Pudafensin sustained-release formulation

Abstract

The present invention relates to a sustained-release formulation comprising the compound pudafensin disclosed herein or a pharmaceutically acceptable salt thereof.

Description

[Technical Field]

[0001] The present invention relates to a sustained-release formulation comprising the compound pudafensin disclosed herein or a pharmaceutically acceptable salt thereof. [Background technology]

[0002] Pudafensin (compound exo7[(8azabicyclo[3.2.1]octan-3-yl)oxy]-3-methoxychromen-2-one, also known as IP2015) is a monoamine reuptake inhibitor in clinical development. In the nervous system, the compound increases levels of neurotransmitters, dopamine and serotonin, which have potential applications in the treatment of central nervous system disorders.

[0003] Considering the effects of the compound on the central nervous system, an oral formulation needs to exhibit a robust release profile. To date, there are no known solid formulations of the compound that demonstrate effective release. The compound suffers from low solubility, which poses challenges in both the manufacture of such formulations and the oral administration of the compound.

[0004] For some applications, it is highly desirable to provide a formulation that can sustainably release the compound over a long period of time without impairing the absorption of the compound or the delivery of a therapeutically effective amount to the patient.

[0005] Therefore, there is a strong and insufficient need for a solid form that can ensure consistent and robust release of pudafensin while providing acceptable exposure to the compound, in order to achieve pharmacological effects without side effects on the patient. [Overview of the project]

[0006] The inventors have, surprisingly, discovered a specific formulation of pudafensin that can provide sustained release of pudafensin while maintaining overall exposure to the compound in humans. The formulation according to this disclosure does not sacrifice overall exposure to the compound in plasma. maxIt provides an increase and a reduction in the peak and variability of the plasma concentration of bufendosin. This is highly advantageous in the clinical application of bufendosin as it enables the long-term presence of bufendosin in the subject without losing the therapeutic efficacy due to loss of exposure while avoiding the presence of adverse events.

[0007] Thus, in one aspect, the present disclosure provides a composition comprising pellets, wherein the pellets a) a pellet core, and b) a drug layer covering the core, the drug layer comprising a compound of formula (I), the drug layer, and

Chemical formula

[0008] In one aspect, the present disclosure provides a unit dosage form comprising the composition described herein.

[0009] In one aspect, the present disclosure provides a method for obtaining a compound of formula (I) at a therapeutically effective plasma concentration in a subject,

Chemical formula

[0010] In one aspect, the present disclosure provides a method for preparing a composition comprising pellets, the method comprising a) providing a pellet core, and b) a compound of formula (I),

Chemical formula

[0011] [Figure 1] The dissolution rates of IR pellets and IR capsules containing 10 mg or 5 mg of pudafensin are shown. A and B show IR pellets containing 10 mg of pudafensin, C shows an IR capsule containing 5 mg of pudafensin, and D shows an IR pellet containing 5 mg of pudafensin. Further details are shown in Example 2. [Figure 2] The dissolution rates of ER pellets and ER capsules containing 10 mg or 5 mg of pudafensin are shown. A and B show ER pellets containing 10 mg of pudafensin, C shows an ER pellet containing 5 mg of pudafensin, and D shows an ER capsule containing 5 mg of pudafensin. Further details are shown in Example 2. [Figure 3] This refers to the concentration of pudafensin in human plasma after administration of pudafensin as a sustained-release formulation, an immediate-release formulation, and an aqueous solution. [Figure 4] Data from a Phase IIb trial using compound IP2015 in ED patients show their responses to Question Q3 of the International Index of Erectile Function 15 (IIEF-15): How often were you able to insert (penetrate) your partner last week when you attempted sexual intercourse? [Figure 5]Data from a Phase IIb trial using compound IP2015 in ED patients show their responses to Question Q4 of the International Index of Erectile Function 15 (IIEF-15): How often were you able to maintain an erection after insertion into your partner during sexual intercourse? [Figure 6] Data from a Phase IIb trial using compound IP2015 in ED patients demonstrate their overall response to the International Index of Erectile Function 15 (IIEF-15) problem.

[0012] definition "C max In pharmacokinetics, "the maximum (or peak) serum concentration of a drug reached in a specific compartment or test area of ​​the body after administration and before administration of a second dose" is a term used to refer to the maximum serum concentration of a drug reached after administration and before administration of a second dose.

[0013] "t max "In pharmacokinetics, C max This is a term used to describe the time period over which something is observed.

[0014] As used herein, the terms “inert core” and “inert sphere” refer to pharmaceutically acceptable cores for use in pharmaceutical formulations in which the core is inert. For example, “inert core” or “inert sphere” refers to a pharmaceutically acceptable pellet that does not contain a drug substance.

[0015] "Pharmacologically acceptable" means useful in preparing pharmaceutical compositions that are generally safe, non-toxic, and not biologically or otherwise undesirable, and includes being acceptable for veterinary and human pharmaceutical use.

[0016] "Pudafensin" means that "IP2015" or "Compound I" refers to the compound of formula I. The compound of formula I is [ka] That is the case.

[0017] The term “pharmaceutically acceptable salt” of a compound refers to a salt that is pharmaceutically acceptable, preferably having the desired pharmacological activity of the parent compound, as defined herein. Pharmaceutically acceptable salts include acid addition salts formed with inorganic or organic acids, salts formed when acidic protons present in the parent compound are replaced by metal ions, or salts that coordinate with organic or inorganic bases.

[0018] As used herein, “formulation” refers to the result of combining different substances, including an active ingredient, to produce a final product.

[0019] As used herein, the term “weight of pellets” refers to the total weight of the pellets in the composition, including the drug layer, barrier coating layer, and sustained-release layer, for example, the total weight of the components including the pellet core, drug layer, barrier coating layer, sustained-release layer, and any other layers on the pellet. In capsule formulations, this does not include the weight of the capsule shell. [Modes for carrying out the invention]

[0020] This disclosure provides a composition comprising pellets, wherein the pellets are a) Pellet core and b) A drug layer covering the core, wherein the drug layer is a compound of formula (I). [ka] Equation (I) A drug layer containing a pharmaceutically acceptable salt thereof, c) A barrier coating layer containing a film-forming agent, wherein the layer covers the drug layer in b), d) A sustained-release layer comprising one or more sustained-release polymers, wherein the sustained-release layer comprises or consists of a sustained-release layer covering the barrier coating in c).

[0021] composition Pellets offer a high degree of flexibility in the design and development of oral dosage forms. Microcrystalline cellulose pellets (MCCs) and sugars are well-known materials in pellet technology for use as core materials. Water-insoluble inert pellet cores are made from microcrystalline cellulose or silica, while water-soluble inert pellet cores consist of sugars such as sucrose, xylitol, mannitol, and lactose, and starch or salts. Both material classes exhibit desirable properties such as a narrow particle size distribution, sphericity, and surface smoothness and can be used according to the present invention. Those skilled in the art will be able to determine suitable materials and suppliers for spheres suitable as cores for pellets of the compositions according to this disclosure.

[0022] 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 multiple size ranges, for example, Cellet® or Celphere®.

[0023] The size of the pellet core can be any suitable size, for example, at least 100 μm. Pellet cores of different sizes can be used, for example, pellet cores with sizes from 100 μm to 1500 μm, for example, 100 μm to 500 μm, for example, 500 μm to 1000 μm, or 1000 μm to 1500 μm.

[0024] Methods for coating pellet compositions are well known in the art. Both can begin with a solution, dispersion, or powder to be coated onto the pellets layer by layer. Well-established methods for coating pellets include, for example, compression coating, vaster coating, pan coating, and fluidized bed technology by centrifugal or rotor coating.

[0025] In one embodiment, the drug layer further comprises a binder. The binder is used to avoid the drug sticking to the pellet and to provide a uniform coating on the pellet. The binder is mixed with the drug in a solution and then coated onto the inert pellet. Surprisingly, it was found that the presence of a binder such as HPMC in the coating solution enabled a uniform coating of pudafensin onto the inert pellet coating, despite the low solubility of the compound.

[0026] Known binders include, for example, sucrose, starch, hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), gelatin, or polyvinylpyrrolidone. Therefore, in one embodiment, the binder is sucrose, starch, hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), gelatin, polyvinylpyrrolidone (PVP), polyalkylene glycol or polyalkylene oxide (e.g., polyethylene oxide (PEO)), or a mixture thereof.

[0027] In one embodiment, the binder is hydroxypropyl methylcellulose (HPMC). HPMC (CAS number 9004-65-3) is a cellulose derivative in which several free hydroxyl groups in cellulose are substituted with hydroxypropyl and methyl groups. Different grades of HPMC with different weights, hydroxypropyl or methyl groups, and viscosities are commercially available and suitable for use in formulation development.

[0028] In one embodiment, the drug layer contains a binder in an amount of 0.5% to 10% by weight of the composition or by weight of the pellet, for example, 0.5% to 5%, for example, 1% to 5%, for example, 2% to 5%, for example, 2%, 3%, 4%, or 5% by weight of the composition or by weight of the pellet. In particular, in one embodiment, the drug layer contains a binder according to this specification in an amount of 0.5% to 10% by weight of the pellet, for example, 0.5% to 5%, for example, 2%, 3%, 4%, or 5% by weight of the pellet.

[0029] In one embodiment, the drug layer contains 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 contains HPMC in an amount of about 1% to 5% by weight of the composition or by weight of the pellet, for example, about 2%, 3%, 4%, or 5% by weight of the composition or by weight of the pellet. In particular, in one embodiment, the drug layer contains HPMC as described herein in an amount of 0.5% to 10% by weight of the pellet, for example, 0.5% to 5%, for example, 2%, 3%, 4%, or 5% by weight of the pellet.

[0030] In one embodiment, the drug layer contains additional excipients such as pH adjusters and / or stabilizers. Unexpectedly, the inventors found that the addition of sodium sulfite (also known as sodium sulfite or Na2SO3, CAS number 7757-83-7) to the drug layer increases the dissolution rate of pudafensin from the drug layer. Therefore, in one embodiment, the drug layer further contains sodium sulfite.

[0031] pH adjusters, stabilizers, or sodium sulfite may be present in amounts of, for example, about 0.05% to about 1.5% by weight of the composition or pellets, for example, 0.05% to about 0.5%, for example 0.5% to 1.0%, for example 1.0% to 1.5% by weight of the composition or pellets. In one embodiment, the stabilizer or sodium sulfite is present in amounts of about 0.05% to about 1.5% by weight of the pellets.

[0032] In one embodiment, sodium sulfite is present in an amount of approximately 0.3% to 0.8% by weight of the pellet. In another embodiment, sodium sulfite is present in an amount of approximately 0.5% by weight of the pellet.

[0033] 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 pellets. For example, the compound of formula I may be present in an amount of 0.5% to 1%, e.g., 1% to 2%, e.g., 2% to 3%, e.g., 3% to 4%, e.g., 4% to 5% by weight of the total composition. In one embodiment, the compound of formula I may be present in an amount of 2.5% to 3.5% by weight of the composition or by weight of the pellets.

[0034] 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%, e.g., 1% to 2%, e.g., 2% to 3%, e.g., 3% to 4%, e.g., 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.

[0035] In one embodiment, the pellets according to this disclosure include a barrier coating between a drug layer and a sustained-release layer, the barrier coating comprising a film-forming agent. The film-forming agent may be a polymer capable of forming a film, and may be aided by the presence of plasticizers and stabilizers. Examples of film-forming agents known in the art are cellulose derivatives, polyacrylates, polymethacrylates, or copolymers of acrylates, methacrylates, and polyvinyl alcohol (PVA). The barrier coating may help reduce the expansion of the pellets.

[0036] In one embodiment, the film-forming agent is HPMC. In one embodiment, HPMC is as described herein.

[0037] 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 pellets. In one embodiment, the barrier coating contains an amount of film-forming agent of 0.5% to 5% by weight of the pellets.

[0038] Therefore, in one embodiment, the barrier coating contains 0.5% to about 5% HPMC by weight of the composition or by weight of the pellets. The amount of HPMC in the barrier coating may be, for example, 1% to 4%, for example 1% to 2%, for example 2% to 3%, for example 3% to 4%, by weight of the composition or by weight of the pellets. In one embodiment, the barrier coating contains about 1% to 4% HPMC by weight of the composition or by weight of the pellets. In particular, in one embodiment, the barrier coating contains 0.5% to 5% by weight of the pellets, for example 0.5% to 5%, for example 2%, 3%, 4%, or 5% of the HPMC described herein.

[0039] The sustained-release layer contains at least one sustained-release polymer. The sustained-release polymer may be, for example, a hydrophobic polymer that is permeable when in contact with water. Examples of sustained-release polymers may be other hydrophobic polymers such as cellulose derivatives modified with hydrophobic groups such as short alkyl groups, or synthetic polyacrylate derivatives having hydrophobic groups such as short alkyl groups.

[0040] In one embodiment, at least one sustained-release polymer is ethylcellulose. Ethylcellulose (EC, CAS number 9004-57-3) is a cellulose derivative in which several free hydroxyl groups in cellulose are substituted with ethyl groups. Different grades of EC with different molecular weights, degrees of ethyl substitution, and viscosities are commercially available and suitable for use in formulation development. EC is a hydrophobic polymer that is insoluble in aqueous media but permeable, contributing to pH-independent drug release.

[0041] In one embodiment, at least one sustained-release polymer is present in an amount of 0.5% to about 10% by weight of the composition or pellet. In particular, in one embodiment, the sustained-release layer contains an amount of sustained-release polymer of 0.5% to about 10% by weight of the pellet.

[0042] Therefore, in one embodiment, the sustained-release layer contains about 0.5% to about 10% by weight of the composition or by weight of the pellets, for example, about 1% to about 10% by weight of the composition or by weight of the pellets, for example, about 2% to about 10%, for example, 3% to about 10%, for example, about 3% to about 4%, for example, about 4% to about 5%, for example, about 5% to about 6%, for example, about 6% to about 7%, for example, about 7% to about 8%, for example, about 8% to about 9%, for example, about 9% to about 10% of ethylcellulose. For example, the sustained-release layer may contain about 1% to about 5% by weight of the composition or by weight of the pellets, for example, about 2% to about 5% of ethylcellulose. In one embodiment, the sustained-release layer contains about 1% to about 10% by weight of the pellets, for example, about 2% to about 5% of the ethylcellulose described herein.

[0043] In one embodiment, the sustained-release layer includes an additional film-forming agent, such as a film-forming agent as described herein for a barrier coating layer. The presence of the film-forming agent may assist in the formation of the sustained-release layer and further contribute to the sustained-release properties of the formulation. In one embodiment, the sustained-release layer further includes HPMC.

[0044] The film-forming agent may be present in the sustained-release layer in an amount of 0.5% to about 5% by weight of the composition or by weight of the pellets. In particular, in one embodiment, the sustained-release layer contains an amount of film-forming agent of 0.5% to about 5% by weight of the pellets.

[0045] Therefore, in one embodiment, the sustained-release layer contains 0.5% to about 5% HPMC by weight of the composition or by weight of the pellets. The amount of HPMC in the sustained-release layer may be, for example, 1% to 4%, for example 1% to 2%, for example 2% to 3%, for example 3% to 4%, by weight of the composition or by weight of the pellets. In one embodiment, the sustained-release layer contains about 1% to 4% HPMC by weight of the composition or by weight of the pellets. In one embodiment, the sustained-release layer contains 0.5% to about 5% HPMC by weight of the pellets as described herein.

[0046] In one embodiment, the sustained-release layer comprises 0.5 to 10% of a sustained-release polymer as specified herein, such as ethylcellulose, and 0.5 to 5% of a film-forming agent as specified herein, such as HPMC.

[0047] In one embodiment, the sustained-release layer further comprises a plasticizer. The plasticizer may help to improve the flexibility and plasticity of the film or layer. This may be done by making the polymer more flexible and pliable. Suitable plasticizers are known to those skilled in the art. For example, in one embodiment, the plasticizer is selected from esters derived from citrate such as triethyl citrate or tributyl citrate, acetylated monoglycerides, esters of phthalates, polyethylene glycol or its derivatives, and sorbitol, or mixtures thereof.

[0048] In one embodiment, the sustained-release layer further comprises triethyl citrate. In one embodiment, the triethyl citrate acts as a plasticizer.

[0049] In one embodiment, the sustained-release layer contains a plasticizer in an amount of about 0.05% to about 5%, for example, 0.1% to about 3%, by the weight of the composition or by the weight of the pellets.

[0050] In one embodiment, the sustained-release layer further comprises an anti-tack agent. The anti-tack agent is added to prevent the formation of lumps in solid form and to mitigate packaging, transport, and / or flowability. Suitable anti-tack agents are known to those skilled in the art. For example, in one embodiment, the anti-tack agent may be selected from calcium or magnesium stearate or fatty acid salts, talc, silica, silicates, or combinations thereof.

[0051] In one embodiment, the sustained-release layer further comprises magnesium stearate.

[0052] In one embodiment, the sustained-release layer contains an anti-tack agent, such as magnesium stearate, in an amount of about 0.05% to about 5%, for example, 0.1% to about 3%, by the weight of the composition or by the weight of the pellets.

[0053] In one embodiment, the sustained release layer is i. Film-forming agents as described herein, ii. Plasticizers as described above in this specification, and iii. Further comprising one or more additional excipients selected from the anti-tack agents described herein.

[0054] In one embodiment, the compound of formula I is the same as that of formula Ia. [ka] or a pharmaceutically acceptable salt thereof.

[0055] In one embodiment, the compound is exo-7-[(-8-azabicyclo[3.2.1]octan-3-yl)oxy]-3-methoxychromen-2-one or a pharmaceutically acceptable salt thereof.

[0056] In one embodiment, a pharmaceutically acceptable salt of the compound of formula (I) or formula (Ia) is a hydrochloride salt.

[0057] In one embodiment, the composition is a sustained-release (ER) composition of the compound of formula I. The sustained-release composition is a t max It provides an increase.

[0058] Therefore, in one embodiment, the present disclosure relates to a compound of formula I, [ka] The present invention provides a composition which is a sustained-release composition of an active ingredient comprising a pharmaceutically acceptable salt thereof, wherein the composition comprises pellets, and the pellets are a) An inert pellet core containing microcrystalline cellulose (MCC), b) A drug layer comprising, by weight of the total composition or by weight of the pellet, an amount of about 0.5% to about 5% of the compound of formula (I) or a pharmaceutically acceptable salt thereof, and by weight of the total composition or by weight of the pellet, an amount of 0.5% to about 5% of HPMC, The drug layer covers the inert core, c) A barrier coating layer comprising approximately 0.5% to approximately 5% HPMC by weight of the total composition or by weight of the pellets, wherein the barrier coating layer covers the drug layer in b), d) A sustained-release layer comprising about 0.5 to 10% by weight of the total composition or by weight of the pellets, wherein the sustained-release layer covers the barrier coating layer in c), and comprises or consists of the above.

[0059] In one embodiment, the present disclosure relates to a compound of formula I, [ka] The present invention provides a composition which is a sustained-release composition of an active ingredient comprising a pharmaceutically acceptable salt thereof, wherein the composition comprises pellets, and the pellets are a) An inert pellet core containing microcrystalline cellulose (MCC), b) A drug layer comprising approximately 0.5% to approximately 5% by weight of the pellet of the compound of formula (I) or a pharmaceutically acceptable salt thereof, and approximately 0.5% to approximately 5% by weight of the pellet of HPMC, The drug layer covers the inert core, c) A barrier coating layer containing approximately 0.5% to 5% HPMC by weight of the pellet, wherein the barrier coating layer covers the drug layer in b), d) A sustained-release layer containing ethylcellulose in an amount of approximately 0.5 to 10% by weight of the pellet, wherein the sustained-release layer covers the barrier coating layer in c), and comprises or consists of the above.

[0060] 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.

[0061] In one embodiment, the sustained release layer is i. A film-forming agent selected from the group consisting of those described herein, ii. Plasticizers selected as described herein, and iii. Further comprising one or more additional excipients selected from the anti-tack agents described herein.

[0062] In one embodiment, the sustained-release layer further comprises the HPMC described herein.

[0063] In one embodiment, the compound of formula I is the same as that of formula Ia. [ka] or a pharmaceutically acceptable salt thereof.

[0064] In one embodiment, the compound is exo7[(8azabicyclo[3.2.1]octan-3-yl)oxy]-3-methoxychromen-2-one or a pharmaceutically acceptable salt thereof.

[0065] In one embodiment, the composition according to the present disclosure contains an amount of the compound of formula I of about 0.5 mg to about 30 mg, for example, 1 mg to about 20 mg, for example, 1 mg to about 16 mg, for example, 1 mg to about 10 mg, for example, 2 mg to about 10 mg, for example, 3 mg to about 10 mg, for example, 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.

[0066] Dosage form This disclosure provides dosage forms, such as pharmaceutical dosage forms, comprising compositions described herein. In one embodiment, the dosage form is a unit dosage form. Methods for producing dosage forms comprising appropriate excipients and materials will be known to those skilled in the art.

[0067] 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.

[0068] The dosage form is designed to facilitate the safe and effective delivery of the active compound to the patient.

[0069] 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.

[0070] In one embodiment, the composition is for oral administration. As demonstrated by the examples, the composition according to the present disclosure provides a sustained release of pudaphensin after oral administration while maintaining the exposure of pudaphensin.

[0071] Sustained release The inventors have surprisingly shown that the composition according to the present disclosure provides a sustained release of pudaphensin in the gastrointestinal tract after oral administration.

[0072] In one embodiment, the composition provides a pharmacokinetic profile having a single mean plasma concentration peak upon oral administration.

[0073] The examples show that the composition according to the present disclosure reduces the C max of the compound of formula I after oral administration as compared to the administration of an aqueous solution of an equal amount of the compound of formula I.

[0074] In one embodiment, the composition reduces the C max of the compound of formula I upon oral administration. In one embodiment, C max is reduced by at least 10%, for example at least 20%, as compared to an aqueous solution of an equal amount of the compound of formula I upon oral administration.

[0075] In one embodiment, the composition has a C of the compound of formula I upon oral administration of 5.0 ng / mL to 12.0 ng / mL, for example 6.0 ng / mL to 10.0 ng / mL, for example 6.0 ng / mL to 8.0 ng / mLmax The present invention provides the average C15 of the compound of formula I when orally administered at concentrations of 6.0 ng / mL to 10.0 ng / mL, for example, 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. max To provide.

[0076] The examples also show that the composition according to this disclosure, compared to the administration of an equivalent volume of aqueous solution of the compound of formula I, results in a t of the compound of formula I after oral administration. max This demonstrates that it is possible to increase it.

[0077] In one embodiment, the composition, compared to an equivalent volume of aqueous solution of the compound of formula I after oral administration, has a t max Increase. In one embodiment, t max It increases by at least 60 minutes, for example, 90 minutes, for example, 120 minutes, for example, 180 minutes, for example, 210 minutes.

[0078] In one embodiment, the composition according to this disclosure contains compounds of formula I for about 4 to 12 hours after oral administration, for example, 5.5 to 8.5 hours. max Provides, for example, a compound of formula I with 5.5, 6.0, 6.5, 7.0, 7.5, 8.0 or 8.5 hours of time. max To provide.

[0079] One unexpected effect of the compositions described herein is that they reduce drug exposure in humans and mammals without reducing t max This refers to the ability to provide sustained release by increasing the amount of the drug. Drug exposure reflects the total amount of the drug that reaches the systemic circulation and remains available for action. Therefore, appropriate exposure to a drug is important to achieve the desired pharmacological effect.

[0080] By extending the release time and thus the duration that pudafensin remains in the gastrointestinal tract, exposure to the compound is expected to decrease due to phenomena that hinder absorption, such as reduced excretion, decomposition, or absorption in the lower gastrointestinal tract. In contrast, exposure to pudafensin after oral administration of the sustained-release composition according to this disclosure has been found to be comparable to the exposure provided by an equivalent amount of the compound in solution.

[0081] 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 known as the "area under the curve" of the "AUC".

[0082] The amount of drug in the bloodstream can be detected at different points in time by methods well known in the art, such as HPLC, LC / MS, ELISA, or other suitable analytical methods. Methods for calculating the integral of the plot are also well known to those skilled in the art. The integral of the plot, or area under the curve, can be calculated within a specific time interval, such as within the first 24, 48, or 72 hours. Generally, this is referred to as "AUC". 0-t The term "AUC" refers to the area under the curve at the first "t" time, for example, "AUC" 0-24 In the case of "AUC," it refers to the area under the curve within the first 24 hours. 0-inf " or "AUC inf The term "area under a curve" refers to the area under a curve where the last point of the integral is extrapolated to infinity.

[0083] Therefore, in one embodiment, the composition according to the present disclosure is the AUC of an equivalent volume of aqueous solution of the compound of formula I when administered orally. 0-72 At least 85%, for example, at least 90%, of the AUC of the compound of formula I after oral administration. 0-72 To provide.

[0084] In one embodiment, the composition according to the present disclosure is the AUC of an equivalent volume of aqueous solution of the compound of formula I when administered orally. 0-inf At least 85%, for example, at least 90%, of the AUC of the compound of formula I after oral administration.0-inf To provide.

[0085] In one embodiment, the composition, when administered orally, has an AUC of 100-500 h·ng / mL of the compound of formula I. 0-inf For example, an AUC of 160-460 h·ng / mL 0-inf , or AUC of 250-350 h·ng / mL 0-inf For example, an AUC of approximately 300 h·ng / mL 0-inf To provide.

[0086] In one embodiment, the composition, when administered orally, has an average AUC of the compound of formula I of 200 h·ng / mL to 400 h·ng / mL. 0-inf For example, the average AUC of 250 h·ng / mL to 350 h·ng / mL 0-inf To provide.

[0087] In one embodiment, the composition according to the present disclosure is a) AUC of an equivalent volume of aqueous solution of the compound of formula I after oral administration 0-72 or AUC 0-inf At least 85%, for example, at least 90%, of the AUC of the compound of formula I after oral administration. 0-72 or AUC 0-inf , and b) The t of the compound of formula I for approximately 4 to 12 hours after oral administration, for example, approximately 5.5 to approximately 8.5 hours. max To provide.

[0088] The compositions according to this disclosure provide sustained release of the compound of formula I. Sustained release can be characterized by the dissolution rate of the active ingredient from the composition. Those skilled in the art know how to determine the dissolution rate of a solid dosage form using a suitable detection method for the active ingredient, such as HPLC, LC / MS, or ELISA, and, for example, according to the United States Pharmacopeia, using, for example, a USP-I or USP-II instrument.

[0089] In one embodiment, when the composition is measured in a USP-I or USP-II instrument at pH 6.8 and 37°C, it releases the compound of formula I at a rate of 35-70% within the first two hours, 60-95% after four hours, and complete release after eight hours.

[0090] In one embodiment, the composition is measured using a USP-I or USP-II instrument at pH 6.8 and 37°C, i. 35-70% of the compound is released within the first two hours, for example, 40-65% is released within the first two hours. ii. 60-95% released after 4 hours, for example, 75-85% released after 4 hours, 5 hours, or 6 hours, and iii. Complete release after 8 hours. It is released at that speed.

[0091] In one embodiment, the composition is measured using a USP-I or USP-II instrument at pH 6.8 and 37°C, i. 35-70% of the compound is released within the first two hours, for example, 40-65% is released within the first two hours. ii. 60-95% released after 4 hours, for example, 75-85% released after 4 hours, and iii. Complete release after 8 hours. It is released at that speed.

[0092] Therefore, in one embodiment, the present disclosure provides an immediate-release composition of a compound of formula (I), the composition being, • C of compound I when orally administered at concentrations of 5.0 ng / mL to 12.0 ng / mL, for example, 6.0 ng / mL to 10.0 ng / mL, for example, 6.0 ng / mL to 7.0 ng / mL. max and, • Approximately 4 to 12 hours after oral administration, for example, 5.5 to 8.5 hours, the t of the compound of formula I. max and, • When administered orally, the AUC of the compound of formula I at 160-450 h·ng / mL 0-inf For example, an AUC of 250-350 h·ng / mL0-inf For example, an AUC of approximately 300 h·ng / mL 0-inf The present invention provides a pharmacokinetic profile at administration characterized by having one or more of the following characteristics.

[0093] In one embodiment, the immediate-release composition comprises a compound of formula (I) as described herein in the section "Compositions", a pellet core, a binder, a pH adjuster, or a stabilizer.

[0094] In one embodiment, the present disclosure provides a method for obtaining a compound of formula (I) at a therapeutically effective plasma concentration in a subject. [ka] Compound t of formula I max The duration is 4 to 12 hours, for example, 5.5 to about 8.5 hours, and the above method includes oral administration of the composition or unit dose described herein.

[0095] In one embodiment, this method provides the AUC of an equivalent volume of aqueous solution of the compound of formula I when administered orally. 0-72 or AUC 0-inf At least 85%, for example, at least 90%, of the AUC of the compound of formula I after oral administration. 0-72 or AUC 0-inf To provide.

[0096] In one embodiment, the subject is a human being.

[0097] Preparation method In one aspect, the present disclosure provides a method for preparing a composition comprising pellets, the method being described as follows: a) To provide a pellet core, b) Compound of formula (I), [ka] To provide a drug layer solution containing a pharmaceutically acceptable salt thereof, c) Forming a drug layer by coating the pellet core with a drug layer solution, d) To provide a barrier coating solution containing a film-forming agent, e) Coating the barrier coating solution onto the drug layer in c) to obtain a barrier coating layer, f) To provide a sustained-release solution containing one or more sustained-release polymers, g) coating a sustained-release solution onto the barrier coating layer in e) to obtain a sustained-release layer, which is a combination of g) and e).

[0098] In one embodiment of this method, the pellet core, drug layer, barrier coating, or sustained-release layer is as described herein in the section "Composition".

[0099] In one embodiment of this method, the drug layer solution comprises a film-forming agent or stabilizer as described herein in the section "Compositions".

[0100] In one embodiment of this method, the drug layer solution comprises a solvent or dispersant, and the solvent or dispersant comprises or consists of an aqueous solution.

[0101] In one embodiment of this method, the barrier coating solution comprises a solvent or dispersant, and the solvent or dispersant comprises or consists of an aqueous solution.

[0102] In one embodiment of this method, the sustained-release layer solution further comprises a film-forming agent, plasticizer, and / or anti-tack agent as described herein in the section "Compositions".

[0103] In one embodiment of this method, the sustained-release layer solution comprises a solvent or dispersant, and the solvent or dispersant comprises or consists of an aqueous solution containing an organic solvent such as isopropanol.

[0104] In one embodiment of this method, the composition is as defined herein in the section "Composition".

[0105] In one embodiment, the present disclosure provides compositions obtained by the methods described herein.

[0106] item Item 1 A composition comprising pellets, wherein the pellets are a) Pellet core and b) A drug layer covering the core, wherein the drug layer is a compound of formula (I), [ka] The drug layer comprising a pharmaceutically acceptable salt thereof, c) A barrier coating layer comprising a film-forming agent, wherein the layer covers the drug layer in b), d) A composition comprising, or consisting of, a sustained-release layer containing one or more sustained-release polymers, wherein the sustained-release layer covers the barrier coating in c).

[0107] Item 2 The composition according to item 1, wherein the drug layer further comprises a cellulose derivative such as hydroxypropyl methylcellulose (HPMC), a polyalkylene glycol such as polyethylene glycol (PEO), and a binder selected from the group consisting of polyvinylpyrrolidone (PVP), hydroxypropylcellulose, and gelatin.

[0108] Item 3 The composition according to any one of the preceding items, wherein the binder is HPMC.

[0109] Item 4 The film-forming agent is selected from the group consisting of hydroxypropyl methylcellulose (HPMC), cellulose derivatives, polyacrylate, polymethacrylate, and copolymers of acrylate, methacrylate, and polyvinyl alcohol (PVA), as described in any one of the preceding items.

[0110] Item 5 The barrier coating layer comprises the composition according to any one of the preceding items, wherein the barrier coating layer contains HPMC in an amount of about 0.5% to about 5% by weight of the composition or by weight of the pellets.

[0111] Item 6 The composition according to any one of the preceding items, wherein the one or more sustained-release polymers are present in an amount of about 0.5% to about 10% by weight of the composition or by weight of the pellets.

[0112] Item 7 The composition according to any one of the preceding items, wherein the sustained-release polymer is ethyl cellulose.

[0113] Item 8 The sustained-release layer further comprises a film-forming agent, as described in any one of the preceding items.

[0114] Item 9 The sustained-release layer further comprises HPMC, the composition according to any one of the preceding items.

[0115] Item 10 The composition according to any one of the preceding items, wherein the sustained-release layer further comprises 0.5% to about 5% of HPMC by weight of the composition or by weight of the pellets.

[0116] Item 11 The composition according to any one of the preceding items, wherein the pellet core consists of or includes spheres made from a material selected from the group consisting of microcrystalline cellulose (MCC), sugars such as sucrose, xylitol, mannitol, and lactose, and starch, silica, tartaric acid, and calcium carbonate.

[0117] Item 12 The composition is a compound of formula I, [ka] A sustained-release composition of an active ingredient comprising a pharmaceutically acceptable salt thereof, wherein the composition comprises pellets, the pellets are a) An inert pellet core containing microcrystalline cellulose (MCC), b) A drug layer comprising, by weight of the total composition or by weight of the pellet, an amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof, and by weight of the total composition or by weight of the pellet, an amount of HPMC of, The drug layer covers the inert core, c) A barrier layer comprising an amount of HPMC 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 in b), d) A composition according to any one of the preceding items, comprising or consisting of a sustained-release layer comprising about 0.5 to 10% by weight of the total composition or by weight of the pellets, wherein the sustained-release layer covers the barrier coating layer in c).

[0118] Item 13 Compound t of formula I max The composition described in any one of the preceding items, wherein the time after oral administration is approximately 4 to 12 hours, for example, 5.5 to 8.5 hours.

[0119] Item 14 After oral administration, the composition, a) AUC of an equal volume of aqueous solution of the compound of formula I after oral administration 0-72 or AUC 0-inf AUC of at least 85% 0-72 or AUC 0-inf , and b) The t of the compound of formula I for approximately 5.5 to 8.5 hours max A composition according to any one of the preceding items, which provides the following:

[0120] Item 15 A unit dosage form comprising the composition described in any one of the preceding items. [Examples]

[0121] Example 1: Preparation of the formulation the purpose The preparation of the composition according to this disclosure will be described.

[0122] Materials and methods Materials: Microcrystalline cellulose spheres (Celphere CP-507, particle size range 500-710 μm), anhydrous sodium sulfite, hydroxypropyl methylcellulose (HPMC, Methocel E5 Premium LV), ethylcellulose (Ethocel STd.7 Premium), triethyl citrate dihydrate (Ph.Eur), magnesium stearate (Ligamed 2V) NF, and pudafensin monohydrate monohydrochloride.

[0123] Drug-based layered pellets. Sodium sulfite, HPMC 5cps, and pudafensin (pre-sieved with a mesh size of #60) are mixed in purified water and then stirred to obtain a homogeneous dispersion. Next, the solution is coated onto an inert pellet core (Celphere CP-507) in a fluidized bed (GPCG 1.1 bowl, gun nozzle size: 1.2 mm, ADP size: Type B).

[0124] Barrier-coated pellets. HPMC is mixed in purified water and stirred to obtain a homogeneous dispersion. The solution is coated onto the drug-layered pellets (GPCG 1.1 bowl, gun nozzle size: 1.2 mm, ADP size: Type B).

[0125] Sustained-release pellets. HPMC, ethylcellulose, triethyl citrate, and magnesium stearate (sieved through a #60 mesh) are mixed in purified water and stirred to obtain a homogeneous dispersion. This solution is then coated onto barrier-coated pellets in a fluidized bed (GPCG 1.1 bowl, Gun nozzle size: 1.2 mm, ADP size: Type B).

[0126] Encapsulation. The composition was encapsulated by filling size 0 Swedish orange capsules with the required amount of pellets to obtain the desired dose. For example, capsules were loaded with pellets equivalent to 5 mg or 10 mg of pudafensin free base.

[0127] The drug substance pudafensin was used as monohydrate and monohydrochloride. Therefore, the amount per bottle, capsule, or dose is calculated based on the amount of free base.

[0128] Samples were prepared: • Immediate-release (IR) compositions corresponding to drug layer pellets, whether or not they are encapsulated, as shown in Table 1. • Sustained-release compositions (ER) corresponding to sustained-release pellets, regardless of whether they are encapsulated or not, as shown in Table 2. A dry guinea bottle (DiB) solution containing IP2015 dissolved in water for injection, with 50 mg / mL of hydroxypropyl 2-beta cyclodextrin (HPβCD) as a dissolution accelerator.

[0129] [Table 1]

[0130] [Table 2] TIFF2026522068000016.tif30159

[0131] Furthermore, two similar ER compositions (ER1 and ER2) were used in the sustained-release layer. ER1: 5% HPMC, 5% ethylcellulose ER2: 5% HPMC, 7.5% ethylcellulose It was prepared using a similar method with the following parameters.

[0132] Solubility test The solubility of IP2015 was measured in both aqueous and non-aqueous vehicles.

[0133] In non-aqueous liquids, solubility was visually confirmed by progressive dilution. The solubility of IP2015 in pH-specific aqueous solutions was evaluated, visually confirmed, and the content was determined by HPLC.

[0134] [Table 3]

[0135] result As can be seen from Table 3, IP2015 has a solubility of less than 1 mg / mL in aqueous solutions across physiological pH ranges. Unexpectedly, the presence of a binder in the solution was found to enable a uniform and consistent distribution of IP2015 in the drug layer. In contrast, when the solubility of IP2015 was improved using a solubilizer such as hydroxypropyl 2-beta-cyclodextrin (HPβCD), the concentration of the compound was not sufficient to form a good drug layer.

[0136] Example 2: Release of IP2015 in solution the purpose The release of IP2015 for the compositions according to this disclosure will be tested.

[0137] Materials and methods The dissolution profiles of IP2015 IR pellets (component-completed IMPs) and IP2015 IR capsules are measured using 0.1N HCl buffer.

[0138] [Table 4]

[0139] [Table 5]

[0140] The dissolved sample was analyzed by gradient reversed-phase HPLC, with the mobile phase being buffer (0.1% orthophosphate and water):acetonitrile (85:15). Detection was performed by DAD.

[0141] To test the effect of sodium sulfite, two different pellet samples were prepared according to Example 1, with and without sodium sulfite. The dissolution rate of the sample corresponding to 5 mg of IP2015 from the unencapsulated pellets was tested.

[0142] To test the effectiveness of encapsulation, the dissolution rates of IP2015 from both encapsulated and unencapsulated pellets were evaluated using samples corresponding to 5 mg of IP2015 prepared according to Example 1. For comparison, the dissolution of an unencapsulated sample corresponding to 10 mg of IP2015 was also evaluated.

[0143] result Table 4 shows the dissolution profiles of samples with and without sodium sulfite.

[0144] [Table 6]

[0145] The effect of sodium sulfite on the dissolution profile was observed. The dissolution profile of scale-up batches containing sodium sulfite in the drug layer coating showed a faster dissolution profile compared to scale-up batches without sodium sulfite in the drug layer coating.

[0146] Figure 1 shows the release profiles of IP2015 IR pellets and capsules. The dissolution profiles are as expected. IP2015 IR capsules release 80% after 10 minutes and over 90% after 20 minutes, meeting the requirements for an immediate-release oral dosage form.

[0147] Figure 2 shows the release profiles of IP2015 ER pellets and capsules. The dissolution profiles are as expected. IP2015 ER capsules meet the sustained-release requirement, releasing 35-70% within 2 hours, 70-90% after 4 hours, and completely after 8 hours. For comparison, pellets containing 10 mg of API were also tested.

[0148] Table 5 shows the release from the ER1 and ER2 pellet formulations described in Example 1.

[0149] [Table 7]

[0150] conclusion The compositions disclosed herein provide suitable sustained release. Surprisingly, the presence of sodium sulfite has been shown to promote release from the drug layer.

[0151] Example 3: In vivo pharmacokinetics of pudafensin IR composition the purpose The pharmacokinetic parameters of the compositions disclosed herein will be tested.

[0152] Materials and methods The pharmacokinetic profiles of different formulations—two sustained-release formulations (ER1 and ER2), one IR formulation (IR), and one dry guinea bottle (DiB) formulation of pudafensin as a reference—were investigated in Gottingen miniature pigs after a single oral administration.

[0153] The animals were fasted before administration. Each formulation was administered to the animals as a single dose, with a 7-day drug-free period permitted after each administration. A single dose of 0.5 mg / kg was administered orally in capsule form with a 7-day drug-free period after each administration. A single dose (0.25 mL / kg) of the reference solution was administered orally by force-feeding.

[0154] Mortality was assessed twice daily. All clinical signs were recorded at baseline and simultaneously each day during the study (approximately 1–1.5, 2–2.5, and 3–3.5 hours after administration). Fasting body weight was recorded on the day of administration and the day before administration.

[0155] On each day of medication administration, blood samples were collected from the jugular vein (other veins were used if necessary) at approximately the time before administration and 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 24, 36, and 48 hours after the first dose.

[0156] At each sampling point, at least 1.0 mL of blood was collected, transferred to a tube containing K2EDTA anticoagulant, centrifuged at room temperature, and divided into two aliquots (approximately 250 μL [Aliquot A] and a second [Aliquot B] containing remaining plasma), and frozen at -70 ± 10°C.

[0157] The concentration of pudafensin in miniature pig plasma was measured by LC-MS / MS by The Bioanalytical Department, Syngene International Ltd. During the analysis, standard and quality control samples were distributed across each batch of test samples analyzed. Plasma concentration data were used for toxicological assessment.

[0158] PK parameters were determined from individual miniature pig plasma concentration-time data by non-compartmental analysis with uniform weighting using Phoenix® WinNonlin® validation version 8.2. The calculated PK parameters were the area under the plasma concentration-time curve (AUClast), AUCall, peak plasma concentration (Cmax), and time to reach peak plasma concentration (t). max This includes Clast, Tlast, AUCinf, and terminal elimination half-life (t1 / 2). Plasma concentrations and TK parameters are shown in ng units.

[0159] result The pharmacokinetic parameters are shown in Tables 6 and 7.

[0160] [Table 8]

[0161] [Table 9]

[0162] conclusion Surprisingly, t max Even during the extended exposure period, the sustained-release formulation was observed to provide exposure equivalent to or greater than that of the IR formulation compared to oral administration of the DiB formulation. It was unexpected that the absorbance did not decrease and exposure was maintained even when pudafensin was exposed for longer periods in the GI tube.

[0163] Example 4. A clinical trial to test the pharmacokinetics of pudafensin preparations in humans. the purpose The pharmacokinetics of the immediate-release (IR) composition of pudafensin according to this disclosure will be investigated in humans.

[0164] Materials and methods This study is a three-way crossover study that examined the pharmacokinetic parameters of the pudafensin compositions disclosed herein after oral administration. One immediate-release capsule composition (IR) disclosed in Table 1 and one sustained-release capsule composition (ER) disclosed in Table 2 were used. For comparison, the results were compared with a solution of pudafensin (DiB). The compositions were prepared as described in Example 1.

[0165] This study was a crossover trial conducted in 12 healthy subjects who received a single dose of 5 mg pudafensin in different formulations with sufficient rinse between them. Plasma levels of pudafensin were monitored at different time points after administration of the formulations.

[0166] result The results are shown in Tables 8 and 9.

[0167] [Table 10]

[0168] [Table 11]

[0169] conclusion Surprisingly, the sustained-release pudafensin composition showed a decrease in Cmax in the sustained-release formulation in humans, t max It has been shown that an increase in the concentration provides equivalent exposure to an equivalent amount formulated as an aqueous solution. This is highly unexpected and advantageous as it allows for safer administration of pudafensin while achieving equivalent systemic exposure to the dry guin bottle formulation.

[0170] Example 5. Clinical trial to test the adverse events and efficacy of IP2015 for the treatment of erectile dysfunction in humans. This study investigated the effects of single-dose, repeated oral administration of IP2015 on the ability of men with erectile dysfunction (ED) to form and maintain erections, as well as the safety and tolerability of single-dose oral administration of IP2015, its effects on penile rigidity and swelling during visual stimulation, its effects on semen count and motility, and any possible relationships between plasma levels of IP2015 and its efficacy and safety.

[0171] Materials and methods Test design The 130 participants were divided into three groups, and the trials were conducted in parallel based on these groups. Each participant received four doses of either 5 mg of IP2015, 10 mg of IP2015, or the corresponding placebo. Within each group, participants were equally randomized to receive one of the three study treatments and received the same treatment at each visit.

[0172] The exam lasted approximately 8 weeks and consisted of the following: • Visit for screening (up to 21 days prior to the baseline visit) • Baseline visit (-7 days) Outpatient visits during the first week (day 1), second week, third week, and fourth week. • Follow-up visits are scheduled at least 7-10 days after the final dose.

[0173] All groups were asked to complete the IIEF-15 questionnaire on day -7, and at weeks 1 (day 1), 2, 3, and 4, as well as at follow-up visits. Group 2 was asked to complete visual stimulus assessments using a RigiScan Plus monitor on day -7, week 1 (day 1), and week 4. Group 2 was also required to provide blood samples for pharmacokinetic assessments at week 1 (day 1) and week 4. Group 3 was required to provide semen samples on day -7 and week 4.

[0174] participants The patient had an IIEF-5 score of ≤16 and a body mass index of 18-35 kg / m². 2 The study included healthy men with erectile dysfunction (ED) as defined by the two extremes (including the end of the range), and ethnicity was not a factor. The subjects were between 18 and 59 years old (including the end of the range).

[0175] Dosage and administration method There were three possible treatment options: 5 mg IP2015, 10 mg IP2015, or the corresponding placebo. In each group, subjects were equally randomized to receive one of the three treatments and the same treatment at each visit. IP2015 or the corresponding placebo was administered orally once in the morning on week 1 (day 1), week 2, week 3, and week 4, under fasting conditions. The dose was taken with 240 mL of water at room temperature. Subjects fasted from 2 hours before administration until 4 hours after administration. Except for 1 hour before and 1 hour after administration, water was freely available.

[0176] evaluation Efficacy was assessed using the International Index of Erectile Function (IIEF)-15 questionnaire. Changes from baseline in responses to IIEF-15 questionnaire questions, including questions on erectile function, orgasmic function, sexual desire, sexual satisfaction, and overall satisfaction domains, were measured at various time points during the study. RigiScan assessments during stimulation evaluation, as well as semen count and motility obtained from semen sampling, were used to assess efficacy. Safety was assessed through AE reporting, 12-lead ECG, vital signs, physical examination, and laboratory assessments. Pharmacokinetics were assessed by blood sampling.

[0177] result Effectiveness of IP2015 Figure 4 shows the results for Q3 (How often were you able to insert your penis into your partner last week when you attempted sexual intercourse?) in the IIEF-15. The results for Q3 were significantly better with treatment with 5 mg of IP2015 at week 3 compared to placebo (p=0.034) and to baseline (p=0.046). There was also a tendency for differences in the overall Q3 score compared to placebo (p=0.07) and to baseline (p=0.07).

[0178] Figure 5 shows the results for Q4 (How often were you able to maintain an erection after insertion into your partner during sexual intercourse?) in the IIEF-15. The results for Q4 were not different from placebo (p=0.44), but there was a tendency for the overall score to be different for 5 mg compared to baseline (p=0.056).

[0179] The overall responses to the IIEF-15 questions are shown in Figure 6. The results were significant compared to baseline at follow-up with treatment with 5 mg of IP2015 (p=0.0046) and a trend compared to placebo (p=0.07), as were the overall scores for 5 mg compared to baseline (p=0.0032) and a trend compared to placebo (p=0.10).

[0180] Figures 4, 5, and 6 show the changes from baseline in patients treated with IP2015 administered in four placebo doses (n=45), 5 mg (n=42), and 10 mg (n=43) concurrently on days 1, 8, 15, and 22. Results are mean ± SE. Statistical differences were calculated using mixed-model repeated measures (MMRM).

[0181] Adverse events Adverse events associated with low-dose (5 mg) IP2015 treatment were comparable to those in the placebo group. TEAEs were dose-dependent, mild to moderate, and slightly increased with higher doses compared to lower doses of IP2015. No serious adverse events were observed at any dose of IP2015 (Table 10).

[0182] The semen analysis results were complete, and the treatment did not adversely affect sperm count, motility, or morphology.

[0183] [Table 12]

[0184] conclusion Overall, these results indicate that a 5 mg dose of IP2015 is effective and safely tolerable in the treatment of erectile dysfunction. Compared to baseline and placebo, a significant effect of 5 mg of IP2015 (pudafensin) was observed on the IIEF-15 score Q3. For the overall IIEF-15 score, there was a trend towards a clinically significant score change of 2, which was significant with the lower dose of IP2015 compared to baseline, with p=0.10 compared to placebo.

[0185] Adverse events associated with treatment with 5 mg of IP2015 were nearly equivalent to those in the placebo group. TEAEs were dose-dependent, and only mild to moderate effects were observed. No serious TEAEs were reported.

[0186] The fact that lower doses yield higher efficacy and a lower incidence of TEAEs compared to higher doses highlights the need for a solid-state formulation of IP2015 that can provide a sustained-release, and therefore more attractive pharmacokinetic profile than high-dose IP2015, without compromising exposure. The compositions of this disclosure provide C without reducing systemic exposure. max Reduces and meets the IP2015 standards. max This effect is achieved by increasing [something].

Claims

1. A composition comprising pellets, wherein the pellets are a) Pellet core and b) A drug layer covering the core, wherein the drug layer comprises a compound of formula (I), 【Chemistry 1】 The drug layer comprising a pharmaceutically acceptable salt thereof, c) A barrier coating layer comprising a film-forming agent, wherein the layer covers the drug layer in b), d) A composition comprising, or consisting of, a sustained-release layer containing one or more sustained-release polymers, wherein the sustained-release layer covers the barrier coating in c).

2. The composition according to claim 1, wherein the drug layer further comprises a cellulose derivative such as hydroxypropyl methylcellulose (HPMC), a polyalkylene glycol such as PEO, and a binder selected from polyvinylpyrrolidone (PVP), hydroxypropylcellulose, and gelatin.

3. The composition according to claim 2, wherein the drug layer contains the binder in an amount of 0.5 to 10% by weight of the pellet.

4. The composition according to any one of claims 2 to 3, wherein the binder is HPMC.

5. The composition according to claim 4, wherein the drug layer contains HPMC in an amount of about 1% to 5% by weight of the pellet.

6. The composition according to any one of the prior claims, wherein the drug layer further comprises an additional excipient selected from pH adjusters and / or stabilizers.

7. The composition according to claim 6, wherein the stabilizer is sodium sulfite.

8. The composition according to any one of claims 6 to 7, wherein the pH adjuster and / or the stabilizer is present in an amount of 0.05% to 1% by weight of the pellets.

9. The composition according to any one of the prior claims, wherein the drug layer further comprises sodium sulfite present in an amount of 0.05% to 1% by weight of the pellet.

10. The composition according to any one of the prior claims, wherein the pellet core comprises or includes spheres made from materials selected from microcrystalline cellulose (MCC), sugars such as sucrose, xylitol, mannitol, and lactose, and starch, silica, tartaric acid, and calcium carbonate.

11. The composition according to any one of the prior claims, wherein the pellet core contains or consists of microcrystalline cellulose (MCC).

12. The composition according to any one of the prior claims, wherein the drug layer contains the compound of formula I in an amount of about 0.5% to about 5% by weight of the pellet.

13. The composition according to any one of the prior claims, wherein the drug layer contains the compound of formula I in an amount of about 2.5% to 3.5% by weight of the pellet.

14. The barrier coating layer comprises the film-forming agent in an amount of 0.5% to 5% by weight of the pellets, according to the composition of any one of the preceding claims.

15. The composition according to any one of the prior claims, wherein the film-forming agent is selected from hydroxypropyl methylcellulose (HPMC), cellulose derivatives, polyacrylate, polymethacrylate, and copolymers of acrylate, methacrylate, and polyvinyl alcohol (PVA).

16. The composition according to any one of the prior claims, wherein the film-forming agent is HPMC.

17. The barrier coating layer comprises HPMC in an amount of about 0.5% to about 5% by weight of the pellets, according to the composition of any one of the prior claims.

18. The barrier coating layer comprises HPMC in an amount of about 1% to 4% by weight of the pellets, according to the composition of any one of the prior claims.

19. The composition according to any one of the prior claims, wherein the one or more sustained-release polymers are present in an amount of about 0.5% to about 10% of the weight of the pellets.

20. The composition according to any one of the prior claims, wherein the one or more sustained-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.

21. The composition according to any one of the prior claims, wherein the sustained-release polymer is ethyl cellulose.

22. The composition according to any one of the prior claims, wherein the sustained-release layer contains ethylcellulose in an amount of about 0.5% to about 10% by weight of the pellets.

23. The composition according to any one of the prior claims, wherein the sustained-release layer contains ethylcellulose in an amount of about 1% to about 5% by weight of the pellets.

24. The composition according to any one of the prior claims, wherein the sustained-release layer further comprises a film-forming agent.

25. The composition according to claim 24, wherein the sustained-release layer contains a film-forming agent in an amount of 0.5% to about 5% by weight of the pellets.

26. The composition according to any one of claims 24 to 25, wherein the film-forming agent is HPMC.

27. The composition according to any one of the prior claims, wherein the sustained-release layer further comprises HPMC.

28. The composition according to any one of the prior claims, wherein the sustained-release layer further comprises HPMC in an amount of 0.5% to about 5% by weight of the pellets.

29. The composition according to any one of the prior claims, wherein the sustained-release layer further comprises HPMC in an amount of 1% to about 4% by weight of the pellets.

30. The composition according to any one of the prior claims, wherein the sustained-release layer further comprises a plasticizer.

31. The composition according to any one of the prior claims, wherein the sustained-release layer further comprises a plasticizer selected from esters derived from citrate such as triethyl citrate or tributyl citrate, acetylated monoglycerides, esters of phthalic acid, polyethylene glycol or its derivatives, and sorbitol, or mixtures thereof.

32. The composition according to any one of claims 30 to 31, wherein the plasticizer is triethyl citrate.

33. The composition according to any one of the prior claims, wherein the sustained-release layer further comprises triethyl citrate.

34. The composition according to any one of the prior claims, wherein the sustained-release layer further comprises an anti-tack agent.

35. The composition according to claim 34, wherein the anti-tack agent is selected from calcium or magnesium stearate or fatty acid salt, talc, silica, and silicate, or a combination thereof.

36. The composition according to claim 35, wherein the anti-tack agent is magnesium stearate.

37. The composition according to any one of the prior claims, wherein the sustained-release layer further comprises magnesium stearate.

38. The aforementioned sustained release layer is i. A film-forming agent according to any one of claims 24 to 26, and / or ii. Plasticizers according to claims 30 to 33, and / or iii. The composition according to any one of the prior claims, further comprising one or more additional excipients selected from the anti-tack agents of claims 34 to 37.

39. The compound of formula I is the one described in formula Ia. 【Chemistry 2】 The composition according to any one of the prior claims, or a pharmaceutically acceptable salt thereof.

40. The composition according to any one of the prior claims, wherein the compound is exo-7-[(8-azabicyclo[3.2.1]octan-3-yl)oxy]-3-methoxychromen-2-one or a pharmaceutically acceptable salt thereof.

41. The composition is a sustained-release (ER) composition of the compound of formula I, as described in any one of the prior claims.

42. The composition is a compound of formula I, 【Transformation 3】 A sustained-release composition of an active ingredient comprising a pharmaceutically acceptable salt thereof, wherein the composition comprises pellets, the pellets are a) An inert pellet core containing microcrystalline cellulose (MCC), b) A drug layer comprising about 0.5% to about 5% by weight of the pellet, the compound of formula (I) or a pharmaceutically acceptable salt thereof, and 0.5% to about 5% by weight of the pellet, HPMC The drug layer covers the inert core, c) A barrier layer containing HPMC in an amount of approximately 0.5% to approximately 5% by weight of the pellet, wherein the barrier coating layer covers the drug layer in b), d) A composition according to any one prior claim, comprising or consisting of a sustained-release layer containing ethylcellulose in an amount of about 0.5 to 10% by weight of the pellets, wherein the sustained-release layer covers the barrier coating layer in c).

43. The composition according to claim 42, wherein the drug layer further comprises sodium sulfite.

44. The aforementioned sustained release layer is i. A film-forming agent according to any one of claims 24 to 26, and / or ii. Plasticizers according to claims 30 to 33, and / or iii. The composition according to any one of claims 42 to 43, further comprising one or more additional excipients selected from the anti-tack agents of claims 34 to 37.

45. The composition according to any one of the prior claims, comprising about 0.5 mg to 30 mg of the compound of formula I.

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

47. The composition described above is in the form of a solid dosage form, as described in any one of the prior claims.

48. The composition according to claim 46, wherein the unit dosage form or the pharmaceutical dosage form is a capsule.

49. The composition described above is for oral administration, as described in any one of the prior claims.

50. The composition is the compound C of formula I. ｍａｘ Reduce the above C ｍａｘ The composition according to any one of the prior claims, wherein the amount is reduced by at least 10%, for example, at least 20%, compared to an equivalent amount of aqueous solution of the compound of formula I after oral administration.

51. The composition contains the compound of formula I when administered orally at a concentration of 5.0 ng / mL to 12.0 ng / mL, for example, 6.0 ng / mL to 10.0 ng / mL, for example, 6.0 ng / mL to 8.0 ng / mL. ｍａｘ A composition according to any one of the prior claims, which provides the following:

52. The composition, compared to an equivalent amount of aqueous solution of the compound of formula I after oral administration, has a t ｍａｘ A composition according to any one of the prior claims, which increases

53. Compound t of formula I ｍａｘ The composition according to any one of the prior claims, wherein the concentration increases by at least 60 minutes, for example 90 minutes, for example 120 minutes, for example 180 minutes, for example 210 minutes, compared to an equivalent amount of aqueous solution of the compound of formula I after oral administration.

54. Compound t of formula I ｍａｘ The composition according to any one of the prior claims, wherein the time after oral administration is approximately 4 to 12 hours, for example, 5.5 to 8.5 hours.

55. The composition is the AUC of an equal volume of aqueous solution of the compound of formula I after oral administration. ０－７２ At least 85% of the compound AUC of formula I when administered orally. ０－７２ A composition according to any one of the prior claims, which provides the following:

56. The composition provides an AUC of an aqueous solution of the compound of formula I after oral administration that is at least 85% of the AUC of the compound of formula I at the time of oral administration. ０－ｉｎｆ ０－ｉｎｆ The composition according to any one of the preceding claims.

57. The above composition, when administered orally, has an AUC of 100 to 500 h·ng / mL of the compound of formula I. ０－ｉｎｆ For example, AUC of 160-460 h·ng / mL ０－ｉｎｆ , or AUC of 250-350 h·ng / mL ０－ｉｎｆ For example, an AUC of approximately 300 h·ng / mL ０－ｉｎｆ A composition according to any one of the prior claims, which provides the following:

58. After oral administration, the composition, a) AUC of an equal volume of aqueous solution of the compound of formula I after oral administration ０－７２ or AUC ０－ｉｎｆ At least 85% of the compound AUC of formula I when administered orally. ０－７２ or AUC ０－ｉｎｆ , and b) The t of the compound of formula I for approximately 5.5 to 8.5 hours ｍａｘ A composition according to any one of the prior claims, which provides the following:

59. When the above composition is measured in a USP-I or USP-II instrument at pH 6.8 and 37°C, the compound of formula I is found to be... i. 35-70% within the first two hours, for example, 40-65% within the first two hours. ii. 60-95% released after 4 hours, for example, 75-85% released after 4 hours, 5 hours, or 6 hours, and iii. Complete release in 8 hours. A composition according to any one of the prior claims, which is released at the speed described above.

60. The composition is the composition according to any one of the prior claims, comprising about 0.5 mg to about 25 mg of the compound of formula (I).

61. The composition according to any one of the prior claims, comprising about 0.5 mg to 25 mg, for example, about 0.5 mg, for example, 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 the compound of formula (I).

62. The composition according to any one of the prior claims, comprising 5 mg or 10 mg of the compound of formula (I).

63. A unit dosage form comprising the composition described in any one of the prior claims.

64. A method for obtaining a compound of formula (I) with a therapeutically effective plasma concentration in a target, 【Chemistry 4】 Compound t of formula I ｍａｘ The duration is 4 to 12 hours, and the method comprises oral administration of the composition according to any one of claims 1 to 62.

65. The method according to claim 64, wherein the subject is a human.

66. The compound AUC of formula I when administered orally. ０－７２ or AUC ０－ｉｎｆ This refers to the AUC of an equivalent volume of aqueous solution of the compound of formula I when administered orally. ０－７２ or AUC ０－ｉｎｆ The method according to claims 64 to 65, wherein the amount is at least 85%, for example, at least 90%.

67. A method for preparing a composition containing pellets, wherein the method is: a) To provide a pellet core, b) Compound of formula (I), 【Transformation 5】 To provide a drug layer solution containing a pharmaceutically acceptable salt thereof, c) Coating the drug layer solution onto the pellet core to form a drug layer, d) To provide a barrier coating solution containing a film-forming agent, e) To obtain a barrier coating layer by coating the drug layer in the barrier coating solution c) with the barrier coating solution, f) To provide a sustained-release solution containing one or more sustained-release polymers, The method comprising g) coating the sustained-release solution onto the barrier coating layer in e) to obtain a sustained-release layer.

68. The method according to 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 barrier coating layer is as described in any one of claims 14 to 18, or the sustained-release layer is as described in any one of claims 19 to 38.

69. The method according to any one of claims 67 to 68, wherein the drug layer solution comprises a binder according to any one of claims 2 to 5, or a pH adjuster and / or stabilizer according to any one of claims 6 to 9.

70. The method according to any one of claims 67 to 69, wherein the drug layer solution comprises a solvent or a dispersant, and the solvent or dispersant comprises or consists of an aqueous solution.

71. The method according to any one of claims 67 to 70, wherein the barrier coating solution comprises a solvent or a dispersant, and the solvent or dispersant comprises or consists of an aqueous solution.

72. The method according to any one of claims 67 to 71, wherein the sustained-release layer solution comprises a film-forming agent according to any one of claims 24 to 26, a plasticizer according to any one of claims 30 to 33, or an anti-tack agent according to any one of claims 34 to 37.

73. The method according to claims 67 to 72, wherein the sustained-release layer solution comprises a solvent or a dispersant, and the solvent or dispersant comprises or consists of an aqueous solution containing an organic solvent such as isopropanol.

74. The method according to any one of claims 67 to 73, wherein the composition is as defined in any one of claims 1 to 59.

75. A composition obtained by the method described in any one of claims 1 to 74.

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