Solid oral formulation of pridafen

Abstract

The present invention relates to a solid formulation of pudafenine, or a pharmaceutically acceptable salt thereof, as described herein.

Description

Technical Field

[0001] This invention relates to solid dosage forms of prodafenoxam or pharmaceutically acceptable salts thereof, as described herein. Background Technology

[0002] Prudafenoxam (compound exo-7-[(-8-azabicyclo[3.2.1]oct-3-yl)oxy]-3-methoxy-chromene-2-one, also known as IP2015) is a monoamine reuptake inhibitor in clinical development. In the nervous system, this compound increases neurotransmitter levels and could be used to treat central nervous system disorders.

[0003] Given the compound's effects on the central nervous system, oral formulations need to possess robust release characteristics. In some applications, it is desirable to achieve complete release of the compound as quickly as possible to achieve a therapeutic effect as soon as possible.

[0004] To date, no known solid dosage form of this compound has been able to produce an effective release of the compound. The compound's low solubility presents challenges to the production of such formulations and to ensuring rapid and complete release after oral administration.

[0005] Therefore, there is an urgent need for a solid form that can ensure stable and rapid release of proximate after oral administration. Summary of the Invention

[0006] The inventors unexpectedly discovered that certain solid formulations of prodafenxin enable rapid release of the compound and exhibit high absorption in the human body, despite the drug's low solubility. As illustrated in the examples, the formulations according to this disclosure enable complete release of the compound within minutes, and the drug is well absorbed in the human body and detectable in plasma. This is highly advantageous for the clinical application of prodafenxin, as it allows for safe and robust administration of the compound, with rapid release and therapeutic onset.

[0007] In one aspect, this disclosure provides a composition comprising microspheres, said microspheres comprising or consisting of the following: a. Micro-pellet core; and b. A drug layer covering the pellet core, the drug layer comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof: Formula (I).

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

[0009] In one aspect, this disclosure provides a method for obtaining therapeutically effective plasma concentrations of the compound of formula (I) in a subject. Formula (I) The t of the compound of formula I max Between 3 and 5 hours, the method includes oral administration of the composition described herein.

[0010] In a final aspect, this disclosure provides a method for preparing a composition comprising microparticles, the method comprising: a) Provide micro-pellet cores, b) Provide a drug layer solution comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof: Formula (I); and c) Coating the drug layer solution onto the micro-pellet core to form a drug layer. Attached Figure Description

[0011] Figure 1 Dissolution rates of IR microspheres and IR capsules containing 10 mg or 5 mg of prodafenoxine. A, B: IR microspheres containing 10 mg of prodafenoxine; C: IR microspheres containing 5 mg of prodafenoxine; D: IR capsules containing 5 mg of prodafenoxine. See Example 2 for further experimental details.

[0012] Figure 2 Data from a Phase IIb study using compound IP2015 in patients with erectile dysfunction (ED) showed their responses to question Q3 of the International Index of Erectile Function Scale 15 (IIEF-15): How often were you able to penetrate your partner when you attempted intercourse in the past week?

[0013] Figure 3 Data from a Phase IIb study using compound IP2015 in patients with erectile dysfunction (ED) showed their response to question Q4 of the International Index of Erectile Function Scale 15 (IIEF-15): How often are you able to maintain an erection during intercourse after you have penetrated your partner?

[0014] Figure 4 Data from a phase IIb study using compound IP2015 in patients with erectile dysfunction (ED) showed their overall responses to questions on the International Index of Erectile Function Scale 15 (IIEF-15).

[0015] definition

[0016] “C max "" is a term used in pharmacokinetics, referring to the maximum (or peak) serum concentration of a drug in a designated compartment or test area of ​​the body after administration and before administration of a second dose.

[0017] “t max"C" is a term used in pharmacokinetics to describe the observed C max The time.

[0018] As used in this article, the terms "inert core" and "inert sphere" refer to pharmaceutically acceptable cores for use in pharmaceutical formulations that are inert. For example, "inert core" or "inert sphere" refers to pharmaceutically acceptable microspheres that do not contain any pharmaceutical substances.

[0019] "Pharmaceutical acceptable" refers to a substance that can be used to prepare a pharmaceutical composition. Such a substance is generally safe, non-toxic, and does not produce adverse effects in any biological or other respects. It is acceptable for both veterinary and human pharmaceutical uses.

[0020] "Pudafensine," "IP2015," or "Compound I" refers to compound I. Compound I is: .

[0021] The term "pharmaceutically acceptable salt" for a compound refers to a pharmaceutically acceptable salt as defined herein, and preferably has the desired pharmacological activity of the parent compound. Pharmaceutically acceptable salts include acid addition salts formed with inorganic acids; or acid addition salts formed with organic acids; or salts formed when an acidic proton present in the parent compound is replaced by a metal ion or coordinated with an organic or inorganic base.

[0022] As used in this article, “formulation” refers to the combination of different substances (including active ingredients) to produce a final product.

[0023] As used herein, the term "microsphere weight" refers to the total weight of microspheres within a composition, including the drug layer, such as the total weight of components comprising the microsphere core, the drug layer, and any other layers on the microsphere. In capsule formulations, this does not include the weight of the capsule shell. Invention Details

[0025] This disclosure provides a composition comprising microspheres, the microspheres comprising or consisting of the following: a) Micro-pellet core; b) A drug layer covering the pellet core, the drug layer comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof: Formula (I).

[0026] Composition

[0027] Microspheres offer a high degree of flexibility in the design and development of oral dosage forms. Microcrystalline cellulose microspheres (MCCs) and sugars are well-known materials used as core materials in microsphere technology. Water-insoluble inert microsphere cores are made from microcrystalline cellulose or silica, while water-soluble inert microsphere cores consist of sugars (such as sucrose, xylitol, mannitol, lactose), starch, or salts. Both types of materials exhibit desired properties, such as 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 core materials for microspheres of compositions according to the present disclosure.

[0028] In one embodiment, the microspheres comprise an inert microsphere core. In another embodiment, the microsphere core comprises or is composed of microcrystalline cellulose (MCC). MCC is a commercially available chemical (CAS 9004-34-6), and its microspheres are available in a variety of sizes, such as Cellet® or Celphere. TM .

[0029] The size of the microparticle core can be any suitable size, for example, at least 100 μm. Microparticle cores of different sizes can be used, for example, from 100 μm to 1500 μm, from 100 μm to 500 μm, from 500 μm to 1000 μm, or from 1000 μm to 1500 μm.

[0030] Methods for coating microsphere compositions are well known in the art. These methods can begin with a solution, dispersion, or powder and coat it layer by layer onto microspheres. Established methods for coating microspheres include, for example, fluidized bed technology, compression coating, würster coating, pan coating, centrifugal or rotor coating.

[0031] In one embodiment, the drug layer further comprises a binder. The binder is used to prevent the drug from adhering to the microcapsules and to provide a uniform coating on the microcapsules. The binder is mixed with the drug in a solution and then coated onto inert microcapsules. Unexpectedly, it was found that the presence of a binder (such as HPMC) in the coating solution, despite the low solubility of the compound, enabled uniform coating of pledexine onto inert microcapsules.

[0032] Known adhesives include, for example, sucrose, starch, hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), gelatin, or polyvinylpyrrolidone. Therefore, in one embodiment, the adhesive is selected from: sucrose, starch, hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), gelatin, or polyvinylpyrrolidone (PVP); polyalkylene glycols or polyalkylene oxides, such as polyethylene oxide (PEO); or mixtures thereof.

[0033] In one embodiment, the drug layer comprises an adhesive present in an amount of 0.5% to 10% by weight of the composition or the microspheres, for example, 0.5% to 5%, 1% to 5%, 2% to 5%, or 2%, 3%, 4%, or 5% by weight of the composition or the microspheres. Specifically, in one embodiment, the drug layer comprises an adhesive as described herein, in an amount of 0.5% to 10% by weight of the microspheres, for example, 0.5% to 5%, or 2%, 3%, 4%, or 5% by weight of the microspheres.

[0034] In one embodiment, the binder is hydroxypropyl methylcellulose (HPMC). HPMC (CAS No. 9004-65-3) is a cellulose derivative in which some of the free hydroxyl groups in the cellulose are replaced by hydroxypropyl and methyl groups. HPMCs of different molecular weights, degrees of hydroxypropyl or methyl substitution, and viscosities are commercially available and suitable for formulation development.

[0035] In one embodiment, the pharmaceutical layer comprises HPMC in an amount of about 0.5% to about 10% by weight of the composition or the microspheres. In another embodiment, the pharmaceutical layer comprises HPMC in an amount of about 1% to 5% by weight of the composition or the microspheres, for example, about 2%, 3%, 4%, or 5% by weight of the composition or the microspheres. Specifically, in one embodiment, the pharmaceutical layer comprises HPMC as described herein in an amount of 0.5% to 10% by weight of the microspheres, for example, 0.5% to 5%, for example, 2%, 3%, 4%, or 5% by weight of the microspheres.

[0036] In one embodiment, the drug layer contains additional excipients, such as pH adjusters and / or stabilizers. The inventors unexpectedly discovered that adding sodium sulfite (also known as sodium sulfite or N-sulfite) to the drug layer... S The presence of sodium sulfite (CAS No. 7757-83-7) increases the dissolution rate of pledafine from the drug layer. Therefore, in one embodiment, the drug layer further comprises sodium sulfite. Examples demonstrate that the presence of sodium sulfite in the drug layer accelerates the dissolution rate of pledafine from the formulation.

[0037] The pH adjuster, stabilizer, or sodium sulfite may be present, for example, in an amount of about 0.05% to about 1.5% by weight of the composition or the pellets, for example, 0.05% to 0.5% by weight, for example, 0.5% to 1.0% by weight, for example, 1.0% to 1.5% by weight of the composition or the pellets. In one embodiment, the stabilizer or sodium sulfite is present in an amount of about 0.05% to about 1.5% by weight of the pellets.

[0038] In one embodiment, the sodium sulfite is present in an amount of about 0.3% to 0.8% by weight of the microspheres. In another embodiment, the sodium sulfite is present in an amount of about 0.5% by weight of the microspheres.

[0039] In one embodiment, the Formula I compound or a pharmaceutically acceptable salt thereof is present in an amount of about 0.5% to about 5% based on the total weight of the composition or the weight of the microspheres. For example, the Formula I compound may be 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% based on the total weight of the composition or the weight of the microspheres. In one embodiment, the Formula I compound may be present in an amount of 2.5% to 3.5% based on the weight of the composition or the weight of the microspheres.

[0040] In one embodiment, the Formula I compound or a pharmaceutically acceptable salt thereof may be present in an amount of about 0.5% to about 5% by weight of the microspheres. For example, the Formula I compound may be 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 microspheres. In one embodiment, the Formula I compound may be present in an amount of 2.5% to 3.5% by weight of the microspheres.

[0041] In one embodiment, the compound of formula I is a compound of formula 1a or a pharmaceutically acceptable salt thereof: Formula (Ia).

[0042] In one embodiment, the compound is exo-7-[(-8-azabicyclo[3.2.1]oct-3-yl)oxy]-3-methoxy-chromene-2-one or a pharmaceutically acceptable salt thereof.

[0043] In one embodiment, the pharmaceutically acceptable salt of the compound of formula (I) or formula (a) is a hydrochloride salt.

[0044] In one embodiment, the composition is an immediate-release (IR) composition of the compound of formula I.

[0045] Therefore, in one embodiment, this disclosure provides a composition that is an immediate-release composition in which the active ingredient is a compound of formula I or a pharmaceutically acceptable salt thereof: Formula (I), The composition comprises microspheres, which contain or consist of the following: a) Inert pellet core containing microcrystalline cellulose (MCC); b) A pharmaceutical 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 the pellets, and HPMC in an amount of 0.5% to about 5% by weight of the total composition or the pellets, the pharmaceutical layer covering the inert pellet core.

[0046] In one embodiment, this disclosure provides a composition of an immediate-release composition of an active ingredient consisting of a compound of formula I or a pharmaceutically acceptable salt thereof: Formula (I), The composition comprises microspheres, which contain or consist of the following: a) Inert microsphere core containing 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 about 0.5% to about 5% by weight of the pellet, the drug layer covering the inert pellet core.

[0047] In one embodiment, the drug layer further comprises additional excipients, such as pH adjusters or stabilizers as described herein. In one embodiment, the drug layer further comprises sodium sulfite as described herein.

[0048] In one embodiment, the drug layer further comprises the HPMC described herein.

[0049] In one embodiment, the composition according to this disclosure comprises about 0.5 mg to about 30 mg, for example 1 mg to 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 of the compound of formula I. For example, the composition may comprise 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 mg of the compound of formula I. In one embodiment, the composition comprises about 5 mg of the compound of formula I.

[0050] Dosage form

[0051] This disclosure provides dosage forms, such as pharmaceutical dosage forms, that comprise the compositions described herein. In one embodiment, the dosage form is a unit dosage form. Methods for producing dosage forms (including suitable excipients and materials) are well known to those skilled in the art.

[0052] The unit dosage form or drug dosage form is, in one embodiment, a solid dosage form. In one embodiment, the unit dosage form or drug dosage form is a capsule.

[0053] Dosage form design aims to facilitate the safe and effective delivery of active compounds to patients.

[0054] Therefore, in one embodiment, the composition according to this disclosure is in the form of a unit dosage form or a pharmaceutical dosage form. In one embodiment, the composition according to this disclosure is a capsule.

[0055] In one embodiment, the composition is for oral administration.

[0056] Immediate release

[0057] The inventors have unexpectedly demonstrated that the compositions according to this disclosure provide a rapid release of ptafenoxanine in the gastrointestinal tract after oral administration.

[0058] Examples demonstrate that the compositions according to this disclosure can provide rapid release of prodafenoxine, which can be completely released within 5 minutes under physiological conditions, and can still be rapidly absorbed despite the poor solubility of the drug.

[0059] In one embodiment, the composition provides pharmacokinetic characteristics with a single peak mean plasma concentration after oral administration.

[0060] In one embodiment, the composition provides the C of the compound of formula I after oral administration. max The C provided by an aqueous solution of an equal amount of compound I after oral administration max 80% to 125% of the compound. In one embodiment, the composition provides the C of the formula I compound after oral administration. max The range is from 5.0 ng / mL to 13.0 ng / mL, for example, from 6.0 ng / mL to 10.0 ng / mL, or from 7.0 ng / mL to 9.5 ng / mL.

[0061] In one embodiment, the composition provides an average C1 of the Formula I compound. max The concentration is 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.

[0062] In one embodiment, the composition, upon oral administration, reduces the concentration of compound I by t compared to an aqueous solution of compound I. max The increase shall not exceed 150 minutes.

[0063] In one embodiment, the composition provides the t of the compound of formula I after oral administration. max It takes approximately 2 to 8 hours, for example, 3 to 5 hours, for example, t max It takes 3, 4 or 5 hours.

[0064] The compositions according to this disclosure provide an immediate release of a compound of formula I. The immediate release can be characterized by the dissolution rate of the active ingredient from the composition. Those skilled in the art are familiar with methods for determining the dissolution rate of solid dosage forms, such as using a USP-I or USP-II apparatus according to the United States Pharmacopeia, and employing suitable methods for detecting the active ingredient, such as HPLC or ELISA.

[0065] In one embodiment, the composition, when measured in a USP-I or USP-II device at 37°C and pH 1.0, releases compound I at a rate of more than 90% within the first hour.

[0066] In one embodiment, when the composition is measured in a USP-I or USP-II device at 37°C and pH 1.0, it releases Formula I compound at a rate of more than 90% within the first 0.5 hours, for example, more than 90% within the first 10 minutes, for example, more than 90% within the first 5 minutes.

[0067] In one embodiment, the composition, when measured in a USP-I or USP-II device at 37°C and pH 1.0, releases compound I at a rate of substantially 100% or complete release within the first 5 minutes. Unexpectedly, the addition of sodium sulfite to the drug layer was found to enhance release, resulting in complete release after 5 minutes in dissolution rate tests simulating gastric pH.

[0068] Exposure to a substance can be measured as the "area under the curve" or "AUC" of the compound in the blood. As is well known in the art, this can be determined by plotting the drug concentration in the blood over time and measuring the integral of the resulting curve (also known as the "area under the curve" or "AUC").

[0069] The amount of drug in blood can be detected at different time points using methods well known in the art, such as HPLC, LC / MS, ELISA, or other suitable analytical methods. Methods for calculating graph integrals are also well known to those skilled in the art. The graph integral or area under the curve can be calculated over specific time intervals, such as the initial 24, 48, or 72 hours. Typically, the term "AUC" is used... 0-t "AUC" refers to the area under the curve in the first "t" hours. 0-24 "AUC" refers to the area under the curve within the first 24 hours. 0-inf "or AUC" inf "Refers to the area under the curve, where the last point of the integral has been extrapolated to infinity."

[0070] In one embodiment, the composition provides the AUC of the Formula I compound after oral administration. 0-72 The AUC of an aqueous solution of an equal amount of compound I after oral administration. 0-72 At least 90%.

[0071] In one embodiment, the composition provides the AUC of the Formula I compound after oral administration. 0-inf The AUC of an aqueous solution of an equal amount of compound I after oral administration. 0-inf At least 90%. In one embodiment, the composition provides the AUC of the Formula I compound after oral administration. 0-inf 150 to 550 h·ng / mL, for example, AUC 0-inf 180 to 480 h·ng / mL, or AUC 0-inf 250 to 350 h·ng / mL, for example, AUC 0-inf It is approximately 300 h·ng / mL.

[0072] In one embodiment, the composition provides the average AUC0- of the Formula I compound after oral administration. inf The range is from 200 h·ng / mL to 400 h·ng / mL, for example, the average AUC0- inf is 250 h·ng / mL to 350 h·ng / mL.

[0073] Therefore, in one aspect, this disclosure provides immediate-release compositions of compounds of formula (I), the pharmacokinetic characteristics provided by said compositions after administration being characterized by having one or more of the following: ● C of compound of formula I max The concentration ranges from 5.0 ng / mL to 13.0 ng / mL, for example, from 6.0 ng / mL to 10.0 ng / mL, and for example, from 7.5 ng / mL to 9.0 ng / mL. ● The t of compound I max It takes approximately 2 to 8 hours, for example, 3 to 5 hours. ● AUC0- of compound I inf The concentration is 180 to 480 h·ng / mL, for example, AUC0- inf 250 to 350 h·ng / mL, for example, AUC0- inf It is approximately 300 h·ng / mL.

[0074] In one embodiment, the immediate-release composition comprises a compound of formula (I) as described in the “Compositions” section herein, a microparticle core, a binder, a pH adjuster, or a stabilizer.

[0075] In one aspect, this disclosure provides a method for obtaining therapeutically effective plasma concentrations of the compound of formula (I) in a subject: Formula (I) The t of the compound of formula I max Between 3 and 5 hours, the method includes oral administration of the composition described herein.

[0076] In one aspect, this disclosure provides a method for using the compositions described herein to obtain therapeutically effective plasma concentrations of the compound of formula (I) in a subject: Formula (I) The t of the compound of formula I max Between 3 and 5 hours, the method includes oral administration of the composition described herein.

[0077] In one implementation, the subject is a human being.

[0078] Preparation method

[0079] In a final aspect, this disclosure provides a method for preparing a composition comprising microspheres, the method comprising: a) Provide micro-pellet cores, b) Provide a drug layer solution comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof: Formula (I); and c) Coating the drug layer solution onto the micro-pellet core to form a drug layer.

[0080] In one embodiment of the method, the microparticle core or the drug layer is as described in the “Composition” section of this document.

[0081] In one embodiment of the method, the drug layer solution comprises a binder or stabilizer as described in the “Composition” section herein.

[0082] In one embodiment of the method, the drug layer solution comprises a solvent or dispersant, wherein the solvent or dispersant comprises or is composed of an aqueous solution.

[0083] project

[0084] 1. A composition comprising microspheres, said microspheres comprising or consisting of the following: a. Micro-pellet core; and b. A drug layer covering the pellet core, the drug layer comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof: Formula (I).

[0085] 2. The composition according to item 1, wherein the pharmaceutical layer further comprises an adhesive selected from: cellulose derivatives, such as hydroxypropyl methylcellulose (HPMC); hydroxypropyl cellulose; gelatin; polyalkylene glycols, such as PEO; and polyvinylpyrrolidone (PVP).

[0086] 3. The composition according to any of the preceding items, wherein the pharmaceutical layer comprises a binder in an amount of 0.5% to 10% by weight of the composition or the pellets.

[0087] 4. The composition according to any of the foregoing items, wherein the adhesive is HPMC.

[0088] 5. The composition according to any of the preceding items, wherein the pharmaceutical layer comprises about 1% to 5% HPMC by weight of the composition or the pellets.

[0089] 6. The composition according to any of the preceding items, wherein the pharmaceutical layer comprises sodium sulfite.

[0090] 7. The composition according to any of the preceding items, wherein the microsphere core comprises or is composed of spheres made of a material selected from: microcrystalline cellulose (MCC); sugars, such as sucrose, xylitol, mannitol, lactose; starch, silicon dioxide, tartaric acid, and calcium carbonate.

[0091] 8. The composition according to any of the foregoing items, wherein the microsphere core comprises or is composed of microcrystalline cellulose (MCC).

[0092] 9. The composition according to any of the preceding items, wherein the composition is an immediate-release composition of an active ingredient consisting of a compound of formula I or a pharmaceutically acceptable salt thereof: Formula (I) The composition comprises microspheres, which contain or consist of the following: a) Inert microsphere core containing microcrystalline cellulose (MCC); b) A pharmaceutical 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 the pellets, and HPMC in an amount of 1% to about 5% by weight of the total composition or the pellets, the layer covering the inert pellet core.

[0093] 10. The composition according to item 9, wherein the pharmaceutical layer further comprises sodium sulfite.

[0094] 11. The composition according to item 9, wherein the sodium sulfite is present in an amount of 0.05% to 1% by weight.

[0095] 12. The composition according to any of the preceding items, wherein the composition provides a t of formula I compound after oral administration. max It takes approximately 2 to 8 hours.

[0096] 13. The composition according to any of the preceding items, wherein the composition releases Formula I compound at a rate of 100% release within the first 5 minutes, as measured in a USP-I or USP-II apparatus at 37°C and pH 1.0.

[0097] 14. The composition according to any of the preceding items, wherein the composition provides an AUC0- of the compound of formula I after oral administration. inf The AUC of an aqueous solution of an equal amount of compound I after oral administration. 0-inf At least 90%.

[0098] 15. A unit dosage form comprising the composition according to any one of items 1-14.

[0099] Example

[0100] Example 1: Preparation of the formulation

[0101] Purpose

[0102] To describe the preparation of the compositions according to this disclosure.

[0103] Materials and Methods

[0104] Materials: Microcrystalline cellulose spheres (Celphere CP-507, particle size range 500-710 µm), anhydrous sodium sulfite, hydroxypropyl methylcellulose (HPMC, Methocel E5 premium LV), and buprofen hydrate hydrochloride.

[0105] Sodium sulfite, HPMC 5cps, and propafenone were mixed in purified water and stirred to obtain a homogeneous dispersion. This solution was then coated onto inert microsphere cores (Celphere CP-507) in a fluidized bed (GPCG 1.1 pot, spray gun nozzle size: 1.2 mm, ADP size: Type B). Finally, the drug-laden microspheres were filled into No. 0 Swedish orange capsules.

[0106] For the preparation of the drug-in-bottle product, the prodexin solution is prepared as follows: Prodexin is dissolved in water for injection containing 50 mg / mL 2-hydroxypropyl-β-cyclodextrin (HPβCD).

[0107] The drug substance Prodafenoxan is used in the form of a monohydrate hydrochloride salt. Therefore, the dosage per bottle, capsule, or administration is calculated based on the amount of free base.

[0108] result

[0109] The IP2015 composition was prepared according to the table below.

[0110] Table 1. Composition of IP2015 Immediate Release (IR) Microparticles

[0111] a The drug substance is a monohydrate hydrochloride salt. The amount of free base can be calculated using methods well-known in the art on an anhydrous and solvent-free basis. For this batch, 60 mg of free base corresponds to 72 mg of the drug substance.

[0112] Solubility test

[0113] The solubility of IP2015 in aqueous and non-aqueous solvents was determined. In non-aqueous liquids, solubility was visually confirmed by stepwise dilution. The solubility of IP2015 in aqueous solutions at specific pH values ​​was evaluated, with visual confirmation and concentration assessment by HPLC.

[0114] Table 2. Solubility of IP2015 in different media

[0115] result

[0116] As shown in Table 2, the solubility of IP2015 in aqueous solutions within the physiological pH range is less than 1 mg / mL. Surprisingly, the presence of a binder in the solution allowed IP2015 to be distributed uniformly and consistently within the drug layer. Conversely, when solubilizers (such as 2-hydroxypropyl-β-cyclodextrin (HPβCD)) were used to increase the solubility of IP2015, the concentration of the compound was insufficient to form a good drug layer.

[0117] Example 2: Release of IP2015 in solution

[0118] Purpose

[0119] To investigate the release of IP2015 from the compositions according to this disclosure.

[0120] Materials and Methods

[0121] Dissolution profiles of IP2015 IR microspheres (partially completed IMPs) and IP2015 IR capsules were determined using 0.1N HCl buffer.

[0122] Dissolution conditions:

[0123] The dissolved samples were analyzed using gradient reversed-phase HPLC. The mobile phase was a buffer solution (0.1% phosphoric acid and water): acetonitrile (85:15). Detection was performed using a digital autoencoder (DAD).

[0124] To investigate the role of sodium sulfite, two different microsphere samples were prepared according to Example 1: one containing sodium sulfite and one without. The dissolution rate of the sample equivalent to 5 mg IP2015 from the unencapsulated microspheres was studied.

[0125] To investigate the effect of encapsulation, the dissolution rate of IP2015 from encapsulated and unencapsulated pellets was evaluated using a sample equivalent to 5 mg of IP2015 prepared according to Example 1. For comparison, the dissolution rate of an unencapsulated sample equivalent to 10 mg of IP2015 was also evaluated.

[0126] result

[0127] The dissolution curves of samples containing and without sodium sulfite are shown in Table 3.

[0128] Table 3. Drug release from 5 mg IP2015 IR microspheres with and without sodium sulfite.

[0129] The effect of sodium sulfite on the dissolution profile was observed. The dissolution profiles of scale-up batches containing sodium sulfite in the drug layer coating showed a faster dissolution rate than those of scale-up batches without sodium sulfite in the drug layer.

[0130] Figure 1 Release profiles for IP2015 IR microspheres and capsules are shown. The dissolution profiles are as expected. IP2015 IR capsules meet the requirements for immediate-release oral dosage forms, with 80% release after 10 minutes and >90% release after 20 minutes.

[0131] in conclusion

[0132] Surprisingly, the presence of sodium sulfite enhanced the dissolution rate of the IR composition.

[0133] Example 3: In vivo pharmacokinetics of the IP2015 IR composition

[0134] Purpose

[0135] In order to study the pharmacokinetic parameters of the compositions according to this disclosure.

[0136] Materials and Methods

[0137] The pharmacokinetic characteristics of different IR pellet formulations of IP2015 and a solution formulation (DiB) as a reference were investigated in Göttingen miniature pigs after a single oral administration.

[0138] Animals were fasted prior to administration. Each formulation was administered to animals by a single dose; a 7-day washout period followed each day of administration. A single dose of 0.5 mg / kg was administered orally via capsules, with a 7-day washout period following each day of administration. A single dose (0.25 mL / kg) of the reference solution was administered orally via gavage.

[0139] Assess mortality twice daily. Record all clinical signs at baseline and at the same times daily during the study period (approximately 1–1.5 hours, 2–2.5 hours, and 3–3.5 hours after administration). Record fasting weight on allocation day and the day before administration.

[0140] On each dosing day, collect blood samples from the jugular vein at approximately the following time points (other veins may be used if necessary): before dosing, and 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 24, 36, and 48 hours after the first administration.

[0141] At each sampling, at least 1.0 mL of blood was collected and transferred to a test tube containing K2EDTA anticoagulant. The sample was centrifuged at room temperature and divided into two equal portions: [Aliquot A] approximately 250 μL, and the second portion [Aliquot B] was the remaining plasma, which was then frozen at -70±10°C.

[0142] The concentration of IP2015 in miniature pig plasma was determined by the Bioanalytical Department of Syngene International Ltd. using LC-MS / MS. During the analysis, standards and quality control samples were included in each batch of study samples. Plasma concentration data were used for toxicokinetic evaluation.

[0143] Using Phoenix® WinNonlin® Validation Version 8.2, PK parameters were calculated from individual miniature pig plasma concentration-time data using non-compartmental analysis and uniform weighting. The calculated PK parameters included the area under the plasma concentration-time curve (AUC) up to the last quantifiable concentration. last ), AUC all Peak plasma concentration (C max ), time to reach peak plasma concentration (T) max C last T last AUC inf and terminal elimination half-life (t 1 / 2 Plasma concentration and TK parameters are presented in ng.

[0144] result

[0145] The results are shown in Tables 4 and 5.

[0146] Table 4. Mean pharmacokinetic parameters of IP2015 in different formulations

[0147] Table 5. Systemic exposure ratio of IR to DiB

[0148] in conclusion

[0149] It was observed that the composition according to this disclosure resulted in T max Slightly increased, C max The level decreased, but the exposure to IP2015 remained the same.

[0150] Example 4. Clinical trial to study the pharmacokinetics of IP2015 formulation in humans.

[0151] Purpose

[0152] In order to study the pharmacokinetics of the IP2015 immediate-release (IR) composition according to this disclosure in humans.

[0153] Materials and Methods

[0154] This study was a three-way crossover study investigating the pharmacokinetic parameters of the IP2015 immediate-release composition according to this disclosure after oral administration. For comparison, the results were compared with those of IP2015 solution. The composition was prepared according to Example 1.

[0155] This study was a crossover study conducted in 12 healthy subjects who received a single 5 mg dose of different formulations of IP2015 with sufficient washout time between doses. Plasma concentrations of IP2015 were monitored at different time points after administration of the compositions.

[0156] result

[0157] The results are shown in Tables 6 and 7.

[0158] Table 6. Pharmacokinetic parameters of the IR and DiB combination

[0159] Table 7. Systemic Exposure Ratio of IR to DiB

[0160] in conclusion

[0161] It was observed that the composition according to this disclosure resulted in t max Slightly increased, C max While the level of IP2015 is reduced, the level of exposure remains constant. Therefore, the compositions of this disclosure provide a rapid release very similar to that of bottled pharmaceutical formulations.

[0162] Example 5. Clinical trial investigating adverse events and efficacy of IP2015 in treating erectile dysfunction in humans.

[0163] This study investigated the effects of repeated single oral doses of IP2015 on the production and maintenance of erectile function in male subjects with erectile dysfunction (ED), as well as the safety and tolerability of single oral doses of IP2015, its effects on penile rigidity and swelling during visual stimulation, its effects on sperm count and motility, and any possible relationship between IP2015 plasma levels and its efficacy and safety.

[0164] Materials and methods

[0165] Research Design

[0166] One hundred and thirty participants were divided into three parallel groups. Each participant received four doses of 5 mg IP2015, 10 mg IP2015, or a matched placebo. Within each group, participants were uniformly randomized to each of the three study treatments and received the same treatment at each visit.

[0167] The study lasted approximately 8 weeks and consisted of the following: Screening visits (maximum 21 days prior to baseline visits) Baseline visit (Day 7) Outpatient visits in week 1 (day 1), week 2, week 3, and week 4 Follow-up visits should be conducted at least 7 to 10 days after the last dose.

[0168] All groups were required to complete the IIEF-15 questionnaire on day -7, week 1 (day 1), week 2, week 3, week 4, and at the follow-up visit. Group 2 was required to complete a visual stimulation assessment using the RigiScan Plus monitor on day -7, week 1 (day 1), and week 4. Group 2 was also required to provide blood samples for pharmacokinetic assessment on week 1 (day 1) and week 4. Group 3 was required to provide semen samples on day -7 and week 4.

[0169] Participants

[0170] Patients were otherwise healthy male subjects with erectile dysfunction (defined by an IIEF-5 score ≤16) and a body mass index between 18 and 35 kg / m². 2 Participants must be between 18 and 59 years of age (inclusive), regardless of race.

[0171] Dosage and administration

[0172] Three potential study treatments were offered: 5 mg IP2015, 10 mg IP2015, or a matched placebo. Within each group, subjects were uniformly randomized to each of the three study treatments and received the same treatment at each visit. IP2015 or the matched placebo was administered once daily in the morning on an empty stomach during weeks 1 (day 1), 2, 3, and 4. The dose was taken with 240 mL of room temperature water. Subjects fasted for 2 hours prior to administration until 4 hours after administration. Fluid intake was permitted freely, except for 1 hour before and 1 hour after administration.

[0173] evaluate

[0174] Efficacy was assessed using the International Index of Erectile Function (IIEF)-15 questionnaire. Changes in responses to IIEF-15 questionnaire questions (including questions on erectile function, orgasmic function, libido, sexual satisfaction, and overall satisfaction) relative to baseline were determined at different time points during the study. Efficacy was evaluated using RigiScan assessments during stimulation assessments, as well as sperm counts and motility obtained from semen sample collection. Safety was assessed via adverse event (AE) reports, 12-lead ECG, vital signs, physical examination, and clinical laboratory evaluations. Pharmacokinetic assessments were performed via blood sample collection.

[0175] result

[0176] The therapeutic effect of IP2015

[0177] Regarding the results of Q3 in IIEF-15, "In the past week, how frequently were you able to penetrate your partner when you attempted sexual intercourse?", Figure 2 As shown. At week 3, the Q3 results in the 5 mg IP2015 treatment group were significantly different from both placebo (p=0.034) and baseline (p=0.046). The overall Q3 score also showed a trend towards difference compared to both placebo (p=0.07) and baseline (p=0.07).

[0178] Regarding the results of Q4 in IIEF-15, "During intercourse, how frequently are you able to maintain an erection after penetration?", Figure 3 As shown in the figure. Results for Q4 showed that 5 mg tended to result in a different overall score compared to baseline (p=0.056), but not compared to placebo (p=0.44).

[0179] The general answers to the questions in IIEF-15 are as follows: Figure 4 As shown, the results of 5 mg IP2015 treatment were significant compared to baseline at follow-up (p=0.0046) and showed a trend compared to placebo (p=0.07). The results of the overall score of 5 mg were also significant compared to baseline (p=0.0032) and showed a trend compared to placebo (p=0.10).

[0180] exist Figure 2 , 3 In Figures 4 and 4, results showed changes from baseline in patients treated with four parallel doses of placebo (n=45), 5 mg (n=42), and 10 mg (n=43) of IP2015 on days 1, 8, 15, and 22. Results are mean ± SE. Statistical differences were calculated using mixed-model repeated measures (MMRM).

[0181] Adverse events

[0182] Adverse effects observed during treatment with the low-dose (5 mg) IP2015 were comparable to those in the placebo group. TEAEs were dose-dependent, ranging from mild to moderate, and slightly increased in the high-dose group compared to the low-dose IP2015 group. No serious side effects were observed at any dose of IP2015 (Table 8).

[0183] The results of the semen analysis are complete, and the treatment has no negative effect on sperm count, motility, or morphology.

[0184] Table 8. Adverse events that occurred during treatment

[0185] in conclusion

[0186] Overall, these results indicate that a 5 mg dose of IP2015 is effective and well-tolerated for the treatment of erectile dysfunction. Compared with baseline and placebo, a 5 mg dose of IP2015 (Pudafencin) significantly improved Q3 of the IIEF-15 score. A trend was observed in the overall IIEF-15 score, showing a clinically significant change of 2 points, which was significant for low-dose IP2015 relative to baseline and compared with placebo (p=0.10).

[0187] Adverse effects observed during treatment with the 5 mg dose of IP2015 were comparable to those in the placebo group. TEAEs were dose-dependent, with only mild to moderate effects observed. No severe TEAEs were observed.

[0188] Compared to 10 mg, 5 mg IP2015 demonstrated higher efficacy and a lower incidence of TEAEs, demonstrating the need for a solid dosage form of the present invention that mimics the pharmacokinetics of the bottled drug (DiB) used in this study without affecting exposure.

Claims

1. A composition comprising microspheres, said microspheres comprising or consisting of the following: a. Micro-pellet core; as well as b. A drug layer covering the pellet core, the drug layer comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof: Equation (I).

2. The composition of claim 1, wherein the pharmaceutical layer further comprises an adhesive selected from: cellulose derivatives, such as hydroxypropyl methylcellulose (HPMC) or hydroxypropyl cellulose (HPC); gelatin; polyalkylene glycols, such as PEO; and polyvinylpyrrolidone (PVP).

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

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

5. The composition according to any one of the preceding claims, wherein the pharmaceutical layer comprises HPMC in an amount of about 1% to 5% by weight of the microparticles.

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

7. The composition according to claim 6, wherein the pH adjuster and / or stabilizer are present in an amount of 0.05% to 1% by weight of the pellets.

8. The composition according to any one of claims 6-7, wherein the stabilizer is sodium sulfite.

9. The composition according to any one of the preceding claims, wherein the pharmaceutical layer comprises sodium sulfite, which is present in an amount of 0.05% to 1% by weight of the microparticles.

10. The composition according to any one of the preceding claims, wherein the microsphere core comprises or is composed of spheres made of a material selected from: microcrystalline cellulose (MCC); sugars, such as sucrose, xylitol, mannitol and lactose; starch, silicon dioxide, tartaric acid and calcium carbonate.

11. The composition according to any of the preceding claims, wherein the microsphere core comprises or is composed of microcrystalline cellulose (MCC).

12. The composition according to any one of the preceding claims, wherein the pharmaceutical layer comprises about 0.5% to about 5% by weight of the compound of formula I or a pharmaceutically acceptable salt thereof.

13. The composition according to any one of the preceding claims, wherein the binder is present in an amount of 0.5% to 5% by weight of the microparticles.

14. The composition according to any one of the preceding claims, wherein the compound of formula I is a compound of formula 1a or a pharmaceutically acceptable salt thereof: Formula (It).

15. The composition according to any one of the preceding claims, wherein the compound is exo-7-[(8-azabicyclo[3.2.1]oct-3-yl)oxy]-3-methoxy-chromene-2-one or a pharmaceutically acceptable salt thereof.

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

17. The composition according to any one of the preceding claims, wherein the composition is an immediate-release composition of an active ingredient consisting of a compound of formula I or a pharmaceutically acceptable salt thereof: Equation (I), The composition comprises microspheres, which contain or consist of the following: a) Inert microsphere core containing 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 about 0.5% to about 5% by weight of the pellet, wherein the drug layer covers the inert pellet core.

18. The composition of claim 17, wherein the pharmaceutical layer further comprises an additional excipient selected from pH adjusters and / or stabilizers.

19. The composition according to any one of claims 17-18, wherein the pharmaceutical layer further comprises sodium sulfite.

20. The composition according to any one of claims 17-19, wherein the pharmaceutical layer comprises sodium sulfite, which is present in an amount of 0.05% to 1% by weight of the microspheres.

21. The composition according to any one of the preceding claims, wherein the composition comprises a compound of formula I in an amount of about 0.5 mg to 10 mg.

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

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

24. The composition according to any one of claims 22-23, wherein the unit dosage form or pharmaceutical dosage form is a capsule.

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

26. The composition according to any one of the preceding claims, wherein the composition provides pharmacokinetic characteristics having a single mean peak plasma concentration after oral administration.

27. The composition according to any one of the preceding claims, wherein the composition provides C upon oral administration. max C provided for an equal amount of compound of formula I to be administered orally in aqueous solution form max 80% to 125%.

28. The composition according to any one of the preceding claims, wherein the composition provides, upon oral administration, the C of the compound of formula I. max The concentration ranges from 5.0 ng / mL to 12.5 ng / mL, for example from 6.0 ng / mL to 10.0 ng / mL, for example from 7 ng / mL to 9 ng / mL.

29. The composition according to any one of the preceding claims, wherein, after oral administration, the composition causes the t of compound I to be less than that of an aqueous solution of compound I. max Add up to 150 minutes.

30. The composition according to any one of the preceding claims, wherein the composition provides a t of formula I compound after oral administration. max It takes about 2 to 8 hours, for example, 3 to 5 hours.

31. The composition according to any one of the preceding claims, wherein the composition provides a t of formula I compound after oral administration. max It takes approximately 2 to 8 hours.

32. The composition according to any one of the preceding claims, wherein the composition provides a t of formula I compound after oral administration. max It takes about 3 to 5 hours.

33. The composition according to any one of the preceding claims, wherein, when measured in a USP-I or USP-II device at 37°C and pH 1.0, the composition releases compound I at a rate of more than 90% within the first hour.

34. The composition according to any of the preceding claims, wherein, when measured in a USP-I or USP-II device at 37°C and pH 1.0, the composition releases compound I at a rate of more than 90% within the first 0.5 hours, for example, more than 90% within the first 10 minutes, for example, more than 90% within the first 5 minutes.

35. The composition according to any of the preceding claims, wherein when measured in a USP-I or USP-II device at 37°C and pH 1.0, the composition releases compound I at a rate of 100% release within the first 5 minutes.

36. The composition according to any one of the preceding claims, wherein, after oral administration, the composition provides an AUC0- of the compound of formula I. 72 AUC0- for an aqueous solution of an equal amount of compound I 72 At least 90%.

37. The composition according to any one of the preceding claims, wherein, after oral administration, the composition provides an AUC0- of the compound of formula I. inf AUC of an aqueous solution of an equal amount of compound I 0-inf At least 90%.

38. The composition according to any one of the preceding claims, wherein the composition provides an AUC0- of the compound of formula I after oral administration. inf The concentration is 180 to 480 h·ng / mL, for example, AUC0- inf 250 to 350 h·ng / mL, for example, AUC0- inf It is approximately 300 h·ng / mL.

39. The composition according to any one of the preceding claims, wherein the composition comprises about 0.1 mg to about 10 mg of the compound of formula (I).

40. The composition according to any one of the preceding claims, wherein the composition comprises 5 mg of the compound of formula (I).

41. A unit dosage form comprising the composition according to any one of the preceding claims.

42. A method for obtaining therapeutically effective plasma concentrations of the compound of formula (I) in a subject: Equation (I) The t of the compound of formula I max Between 3 and 5 hours, the method includes oral administration of the composition according to any of the preceding claims.

43. The method of claim 42, wherein the subject is a human being.

44. A method for preparing a composition comprising microspheres, the method comprising: a) Provide micro-pellet cores, b) Provide a drug layer solution comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof: Formula (I); and c) Coating the drug layer solution onto the micro-pellet core to form a drug layer.

45. The method according to claim 44, wherein: a. The micro-pellet core as described in any one of claims 10-11, and / or b. The drug layer solution comprises a binder, a pH adjuster or a stabilizer, and / or a compound of formula I as described in any one of claims 1-10 and 12-15.

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