acidic proton present in the parent compound either is replaced by a metal ion; or coordinates with an organic or inorganic base.

[0027] As used herein, “formulation” is the result of combining different substances, including the active ingredient, to produce a final product.

[0028] As used herein the terms "about", "substantially", "generally", and other relative terms refer to approximately or reasonably close to with respect to the value indicated. In some cases the relative terms can refer to plus or minus 10%. In some cases the relative terms can refer to plus or minus 5%. In some cases the relative terms can refer to plus or minus 2%. In some cases the relative terms can refer to plus or minus 1%.

[0029] As used herein, the term ‘weight of the composition’ refers to the total weight of all constituents within the composition, e.g., the total weight of the components comprising the pellet core, drug layer and excipients of the composition. In capsule or tablet formulations, this includes the weight of the capsule shell or the total weight of the tablet respectively.

[0030] As used herein, the term ‘weight of the pellets’ refers to the total weight of the pellets including the drug layer within the composition, e.g., the total weight of the components comprising the pellet core, and drug layer. In capsule formulations, this does not include the weight of the capsule shell.

[0031] Numbers are expressed using for marking the decimal position and as a separator for the thousands of units (e.g one thousand is 1 ,000).

[0032] Pharmaceutical

[0033] The present disclosure provides for a pharmaceutical composition comprising pellets, said pellets comprising; a. a pellet core; b. a drug layer comprising a compound of formula (I); formula (I), or a pharmaceutically acceptable salt thereof, said drug layer covering the pellet core.

[0034] In some embodiments, the pharmaceutical composition further comprises one or more adjuvants, excipients, carriers, buffers, diluents, and / or other customary pharmaceutical auxiliaries.

[0035] Film forming agents

[0036] When used herein, the term "film-forming agent" refers to a substance that is capable of forming a film over (or within), or coating over, another substance (which may be in particulate form). Such agents can be applied onto solid dosage forms, such as pellets, tablets, and granules to obtain the desired release profile. Known film-forming agents include cellulose derivatives, such as hydroxypropylmethylcellulose (also known as Hypromellose or HPMC), methylcellulose, hydroxypropylcellulose, carboxy methylcellulose;, polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP); polyacrylates, such as polymethacrylates; and derivatives thereof, or mixtures thereof.

[0037] In one embodiment, the drug layer comprises a film-forming agent. In some embodiments, the film forming agent is selected from the group consisting of cellulose derivatives, particularly hydroxypropyl methyl cellulose (HPMC); polyacrylates, such as polymethacrylates or copolymers of acrylate and methacrylate; and polyvinylalcohol (PVA). In some embodiments, the film forming agent is HPMC.

[0038] In one embodiment, the HPMC has a weight-average molecular weight of up to 150,000 g / mol. In one embodiment, the HPMC has a weight-average molecular weight of up to 60,000 g / mol. In one embodiment, the HPMC has a weight-average molecular weight of up to 36,000 g / mol.

[0039] In one embodiment, the HPMC has a viscosity of up to 100,000 mPa s when measured under standard conditions (2% HPMC w / w aqueous solution at 20 °C). In one embodiment, the HPMC has a viscosity of up to 100 mPa s when measured under standard conditions (2% HPMC w / w aqueous solution at 20 °C). In one embodiment, the HPMC has a viscosity of up to 15 mPa s when measured under standard conditions (2% HPMC w / w aqueous solution at 20 °C).

[0040] In one embodiment, HPMC has a viscosity of 3 to 15 mPa s when measured under standard conditions (2% HPMC w / w aqueous solution at 20 °C). In one embodiment, the HPMC has a viscosity of 3 to 10 mPa s when measured under standard conditions (2% HPMC w / w aqueous solution at 20 °C). In one embodiment, the HPMC has a viscosity of 4 to 8 mPa s, when measured under standard conditions (2% HPMC w / w aqueous solution at 20 °C). In one embodiment, the HPMC has a viscosity of 6 mPa s, when measured under standard conditions (2% HPMC w / w aqueous solution at 20 °C).

[0041] In one embodiment, the HPMC has a weight-average molecular weight of 10,000-70,000 g / mol. In one embodiment, the HPMC has a weight-average molecular weight of 10, GOO- 25, 000 g / mol. In one embodiment, the HPMC has a weight-average molecular weight of 20,000-40,000 g / mol. In one embodiment, the HPMC has a weight-average molecular weight of 30,000-40,000 g / mol.

[0042] In one embodiment, the HPMC has a weight-average molecular weight of up to 70,000 g / mol and a viscosity of up to 25 mPa s when measured under standard conditions (2% HPMC w / w aqueous solution at 20 °C).

[0043] In one embodiment, the HPMC has a weight-average molecular weight of 10,000-70,000 g / mol and a viscosity and a viscosity of 3 to 15 mPa s when measured under standard conditions (2% HPMC w / w aqueous solution at 20 °C).

[0044] In one embodiment, the HPMC has a weight-average molecular weight of 20,000-40,000 g / mol, such as 36,000 g / mol; and a viscosity of 4 to 8 mPa s, such as 6 mPa s, when measured under standard conditions (2% HPMC w / w aqueous solution at 20 °C).

[0045] In one embodiment, the HPMC has a weight-average molecular weight of up to 150,000 g / mol and a viscosity of 100 to 100,000 mPa s when measured under standard conditions (2% HPMC w / w aqueous solution at 20 °C).

[0046] In one embodiment, the HPMC has a methoxy group substitution content of 19% to 24% and a hydroxypropoxy group substitution content of 4% to 12%. In one embodiment, the HPMC has a methoxy group substitution content of 27% to 30% and a hydroxypropoxy group substitution content of 4% to 7.5%.

[0047] In one embodiment, the HPMC has a methoxy group substitution content of 28% to 30% and a hydroxypropoxy group substitution content of 7% to 12%.

[0048] In one embodiment, the HPMC has a weight-average molecular weight of 20,000- 40,000 g / mol, such as 36,000 g / mol; a viscosity of 4 to 8 mPa s, such as 6 mPa s, when measured under standard conditions (2% HPMC w / w aqueous solution at 20 °C), a methoxy group substitution content of 28% to 30% and a hydroxypropoxy group substitution content of 7% to 12%.

[0049] In one embodiment, the HPMC is Pharmacoat 603, SB-4, Pharmacoat 645, Pharmacoat 606 (Hypromellose 6), Pharmacoat 615, Metolose 65SH-50, Metolose 60SH-50, or any other HPMC with comparable weight-average molecular weight and / or viscosity when measured under standard conditions (2% HPMC w / w aqueous solution at 20 °C) to any of the former HPMCs.

[0050] The weight-average molecular weight as described herein can be measured by standard techniques in the art known to the skilled person, such as common techniques employed by manufacturers of pharmaceutical excipients. For example, this includes, but is not limited to size exclusion chromatography (SEC) compared to standards of known molecular weight or SEC analyzed using light scattering (e.g. multi-angle laser light scattering). In some embodiments, the weight-average molecular weight is measured by SEC analysed with a light scattering detector, such as multi-angle laser light scattering.

[0051] The viscosity, and content of hydroxypropoxy and methoxy roups in HPMC can be determined by common methods known in the art. For example, viscosity may be measured by e.g. capillary viscometry or rotational viscometry under standard conditions of 2% w / w in aqueous solution at 20 °C. The content of methoxy and hydroxypropoxy groups in HPMC can be determined using standard methods as described in the US pharmacopeia (USP) or the European pharmacopeia (Ph. Eur.).

[0052] Based on the examples provided herein and common general knowledge in the field, the skilled person will understand how to select and handle various grades of HPMC for use in the present invention. In particular, the skilled person will know how to work with HPMC grades differing in weight-average molecular weight and / or viscosity for the purpose of preparing formulations as disclosed herein.

[0053] In one embodiment, the drug layer comprises the film-forming agent in an amount from 0.1 to 10% by weight of the composition or by weight of the pellets. In one embodiment, the drug layer comprises the film-forming agent in an amount from 0.1 to 5% by weight of the composition or by weight of the pellets.

[0054] In some embodiments, the drug layer comprises HPMC in an amount from about 0.1% to 10%, such as 0.1% to 5%, such as 0.1% to 2% by weight of the composition or by weight of the pellets. In some embodiments, the drug layer comprises HPMC in an amount from about 0.1% to 5% by weight of the pellets. In some embodiments, the drug layer comprises HPMC in an amount from about 0.1% to 2% by weight of the pellets, such as about 1% by weight of the pellets. Pellet core

[0055] Pellets offer a high degree of flexibility in the design and development of oral dosage forms. Microcrystalline cellulose pellets (MCC) and sugar are well-known materials in pellet technology which are used as core materials. The pellet core is so-called a neutral or inert pellet core, meaning that it does not comprise an active ingredient. Water-insoluble pellet cores are made of microcrystalline cellulose or silica, while water-soluble pellets cores are composed of sugar, such as sucrose, xylitol, mannitol, lactose; starch or salts. Both material classes show desirable characteristics, such as a narrow particle size distribution, sphericity and surface smoothness and may be used accordingly in the invention disclosed herein. A person of skill in the art will be able to determine suitable materials and suppliers of spheres suitable as core for pellets of the compositions according to the present disclosure.

[0056] In one embodiment, the pellet core consists of or comprises spheres made of a material selected form the group consisting of: sugars, such as sucrose, xylitol, mannitol, lactose; microcrystalline cellulose (MCC); starch, silica, tartaric acid and calcium carbonate.

[0057] In one embodiment, the pellet core comprises or consists of sucrose and / or starch. In some embodiments, the pellet core comprises or consists of sucrose and starch. Pellets comprising sucrose and / or starch are commercially available in multiple size ranges, for example Suglets®by Colorcon.

[0058] In one embodiment, the pellet core comprises or consists of microcrystalline cellulose (MCC). MCC is a commercially available chemical (CAS 9004-34-6) and its pellets are commercially available in multiple size ranges, for example Cellet®or Celphere™.

[0059] As used herein, “average size” or “mean size” refers to an arithmetic average of the particle size (pm) of the pellets within the pellet core. As aforementioned, pellets of the invention are commercially available in multiple size ranges, thus the “average size” or “mean size” may be commercially known. Average size or mean size of the pellets may be determined according to any conventional methods of particle size analysis known by the skilled person, such as sieving, laser diffraction, dynamic light scattering and image analysis. In one embodiment, the pellet core has an average size of between 500 pm and 1500 pm, such as between 600 pm and 1500 pm, such as between 700 pm and 1500 pm, such as between 900 pm and 1500 pm, such as between 1000 pm and 1500 pm, such as between 1100 pm and 1400 pm. In some embodiments, the pellet core has an average size of at least 1000 pm, such as at least 1100 pm.

[0060] The inventors surprisingly found that when the drug layered pellets were prepared with Suglets PF010 (710-850 pm), segregation of the active ingredient in the IP2018 IR tablet composition was reduced in comparison to when the drug layered pellets were prepared with Suglets PF018 (1180-1400 pm) of larger average size. Segregation refers to the process which results in an uneven distribution of particles due to differences in their shape, size, density or active ingredient content. In the formulation of pharmaceutical dosages, segregation is undesirable as it leads to lack of uniformity of active ingredients in the dosage unit, unpredictable release rates and may affect pharmacokinetics of the dosage units.

[0061] Thus, in some embodiments, the pellets have an average size of at the most 1000 pm. In some embodiments, the pellets have an average size of at the most 900 pm. In some embodiments, the pellets have an average size of at the most 850 pm. In some embodiments, the pellets have an average size of between 700 pm and 900 pm. In some embodiments, the pellets have an average size of between 700 pm and 850 pm.

[0062] The particle size distribution of pellets may be determined by the percentage of particles that are retained using sets of standardized sieves of different mesh sizes as defined in USP or Phr.Eu.

[0063] In some embodiments, the pellets have an average size between 500 pm and 1500 pm, and a particle size distribution such that no more than 10% of pellets pass through a first sieve, and no more than 10% of pellets are retained through a second sieve, wherein the size difference between the first sieve and the second sieve is not more than 200 pm, preferably not more than 150 pm. In some embodiments, the pellets have a size distribution such that no more than 10% of the pellets pass through a US Sieve No. 25 (710 pm) and no more than 10% of the pellets are retained through a US Sieve No. 20 (850 pm).

[0064] In one embodiment, the pellets have an average size from 710 pm to 850 pm and a particle size distribution such that no more than 10% of the pellets pass through a US Sieve No. 25 (710 pm) and no more than 10% of the pellets are retained through a US Sieve No. 20 (850 pm).

[0065] In some embodiments, the pellets have a sphericity of above 0.9, more preferably of 0.94 to 1.0.

[0066] In some embodiments, the drug layer comprises the compound of formula I in an amount of about 0.01% to about 5% by weight of the composition or by weight of the pellets. In some embodiments, the drug layer comprises the compound of formula I in an amount of about 0.01% to about 1% by weight of the composition or by weight of the pellets. In some embodiments, the drug layer comprises the compound of formula I in an amount of from about 0.05% to 0.5% by weight of the composition or by weight of the pellets. In some embodiments, the drug layer comprises the compound of formula I in an amount of from about 0.01% to 0.2% by weight of the composition or by weight of the pellets.

[0067] Methods to coat pellet compositions are well known in the art. They may include starting with a solution, dispersion or powder that is coated onto the pellets. Well-established methods to coat pellets are for example: a fluidized bed technology, by compression coating, wurster coating, pan coating, centrifugal or rotor coating.

[0068] Compounds

[0069] In one embodiment, the compound is exo- 7-(8- H- 8- aza- bicyclo [3.2.1] oct- 3-yloxy)- chromen-2-one; or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is exo- 7-(8- H- 8- aza- bicyclo [3.2.1] oct- 3-yloxy)-chromen-2-one hydrochloric acid salt.

[0070] IR compositions

[0071] In one embodiment, the composition is an immediate release (IR) composition of the compound of formula I. In one embodiment, the composition is an immediate release composition of an active ingredient, said active ingredient consisting of a compound of formula I, formula (I), or a pharmaceutically acceptable salt thereof, the composition comprising pellets, said pellets comprising or consisting of: a) an pellet core comprising sucrose and / or starch; b) a drug layer comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof in an amount of about 0.01% to about 5% by weight of the total composition or by weight of the pellets and HPMC in an amount of 0.1% to about 10% by weight of the total composition or by weight of the pellets, wherein, the drug layer covers the pellet core.

[0072] In one embodiment, the drug layer comprises the compound of formula (I) or a pharmaceutically acceptable salt thereof in an amount of about 0.01% to about 1% by weight of the total composition or by weight of the pellets and HPMC in an amount of 0.1% to about 5% by weight of the total composition or by weight of the pellets.

[0073] Filler materials

[0074] In one embodiment, the composition further comprises at least one filler material. In one embodiment, the at least one filler material is present in an amount from 50% to 99% by total weight of the composition, such as from 50% to 90%, such as from 60% to 90%, such as from 60% to 70%, such as from 70% to 80%, such as from 80% to 90% by total weight of the composition.

[0075] In one embodiment, the at least one filler material is selected from the group comprising or consisting of: inert pellets, a sugar, such as sucrose, mannitol, or lactose; starch, microcrystalline cellulose, croscarmellose, and magnesium stearate, or any combination thereof. As used herein, “croscarmellose” or “croscarmellose sodium” or “CSS” refers to an internally cross-linked carboxy methyl cellulose.

[0076] In one embodiment, the at least one filler material comprises inert pellets, wherein the pellets comprise or consist of spheres made of a material selected form the group comprising or consisting of: sugars, such as sucrose, xylitol, mannitol, lactose; microcrystalline cellulose (MCC); starch, silica, tartaric acid and calcium carbonate. In one embodiment, the pellets comprise or consist of spheres made of a sucrose and / or starch.

[0077] In one embodiment, at least one filler material comprises inert pellets wherein the pellets have an average size of 500 pm to 1500 pm, such as 500 pm to 1000 pm, such as 600 pm to 1000 pm, such as 700 pm to 950 pm, such as 700 pm to 900 pm. In some embodiments, the pellets have an average size of at the most 1000 pm. In some embodiments, the pellets have an average size of between 700 pm to 900 pm.

[0078] In one embodiment, the at least one filler material comprises or consists of microcrystalline cellulose. In one embodiment, the at least one filler material comprises or consists of a sugar, such as mannitol. In one embodiment, the at least one filler material comprises or consists of starch, such as pre-gelatinized starch. In one embodiment, the at least one filler material consists or comprises of microcrystalline cellulose, mannitol, and starch.

[0079] In one embodiment, the at least one filler material comprises or consists of an internally cross-linked carboxymethylcellulose, such as croscarmellose sodium. In one embodiment, the internally cross-linked caroxymethylcellulose, such as croscarmellose, is present in an amount from 0.5% to 5% by weight of the composition.

[0080] In one embodiment, the at least one filler material comprises or consists of magnesium stearate. In one embodiment, the magnesium stearate is present in an amount from 0.1% to 2.0% by weight of the composition. In one embodiment, the magnesium stearate is present in an amount from 0.1% to 1 .0% by weight of the composition. In one embodiment, the filler material comprises a granulate mix, said granulate mix comprising or consisting of: microcrystalline cellulose, mannitol, and starch. In one embodiment, the granulate mix comprises microcrystalline cellulose in an amount from 50%-75% by weight of the granulate mix, mannitol in an amount from 20%-40% by weight of the granulate mix and pre-gelatinized starch in an amount from 1% to 10% by weight of the granulate mix.

[0081] In one embodiment, the composition is an immediate release composition of an active ingredient of a compound of formula I, formula (I), or a pharmaceutically acceptable salt thereof, the composition comprising pellets, said pellets comprising or consisting of: a) a pellet core comprising sucrose and / or starch; b) a drug layer comprising: the compound of formula (I) or a pharmaceutically acceptable salt thereof in an amount of about 0.01% to about 5% by weight of the total composition or by weight of the pellets and HPMC in an amount of 0.1% to about 10% by weight of the total composition or by weight of the pellets, wherein said drug layer covers the pellet core, wherein, said composition further comprises at least one filler material, said at least one filler material comprising or consisting of: pellets, microcrystalline cellulose, mannitol, pre-gelatinized starch, croscarmellose and magnesium stearate, said filler material being present in an amount of 60% to 99% by total weight of the composition.

[0082] In one embodiment, the composition is an immediate release composition of an active ingredient of a compound of formula I, formula (I), or a pharmaceutically acceptable salt thereof, the composition comprising pellets, said pellets comprising or consisting of: a) a pellet core comprising sucrose and / or starch; b) a drug layer comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof in an amount of about 0.01% to about 5% by weight of the total composition or by weight of the pellets and HPMC in an amount of 0.1% to about 10% by weight of the total composition or by weight of the pellets, wherein said drug layer covers the pellet core, wherein, said composition further comprises at least one filler material, said at least one filler material comprising or consisting of: inert pellets, croscarmellose and magnesium stearate, said filler material being present in an amount of 60% to 99% by total weight of the composition.

[0083] In one embodiment, the composition is an immediate release composition of an active ingredient of a compound of formula I, formula (I), or a pharmaceutically acceptable salt thereof, the composition comprising pellets comprising or consisting of: a) a pellet core comprising sucrose and / or starch; b) a drug layer comprising: the compound of formula (I) or a pharmaceutically acceptable salt thereof in an amount of about 0.01% to about 5% by weight of the total composition or by weight of the pellets and HPMC in an amount of 0.1% to about 10% by weight of the total composition or by weight of the pellets, wherein said drug layer covers the pellet core, wherein, said composition further comprises at least one filler material, said at least one filler material comprising: a granulate mix as described herein, croscarmellose sodium and magnesium stearate, said filler material being present in a total amount of about 60% to 99% by total weight of the composition.

[0084] In some embodiments, the composition comprises the pellets comprising the drug layer as described herein in an amount of 1% to 40% by weight of the composition. For example, the pellets comprising the drug layer may be present in an amount of 10% to 30% by weight of the composition. In some embodiments, the drug layer of the immediate release composition comprises: the compound of formula (I) or a pharmaceutically acceptable salt thereof in an amount of about 0.01% to about 5% by weight of the total composition or by weight of the pellets and HPMC in an amount of 0.1% to about 5% by weight of the total composition or by weight of the pellets, wherein said drug layer covers the pellet core. In some embodiments, the drug layer of the immediate release composition comprises: the compound of formula (I) or a pharmaceutically acceptable salt thereof in an amount of about 0.01% to about 1% by weight of the total composition or by weight of the pellets and HPMC in an amount of 0.1% to about 10% by weight of the total composition or by weight of the pellets, wherein said drug layer covers the pellet core. In some embodiments, the drug layer of the immediate release composition comprises: the compound of formula (I) or a pharmaceutically acceptable salt thereof in an amount of about 0.01% to about 1% by weight of the total composition or by weight of the pellets and HPMC in an amount of 0.1% to about 5% by weight of the total composition or by weight of the pellets, wherein said drug layer covers the pellet core.

[0085] In some embodiments, the drug layer of the immediate release composition comprises: the compound of formula (I) or a pharmaceutically acceptable salt thereof in an amount of about 0.01% to about 5% by weight of the total composition or by weight of the pellets and HPMC in an amount of 0.1% to about 10% by weight of the total composition or by weight of the pellets, wherein said drug layer covers the pellet core.

[0086] In one embodiment, the composition comprises an amount of the compound of formula I of about 0.01 mg to 5 mg.

[0087] In one embodiment, the composition comprises an amount of the compound of formula I of about 0.01 mg to 5 mg.

[0088] In one embodiment, the composition comprises an amount of the compound of formula I of about 0.01 mg to 5 mg, such as about 0.05 mg to 5 mg, such as about 0.1 mg to 5 mg, such as about 0.2 mg to 5 mg, such as about 0.25 mg to 5 mg, such as about 0.01 mg to 4 mg, such as about 0.01 mg to 3 mg, such as about 0.01 mg to 2 mg, such as about 0.01 mg to 1 mg, such as about 0.01 mg to 0.75 mg, such as about 0.01 mg to 0.5 mg, such as 0.25 mg to 0.5 mg. In one embodiment, the composition is obtained by the methods as described in section ‘method of preparation’.

[0089] Immediate release

[0090] The inventors have surprisingly shown that the compositions according to the present disclosure provide for a fast and immediate release of the formula I, under physiological conditions. The examples demonstrate that the composition according to the present disclosure provide for a fast release of the compound of formula I, with complete release upon 30 minutes under physiological conditions, allowing for a fast absorption of the drug despite its poor solubility.

[0091] Thus, in one embodiment, the composition according to the present disclosure releases the compound of formula I at a rate of 90% or more released in the first hour as measured in a USP-II apparatus in purified water, such as 90% or more release in the first 50, 40, or 30 minutes as measured in a USP-II in purified water.

[0092] Dosage form

[0093] The present disclosure provides for a dosage form, such as a pharmaceutical dosage form, comprising the composition as described herein. In one embodiment, the dosage form is a pharmaceutical dosage form or a unit dosage form. In one embodiment, the composition is in the form of a solid dosage form. In one embodiment, the unit dosage form or pharmaceutical dosage form is a capsule. In one embodiment, the unit dosage form or pharmaceutical dosage form is a tablet.

[0094] Dosage forms are designed to facilitate the safe and effective delivery of active compounds to patients. Methods for the preparation of dosage forms such as capsules or tablets are well known to the person of skill in the art. Thus, in one embodiment, the composition according to the present disclosure is in the form of a unit dosage form or a pharmaceutical dosage form. In one embodiment, the composition according to the present disclosure is a capsule. In one embodiment, the composition is for oral administration. Method of

[0095] Pharmaceutical compositions of the present invention may be prepared according to any conventional methods of chemical synthesis known by the skilled person, e.g. those described in the working examples. The starting materials for the processes described in the present application are known or may readily be prepared by conventional methods known by the skilled artisan from commercially available chemicals.

[0096] In one aspect, the present invention provides for a method of preparing a composition comprising pellets, the method comprising: a) providing a pellet core, b) providing a drug layer solution comprising a compound of formula (I)

[0097] / I I formula (I), or a pharmaceutically acceptable salt thereof and at least one film-forming agent(s), and c) coating the drug layer solution onto the pellet core.

[0098] In one embodiment, the drug layer solution comprises a solvent or dispersant, wherein said solvent or dispersant comprises or consists of an aqueous solution. In some embodiments, the solvent or dispersant comprises or consists of an organic solvent suitable for pharmaceutical use. In some embodiments, the solvent or dispersant is purified water.

[0099] In one aspect, the present invention provides for a method of preparing a tablet, the method comprising: a) providing a composition comprising pellets, said pellets comprising a pellet core and a drug layer as described herein, b) mixing the composition in step a) with at least one filler material, to obtain a blend, c) compressing the blend in b), to obtain a tablet. In one embodiment, the film forming agent is selected from the group consisting of hydroxypropyl methyl cellulose (HPMC), cellulose derivatives, polyacrylates, polymethacrylates or copolymers of acrylate and methacrylate and polyvinylalcohol (PVA). In some embodiments, the film forming agent is HPMC.

[0100] As the skilled person will be aware of, both low and high viscosity grades of HPMC may be used for film-coating (Rowe et al.). The skilled person would know how to handle HPMC of any grade of viscosity for the purpose of the present application. In particular, the skilled person knows how to measure out appropriate amounts of HPMC, solvent, and drug, in order to obtain a drug solution comprising HPMC, to be applied to a pellet core, that complies with optimal spraying conditions. For example, when a low or high viscosity grade of HPMC is used, the skilled person would know how to adjust the resulting viscosity of the solution to be applied to a pellet core by adjusting the concentration of HPMC and selecting an appropriate solvent, in order to obtain a drug solution that complies with optimal spraying conditions.

[0101] In one embodiment of the methods disclosed herein, the pellet core and / or the drug layer are as described in the section ‘pharmaceutical compositions’.

[0102] In one embodiment of the methods disclosed herein, the drug layer solution comprises a film forming agent as described in the section ‘pharmaceutical compositions’.

[0103] In one embodiment of the methods disclosed herein, the at least one filler material is as described in the section ‘pharmaceutical compositions’.

[0104] In one embodiment of the methods disclosed herein, the composition is as described in the section ‘pharmaceutical compositions’. Items

[0105] 1 . A pharmaceutical composition comprising pellets, said pellets comprising; a. a pellet core; b. a drug layer comprising a compound of formula (I); formula (I), or a pharmaceutically acceptable salt thereof, said drug layer covering the pellet core.

[0106] 2. The pharmaceutical composition of item 1 , wherein the drug layer comprises a film-forming agent.

[0107] 3. The pharmaceutical composition of item 2, wherein the film forming agent is selected from the group consisting of hydroxypropyl methyl cellulose (HPMC), cellulose derivatives, polyacrylates, polymethacrylates or copolymers of acrylate and methacrylate, and polyvinyl alcohol (PVA).

[0108] 4. The pharmaceutical composition according to items 2-3, wherein the film forming agent is HPMC.

[0109] 5. The pharmaceutical composition according to any one of items 2-4, wherein the HPMC has a viscosity of up to 100 mPa s when measured under standard conditions of a 2% HPMC w / w aqueous solution at 20 °C.

[0110] 6. The pharmaceutical composition according to to any one of items 2-5, wherein the HPMC has a viscosity of 3 to 15 mPa s when measured under standard conditions of a 2% HPMC w / w aqueous solution at 20 °C.

[0111] 7. The pharmaceutical composition according to items 2-4, wherein the drug layer comprises the film-forming agent in an amount from 0.1 to 10% by weight of the composition or by weight of the pellets. 8. The composition according to items 2-7, wherein the drug layer comprises the film-forming agent in an amount from 0.1 to 5% by weight of the composition or by weight of the pellets.

[0112] 9. The pharmaceutical composition according to item 2-8, wherein the drug layer comprises HPMC in an amount from about 0.1% to 10% by weight of the composition or by weight of the pellets.

[0113] 10. The pharmaceutical composition according to item 2-9, wherein the drug layer comprises HPMC in an amount from about 0.1% to 5% by weight of the composition or by weight of the pellets.

[0114] 11. The pharmaceutical composition according to any one of the preceding items, wherein the pellet core consists of or comprises spheres made of a material selected form the group consisting of: sugars, such as sucrose, xylitol, mannitol, lactose; microcrystalline cellulose (MCC); starch, silica, tartaric acid and calcium carbonate.

[0115] 12. The pharmaceutical composition according to any one of the preceding items, wherein the pellet core comprises or consists of microcrystalline cellulose (MCC).

[0116] 13. The pharmaceutical composition according to any one of the preceding items, wherein the pellet core comprises or consists of sucrose and / or starch.

[0117] 14. The pharmaceutical composition according to any one of the preceding items, wherein the pellet core comprises or consists of sucrose and starch.

[0118] 15. The pharmaceutical composition according to any one of the preceding items, wherein the pellet core has an average size between 500 pm and 1500 pm, such as between 600 pm and 1500 pm, such as between 700 pm and 1500 pm, such as between 900 pm and 1500 pm, such as between 1000 pm and 1500 pm, such as between 1100 pm and 1400 pm. The pharmaceutical composition according to any one of the preceding items, wherein the pellet core has an average size of at least 1000 pm, such as at least 1100 pm. The pharmaceutical composition according to any one of the preceding items, wherein the pellets have a size distribution such that no more than 10% of the pellets pass through a US Sieve No. 25 (710 pm) and no more than 10% of the pellets are retained through a US Sieve No. 20 (850 pm). The pharmaceutical composition according to any one of the preceding items, wherein the drug layer comprises the compound of formula I in an amount of about 0.01 % to about 5% by weight of the composition or by weight of the pellets. The pharmaceutical composition according to any one of the preceding items, wherein the drug layer comprises the compound of formula I in an amount of about 0.01 % to about 1 % by weight of the composition or by weight of the pellets. The pharmaceutical composition according to any one of the preceding items, wherein the drug layer comprises the compound of formula I in an amount of from about 0.05% to 0.5% by weight of the composition or by weight of the pellets. The pharmaceutical composition according to any one of the preceding items, wherein the compound is exo- 7-(8- H- 8- aza- bicyclo [3.2.1] oct- 3-yloxy)- chromen-2-one or a pharmaceutically acceptable salt thereof. The pharmaceutical composition according to any one of the preceding items, wherein the compound is exo- 7-(8- H- 8- aza- bicyclo [3.2.1] oct- 3-yloxy)- chromen-2-one hydrochloric acid salt. The pharmaceutical composition according to any one of the preceding items, wherein the composition is an immediate release (IR) composition of the compound of formula I. 24. The pharmaceutical composition according to any one of the preceding items, wherein the composition is an immediate release composition of an active ingredient, said active ingredient consisting of a compound of formula I, formula (I), or a pharmaceutically acceptable salt thereof, the composition comprising pellets, said pellets comprising or consisting of: a) a pellet core comprising sucrose and / or starch; b) a drug layer comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof in an amount of about 0.01% to about 5% by weight of the total composition or by weight of the pellets and HPMC in an amount of 0.5% to about 10% by weight of the total composition or by weight of the pellets, wherein, the drug layer covers the pellet core.

[0119] 25. The pharmaceutical composition according to item 24, wherein the drug layer comprises the compound of formula (I) or a pharmaceutically acceptable salt thereof in an amount of about 0.01% to about 1% by weight of the total composition or by weight of the pellets and HPMC in an amount of 0.5% to about 5% by weight of the total composition or by weight of the pellets.

[0120] 26. The pharmaceutical composition according to any one of the preceding items, wherein the composition further comprises at least one filler material.

[0121] 27. The pharmaceutical composition according to item 26, wherein the at least one filler material is present in an amount from 50% to 99% by total weight of the composition, such as from 50% to 90%, such as from 60% to 90%, such as from 60% to 70%, such as from 70% to 80%, such as from 80% to 90% by total weight of the composition.

[0122] 28. The pharmaceutical composition according to items 26-27, wherein the at least one filler material is selected from the group comprising or consisting of: inert pellets, a sugar, such as sucrose, mannitol, or lactose; starch, microcrystalline cellulose, croscarmellose, and magnesium stearate, or any combination thereof. The pharmaceutical composition according to items 26-28, wherein the at least one filler material comprises or consists of inert pellets, wherein the inert pellets comprise or consist of spheres made of a material selected form the group consisting of: sugars, such as sucrose, xylitol, mannitol, lactose; microcrystalline cellulose (MCC); starch, silica, tartaric acid and calcium carbonate. The pharmaceutical composition according to items 28-29, wherein the inert pellets comprise or consist of spheres made of a sucrose and / or starch. The pharmaceutical composition according to items 28-30, wherein the inert pellets have an average size of 500 pm to 1500 pm, such as 500 pm to 1000 pm, such as 600 pm to 1000 pm, such as 700 pm to 950 pm, such as 700 pm to 900 pm. The pharmaceutical composition according to items 28-31 , wherein the inert pellets have an average size of at the most 1000 pm. The pharmaceutical composition according to items 28-32, wherein the inert pellets have an average size of 700 pm to 900 pm. The pharmaceutical composition according to any one of items 26-33, wherein the at least one filler material comprises or consists of microcrystalline cellulose. The pharmaceutical composition according to any one of items 26-34, wherein the at least one filler material comprises or consists of a sugar, such as mannitol. The pharmaceutical composition according to any one of items 26-35, wherein the at least one filler material comprises or consists of starch, such as pregelatinized starch. 37. The pharmaceutical composition according to any one of items 26-36, wherein the at least one filler material consists of or comprises of microcrystalline cellulose, mannitol, and starch.

[0123] 38. The pharmaceutical composition according to any one of items 26-37, wherein the at least one filler material comprises a granulate mix, said granulate mix comprising or consisting of: microcrystalline cellulose, mannitol, and starch.

[0124] 39. The pharmaceutical composition according to item 38, wherein the granulate mix comprises microcrystalline cellulose in an amount from 50%-75% by weight of the granulate mix, mannitol in an amount from 20%-40% by weight of the granulate mix and pre-gelatinized starch in an amount from 1% to 10% by weight of the granulate mix.

[0125] 40. The pharmaceutical composition according to any one of items 26-39, wherein the at least one filler material comprises or consists of an internally cross-linked carboxymethylcellulose, such as croscarmellose sodium.

[0126] 41 . The pharmaceutical composition according to item 40, wherein the internally cross-linked caroxymethylcellulose, such as croscarmellose, is present in an amount from 0.5% to 5% by weight of the composition.

[0127] 42. The pharmaceutical composition according to any one of items 26-41 , wherein the at least one filler material comprises or consists of magnesium stearate.

[0128] 43. The pharmaceutical composition according to item 42, the magnesium stearate is present in an amount from 0.1% to 2.0% by weight of the composition.

[0129] 44. The pharmaceutical composition according to any one of items 42-43, the magnesium stearate is present in an amount from 0.1% to 1 .0% by weight of the composition. The pharmaceutical composition according to any one of the preceding items, wherein the composition is an immediate release composition of an active ingredient consisting of a compound of formula I, formula (I), or a pharmaceutically acceptable salt thereof, the composition comprising pellets, said pellets comprising or consisting of: a) a pellet core comprising sucrose and / or starch; b) a drug layer comprising: the compound of formula (I) or a pharmaceutically acceptable salt thereof in an amount of about 0.01% to about 5% by weight of the pellets and HPMC in an amount of 0.5% to about 10% by weight of the pellets, wherein said drug layer covers the pellet core, wherein, said composition further comprises at least one filler material, said at least one filler material comprising or consisting of: inert pellets, microcrystalline cellulose, mannitol, pre-gelatinized starch, croscarmellose and magnesium stearate, said filler material being present in an amount of 60% to 99% by total weight of the composition. The pharmaceutical composition according to any one of the preceding items, wherein the composition is an immediate release composition of an active ingredient of a compound of formula I, formula (I), or a pharmaceutically acceptable salt thereof, the composition comprising pellets, said pellets comprising or consisting of: a) a pellet core comprising sucrose and / or starch; b) a drug layer comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof in an amount of about 0.01% to about 5% by weight of the pellets and HPMC in an amount of 0.5% to about 10% by weight of the pellets, wherein said drug layer covers the pellet core, wherein, said composition further comprises at least one filler material, said at least one filler material comprising or consisting of: inert pellets, croscarmellose and magnesium stearate, said filler material being present in an amount of 60% to 99% by total weight of the composition. The pharmaceutical composition according to any one of the preceding items, wherein the composition is an immediate release composition of an active ingredient consisting of a compound of formula I, formula (I), or a pharmaceutically acceptable salt thereof, the composition comprising pellets comprising or consisting of: a) a pellet core comprising sucrose and / or starch; b) a drug layer comprising: the compound of formula (I) or a pharmaceutically acceptable salt thereof in an amount of about 0.01% to about 5% by weight of the pellets and HPMC in an amount of 0.5% to about 10% by weight of the pellets, wherein said drug layer covers the pellet core, wherein, said composition further comprises at least one filler material, said at least one filler material comprising or consisting of: a granulate mix, croscarmellose sodium and magnesium stearate, in a total amount of about 60% to 99% by total weight of the composition. The pharmaceutical composition according to item 47, wherein the granulate mix comprises microcrystalline cellulose, mannitol, and starch. The pharmaceutical composition according to any one of the preceding items, wherein the composition comprises an amount of the compound of formula I of about 0.01 mg to 5 mg. 50. The pharmaceutical composition according to any one of the preceding items, wherein the composition comprises an amount of the compound of formula I of about 0.01 mg to 5 mg, such as about 0.05 mg to 5 mg, such as about 0.1 mg to 5 mg, such as about 0.2 mg to 5 mg, such as about 0.25 mg to 5 mg, such as about 0.01 mg to 4 mg, such as about 0.01 mg to 3 mg, such as about 0.01 mg to 2 mg, such as about 0.01 mg to 1 mg, such as about 0.01 mg to 0.75 mg, such as about 0.01 mg to 0.5 mg.

[0130] 51 . The pharmaceutical composition according to any one of the preceding items, wherein the composition comprises an amount of the compound of formula I of about 0.25 mg to 0.5 mg.

[0131] 52. The pharmaceutical composition according to any one of the preceding items, wherein the composition is in the form of a pharmaceutical dosage form or a unit dosage form.

[0132] 53. The pharmaceutical composition according to any one of the preceding items, wherein the composition is in the form of a solid dosage form.

[0133] 54. The pharmaceutical composition according to any one of the preceding items, wherein the unit dosage form or pharmaceutical dosage form is a capsule.

[0134] 55. The pharmaceutical composition according to any one of the preceding items, wherein the unit dosage form or pharmaceutical dosage form is a tablet.

[0135] 56. The pharmaceutical composition according to any one of the preceding items, wherein the composition is for oral administration.

[0136] 57. The pharmaceutical composition according to any one of the preceding items, wherein compound of formula I is released at a rate of at least 90% in one hour as measured in a USP-II apparatus in purified water, such as at least 90% in the first 50, 40, or 30 minutes as measured in a USP-II in purified water. 8. A method of preparing a pharmaceutical composition, the method comprising: a) providing pellet core, b) providing a drug layer solution comprising a compound of formula (I) formula (I), or a pharmaceutically acceptable salt thereof and at least one film-forming agent(s), and c) coating the drug layer solution on to the pellet core. 9. The method according to item 58, wherein the film forming agent is selected from the group consisting of hydroxypropyl methyl cellulose (HPMC), cellulose derivatives, polyacrylates, polymethacrylates or copolymers of acrylate and methacrylate and polyvinylalcohol (PVA).

[0137] 60. The method according to any one of items 58-59, wherein the film forming agent is HPMC. 1. The method according to any one of items 58-60, wherein the pellet core is according to any one of items 11 -16, and the drug layer is according to any one of items 2-9 and / or 18-20.

[0138] 62. The method according to any one of items 58-61 , wherein the drug layer solution comprises a film forming agent according any one of items 2-9.

[0139] 63. The method according to any one of items 58-62, wherein the drug layer solution comprises a solvent or dispersant, wherein said solvent or dispersant comprises or consist of an aqueous solution. 4. A method of preparing a tablet, the method comprising: a) providing a composition according to any one of items 1 to 24, or the composition obtained by the method according to any one of items 58-63, b) mixing the coated pellet core with at least one filler material, to obtain a blend, c) compressing the blend in b), to obtain a tablet. 65. The method according to item 64, wherein the at least one filler material is according to any one of items 26-43.

[0140] 66. The method according to any one of the preceding items, wherein the composition is as defined in any one of items 1 -56.

[0141] 67. A composition obtained by the method according to any one of items 58-66.

[0142] Items A

[0143] 1 . A pharmaceutical composition comprising pellets, said pellets comprising; a) a pellet core; b) a drug layer comprising a compound of formula (I); formula (I), or a pharmaceutically acceptable salt thereof, said drug layer covering the pellet core.

[0144] 2. The pharmaceutical composition of item A1 , wherein the drug layer comprises a film-forming agent.

[0145] 3. The pharmaceutical composition of item A2, wherein the film forming agent is selected from the group consisting of hydroxypropyl methyl cellulose (HPMC), cellulose derivatives, polyacrylates, polymethacrylates or copolymers of acrylate and methacrylate and polyvinylalcohol (PVA).

[0146] 4. The pharmaceutical composition of any one of items A1 -A3, wherein the film forming agent is HPMC.

[0147] 5. The pharmaceutical composition according to items A1 -A4, wherein the drug layer comprises the film-forming agent in an amount from 0.1 to 10% by weight of the pellets. 6. The pharmaceutical composition according to any one of the preceding items, wherein the pellet core consists of or comprises spheres made of a material selected form the group consisting of: sugars, such as sucrose, xylitol, mannitol, lactose; microcrystalline cellulose (MCC); starch, silica, tartaric acid and calcium carbonate.

[0148] 7. The pharmaceutical composition according to any one of the preceding items, wherein the pellet core has an average size between 500 pm and 1500 pm, such as between 600 pm and 1500 pm, such as between 700 pm and 1500 pm, such as between 900 pm and 1500 pm, such as between 1000 pm and 1500 pm, such as between 1100 pm and 1400 pm.

[0149] 8. The pharmaceutical composition according to any one of the preceding items, wherein the drug layer comprises the compound of formula I in an amount of about 0.01% to about 5% by weight of the pellets.

[0150] 9. The pharmaceutical composition according to any one of items A1 -A8, wherein the composition further comprises at least one filler material.

[0151] 10. The pharmaceutical composition according to item A9, wherein the at least one filler material is present in an amount from 50% to 99% by total weight of the composition, such as from 50% to 90%, such as from 60% to 90%, such as from 60% to 70%, such as from 70% to 80%, such as from 80% to 90% by total weight of the composition.

[0152] 11 . The pharmaceutical composition according to items A9-A10, wherein the at least one filler material is selected from the group consisting of: pellets, a sugar, such as sucrose, mannitol, or lactose; starch, microcrystalline cellulose, croscarmellose, and magnesium stearate, or any combination thereof.

[0153] 12. The pharmaceutical composition according to any one of items A1 -A11 , wherein the composition is a capsule. 13. The pharmaceutical composition according to any one of items A1 -A12, wherein the composition is a tablet.

[0154] 14. A method of preparing a pharmaceutical composition comprising pellets, the method comprising: a) providing a pellet core, b) providing a drug layer solution comprising a compound of formula (I) formula (I), or a pharmaceutically acceptable salt thereof and at least one film-forming agent(s), and c) coating the drug layer solution onto the pellet core.

[0155] 15. A method of preparing a pharmaceutical composition comprising pellets compressed into a tablet, the method comprising: a) providing a composition comprising a coated pellet core according to any one of items A1 -A10, b) mixing the coated pellet core with at least one filler material, to obtain a blend, c) compressing the blend in b), to obtain a tablet.

[0156] Examples

[0157] Example 1: Preparation of IP2018 formulations - API distribution on carrier

[0158] Aim

[0159] To describe the preparation of compositions according to the present disclosure having acceptable and reproducible distribution of active ingredient.

[0160] Materials and Methods

[0161] Incorporation onto carrier materials. Incorporation of IP2018 onto a polymeric carrier was attempted by high shear granulation or by spray granulation. Briefly, IP2018 was dissolved in different solvents: water, ethanol or isopropanol and poured onto different powder carrier materials: HPMC (Hypromellose 90SH-100.000SR), lactose or mixtures of HPMC / lactose in a high shear mixer. Spray granulation was tested on to lactose. Results

[0162] The initial attempts to incorporate IP2018 onto different powder carriers materials by high shear mixing or spray granulation were unsuccessful due to the inability to achieve as an acceptable distribution of the active ingredient with the required dosage strength in the resulting formulations.

[0163] Conclusion

[0164] It was not possible to incorporate IP2018 onto a powder carrier with an acceptable distribution of the active ingredient with the required dosage strength in the resulting formulations. These tests highlighted the difficulty in achieving and acceptable distribution of IP2018.

[0165] Preparation of capsule formulation. Sugar spheres (size range 1180-1400 pm, Suglets PF018, Colorcon), Hypromellose 6 (Pharmacoat 606, HPMC), purified water and IP2018 hydrochloride.

[0166] IP2018 hydrochloride and Hypromellose 6 were dissolved in purified water to form a drug layer composition, and stirred to obtain uniform solution. Then the drug layer composition was sprayed onto inert pellets (Suglets PF018) in a fluidized bed equipped with button spray and wurster to obtain the layered pellet core. For production of 250 g sugar spheres, approx. 50 g of spray solution of the drug layer composition was produced to be able to layer IP2018 hydrochloride on the inert pellets, as described in Table 1. Spraying conditions were controlled to an outlet air temperature of 35 to 36°C.

[0167] Finally, the drug-layered pellets were free-flowing and filled into 200 white, empty HPMC capsules size 3 was filled with approximately 200 mg drug-layered pellets.

[0168] IP2018 IR capsules were analysed by high performance liquid chromatography (HPLC) for active ingredient content and content uniformity; the acceptance values for content uniformity were determind as described in European Pharmacopoeia 10.0, chapter 2.9.40, Uniformity of dosage units and USP (Eur. Ph. 2.9.40). Acceptable AV-values were defined as below 15.

[0169] Results

[0170] IP2018 drug layered pellets were prepared according to Table 1 . The estimated amounts of IP2018 base and HPMC in the pellet composition is shown in Table 2.

[0171] Table 1. Preparation of IP2018 layered pellets.

[0172] Table 2. Composition of IP2018 pellet composition. % w / w: % weight by weight of the pellets

[0173] Average fill weight of loaded pellet into the capsules was found to be 218.19 mg with an RSD% of 1 .99%, minimum weight of 206.3 mg and maximum weight of 225.0 mg. This means that an average of 9.45% was dosed, and capsule active ingredient content was expected to be 0.274 mg. The analysis of the capsule formulation of IP2018 drug layered pellets with HPMC as film forming agent is presented in Table 3. The assay values were in accordance with the expected active ingredient content , wherein the measured active ingredient content was 0.289 mg. The acceptance value (AV-value) was 6.7, thus, the IP2018 capsule formulations met the requirement of an AV-value of below 15. 0.25 mg IP2018 base was equivalent to 200.0 mg loaded pellets.

[0174] Table 3. Analysis of capsule formulation of IP2018.

[0175] Example 3: IP2018 immediate release (IR) capsules release in solution

[0176] Aim

[0177] To study the release of IP2018 IR capsules according to the present disclosure.

[0178] Materials and methods

[0179] The dissolution profile of IP2018 IR capsules was determined in an USP 2 apparatus with paddles; rotation speed was 50 rpm and using 500 ml purified water as dissolution medium. Samples were analysed by UV spectrometry at 325 nm.

[0180] Results

[0181] The release profile of IP2018 IR capsules is presented in Figure 1 . The dissolution profile is expected, and in accordance with the requirements for an immediate release oral dosage form, with 95% released after 20 min.

[0182] Conclusion

[0183] The compositions according to the present disclosure provide for precise and reproducible dosage of IP2018 in solid formulations that achieve complete and fast release. Example 4: Preparation of IP2018 tablet formulation

[0184] Aim

[0185] To prepare tablet formulations of IP2018 with uniform active ingredient distribution and fast release.

[0186] Materials and methods

[0187] Sugar spheres (size range 710-850 pm, Suglets PF010, Colorcon), sugar spheres (size range 1180-1400 pm, Suglets PF018, Colorcon), Hypromellose 6 (Pharmacoat 606, HPMC), purified water, IP2018 hydrochloride, microcrystalline cellulose, mannitol, pregelatinized starch, croscarmellose sodium and magnesium stearate.

[0188] IP2018 hydrochloride and Hypromellose 6 were mixed in purified water to form a drug layer composition, and stirred to obtain uniform dispersion. The drug layer composition is as presented in Table 4. Then the drug layer composition was coated onto inert pellets (Suglets PF010) in a fluidized bed equipped with button spray and Wurster, to obtain the layered pellet core. Spraying conditions were controlled to an outlet air temperature of 36 to 38°C. 222 g of the drug layer composition was applied to 294.0 g of pellets, giving drug-layered pellets holding 0.859% w / w of IP2018 base.

[0189] Table 4. Drug layer composition used in IP2018 tablet formulation.

[0190] The pellets were mixed with different filler materials. One sample was prepared using inert (without drug) suglets PF010 in the filler materials, while another sample was prepared using a granulate mixture in the filler materials. The composition of the tablets can be shown in Table 5. The composition of the granulate mix can be seen in Table 6. Table 5. Composition of IP2018 immediate release (IR) tablet.

[0191] % w / w: % weight by total weight of tablet

[0192] Table 6. Composition of granulate mix used in the filler material for tablet preparation.

[0193] The mixtures where compressed an 8 mm rounding tool to form 8 mm x 3.2 mm (diameter x height) tablets. Each tablet has expected weight of 200 mg.

[0194] IP2018 IR tablets were analysed by high performance liquid chromatography (HPLC) for active ingredient content and content uniformity.

[0195] Results

[0196] The tablets prepared with the granulate mix in the filler materials had a disintegration time of approx. 4 min 30 sec, whereas the tablets using inert suglets PF010 in the filler materials had a disintegration time of more than 10 minutes.

[0197] The results of the analysis of tablet formulations using granulate mix in the filler materials are shown in Table 7. Table 7. Analysis of tablet formulation.

[0198] It was observed that segregation of the active ingredient in the IP2018 IR tablet composition when the drug layered pellets were prepared with Suglets PF010 (710-850 pm) was reduced compared with when the drug layered pellets were prepared with Suglets PF018 (1180-1400 pm), of larger average size.

[0199] Conclusion

[0200] Tablet formulations of IP2018 with acceptable strengths were prepared.

[0201] References

[0202] Rowe et al. Handbook of Pharmaceutical Excipients. 5th ed. Pharmaceutical Press and American Pharmacists Association 2006, p. 346-348.

Claims

Claims1 . A pharmaceutical composition comprising pellets, said pellets comprising; a) a pellet core; b) a drug layer comprising a compound of formula (I);formula (I), or a pharmaceutically acceptable salt thereof, and hydroxypropyl methylcellulose (HPMC) in an amount from 0.1 to 10% by weight of the pellets; said drug layer covering the pellet core.

2. The pharmaceutical composition according to claim 1 , wherein the drug layer comprises the HPMC in an amount from about 0.1% to 5% by weight of the pellets.

3. The pharmaceutical composition according to any one of the preceding claims, wherein the HPMC has a viscosity of up to 100 mPa s when measured under standard conditions of a 2% HPMC w / w aqueous solution at 20 °C.

4. The pharmaceutical composition according to any one of the preceding claims, wherein the HPMC has a viscosity of 3 to 15 mPa s when measured under standard conditions of a 2% HPMC w / w aqueous solution at 20 °C.

5. The pharmaceutical composition according to any one of the preceding claims, wherein the pellet core consists of or comprises spheres made of a material selected form the group consisting of: sugars, such as sucrose, xylitol, mannitol, lactose; microcrystalline cellulose (MCC); starch, silica, tartaric acid and calcium carbonate.

6. The pharmaceutical composition according to any one of the preceding claims, wherein the pellet core comprises or consists of microcrystalline cellulose (MCC).

7. The pharmaceutical composition according to any one of the preceding claims, wherein the pellet core comprises or consists of sucrose and / or starch.

8. The pharmaceutical composition according to any one of the preceding claims, wherein the pellet core comprises or consists of sucrose and starch.

9. The pharmaceutical composition according to any one of the preceding claims, wherein the pellet core has an average size between 500 pm and 1500 pm, such as between 600 pm and 1500 pm, such as between 700 pm and 1500 pm, such as between 900 pm and 1500 pm, such as between 1000 pm and 1500 pm, such as between 1100 pm and 1400 pm.

10. The pharmaceutical composition according to any one of the preceding claims, wherein the pellet core has an average size of at most 1000 pm, such as at least at most 900 pm, preferably an average size of between 700 pm and 900 pm.

11. The pharmaceutical composition according to any one of the preceding claims, wherein the drug layer comprises the compound of formula I in an amount of about 0.01% to about 5% by weight of the pellets.

12. The pharmaceutical composition according to any one of the preceding claims, wherein the drug layer comprises the compound of formula I in an amount of about 0.01% to about 1% by weight of the pellets.

13. The pharmaceutical composition according to any one of the preceding claims, wherein the drug layer comprises the compound of formula I in an amount of from about 0.05% to 0.5% by weight of the pellets.

14. The pharmaceutical composition according to any one of the preceding claims, wherein the compound is exo-7-(8-H-8-aza-bicyclo[3.2.1]oct-3-yloxy)-chromen- 2-one or a pharmaceutically acceptable salt thereof.

15. The pharmaceutical composition according to any one of the preceding claims, wherein the compound is exo-7-(8-H-8-aza-bicyclo[3.2.1]oct-3-yloxy)-chromen- 2-one hydrochloric acid salt.

16. The pharmaceutical composition according to any one of the preceding claims, wherein the composition is an immediate release (IR) composition of the compound of formula I.

17. The pharmaceutical composition according to any one of the preceding claims, wherein the composition is an immediate release composition of the compound of formula I,— a formula (I), or a pharmaceutically acceptable salt thereof, the composition comprising pellets, said pellets comprising or consisting of: c) a pellet core comprising sucrose and / or starch; d) a drug layer comprising the compound of formula (I), or a pharmaceutically acceptable salt thereof, in an amount of about 0.01% to about 5% by weight of the pellets; andHPMC in an amount of 0.5% to about 10% by weight of the pellets, wherein, the drug layer covers the pellet core.

18. The pharmaceutical composition according to claim 17, wherein the drug layer comprises the compound of formula (I) or a pharmaceutically acceptable salt thereof in an amount of about 0.01% to about 1% by weight of the pellets and HPMC in an amount of 0.5% to about 5% by weight of the pellets.

19. The pharmaceutical composition according to any one of the preceding claims, wherein the composition further comprises at least one filler material.

20. The pharmaceutical composition according to claim 19, wherein the at least one filler material is present in an amount from 50% to 99% by total weight of the composition, such as from 50% to 90%, such as from 60% to 90%, such as from 60% to 70%, such as from 70% to 80%, such as from 80% to 90% by total weight of the composition.21 . The pharmaceutical composition according to claims 19-20, wherein the at least one filler material is selected from the group comprising or consisting of: inert pellets, a sugar, such as sucrose, mannitol, or lactose; starch, microcrystalline cellulose, croscarmellose, and magnesium stearate, or any combination thereof.

22. The pharmaceutical composition according to claims 19-21 , wherein the at least one filler material comprises or consists of inert pellets, wherein the inert pellets comprise or consist of spheres made of a material selected form the group consisting of: sugars, such as sucrose, xylitol, mannitol, lactose; microcrystalline cellulose (MCC); starch, silica, tartaric acid and calcium carbonate.

23. The pharmaceutical composition according to claims 21 -22, wherein the inert pellets comprise or consist of spheres made of a sucrose and / or starch.

24. The pharmaceutical composition according to claims 21 -23, wherein the inert pellets have an average size of 500 pm to 1500 pm, such as 500 pm to 1000 pm, such as 600 pm to 1000 pm, such as 700 pm to 950 pm, such as 700 pm to 900 pm.

25. The pharmaceutical composition according to claims 21 -24, wherein the inert pellets have an average size of at the most 1000 pm.

26. The pharmaceutical composition according to claims 21 -25, wherein the inert pellets have an average size of 700 pm to 900 pm.

27. The pharmaceutical composition according to claims 21 -26, wherein the pellets have a size distribution such that no more than 10% of the pellets pass through a US Sieve No. 25 (710 pm) and no more than 10% of the pellets are retained through a US Sieve No. 20 (850 pm).

28. The pharmaceutical composition according to any one of claims 19-27, wherein the at least one filler material comprises or consists of microcrystalline cellulose.

29. The pharmaceutical composition according to any one of claims 19-28, wherein the at least one filler material comprises or consists of a sugar, such as mannitol.

30. The pharmaceutical composition according to any one of claims 19-29, wherein the at least one filler material comprises or consists of starch, such as pregelatinized starch.31 . The pharmaceutical composition according to any one of claims 19-30, wherein the at least one filler material consists of or comprises of microcrystalline cellulose, mannitol, and starch.

32. The pharmaceutical composition according to any one of claims 19-31 , wherein the at least one filler material comprises a granulate mix, said granulate mix comprising or consisting of: microcrystalline cellulose, mannitol, and starch.

33. The pharmaceutical composition according to claim 32, wherein the granulate mix comprises microcrystalline cellulose in an amount from 50%-75% by weight of the granulate mix, mannitol in an amount from 20%-40% by weight of the granulate mix and pre-gelatinized starch in an amount from 1% to 10% by weight of the granulate mix.

34. The pharmaceutical composition according to any one of claims 19-33, wherein the at least one filler material comprises or consists of an internally cross-linked carboxymethylcellulose, such as croscarmellose sodium.

35. The pharmaceutical composition according to claim 34, wherein the internally cross-linked carboxymethylcellulose, such as croscarmellose, is present in an amount from 0.5% to 5% by weight of the composition.

36. The pharmaceutical composition according to any one of claims 19-35, wherein the at least one filler material comprises or consists of magnesium stearate.

37. The pharmaceutical composition according to claim 36, the magnesium stearate is present in an amount from 0.1% to 2.0% by weight of the composition.

38. The pharmaceutical composition according to any one of claims 36-37, the magnesium stearate is present in an amount from 0.1% to 1 .0% by weight of the composition.

39. The pharmaceutical composition according to claim 1 , wherein the composition is an immediate release composition the compound of formula I,formula (I), or a pharmaceutically acceptable salt thereof, the composition comprising pellets, said pellets comprising or consisting of: a) a pellet core comprising sucrose and / or starch; b) a drug layer comprising: the compound of formula (I), or a pharmaceutically acceptable salt thereof, in an amount of about 0.01% to about 5% by weight of the pellets; andHPMC in an amount of 0.5% to about 10% by weight of the pellets, wherein said drug layer covers the pellet core, wherein, said composition further comprises at least one filler material, said at least one filler material comprising or consisting of: inert pellets, microcrystalline cellulose, mannitol, pre-gelatinized starch, croscarmellose and magnesium stearate, said filler material being present in an amount of 60% to 99% by total weight of the composition.

40. The pharmaceutical composition according to claim 1 , wherein the composition is an immediate release composition the compound of formula I,formula (I), or a pharmaceutically acceptable salt thereof, the composition comprising pellets, said pellets comprising or consisting of: a) a pellet core comprising sucrose and / or starch; b) a drug layer comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof in an amount of about 0.01% to about 5% by weight of the pellets; andHPMC in an amount of 0.5% to about 10% by weight of the pellets, wherein said drug layer covers the pellet core, wherein, said composition further comprises at least one filler material, said at least one filler material comprising or consisting of: inert pellets, croscarmellose and magnesium stearate, said filler material being present in an amount of 60% to 99% by total weight of the composition.41 . The pharmaceutical composition according to claim 1 , wherein the composition is an immediate release composition of an active ingredient consisting of a compound of formula I,formula (I), or a pharmaceutically acceptable salt thereof, the composition comprising pellets comprising or consisting of: a) a pellet core comprising sucrose and / or starch; b) a drug layer comprising: the compound of formula (I) or a pharmaceutically acceptable salt thereof in an amount of about 0.01% to about 5% by weight of the pellets; andHPMC in an amount of 0.5% to about 10% by weight of the pellets, wherein said drug layer covers the pellet core,wherein, said composition further comprises at least one filler material, said at least one filler material comprising or consisting of: a granulate mix, croscarmellose sodium and magnesium stearate, in a total amount of about 60% to 99% by total weight of the composition.

42. The pharmaceutical composition according to any one of claims 32, 33, or 41 , wherein the granulate mix comprises microcrystalline cellulose, mannitol, and starch.

43. The pharmaceutical composition according to claim 42, wherein the the granulate mix comprises microcrystalline cellulose in an amount from 50%-75% by weight of the granulate mix, mannitol in an amount from 20%-40% by weight of the granulate mix and pre-gelatinized starch in an amount from 1% to 10% by weight of the granulate mix.

44. The pharmaceutical composition according to any one of the preceding claims, wherein the composition comprises an amount of the compound of formula I of about 0.01 mg to 5 mg.

45. The pharmaceutical composition according to any one of the preceding claims, wherein the composition comprises an amount of the compound of formula I of about 0.01 mg to 5 mg, such as about 0.05 mg to 5 mg, such as about 0.1 mg to 5 mg, such as about 0.2 mg to 5 mg, such as about 0.25 mg to 5 mg, such as about 0.01 mg to 4 mg, such as about 0.01 mg to 3 mg, such as about 0.01 mg to 2 mg, such as about 0.01 mg to 1 mg, such as about 0.01 mg to 0.75 mg, such as about 0.01 mg to 0.5 mg.

46. The pharmaceutical composition according to any one of the preceding claims, wherein the composition comprises an amount of the compound of formula I of about 0.25 mg to 0.5 mg.

47. The pharmaceutical composition according to any one of the preceding claims, wherein the composition is in the form of a pharmaceutical dosage form or a unit dosage form.

48. The pharmaceutical composition according to any one of the preceding claims, wherein the composition is in the form of a solid dosage form.

49. The pharmaceutical composition according to any one of the preceding claims, wherein the unit dosage form or pharmaceutical dosage form is a capsule.

50. The pharmaceutical composition according to any one of the preceding claims, wherein the unit dosage form or pharmaceutical dosage form is a tablet.

51. The pharmaceutical composition according to any one of the preceding claims, wherein the composition is for oral administration.

52. The pharmaceutical composition according to any one of the preceding claims, wherein compound of formula I is released at a rate of at least 90% in one hour as measured in a USP-II apparatus in purified water, such as at least 90% in the first 50, 40, or 30 minutes as measured in a USP-II in purified water.

53. A method of preparing a pharmaceutical composition, the method comprising: a) providing pellet core, b) providing a drug layer solution comprising a compound of formula (I)formula (I), or a pharmaceutically acceptable salt thereof and HPMC in an amount from 0.1 to 10% by weight of the pellets, and c) coating the drug layer solution on to the pellet core.

54. The method according to any one of claims 53, wherein the pellet core is according to any one of claims 3-8, and the drug layer is according to any one of claims 1 and / or 9-11.

55. The method according to any one of claims 53-54, wherein the drug layer solution comprises a solvent or dispersant, wherein said solvent or dispersant comprises or consist of an aqueous solution.

56. A method of preparing a tablet, the method comprising: a) providing a composition according to any one of claims 1 to 51 , or the composition obtained by the method according to any one of claims 52-54, b) mixing the coated pellet core with at least one filler material, to obtain a blend, c) compressing the blend in b), to obtain a tablet.

57. The method according to claim 56, wherein the at least one filler material is according to any one of claims 17-35.

58. The method according to any one of the preceding claims, wherein the composition is as defined in any one of claims 1 -52.

59. A composition obtained by the method according to any one of claim 53-58.

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