TW202504582A - Extended release formulation of pudafensine - Google Patents

Abstract

The present invention relates to extended release formulations comprising the compound pudafensine or a pharmaceutically acceptable salt thereof as disclosed herein.

Description

Prodafencin extended release formulation

The present invention relates to an extended release formulation comprising the compound pudafensine disclosed herein or a pharmaceutically acceptable salt thereof.

Pudafensine (compound exo-7-[(-8-azabicyclo[3.2.1]oct-3-yl)oxy]-3-methoxy-indole-2-one, also known as IP2015) is a monoamine reuptake inhibitor in clinical development. In the nervous system, the compound increases the levels of neurotransmitters (dopamine and serotonin), which can be used to treat central nervous system disorders.

In view of the compound's effects on the central nervous system, an oral formulation must exhibit a robust release profile. To date, no known solid formulation of the compound has been shown to effectively release the compound. The compound has low solubility, which poses challenges to the manufacture of such a formulation and oral administration of the compound.

In some applications, it is highly desirable to provide formulations that are capable of sustained release of a compound over an extended period of time without compromising absorption of the compound or delivering a therapeutically effective dose to the patient.

Therefore, there is a strong unmet need for solid forms that can ensure consistent and robust release of podafensine while providing acceptable exposure of the compound to achieve pharmacological effects without adverse effects on the patient.

The inventors have unexpectedly discovered a specific formulation of podafensine that can provide extended release of podafensine while maintaining the overall exposure of the compound in the human body. The formulation according to the present disclosure provides an increase in _tmax and a decrease in peak and variability of podafensine plasma concentration without sacrificing the overall exposure of the compound in plasma. This is very advantageous in the clinical application of podafensine because it allows podafensine to be present in an individual for a longer period of time without compromising therapeutic efficacy due to exposure loss, while avoiding the presence of adverse events.

Thus, in one aspect, the present disclosure provides a composition comprising a pellet, the pellet comprising or consisting of: a) a pellet core; b) a drug layer covering the core, the drug layer comprising a compound of formula (I), Formula (I), c) a barrier coating layer comprising a film-forming agent, wherein the layer covers the drug layer b), and d) a delayed release layer comprising one or more delayed release polymers; wherein the delayed release layer covers the barrier coating in c).

In one aspect, the disclosure provides a unit dosage form comprising a composition described herein.

In one aspect, the present disclosure provides a method for obtaining a therapeutically effective plasma concentration of a compound of formula (I) in a subject, Formula (I) wherein the _tmax of the compound of Formula I is between 4 and 12 hours, the method comprising orally administering a composition described herein.

In one aspect, the present disclosure provides a method for preparing a composition comprising pellets, the method comprising: a) providing a pellet core, b) providing a composition comprising a compound of formula (I) c) applying the drug layer solution to the pellet core to form a drug layer; d) providing a barrier coating solution comprising a film former; e) applying the barrier coating solution to the top of the drug layer in c) to obtain a barrier coating layer; f) providing a delayed release solution comprising one or more delayed release polymers; g) applying the delayed release solution to the barrier coating layer in e) to obtain a delayed release layer.

Definition

" _Cmax " is a term used in pharmacokinetics to refer to the maximum (or peak) serum concentration of a drug achieved in a specified compartment or test area of the body after the drug has been administered and before a second dose is administered.

" _Tmax " is a term used in pharmacokinetics to describe the time at which _Cmax is observed.

As used herein, the terms "inert core" and "inert sphere" refer to a pharmaceutically acceptable core used in a pharmaceutical formulation in which the core is inert. For example, "inert core" and "inert sphere" refer to a pharmaceutically acceptable pellet that does not contain a drug substance.

"Pharmaceutically acceptable" means that it is suitable for use in preparing pharmaceutical compositions that are generally safe, nontoxic, and not biologically or otherwise undesirable, and includes pharmaceutical compositions that are acceptable for veterinary as well as human medical uses.

"Pudafensine", "IP2015" or "Compound I" refers to a compound of formula I. The compound of formula I is: .

As defined herein, the term "pharmaceutically acceptable salt" of a compound refers to a salt that is pharmaceutically acceptable and preferably has the desired pharmacological activity of the parent compound. Pharmaceutically acceptable salts include acid addition salts formed with inorganic acids; or salts formed with organic acids; or salts formed when an acidic proton present in the parent compound is replaced by a metal ion; or salts coordinated with an organic or inorganic base.

As used herein, a "formulation" is the result of combining different substances (including active ingredients) to produce a final product.

As used herein, the term "weight of pellets" refers to the total weight of the pellets including the drug layer, barrier coating layer and extended release layer in the composition, for example, the total weight of the components including the pellet core, drug layer, barrier coating layer, extended release layer, and any other layers on the pellets. In capsule formulations, this does not include the weight of the capsule shell.

The present disclosure provides a composition comprising a pellet, wherein the pellet comprises or consists of: a) a pellet core; b) a drug layer covering the core, wherein the drug layer comprises a compound of formula (I), Formula (I), or a pharmaceutically acceptable salt thereof; c) a barrier coating layer comprising a film-forming agent, wherein the layer covers the drug layer b), and d) a delayed release layer comprising one or more delayed release polymers; wherein the delayed release layer covers the barrier coating in c). Composition

Pellets offer a high degree of flexibility in the design and development of oral dosage forms. Microcrystalline cellulose (MCC) pellets and sugars are well-known materials used as core materials in pellet technology. The water-insoluble inert pellet core is made of microcrystalline cellulose or silicon dioxide, while the water-soluble inert pellet core is composed of sugars (such as sucrose, xylitol, mannitol and lactose; starch or salt). Both material classes show desirable characteristics, such as narrow particle size distribution, sphericity and surface smoothness, and can be used in accordance with the present invention. Those skilled in the art will be able to determine suitable materials and suppliers for spheres suitable as the core of pellets of the composition according to the present disclosure.

In one embodiment, the pellet comprises an inert pellet core. 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 a range of sizes, for example ^Cellet® or Celphere ^™ .

The size of the pellet core may be any suitable size, for example at least 100 μm. Pellets of different sizes may be used, for example pellet cores of 100 μm to 1500 μm, such as 100 μm to 500 μm, such as 500 μm to 1000 μm or 1000 μm to 1500 μm.

Methods for coating the pellet compositions are well known in the art. They can all start from a solution, dispersion or powder which is applied to the pellet layer. Recognized methods for coating the pellets are, for example: fluidized bed technology by compression coating, Würster coating, disk coating, centrifugal or rotor coating.

In one embodiment, the drug layer further comprises a binder. The binder is used to prevent the drug from sticking to the pellets and to provide a uniform coating on the pellets. The binder is mixed with the drug in a solution and then coated on the inert pellets. It was unexpectedly found that the presence of a binder (such as HPMC) in the coating solution allows for uniform coating of Podofencin on the inert pellet coating despite the low solubility of the compound.

Known binders are, for example, sucrose, starch, hydroxypropyl methyl cellulose (HPMC), hydroxypropyl cellulose (HPC), gelatin or polyvinylpyrrolidone. Therefore, in a specific example, the binder is: sucrose, starch, hydroxypropyl methyl cellulose (HPMC), hydroxypropyl cellulose (HPC), gelatin, polyvinylpyrrolidone (PVP); polyalkylene glycol or polyoxyalkylene, such as polyethylene oxide (PEO); or a mixture thereof.

In one specific example, the binder is hydroxypropyl methyl cellulose (HPMC). HPMC (CAS No. 9004-65-3) is a cellulose derivative in which some of the free hydroxyl groups in the cellulose are substituted by hydroxypropyl and methyl groups. Different grades of HPMC with different weights, degrees of hydroxypropyl or methyl groups and viscosities are commercially available and suitable for formulation development.

In one embodiment, the drug layer comprises the following amount of binder: 0.5% to 10% by weight of the composition or by weight of the pellet, such as 0.5% to 5%, such as 1% to 5%, such as 2% to 5%, such as 2%, 3%, 4% or 5% by weight of the composition or by weight of the pellet. Specifically, in one embodiment, the drug layer comprises the following amount of binder described herein: 0.5% to 10% by weight of the pellet, such as 0.5% to 5%, such as 2%, 3%, 4% or 5% by weight of the pellet.

In one embodiment, the drug layer comprises HPMC in an amount of about 0.5% to about 10% by weight of the composition or by weight of the pellet. In one embodiment, the drug layer comprises HPMC in an amount of about 1% to 5% by weight of the composition or by weight of the pellet, such as about 2%, 3%, 4% or 5% by weight of the composition or by weight of the pellet. Specifically, in one embodiment, the drug layer comprises HPMC described herein in an amount of 0.5% to 10%, such as 0.5% to 5%, such as 2%, 3%, 4% or 5% by weight of the pellet.

In one embodiment, the drug layer comprises additional excipients, such as pH adjusters and/or stabilizers. The inventors unexpectedly found that adding sodium sulfite (also known as sodium sulfite or Na ₂ SO ₃ , CAS No. 7757-83-7) to the drug layer increases the dissolution rate of pudafensine from the drug layer. Therefore, in one embodiment, the drug layer further comprises sodium sulfite.

The pH adjuster, stabilizer or sodium sulfite may be present in an amount of, for example, about 0.05% to about 1.5% by weight of the composition or pellet, such as 0.05% to 0.5% by weight, such as 0.5% to 1.0% by weight, such as 1.0% to 1.5% by weight of the composition or by weight of the pellet. In a specific example, the stabilizer or sodium sulfite is present in an amount of about 0.05% to about 1.5% by weight of the pellet.

In one embodiment, the sodium sulfite is present in an amount of about 0.3% to 0.8% by weight of the pellet. In one embodiment, the sodium sulfite is present in an amount of about 0.5% by weight of the pellet.

In one embodiment, the compound of formula I or a pharmaceutically acceptable salt thereof is present in an amount of about 0.5% to about 5% by weight of the total composition or by weight of the pellet. For example, the compound of formula I may be present in an amount of 0.5% to 1% by weight of the total composition or by weight of the pellet, such as 1% to 2%, such as 2% to 3%, such as 3% to 4%, such as 4% to 5%. In one embodiment, the compound of formula I may be present in 2.5% to 3.5% by weight of the composition or by weight of the pellet.

In one embodiment, the compound of formula I or a pharmaceutically acceptable salt thereof is present in an amount of about 0.5% to about 5% by weight of the pellet. For example, the compound of formula I is present in an amount of 0.5% to 1%, such as 1% to 2%, such as 2% to 3%, such as 3% to 4%, such as 4% to 5% by weight of the pellet. In one embodiment, the compound of formula I is present in an amount of 2.5% to 3.5% by weight of the pellet.

In one specific embodiment, the pellets according to the present disclosure comprise a barrier coating between the drug layer and the extended release layer, the barrier coating comprising a film former. The film former may be a polymer capable of forming a film and may be assisted by the presence of a plasticizer and a stabilizer. Examples of film formers known in the art are cellulose derivatives, polyacrylates, polymethacrylates, or copolymers of acrylates and methacrylates with polyvinylalcohol (PVA). The barrier coating may help reduce swelling of the pellets.

In one embodiment, the film former is HPMC. In one embodiment, HPMC is as described herein.

The film-forming agent may be present in the barrier coating in an amount of 0.5% to about 5% by weight of the composition or by weight of the pellet. In a specific example, the barrier coating comprises a film-forming agent in an amount of 0.5% to 5% by weight of the pellet.

Thus, in one embodiment, the barrier coating comprises HPMC in an amount of 0.5% to about 5% by weight of the composition or by weight of the pellet. The amount of HPMC in the barrier coating may be, for example, 1% to 4%, such as 1% to 2%, such as 2% to 3%, such as 3% to 4%, by weight of the composition or by weight of the pellet. In one embodiment, the barrier coating comprises HPMC in an amount of about 1% to 4%, by weight of the composition or by weight of the pellet. Specifically, in one embodiment, the barrier coating comprises HPMC described herein in an amount of 0.5% to 5%, such as 0.5% to 5%, such as 2%, 3%, 4% or 5%, by weight of the pellet.

The extended release layer comprises at least one extended release polymer. The extended release polymer may be, for example, a hydrophobic polymer that is permeable when in contact with water. Examples of extended release polymers may be, for example, cellulose derivatives modified with hydrophobic groups such as short alkyl groups, or other hydrophobic polymers such as synthetic polyacrylate derivatives having hydrophobic groups such as short alkyl groups.

In one embodiment, at least one extended release polymer is ethyl cellulose. Ethyl cellulose (EC, CAS No. 9000-57-3) is a cellulose derivative in which some of the free hydroxyl groups in cellulose have been substituted with ethyl groups. Different grades of EC with different molecular weights, ethyl substitution degrees and viscosities are commercially available and suitable for formulation development. EC is a hydrophobic polymer that is insoluble in aqueous media but permeable and promotes pH-independent drug release.

In one embodiment, the at least one extended release polymer is present in an amount of 0.5% to about 10% by weight of the composition or by weight of the pellet. Specifically, in one embodiment, the extended release layer comprises an extended release polymer in an amount of 0.5% to about 10% by weight of the pellet.

Thus, in one specific example, the extended release layer comprises ethyl cellulose in an amount of about 0.5% to about 10% by weight of the composition or by weight of the pellet, such as about 1% to about 10% by weight of the composition or by weight of the pellet, such as about 2% to about 10%, such as 3% to about 10%, such as about 3% to about 4%, such as about 4% to about 5%, such as about 5% to about 6%, such as about 6% to about 7%, such as about 7% to about 8%, such as about 8% to about 9%, such as about 9% to about 10%. For example, the extended release layer may comprise ethyl cellulose in an amount of about 1% to about 5%, such as about 2% to about 5%, by weight of the composition or by weight of the pellet. In one specific example, the extended release layer comprises ethyl cellulose described herein in an amount of 1% to about 10% by weight of the pellet, such as about 2% to about 5% by weight of the pellet.

In one embodiment, the extended release layer comprises an additional film former, such as the film former described above for the barrier coating layer. The presence of the film former helps to form the extended release layer and may also further contribute to the extended release properties of the formulation. In one embodiment, the extended release layer further comprises HPMC.

The film former may be present in the extended release layer in an amount of 0.5% to about 5% by weight of the composition or by weight of the pellet. Specifically, in one embodiment, the extended release layer comprises a film former in an amount of 0.5% to about 5% by weight of the pellet.

Therefore, in a specific example, the extended release layer comprises HPMC in an amount of 0.5% to about 5% by weight of the composition or by weight of the pellet. The amount of HPMC in the extended release layer can be, for example, 1% to 4%, such as 1% to 2%, such as 2% to 3%, such as 3% to 4% by weight of the composition or by weight of the pellet. In a specific example, the extended release layer comprises HPMC in an amount of about 1% to 4% by weight of the composition or by weight of the pellet. In a specific example, the extended release layer comprises HPMC described herein in an amount of 0.5% to about 5% by weight of the pellet.

In one specific example, the extended release layer comprises: an extended release polymer described herein, such as ethyl cellulose, in an amount of 0.5% to 10%; and a film former described herein, such as HPMC, in an amount of 0.5% to 5%.

In one embodiment, the extended release layer further comprises a plasticizer. The plasticizer can help enhance the flexibility and plasticity of the film or layer. This can be achieved by making the polymer more flexible and soft. Suitable plasticizers are known to those skilled in the art. For example, in one embodiment, the plasticizer is selected from: esters derived from citric acid, such as triethyl citrate or tributyl citrate; acetylated monoglycerides; phthalates; polyethylene glycol or its derivatives; and sorbitol or a mixture thereof.

In one embodiment, the extended release layer further comprises triethyl citrate. In one embodiment, triethyl citrate acts as a plasticizer.

In one embodiment, the extended release layer comprises a plasticizer in an amount of about 0.05% to about 5%, such as 0.1% to about 3%, by weight of the composition or by weight of the pellet. In one embodiment, the extended release layer comprises a plasticizer in an amount of about 0.05% to about 5%, such as 0.1% to about 3%, by weight of the pellet.

In one embodiment, the extended release layer further comprises an antitack agent. The antitack agent is added to prevent the formation of lumps in solid form and facilitate packaging, transportation and/or fluidity. Suitable antitack agents are known to those skilled in the art. For example, in one embodiment, the antitack agent can be selected from: calcium or magnesium stearate or fatty acid salt, talc, silicon dioxide, silicate or a combination thereof.

In one embodiment, the extended release layer further comprises magnesium stearate.

In one specific example, the extended release layer comprises an anti-tack agent, such as magnesium stearate, in an amount of about 0.05% to about 5%, such as 0.1% to about 3%, by weight of the composition or by weight of the pellet.

In one embodiment, the extended release layer further comprises one or more additional shaping agents selected from: i. a film former as described above; ii. a plasticizer as described above; and iii. an anti-adhesive agent as described above.

In one embodiment, the compound of formula I is according to formula Ia, Formula (Ia), or a pharmaceutically acceptable salt thereof.

In one embodiment, the compound is exo-7-[(-8-azabicyclo[3.2.1]oct-3-yl)oxy]-3-methoxy-1-en-2-one or a pharmaceutically acceptable salt thereof.

In one embodiment, the pharmaceutically acceptable salt of the compound of formula (I) or formula (Ia) is a hydrochloride salt.

In one embodiment, the composition is an extended release (ER) composition of the compound of Formula I. The extended release composition increases the _tmax of the compound of Formula I.

Therefore, in one embodiment, the present disclosure provides a composition comprising a compound of formula I A composition for extended release of an active ingredient composed of formula (I) or a pharmaceutically acceptable salt thereof, the composition comprising pellets, the pellets comprising or consisting of: a) an inert pellet core comprising microcrystalline cellulose (MCC); b) a drug layer comprising: a compound of formula (I) or a pharmaceutically acceptable salt thereof in an amount of about 0.5% to about 5% by weight of the total composition or by weight of the pellet; and HPMC in an amount of 0.5% to about 5% by weight of the total composition or by weight of the pellet, wherein the drug layer covers the inert core; c) a barrier coating layer comprising HPMC in an amount of about 0.5% to about 5% by weight of the total composition or by weight of the pellets, wherein the barrier coating layer covers the drug layer b); and d) an extended release layer comprising ethyl cellulose in an amount of about 0.5% to 10% by weight of the total composition or by weight of the pellets, wherein the extended release layer covers the barrier coating layer c).

In one embodiment, the present disclosure provides a composition comprising a compound of formula I A composition for extended release of an active ingredient composed of formula (I) or a pharmaceutically acceptable salt thereof, the composition comprising pellets, the pellets comprising or consisting of: a) an inert pellet core comprising microcrystalline cellulose (MCC); b) a drug layer comprising: a compound of formula (I) or a pharmaceutically acceptable salt thereof in an amount of about 0.5% to about 5% by weight of the pellet; and HPMC in an amount of 0.5% to about 5% by weight of the pellet, wherein the drug layer covers the inert core; c) a barrier coating layer comprising HPMC in an amount of about 0.5% to about 5% by weight of the pellet, wherein the barrier coating layer covers the drug layer b); and d) a delayed release layer comprising ethyl cellulose in an amount of about 0.5% to 10% by weight of the pellet, wherein the delayed release layer covers the barrier coating layer c).

In one embodiment, the drug layer further comprises other excipients, such as pH adjusters or stabilizers, as described herein. In one embodiment, the drug layer further comprises sodium sulfite, as described herein.

In one embodiment, the extended release layer further comprises one or more additional formulators selected from: i. a film former selected from the group as described herein; ii. a plasticizer selected as described herein; and iii. an anti-adhesive agent as described herein.

In one embodiment, the extended release layer further comprises HPMC as described herein.

In one embodiment, the compound of formula I is according to formula Ia, Formula (Ia), or a pharmaceutically acceptable salt thereof.

In one embodiment, the compound is exo-7-[(-8-azabicyclo[3.2.1]oct-3-yl)oxy]-3-methoxy-1-en-2-one or a pharmaceutically acceptable salt thereof.

In a specific example, the composition according to the present disclosure contains a compound of formula I in an amount of about 0.5 mg to about 30 mg, such as 1 mg to 20 mg, such as 1 mg to about 16 mg, such as 1 mg to about 10 mg, such as 2 mg to about 10 mg, such as 3 mg to about 10 mg, such as 4 mg to about 10 mg. For example, the composition may contain 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 mg of the compound of formula I. Dosage form

The present disclosure provides dosage forms, such as pharmaceutical dosage forms, comprising the compositions described herein. In one embodiment, the dosage form is a unit dosage form. Methods for making dosage forms, including appropriate formulations and materials, will be known to those skilled in the art.

In one embodiment, the unit dosage form or pharmaceutical dosage form is a solid dosage form. In one embodiment, the unit dosage form or pharmaceutical dosage form is a capsule.

The dosage form is designed to facilitate safe and effective delivery of the active compound to the patient.

Therefore, 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. As demonstrated by the examples, the composition according to the present disclosure provides extended release of pudafensine after oral administration while maintaining exposure to pudafensine. Extended release

The inventors have surprisingly shown that the compositions according to the present disclosure provide a prolonged release of Prudafencin in the gastrointestinal tract after oral administration.

In one embodiment, the composition provides a pharmacokinetic profile having a single mean peak plasma concentration upon oral administration.

The Examples demonstrate that the compositions according to the present disclosure are capable of reducing the _Cmax of the compound of Formula I after oral administration, compared to administration of an equivalent amount of the compound of Formula I in an aqueous solution.

In one embodiment, the composition reduces the _Cmax of the compound of Formula I after oral administration. In one embodiment, the _Cmax is reduced by at least 10%, at least 20%, such as compared to an aqueous solution of an equivalent amount of the compound of Formula I after oral administration.

In one embodiment, the composition is such that the _Cmax of the compound of Formula I after oral administration is 5.0 ng/mL to 12.0 ng/mL, such as 6.0 ng/mL to 10.0 ng/mL, such as 6.0 ng/mL to 8.0 ng/mL. In one embodiment, the composition is such that the average _Cmax of the compound of Formula I after oral administration is 6.0 ng/mL to 10.0 ng/mL, such as 6.0 ng/mL to 7.0 ng/mL, or 7.0 ng/mL to 8.0 ng/mL, or 8.0 ng/mL to 9.0 ng/mL, or 9.0 ng/mL to 10.0 ng/mL.

The Examples also demonstrate that the compositions according to the present disclosure are capable of increasing the _tmax of the compound of Formula I after oral administration, compared to administration of an equivalent amount of the compound of Formula I in aqueous solution.

In one embodiment, the composition increases the _tmax of the compound of formula I compared to an aqueous solution of the same amount of the compound of formula I after oral administration. In one embodiment, _tmax is increased by at least 60 minutes, such as by 90 minutes, such as by 120 minutes, such as by 180 minutes, such as by 210 minutes.

In one embodiment, the composition according to the present disclosure provides a _tmax of about 4 to 12 hours, such as 5.5 to 8.5 hours, for a compound of Formula I after oral administration. For example, the composition provides a _tmax of 5.5, 6.0, 6.5, 7.0, 7.5, 8.0 or 8.5 hours for a compound of Formula I.

One of the unintended effects of the compositions according to the present disclosure is the ability to provide extended release by increasing _tmax without reducing the exposure of the drug in humans and mammals. The exposure of a drug reflects the total amount of drug that reaches the systemic circulation and is still available to exert its effects. Therefore, adequate exposure of the drug is crucial to achieving the desired pharmacological effect.

It is expected that by extending the release time, and therefore the time that podafensine is retained in the gastrointestinal tract, exposure to the compound will be reduced due to phenomena that impair absorption, such as secretion, degradation, or reduced absorption in the lower parts of the gastrointestinal tract. In contrast, the exposure to podafensine following oral administration of an extended release composition according to the present disclosure was found to be comparable to the exposure provided by an equivalent amount of the compound in solution.

Exposure to a substance can be measured as the "area under the curve" or "AUC" of the compound in the bloodstream. As is well known in the art, this can be calculated by plotting the concentration of the drug in the bloodstream against time and determining the integral of the resulting curve (also called the "area under the curve" or "AUC").

The amount of drug in the bloodstream can be detected at different time points by methods well known in the art, such as HPLC, LC/MS, ELISA or other suitable analytical methods. Methods for calculating the integration of the plots are also well known to those skilled in the art. The integral or area under the curve of the plot can be calculated over a specific time interval, such as over the first 24, 48 or 72 hours. In general, the term "AUC _0-t " refers to the area under the curve over the first "t" hours, for example, "AUC _0-24 " refers to the area under the curve over the first 24 hours. The term "AUC ₀ - _inf " or "AUC _inf " refers to the area under the curve from the last integration point extrapolated to infinity.

Thus, in one embodiment, the composition according to the present disclosure provides an AUC _0-72 of a compound of Formula I after oral administration that is at least 85%, such as at least 90%, of the AUC _0-72 of an aqueous solution of an equivalent amount of the compound of Formula I after oral administration.

In one embodiment, the composition according to the present disclosure provides an AUC _0-inf of a compound of Formula I after oral administration that is at least 85%, such as at least 90%, of the AUC _0-inf of an aqueous solution of an equivalent amount of the compound of Formula I after oral administration.

In one embodiment, the composition is such that after oral administration the AUC _0-inf of the compound of Formula I is 100 to 500 h·ng/mL, such as AUC _0-inf 160 to 460 h·ng/mL, or AUC _0-inf 250 to 350 h·ng/mL, such as AUC _0-inf about 300 h·ng/mL.

In one embodiment, the composition provides an average AUC _0-inf of the compound of Formula I after oral administration of 200 h·ng/mL to 400 h·ng/mL, such as an average AUC _0-inf of 250 h·ng/mL to 350 h·ng/mL.

In one embodiment, the composition according to the present disclosure is such that: a) the AUC _{0-72 or AUC 0-inf of the compound of Formula I after oral administration is at least 85%, such as at least 90%, of the AUC 0-72 or AUC 0-inf of an} aqueous solution of an equivalent amount of the compound of Formula I after oral administration, and b) the t _max of the compound of Formula I is about 4 to 12 hours, such as about 5.5 to about 8.5 hours after oral administration.

The compositions disclosed herein provide extended release of the compound of formula I. The extended release may be characterized by the dissolution rate of the active ingredient from the composition. Those skilled in the art know methods for determining the dissolution rate of a solid dosage form of an active ingredient, such as according to the US Pharmacopeia, such as using USP-I or USP-II equipment, and suitable detection methods such as HPLC, LC/MS or ELISA.

In a specific example, the composition releases the compound of Formula I at the following rates: 35% to 70% release within the first 2 hours; 60% to 95% release after 4 hours and complete release after 8 hours, measured in a USP-I or USP-II apparatus at pH 6.8, 37°C.

In one embodiment, the composition releases the compound of formula I at the following rates: i. 35% to 70% of the compound is released within the first 2 hours, such as 40% to 65% is released within the first 2 hours; ii. 60% to 95% is released after 4 hours, such as 75% to 85% is released after 4 to 6 hours (such as after 4 hours, 5 hours or 6 hours); and iii. Complete release after 8 hours It is measured in USP-I or USP-II equipment at pH 6.8 and 37°C.

In one embodiment, the composition releases the compound of formula I at the following rates: i. 35% to 70% of the compound is released within the first 2 hours, such as 40% to 65% is released within the first 2 hours; ii. 60% to 95% is released after 4 hours, such as 75% to 85% is released after 4 hours; and iii. Complete release after 8 hours It is measured in USP-I or USP-II equipment at pH 6.8 and 37°C.

Therefore, in one embodiment, the present disclosure provides an immediate release composition of a compound of formula (I), which, when administered, provides pharmacokinetic characteristics characterized by one or more of the following: ● The C _max of the compound of formula I after oral administration is 5.0 ng/mL to 12.0 ng/mL, such as 6.0 ng/mL to 10.0 ng/mL, such as 6.0 ng/mL to 7.0 ng/mL, ● The t _max of the compound of formula I after oral administration is approximately 4 to 12 hours, such as 5.5 hours to 8.5 hours, ● The AUC _0-inf of the compound of formula I after oral administration is 160 to 450 h·ng/mL, such as AUC _0-inf of 250 to 350 h·ng/mL, such as AUC _0-inf of approximately 300 h·ng/mL.

In one embodiment, the immediate release composition comprises a compound of formula (I), a pellet core, a binder, a pH adjuster or a stabilizer as described herein in the section "Composition".

In one aspect, the present disclosure provides a method for obtaining a therapeutically effective plasma concentration of a compound of formula (I) in a subject, Formula (I) wherein the compound of Formula I has a _tmax between 4 and 12 hours, such as between 5.5 to about 8.5 hours, the method comprising orally administering a composition described herein or a unit dosage form described herein.

In one embodiment, the method provides an AUC _0-72 or AUC _0-inf of a compound of Formula I after oral administration that is at least 85%, such as at least 90%, of the AUC _0-72 or AUC _0-inf of an equivalent amount of a compound of Formula I in an aqueous solution after oral administration.

In one specific embodiment, the individual is a human. Preparation method

In one aspect, the present disclosure provides a method for preparing a composition comprising pellets, the method comprising: a) providing a pellet core, b) providing a composition comprising a compound of formula (I) c) applying the drug layer solution to the pellet core to form a drug layer; d) providing a barrier coating solution comprising a film former; e) applying the barrier coating solution to the top of the drug layer in c) to obtain a barrier coating layer; f) providing a delayed release solution comprising one or more delayed release polymers; g) applying the delayed release solution to the barrier coating layer in e) to obtain a delayed release layer.

In one specific embodiment of the method, the pellet core, drug layer, barrier coating or extended release layer are described herein in the section "Composition".

In one embodiment of the method, the drug layering solution comprises a film former or stabilizer as described herein in the section "Composition".

In one embodiment of the method, the drug layering solution comprises a solvent or a dispersion, wherein the solvent or dispersion comprises or consists of an aqueous solution.

In one embodiment of the method, the barrier coating solution comprises a solvent or a dispersant, wherein the solvent or dispersant comprises or consists of an aqueous solution.

In one embodiment of the method, the extended release layer solution further comprises a film former, a plasticizer and/or an anti-adhesive agent as described herein in the section "Composition".

In one embodiment of the method, the extended release layer solution comprises a solvent or a dispersant, wherein the solvent or the dispersant comprises or consists of an aqueous solution comprising an organic solvent, such as isopropyl alcohol.

In a specific example of the method, the composition is defined in the section "Composition" herein.

In one aspect, the present disclosure provides a composition obtained by the method described herein. Clause 1. A composition comprising a pellet, the pellet comprising or consisting of: a) a pellet core; b) a drug layer covering the core, the drug layer comprising a compound of formula (I), Formula (I), or a pharmaceutically acceptable salt thereof, c) a barrier coating layer comprising a film former, wherein the layer covers the drug layer b), and d) a delayed release layer comprising one or more delayed release polymers; wherein the delayed release layer covers the barrier coating in c). 2. A composition as in item 1, wherein the drug layer further comprises a binder selected from the group consisting of: cellulose derivatives, such as hydroxypropyl methyl cellulose (HPMC); polyalkylene glycols, such as polyethylene glycol (PEO) and polyvinyl pyrrolidone (PVP), hydroxypropyl cellulose and gelatin. 3. A composition as in any of the preceding items, wherein the binder is HPMC. 4. A compound as in any of the preceding clauses, wherein the film former is selected from the group consisting of hydroxypropylmethylcellulose (HPMC), cellulose derivatives, polyacrylates, polymethacrylates, and copolymers of acrylates and methacrylates and polyvinyl alcohol (PVA). 5. A composition as in any of the preceding clauses, wherein the barrier coating layer comprises HPMC in an amount of about 0.5% to about 5% by weight of the composition or by weight of the pellet. 6. A composition as in any of the preceding clauses, wherein the one or more extended release polymers are present in an amount of about 0.5% to about 10% by weight of the composition or by weight of the pellet. 7. A composition as in any of the preceding clauses, wherein the extended release polymer is ethyl cellulose. 8. A composition as in any of the preceding clauses, wherein the extended release layer further comprises a film former. 9. A composition as in any of the preceding clauses, wherein the extended release layer further comprises HPMC. 10. A composition as in any of the preceding clauses, wherein the extended release layer further comprises HPMC in an amount of 0.5% to about 5% by weight of the composition or by weight of the pellet. 11. A composition as in any of the preceding clauses, wherein the pellet core consists of or comprises spheres made of a material selected from the group consisting of: microcrystalline cellulose (MCC); sugars such as sucrose, xylitol, mannitol and lactose; starch, silicon dioxide, tartaric acid and calcium carbonate. 12. A composition as in any of the preceding clauses, wherein the composition is composed of a compound of formula I A composition for extended release of an active ingredient composed of formula (I) or a pharmaceutically acceptable salt thereof, the composition comprising pellets, the pellets comprising or consisting of: a) an inert pellet core comprising microcrystalline cellulose (MCC); b) a drug layer comprising: a compound of formula (I) or a pharmaceutically acceptable salt thereof in an amount of about 0.5% to about 5% by weight of the total composition or by weight of the pellet; and HPMC in an amount of 0.5% to about 5% by weight of the total composition or by weight of the pellet, wherein the drug layer covers the inert core; c) a barrier layer comprising HPMC in an amount of about 0.5% to about 5% by weight of the total composition or by weight of the pellet, wherein the barrier coating layer covers the drug layer b); and d) an extended release layer comprising ethyl cellulose in an amount of about 0.5% to 10% by weight of the total composition or by weight of the pellet, wherein the extended release layer covers the barrier coating layer c). 13. The composition of any of the preceding clauses, wherein the _tmax of the compound of formula I after oral administration is about 4 to 12 hours, such as 5.5 to 8.5 hours. 14. A composition according to any of the preceding clauses, wherein after oral administration, the composition is such that: a) AUC _0-72 or AUC _0-inf is at least 85% of the AUC _0-72 or AUC _0-inf of an aqueous solution of an equivalent amount of a compound of Formula I after oral administration, and b) the t _max of the compound of Formula I is about 5.5 to 8.5 hours. 15. A unit dosage form comprising a composition according to any of the preceding clauses. Examples Example 1: Purpose of Preparation of Formulations

The preparation of the compositions according to the present disclosure is described. Materials and Methods

Materials . Microcrystalline cellulose spheres (Celphere CP-507, particle size range 500 to 710 µm), anhydrous sodium sulfite, hydroxypropyl methylcellulose (HPMC, Methocel E5 premium LV), ethyl cellulose (Ethocel STd. 7 Premium), triethyl citrate dihydrate (European Pharmacopoeia), magnesium stearate (Ligamed 2V) NF, and pudafensine monohydrate monohydrochloride.

Drug layered pellets . Sodium sulfite, HPMC 5cps and Podofencin (pre-screened through sieve size #60) were mixed in pure water and then stirred to obtain a uniform dispersion. The solution was then coated onto inert pellet cores (Celphere CP-507) in a fluidized bed (GPCG 1.1 bowl, gun nozzle size: 1.2 mm, ADP size: B type).

Isolate coated pellets . Mix HPMC in pure water and stir to obtain a uniform dispersion. Spread the solution onto drug layered pellets (GPCG 1.1 bowl, gun nozzle size: 1.2 mm, ADP size: B type).

Extended Release Pellets . HPMC, ethyl cellulose, triethyl citrate and magnesium stearate (sieved through mesh size #60) were mixed in pure water and stirred to obtain a uniform dispersion. The solution was applied onto the isolation coated pellets in a fluidized bed (GPCG 1.1 bowl, gun nozzle size: 1.2 mm, ADP size: type B).

Encapsulation . Encapsulation of the composition is accomplished by filling the required amount of pellets into size 0 Swedish orange capsules to obtain the desired dosage. For example, an amount of pellets equivalent to 5 mg or 10 mg of Prudafencin free base is loaded onto the capsule.

The drug substance Prudafensine is used as a monohydrate and monohydrochloride. Therefore, the amount per vial or capsule or administration is calculated based on the amount of free base.

Samples were prepared: ● Immediate release (IR) compositions, corresponding to drug-layered pellets, with and without encapsulation, as shown in Table 1. ● Extended release compositions (ER), corresponding to extended release pellets, with and without encapsulation, as shown in Table 2. ● Drug-in-bottle (DiB) solutions, IP2015 dissolved in water for injection, with 50 mg/mL hydroxypropyl 2-β-cyclodextrin (HPβCD) as a solubility enhancer. Table 1. Composition of IP2015 immediate release (IR) pellets IP2015 IR pellets S. No use Element Quantity ( g ) % w/w Drug stratification 1 Core Pellets Celphere CP-507 1400.0 92.729 2 Drug substances ^IP2015a 48.37 3.204 3 Adhesive HPMC E5 (Methocel E5 premium LV) 53.40 3.537 4 pH adjuster/alkalizer Anhydrous sodium sulfite 8.00 0.530 5 Dispersants Pure water qs qs Total 1509.6 100.000 ^aThe drug substance is a monohydrate and a monohydrochloride. The amount of free base can be calculated by analyzing the anhydrous and solvent-free base using methods well known in the art. For this batch, 60 mg of free base corresponds to 72 mg of drug substance. Table 2. Composition of IP2015 Extended Release ( ER ) Pellets IP2015 ER Pellets S. No use Element Quantity ( g ) % w/w Drug stratification 1 Core Pellets Celphere CP-507 1400.0 83.762 2 Drug substances ^IP2015a 48.37 2.894 3 Adhesive HPMC E5 (Methocel E5 premium LV) 53.40 3.195 4 pH adjuster/alkalizer Anhydrous sodium sulfite 8.00 0.479 5 Dispersants Pure water qs qs Drug stratification sum 1509.6 90.330 HPMC Isolation Coating 6 - IP2015 Layered Pellets 1509.6 90.330 7 Film former for sealing coating HPMC E5 (Methocel E5 premium LV) 42.80 2.561 8 Dispersants Pure water qs qs HPMC isolation layer sum 1552.6 92.891 Extended release layer 9 - Isolation coating pellets 1552.6 92.891 10 Extended release polymers Ethocel Std. 7 Premium (Ethyl Cellulose) 53.05 3.174 11 Film former HPMC E5 (Methocel E5 premium LV) 53.05 3.174 12 Plasticizer Triethyl citrate dihydrate (European Pharmacopoeia) 3.712 0.222 13 Anti-adhesive Magnesium stearate (Ligamed 2V) NF 9.012 0.539 14 Dispersants Pharmacopoeia Grade Isopropyl Alcohol qs qs Total weight of ER coated pellets 1671.4 100.000 ^aDrug substance is available as a monohydrate and monohydrochloride. The amount of free base can be calculated by analyzing the anhydrous and solvent-free base using methods well known in the art. For this batch, 60 mg of free base corresponds to 72 mg of drug substance.

In addition, two similar ER compositions (ER1 and ER2) were prepared in a similar manner in the extended release layer using the following parameters: ● ER1: 5% HPMC, 5% ethyl cellulose ● ER2: 5% HPMC, 7.5 ethyl cellulose Solubility Testing

The solubility of IP2015 in aqueous and non-aqueous media was determined. In non-aqueous liquids, the solubility was confirmed visually by gradual dilution. The solubility of IP2015 in pH-specific aqueous solutions was evaluated, the solubility was confirmed visually, and the content was evaluated by HPLC. Table 3. Solubility of IP2015 in different media. Medium Solubility ( mg/ml ) Corollary (European Pharmacopoeia) Ethanol ＜1 Very slightly soluble N,N-Dimethylacetamide ＜1 Very slightly soluble Dimethyl sulfoxide 5 to 10 Slightly soluble N-Methyl-2-pyrrolidone ＜1 Very slightly soluble Propylene glycol 1 to 5 Slightly soluble Polyethylene glycol 400 ＜1 Very slightly soluble glycerin ＜1 Very slightly soluble pH 1.2 HCl (0.1N) 0.017 Very slightly soluble pH 3.0 Citrate Buffer 0.839 Very slightly soluble pH 4.0 Citrate Buffer 0.849 Very slightly soluble pH 3.0 Acetate buffer 1.173 Slightly soluble pH 4.5 Acetate Buffer 0.981 Very slightly soluble pH 5.8 potassium phosphate buffer 0.104 Very slightly soluble pH 6.8 potassium phosphate buffer 0.146 Very slightly soluble pH 7.5 potassium phosphate buffer 0.084 Very slightly soluble Pure water 0.738 Very slightly soluble result

As can be seen from Table 2, the solubility of IP2015 in aqueous solutions at all physiological pH is less than 1 mg/mL. Unexpectedly, the presence of a binder in the solution resulted in a homogeneous and consistent distribution of IP2015 in the drug layer. In contrast, when a solubility enhancer (such as hydroxypropyl 2-β-cyclodextrin (HPβCD) was used to increase the solubility of IP2015), the concentration of the compound was insufficient to form a good drug layer. Example 2: Release of IP2015 in Solution Purpose

The release of IP2015 from the compositions according to the present disclosure was studied. Materials and Methods

The dissolution characteristics of IP2015 IR pellets (part of the finished IMP) and IP2015 IR capsules were determined using 0.1N HCl buffer. IR sample dissolution conditions: Parameters condition Medium 0.1N HCl buffer quantity 900 mL equipment USP-I (Basket) RPM 50 temperature 37.0℃ + 0.5℃ Sampling volume 10 mL Time point 5, 10, 15, 30 min ER sample dissolution conditions:

The dissolution characteristics of IP2015 ER pellets (part of the finished IMP) and IP2015 ER capsules were determined as follows: Parameters condition Medium pH 6.8 phosphate buffer quantity 900 mL equipment USP-I (Basket) RPM 50 temperature 37.0℃ + 0.5℃ Sampling volume 10 mL

The dissolved samples were analyzed by gradient reverse phase HPLC with the mobile phase consisting of buffer solution (0.1% orthophosphoric acid and water): acetonitrile (85:15). Detection was performed by DAD.

To study the effect of sodium sulfite, two different pellet samples, with and without sodium sulfite, were prepared according to Example 1. The dissolution rate in the unencapsulated pellets corresponding to 5 mg IP2015 was studied.

To investigate the effect of encapsulation, the dissolution rate of IP2015 from both encapsulated and unencapsulated pellets was evaluated using samples corresponding to 5 mg IP2015 prepared according to Example 1. For comparison, the dissolution of unencapsulated samples corresponding to 10 mg IP2015 was also evaluated. Results

The dissolution characteristics of samples with and without sodium sulfite are shown in Table 4. Table 4. Drug Release from 5 mg IP2015 IR Pellets Samples with and without Sodium Sulfite Time / Minutes Drug release ( % ) Contains Na ₂ SO ₃ Does not contain Na ₂ SO ₃ 5 96 103 10 97 107 15 98 108 20 99 108 30 99 108 45 99 108 60 99 108

The effect of sodium sulfite on the dissolution profile was observed. The dissolution profile of the scale-up batches with sodium sulfite in the drug layer coating showed faster dissolution profile compared to the scale-up batches without sodium sulfite in the drug layer coating.

Figure 1 shows the release characteristics of IP2015 IR pellets and capsules. The dissolution characteristics were as expected. IP2015 IR capsules fulfilled the requirements of an immediate release oral dosage form with 80% release after 10 min and >90% release after 20 min.

Figure 2 shows the release profiles of IP2015 ER pellets and capsules. The dissolution profile was as expected. IP2015 ER capsules fulfilled the extended release requirements with 35% to 70% release within 2 hours, 70% to 90% release after 4 hours and complete release after 8 hours. For comparison, pellets containing 10 mg API were also tested.

Table 5 shows the release from the ER1 and ER2 pellet formulations described in Example 1. Table 5. Release from ER1 and ER2 pellets Time / Minutes Drug release ( % ) ER1 ER2 120 44 31 240 69 53 360 77 60 480 82 64 600 87 68 720 91 71 840 94 74 Conclusion

The composition according to the present disclosure provides sufficient extended release. Unexpectedly, the presence of sodium sulfite enhances the release of the drug layer. Example 3: In vivo pharmacokinetic study of the composition of Pudafensine IR

The pharmacokinetic parameters of the compositions according to the present disclosure were studied. Materials and Methods

The pharmacokinetic properties of the different formulations were investigated in Göttingen minipigs after a single oral administration in two extended release formulations (ER1 and ER2), one IR formulation (IR) and one drug-loaded (DiB) formulation of Pudafensine as a reference in vials.

Animals were fasted prior to dosing. Each formulation was administered to animals by single administration; a 7-day washout period was allowed after daily dosing. A single dose of 0.5 mg/kg was administered orally via capsule, with a 7-day washout period after daily dosing. A single dose (0.25 mL/kg) of the reference item solution was administered orally via feed tube.

Mortality assessments were performed twice daily. All clinical signs were recorded at baseline and at the same time each day during the study (approximately 1 to 1.5, 2 to 2.5, and 3 to 3.5 hours after dosing). Fasting body weight was recorded on the day of allocation and the day before dosing.

On each day of dosing, blood samples were collected from the cervical vein (and other veins if necessary) at approximately the following times: pre-dose, and 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 24, 36, and 48 hours after the first dose.

At each sampling time, at least 1.0 mL of blood was collected and transferred to tubes containing K ₂ EDTA anticoagulant, and centrifuged at room temperature, divided into two aliquots: approximately 250 μL [Aliquot A] and a second [Aliquot B] with residual plasma) and frozen at -70 ± 10°C.

The concentration of ptafensin in miniature pig plasma was determined by LC-MS/MS method from Syngene International Bioanalytical Division. During the analysis, standard samples and quality control samples were distributed to each batch of study samples analyzed. The plasma concentration data were used for the toxicokinetic evaluation.

PK parameters were determined from individual minipig plasma concentration versus time data by uniformly weighted non-compartmental analysis using Phoenix® WinNonlin® validated version 8.2. Calculated PK parameters included the area under the plasma concentration-time curve until the last quantifiable concentration (AUClast), AUCall, peak plasma concentration ( _Cmax ), time to peak plasma concentration ( _Tmax ), _Clast , _Tlast , _AUCinf , and terminal elimination half-life (t1/2). Plasma concentration and TK are in ng. Results

The pharmacokinetic parameters are shown in Tables 6 and 7. Table 6. Average pharmacokinetic parameters of Prudafencin in different formulations of ER pellets. IR ER1 ER2 B Dosage (mg/kg) 0.5 0.5 0.5 0.5 C _max (ng/mL) 17.026 19.124 11.682 25.135 t _max (h) 3.33 7.33 10.67 2.5 AUC _0-48h (h*ng/mL) 336.317 371.828 310.013 399.6 C _last 2.226 2.791 2.718 2.416 T _last 48 48 48 48 Half-life (h) 13.58 15.51 13.93 15.03 AUC _last (h*ng/mL) 336.317 371.828 310.013 399.6 AUC _{INF_obs} (h*ng/mL) 390.254 445.372 375.361 459.579 Table 7. Systemic exposure ratios of ER and IR formulations compared to DiB IR/DiB Ratio ER1/DiB ratio ER2/DiB ratio C _max 0.68 0.76 0.46 AUC _0-48h 0.84 0.93 0.78 t _max 1.3 2.9 4.3 Conclusion

It was unexpectedly observed that even while prolonging _tmax , the extended release formulations provided equal or higher exposure than the IR formulations when compared to the DiB formulations administered orally. Surprisingly, despite the longer exposure of Podafensine in the GI tract, the absorbance did not decrease and the exposure remained unchanged. Example 4. Clinical trials to investigate the pharmacokinetics of Podafensine formulations in humans. Objective

The pharmacokinetics of the immediate release (IR) composition of Prudafencin according to the present disclosure in human body were studied. Materials and Methods

The study was a 3-way crossover study in which the pharmacokinetic parameters of the podafensine composition according to the present disclosure after oral administration were studied. An immediate release capsule composition (IR) disclosed in Table 1 and an extended release capsule composition (ER) disclosed in Table 2 were used. For comparison, the results were compared with a solution of podafensine (DiB). The composition was prepared as described in Example 1.

The study was a crossover study in 12 healthy subjects who received a single dose of 5 mg of Prudafensine in different formulations with adequate washout. Plasma levels of Prudafensine were monitored at different time points after administration of the formulations.

The results are shown in Tables 8 and 9. Table 8. Pharmacokinetic parameters of the compositions. T _lag (h) t _max (h) C _max (ng/mL) AUC _last (h*ng/mL) AUC _inf (h*ng/mL) AUC _0-24 (h*ng/mL) ER N 12 12 12 12 9 12 Minimum 0 4.13 5.58 153 168 81.5 Median 0.25 7 6.95 251 301 118 maximum 1.08 11.93 11.4 361 454 195 IR N 12 12 12 12 10 12 Minimum 0 1.97 5.39 182 193 98.7 Median 0 4.98 8.81 260 301 146 maximum 0 7.95 12.5 410 479 209 B N 12 12 12 12 9 12 Minimum 0 0.98 6.25 186 199 106 Median 0 3.5 8.69 251 284 147 maximum 0 6.07 14.4 402 496 219 Table 9. Systemic exposure ratios Cmax AUClast AUCinf ER/IR ratio N 12 12 8 Minimum 0.61 0.72 0.73 Median 0.79 0.94 0.94 maximum 1.14 1.21 1.2 Geometric mean ( CV% ) 0.797(20.83%) 0.952(15.08%) 0.957(16.76%) ER/DiB ratio N 12 12 7 Minimum 0.65 0.74 0.77 Median 0.8 0.98 0.87 maximum 0.96 1.18 1.15 Geometric mean ( CV% ) 0.806(12.78%) 0.955(14.56%) 0.907 (15.60%) IR/DiB ratio N 12 12 8 Minimum 0.84 0.9 0.88 Median 1.03 0.99 1 maximum 1.23 1.16 1.18 Geometric mean ( CV% ) 1.001(11.91%) 1.004(8.05%) 1.012(10.55%) Conclusion

Unexpectedly, the extended release podafensine composition was shown to provide equivalent exposure to an equivalent amount formulated as an aqueous solution. The _Cmax of the extended release formulation in humans was reduced and the _tmax was increased. This is highly unexpected and advantageous because it allows for safer administration of podafensine while achieving equivalent systemic exposure to the bottled drug formulation. Example 5. Clinical trial to investigate the efficacy of IP2015 in treating adverse events of erectile dysfunction in humans

This study investigated the effects of repeated single oral doses of IP2015 on the ability to develop and maintain an erection in males with erectile dysfunction (ED), as well as the safety and tolerability of a single oral dose of IP2015, the effects on penile rigidity and swelling during visual stimulation, the effects on sperm count and motility, and any possible relationship between the plasma content of IP2015, its efficacy, and its safety.

130 subjects were divided into 3 groups and studied simultaneously. Each subject received 5 mg IP2015, 10 mg IP2015 or matching placebo four times. In each group, subjects were evenly randomized to each of the three study treatments and received the same treatment at each visit.

The study lasted approximately 8 weeks and consisted of the following: ●   Screening visit (up to 21 days before the baseline visit) ●   Baseline visit (Day 7) ●   Outpatient visits at Week 1 (Day 1), Week 2, Week 3, and Week 4 ●   Follow-up visit at least 7 to 10 days after the final dose.

All groups were asked to complete the IIEF-15 questionnaire on day 7 and at week 1 (Day 1), week 2, week 3, week 4, and at follow-up visits. Group 2 was asked to complete the visual stimulation assessment using the RigiScan Plus Monitor on day 7, week 1 (Day 1), and week 4. Group 2 was also asked to provide blood samples for pharmacokinetic assessments at week 1 (Day 1) and week 4. Group 3 was asked to provide semen samples on day 7 and week 4. Participants

Patients were healthy male individuals with ED as determined by IIEF-5 score ≤16, body mass index 18 to 35 kg/m ² (inclusive), of any race. Individuals were aged between 18 and 59 years (inclusive). Dosage and Mode of Administration

There were three possible study treatments: 5 mg IP2015, 10 mg IP2015, or matching placebo. Subjects were randomly assigned to each of the three study treatments evenly within each group and received the same treatment at each visit. IP2015 or matching placebo was administered once as an oral solution in the morning of Week 1 (Day 1), Week 2, Week 3, and Week 4 in the fasting state. The dose was taken with 240 mL at room temperature. Subjects fasted from 2 hours before dosing until 4 hours after dosing. Water was allowed ad libitum except for 1 hour before and 1 hour after dosing. Assessments

Efficacy was assessed by the International Index of Erectile Function (IIEF-15) questionnaire. Changes from baseline in responses to questions on the IIEF-15 questionnaire, which included domain scores for erectile function, orgasmic function, sexual desire, intercourse satisfaction, and overall satisfaction, were determined at various time points in the study. RigiScan assessments during stimulation assessments and sperm count and motility from semen sample collection were used for efficacy assessments. Safety was assessed by AE reports, 12-lead ECG, vital signs, physical examination, and clinical laboratory assessments. Pharmacokinetics were assessed by blood sampling. Results Efficacy of IP2015

The results for Q3 in the IIEF-15 are shown in Figure 4 as follows: "When you attempted sexual intercourse, how often were you able to penetrate (enter) your partner last week?" The results for Q3 were significant for treatment with 5 mg IP2015 at Week 3 compared to placebo (p=0.034) and baseline (p=0.046). There was also a trend of difference in the total score for Q3 compared to placebo (p=0.07) and baseline (p=0.07).

The results for Q4 of the IIEF-15 are shown in Figure 5 as follows: "During sexual intercourse, how often were you able to maintain an erection after you penetrated (entered) your partner?" The results for Q4 showed that although there was no difference compared to placebo (p=0.44), there was a trend towards a difference in the total score for 5 mg compared to baseline (p=0.056).

The overall responses to the IIEF-15 questions are shown in Figure 6, with significant trends for treatment with 5 mg IP2015 compared to baseline (p=0.0046) and compared to placebo (p=0.07) at follow-up, and the same trend for the total score for 5 mg compared to baseline (p=0.0032) and compared to placebo (p=0.10).

In Figures 4, 5, and 6, the results show the changes from baseline in patients treated with four doses of placebo (n=45), 5 mg (n=42), and 10 mg (n=43) IP2015 given concurrently on Days 1, 8, 15, and 22. Results are mean ± SE. Mixed Model Repeated Measure (MMRM) was used for statistical differences. Adverse Events

Treatment-induced adverse reactions at low doses (5 mg) of IP2015 were comparable to those in the placebo group. TEAEs were dose-dependent, mild and moderate, and slightly increased at high doses compared to low doses of IP2015. No serious side effects were observed at any dose of IP2015 (Table 10).

Results of semen analysis were intact and treatment had no negative effects on sperm count, motility, or morphology. Table 10. Treatment-emergent adverse events TEAE IP2015 5mg, N=42 IP2015 10 mg, N=43 Placebo, N=45 Any TEAE 32 (76.2 %), 61 34 (79.1%), 141 31 (68.9 %), 63 Related* 10 (23.8 %), 19 23 (53.5 %), 84 8 (17.8 %), 11 Mild 29 (69.0 %), 56 33 (76.7%), 132 27 (60.0%), 57 Moderate 3 (7.1%), 5 7 (16.3%), 9 6 (13.3%), 6 severe 0 0 0 headache 11 (26.2 %), 15 16 (37.2 %), 27 14 (31.1 %), 21 Dizziness 3 (7.1 %), 3 12 (27.9 %), 15 2 (4.4 %), 2 Nausea 1 (2.4 %), 1 8 (18.6 %), 15 1 (2.2 %), 1 Conclusion

Overall, these results suggest that IP2015 at a 5 mg dose is effective in treating erectile dysfunction and is safely tolerated. IP2015 (Pudafensine) at a 5 mg dose had a significant effect on Q3 of the IIEF-15 score compared to baseline and placebo. There was a trend for the IIEF-15 overall score, showing a clinically significant score change of 2, which was significant for the low dose of IP2015 relative to baseline and p=0.10 compared to placebo.

Treatment-induced adverse reactions of IP2015 at a dose of 5 mg were comparable to those of the placebo group. TEAEs were dose-dependent, with only mild and moderate effects observed. There were no severe TEAEs.

Compared to higher doses, lower doses have higher efficacy and lower TEAE incidence, which highlights the need for a solid dosage form formulation of IP2015 that can cause extended release and thus have more attractive pharmacokinetic properties for high doses of IP2015; without affecting exposure. The composition of the present disclosure provides such effects by reducing the _Cmax of IP2015 and increasing _tmax without reducing systemic exposure.

without

[Figure 1]: Dissolution rate of IR pellets and IR capsules with 10 mg or 5 mg of pudafensine. A , B : IR pellets 10 mg pudafensine; C : IR capsules 5 mg pudafensine; D : IR pellets 5 mg pudafensine. More details are given in Example 2.

[Figure 2]: Dissolution rate of ER pellets and ER capsules with 10 mg or 5 mg of pudafensine. A , B : ER pellets 10 mg pudafensine; C : ER pellets 5 mg pudafensine; D : ER capsules 5 mg pudafensine. More details are given in Example 2.

[Figure 3]: Concentrations of pedafencin in human plasma after administration of pedafencin in the form of extended-release formulation, immediate-release formulation, and aqueous solution.

[Figure 4]: Data from a Phase IIb study of compound IP2015 in patients with ED showed responses to question Q3 of the International Index of Erectile Function Scale 15 (IIEF-15): When you attempted sexual intercourse, how often were you able to penetrate (enter) your partner in the last week?

[Figure 5]: Data from a Phase IIb study of compound IP2015 in patients with ED showed responses to question Q4 of the International Index of Erectile Function-15 (IIEF-15): During sexual intercourse, how often are you able to maintain an erection after you penetrate (enter) your partner?

[Figure 6]: Data from a Phase IIb study of compound IP2015 in patients with ED showed its overall response to questions on the International Index of Erectile Function Scale-15 (IIEF-15).

Claims (75)

A composition comprising a pellet, the pellet comprising or consisting of: a) a pellet core; b) a drug layer covering the core, the drug layer comprising a compound of formula (I), Formula (I), or a pharmaceutically acceptable salt thereof, c) a barrier coating layer comprising a film-forming agent, wherein the layer covers the drug layer in b), and d) a delayed release layer comprising one or more delayed release polymers; wherein the delayed release layer covers the barrier coating in c). The composition of claim 1, wherein the drug layer further comprises a binder selected from the group consisting of: cellulose derivatives, such as hydroxypropyl methylcellulose (HPMC); polyalkylene glycols, such as PEO and polyvinylpyrrolidone (PVP), hydroxypropyl cellulose and gelatin. The composition of claim 2, wherein the drug layer comprises the binder in an amount of 0.5% to 10% by weight of the pellet. A composition as claimed in any one of claims 2 to 3, wherein the binder is HPMC. The composition of claim 4, wherein the drug layer comprises HPMC in an amount of about 1% to 5% by weight of the pellet. The composition of any of the preceding claims, wherein the drug layer further comprises an additional excipient selected from the group consisting of a pH adjuster and/or a stabilizer. The composition of claim 6, wherein the stabilizer is sodium sulfite. A composition as claimed in any one of claims 6 to 7, wherein the pH adjuster and/or stabilizer is present in an amount of 0.05% to 1% by weight of the pellet. The composition of any of the preceding claims, wherein the drug layer further comprises sodium sulfite present in an amount of 0.05% to 1% by weight of the pellet. A composition as claimed in any of the preceding claims, wherein the pellet core consists of or comprises spheres made of a material selected from the group consisting of: microcrystalline cellulose (MCC); sugars such as sucrose, xylitol, mannitol and lactose; starch, silicon dioxide, tartaric acid and calcium carbonate. A composition as claimed in any preceding claim, wherein the pellet core comprises or consists of microcrystalline cellulose (MCC). The composition of any of the preceding claims, wherein the drug layer comprises the compound of formula I in an amount of about 0.5% to about 5% by weight of the pellet. The composition of any of the preceding claims, wherein the drug layer comprises the compound of formula I in an amount of about 2.5% to about 3.5% by weight of the pellet. A composition as in any of the preceding claims, wherein the barrier coating layer comprises the film-forming agent in an amount between 0.5% and 5% by weight of the pellet. A composition as claimed in any of the preceding claims, wherein the film former is selected from hydroxypropyl methylcellulose (HPMC), cellulose derivatives, polyacrylates, polymethacrylates, and copolymers of acrylates and methacrylates and polyvinyl alcohol (PVA). A composition as claimed in any of the preceding claims, wherein the film former is HPMC. The composition of any of the preceding claims, wherein the barrier coating comprises HPMC in an amount of about 0.5% to about 5% by weight of the pellet. The composition of any of the preceding claims, wherein the barrier coating layer comprises HPMC in an amount of about 1% to 4% by weight of the pellet. A composition as claimed in any of the preceding claims, wherein the one or more extended release polymers are present in an amount of about 0.5% to about 10% by weight of the pellet. A composition as claimed in any of the preceding claims, wherein the one or more extended release polymers are selected from: cellulose derivatives modified with hydrophobic groups (such as short alkyl groups); or other hydrophobic polymers, such as synthetic polyacrylate derivatives having hydrophobic groups (such as short alkyl groups). A composition as claimed in any preceding claim, wherein the extended release polymer is ethyl cellulose. The composition of any of the preceding claims, wherein the extended release layer comprises ethyl cellulose in an amount of about 0.5% to about 10% by weight of the pellet. A composition as in any of the preceding claims, wherein the extended release layer comprises ethyl cellulose in an amount of about 1% to about 5% by weight of the pellet. A composition as claimed in any of the preceding claims, wherein the extended release layer further comprises a film former. The composition of claim 24, wherein the extended release layer comprises the film former in an amount of 0.5% to about 5% by weight of the pellet. The composition of any one of claims 24 to 25, wherein the film former is HPMC. The composition of any of the preceding claims, wherein the extended release layer further comprises HPMC. The composition of any of the preceding claims, wherein the extended release layer further comprises HPMC in an amount of 0.5% to about 5% by weight of the pellet. The composition of any of the preceding claims, wherein the extended release layer further comprises HPMC in an amount of 1% to about 4% by weight of the pellet. A composition as claimed in any of the preceding claims, wherein the extended release layer further comprises a plasticizer. A composition as claimed in any of the preceding claims, wherein the extended release layer further comprises a plasticizer selected from the group consisting of esters derived from citric acid, such as triethyl citrate or tributyl citrate; acetylated monoglycerides; phthalates; polyethylene glycol or its derivatives; and sorbitol or mixtures thereof. A composition as in any one of claims 30 to 31, wherein the plasticizer is triethyl citrate. A composition as claimed in any of the preceding claims, wherein the extended release layer further comprises triethyl citrate. The composition of any of the preceding claims, wherein the extended release layer further comprises an antitacking agent. The composition of claim 34, wherein the anti-adhesive agent is selected from: calcium or magnesium stearate or fatty acid salt, talc, silicon dioxide, and silicate or a combination thereof. The composition of claim 35, wherein the anti-sticking agent is magnesium stearate. A composition as claimed in any of the preceding claims, wherein the extended release layer further comprises magnesium stearate. A composition as in any of the preceding claims, wherein the extended release layer further comprises one or more additional formulators selected from the following: i. a film former as in claims 24 to 26; and/or ii. a plasticizer as in claims 30 to 33; and/or iii. an anti-adhesive as in claims 34 to 37. A composition as claimed in any of the preceding claims, wherein the compound of formula I is according to formula Ia, Formula (Ia), or a pharmaceutically acceptable salt thereof. The composition of any of the preceding claims, wherein the compound is exo-7-[(8-azabicyclo[3.2.1]oct-3-yl)oxy]-3-methoxy-2-en-2-one or a pharmaceutically acceptable salt thereof. A composition as claimed in any preceding claim, wherein the composition is an extended release (ER) composition of the compound of formula I. A composition as claimed in any of the preceding claims, wherein the composition is a compound of formula I A composition for extended release of an active ingredient composed of formula (I) or a pharmaceutically acceptable salt thereof, the composition comprising pellets, the pellets comprising or consisting of: a) an inert pellet core comprising microcrystalline cellulose (MCC); b) a drug layer comprising: a compound of formula (I) or a pharmaceutically acceptable salt thereof in an amount of about 0.5% to about 5% by weight of the pellet; and HPMC in an amount of 0.5% to about 5% by weight of the pellet, wherein the drug layer covers the inert core; c) a barrier layer comprising HPMC in an amount of about 0.5% to about 5% by weight of the pellet, wherein the barrier coating layer covers the drug layer in b); and d) an extended release layer comprising ethyl cellulose in an amount of about 0.5% to 10% by weight of the pellet, wherein the extended release layer covers the barrier coating layer in c). The composition of claim 42, wherein the drug layer further comprises sodium sulfite. A composition as claimed in any one of claims 42 to 43, wherein the extended release layer further comprises one or more additional formulators selected from the following: i. a film former as claimed in claims 24 to 26; and/or ii. a plasticizer as claimed in claims 30 to 33; and/or iii. an anti-adhesive agent as claimed in claims 34 to 37. The composition of any of the preceding claims, wherein the composition comprises the compound of formula I in an amount of about 0.5 mg to 30 mg. A composition as claimed in any of the preceding claims, wherein the composition is in the form of a pharmaceutical dosage form or a unit dosage form. A composition as claimed in any preceding claim, wherein the composition is in the form of a solid dosage form. The composition of claim 46, wherein the unit dosage form or pharmaceutical dosage form is a capsule. The composition of any of the preceding claims, wherein the composition is for oral administration. The composition of any of the preceding claims, wherein the composition reduces the _Cmax of the compound of formula I, wherein the _Cmax is reduced by at least 10%, such as at least 20%, compared to an aqueous solution of an equivalent amount of the compound of formula I after oral administration. The composition of any of the preceding claims, wherein the composition is such that upon oral administration the _Cmax of the compound of Formula I is 5.0 ng/mL to 12.0 ng/mL, such as 6.0 ng/mL to 10.0 ng/mL, such as 6.0 ng/mL to 8.0 ng/mL. 4. The composition of any preceding claim, wherein the composition increases the _tmax of the compound of formula I compared to an aqueous solution of an equivalent amount of the compound of formula I after oral administration. The composition of any of the preceding claims, wherein the _tmax of the compound of formula I upon oral administration is increased by at least 60 minutes, such as 90 minutes, such as 120 minutes, such as 180 minutes, such as 210 minutes, compared to an aqueous solution of the same amount of the compound of formula I after oral administration. The composition of any of the preceding claims, wherein the compound of formula I has a _tmax of about 4 to 12 hours, such as 5.5 to 8.5 hours, after oral administration. The composition of any of the preceding claims, wherein the composition is such that upon oral administration the AUC _0-72 of the compound of Formula I is at least 85% of the AUC _0-72 of an aqueous solution of an equivalent amount of the compound of Formula I after oral administration. The composition of any of the preceding claims, wherein the composition is such that upon oral administration the AUC _0-inf of the compound of Formula I is at least 85% of the AUC _0-inf of an aqueous solution of the compound of Formula I after oral administration. A composition as claimed in any of the preceding claims, wherein the composition is such that upon oral administration the AUC _0-inf of the compound of Formula I is 100 to 500 h·ng/mL, such as AUC _0-inf 160 to 460 h·ng/mL, or AUC _0-inf 250 to 350 h·ng/mL, such as AUC _0-inf about 300 h·ng/mL. A composition as in any of the preceding claims, wherein after oral administration, the composition is such that: a) the AUC _0-72 or AUC _0-inf of the compound of Formula I upon oral administration is at least 85% of the AUC _0-72 or AUC _0-inf of an equivalent amount of an aqueous solution of the compound of Formula I after oral administration, and b) the t _max of the compound of Formula I is about 5.5 to 8.5 hours. A composition as claimed in any of the preceding claims, wherein the composition releases the compound of formula I at the following rates: i. 35% to 70% released within the first 2 hours, such as 40% to 65% released within the first 2 hours; ii. 60% to 95% released after 4 hours, such as 75% to 85% released after 4 to 6 hours (such as 4 hours, 5 hours or 6 hours); and iii. Complete release after 8 hours which is measured in USP-I or USP-II equipment at pH 6.8 and 37°C. A composition as claimed in any preceding claim, wherein the composition comprises from about 0.5 mg to about 25 mg of a compound of formula (I). The composition of any of the preceding claims, wherein the composition comprises about 0.5 mg to 25 mg, such as about 0.5 mg, such as about 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg or 25 mg of a compound of formula (I). A composition as claimed in any preceding claim, wherein the composition comprises 5 mg or 10 mg of a compound of formula (I). A unit dosage form comprising a composition as claimed in any of the preceding claims. A method for obtaining a therapeutically effective plasma concentration of a compound of formula (I) in an individual, Formula (I) wherein the _tmax of the compound of formula I is between 4 and 12 hours, the method comprising orally administering a composition as claimed in any one of claims 1 to 62. The method of claim 64, wherein the individual is a human. The method of claim 64 to 65, wherein the AUC _0-72 or AUC _0-inf of the compound of Formula I when administered orally is at least 85%, such as at least 90%, of the AUC _0-72 or AUC _0-inf of an equivalent amount of the compound of Formula I in aqueous solution when administered orally. A method for preparing a composition comprising pellets, the method comprising: a) providing a pellet core, b) providing a composition comprising a compound of formula (I) c) applying the drug layer solution to the pellet core to form a drug layer; d) providing a barrier coating solution comprising a film former; e) applying the barrier coating solution to the top of the drug layer in c) to obtain a barrier coating layer; f) providing a delayed release solution comprising one or more delayed release polymers; g) applying the delayed release solution to the barrier coating layer in e) to obtain a delayed release layer. A method as claimed in claim 67, wherein the pellet core is as described in any one of claims 10 to 11, the drug layer is as described in any one of claims 1 to 9 or 12 to 13, the isolation coating layer is as described in any one of claims 14 to 18, or the extended release layer is as described in any one of claims 19 to 38. The method of any one of claims 67 to 68, wherein the drug layer solution comprises a binder as described in any one of claims 2 to 5 or a pH adjuster and/or stabilizer as described in any one of claims 6 to 9. The method of any one of claims 67 to 69, wherein the drug layer solution comprises a solvent or a dispersant, wherein the solvent or dispersant comprises or consists of an aqueous solution. The method of any one of claims 67 to 70, wherein the barrier coating solution comprises a solvent or a dispersant, wherein the solvent or dispersant comprises or consists of an aqueous solution. A method as in any one of claims 67 to 71, wherein the extended release layer solution comprises a film former as described in any one of claims 24 to 26, or a plasticizer as described in any one of claims 30 to 33, or an anti-adhesive agent as described in any one of claims 34 to 37. A method as in any one of claims 67 to 72, wherein the extended release layer solution comprises a solvent or a dispersant, wherein the solvent or dispersant comprises or consists of an aqueous solution comprising an organic solvent (such as isopropyl alcohol). A method as in any one of claims 67 to 73, wherein the composition is as defined in any one of claims 1 to 59. A composition obtained by the method of any one of claims 1 to 74.