Sustained release formulations of milvexian

Abstract

The present invention relates to novel sustained release formulation of milvexian, which are useful for the treatment or prevention of thromboembolic events. The invention is particularly suitable for once-a-day administration of milvexian, releasing a therapeutically effective amount of the milvexian over an extended time.

Description

SUSTAINED RELEASE FORMULATIONS OF MILVEXIANFIELD OF THE INVENTION

[0001] The present invention relates to novel sustained release formulation of milvexian, which are useful for the treatment or prevention of thromboembolic events. The invention is particularly suitable for once-a-day administration of milvexian, releasing a therapeutically effective amount of the milvexian over an extended time.BACKGROUND

[0002] Milvexian, also known as (9R,13S)-13-{4-[5-chloro-2-(4-chloro-lH-l,2,3- triazol- 1 -yl)phenyl]-6-oxo- 1 ,6-dihydropyrimidin- 1 -yl } -3 -(difluoromethyl)-9-methyl- 3,4,7, 15-tetraazatricyclo[12.3.1.02,6]octadeca-l(18),2(6),4,14,16-pentaen-8-one, is an inhibitor of FXIa that may be useful in the treatment of thromboembolic diseases. Solid dosage forms of Milvexian (e.g., Milvexian tablets) have been studied for the treatment of Ischemic Stroke, Acute Coronary Syndrome and Atrial Fibrillation.

[0003] Immediate release solid dosage forms permit the release of most or all of the active ingredient over a short period of time, such as 60 minutes or less, and make rapid absorption of the drug possible. Modified release solid oral dosage forms permit the sustained release of the active ingredient over an extended period of time in an effort to maintain therapeutically effective plasma levels over similarly extended time intervals and / or to modify other pharmacokinetic properties of the active ingredient.

[0004] Milvexian clinical data published to date relates to dosing of an immediate-release oral formulation, which is administered as a twice daily dosing regimen. This may be undesirable because patient compliance decreases as the frequency of taking a drug increases. Moreover, administration of an immediate-release oral formulation can lead to greater frequency of adverse events due to a faster rate of absorption. Given that the primary indications for the drug are an affliction that becomes more prevalent with advancing age, a once daily sustained release formulation containing milvexian with reliable slower absorption over a targeted period of time would be useful in enhancing compliance among elderly patients.

[0005] A once-a-day administration of milvexian is advantageous over the twice-a-day administration in terms of both patient compliance and reduced adverse events, thus providing better treatment of the conditions for which milvexian is used.

[0006] Accordingly, there is a need for new and improved formulations of milvexian that achieves therapeutic efficacy and facilitate administration by reducing the number of dosesrequired to achieve a therapeutic effect. The sustained-release formulations provided herein help meet these and other needs.SUMMARY OF THE INVENTION

[0007] The present invention is directed to a sustained release formulation comprising milvexian. The present invention is also directed to a sustained release dosage form wherein the milvexian is present in the dosage form in an amount of about 25 mg to about 200 mg.

[0008] The present invention is further directed to treatment or prevention of thromboembolic events in a patient in need thereof, comprising administering once daily a sustained release dosage form of the invention.BRIEF DESCRIPTION OF FIGURES

[0009] FIG. 1 : Comparative dissolution profile of 2 X 25 mg immediate release tablets of Example 5 vs 50 mg tablet of Example 4 in pH 6.8 phosphate buffer + 0.25% SLS.

[0010] FIG. 2: Dissolution Profile of 25 mg immediate release tablet in pH 1.2 HC1 buffer + 1% SLS.

[0011] FIG. 3: Simulated plasma concentration vs time profile of once daily 50 mg sustained release formulation in pH 6.8 + 0.25% SLS and twice daily 25 mg immediate release formulation in pH 1.2 + 0.25% SLS.

[0012] FIG. 4: Simulated plasma concentration vs time profile of once daily 50 mg sustained release formulation in pH 6.8 + 0.25% SLS and twice daily 25 mg immediate release formulation in pH 6.8 + 0.25% SLS.

[0013] FIG. 5: Simulated plasma concentration vs time profile of once daily 50 mg sustained release formulation in pH 6.8 + 0.25% SLS and twice daily 25 mg immediate release formulation in pH 1.2 + 1% SLS.DETAILED DESCRIPTION

[0014] The present application provides sustained released dosage form comprising milvexian. As used herein, “sustained release” refers to a formulation designed to slowly release the active ingredient into a patient body over an extended period after oral administration and to maintain an essentially steady, therapeutically effective plasma level of active ingredient over a relatively long period of time, such as about 8 to about 24 hours or longer. The sustained release as mentioned herein encompasses prolonged, controlled,extended release, or combinations thereof. As used herein, the term “dosage form” is meant to refer to a physically discrete unit of sustained release formulation of the invention to be administered to a patient. Example dosage forms include tablets, caplets, capsules, and the like, containing any of the sustained release formulations described herein.

[0015] The present application provides sustained released dosage form comprising milvexian which can be administered to a human patient for the treatment or prevention of thromboembolic events.

[0016] In some embodiments, the sustained release dosage form comprising milvexian can be administered to a human patient orally.

[0017] In some embodiments, the sustained release dosage form comprising milvexian is released at a rate which results in a reduction in the frequency or severity of at least one side effect associated with the milvexian treatment.

[0018] In some embodiments, the sustained release dosage form comprising milvexian can be administered to a human patient once daily.

[0019] In some embodiments, the present application provides sustained release dosage form which is suitable for a once daily administration to a human patient.

[0020] In some embodiments, the present application provides a sustained release dosage form comprising from about 25 mg to about 400 mg of milvexian.

[0021] In some embodiments, the present application provides a sustained release dosage form comprising from about 25 mg to about 200 mg of milvexian.

[0022] In some embodiments, the present application provides a sustained release dosage form comprising about 25 mg of milvexian.

[0023] In some embodiments, the present application provides a sustained release dosage form comprising about 50 mg of milvexian.

[0024] In some embodiments, the present application provides a sustained release dosage form comprising about 100 mg of milvexian.

[0025] In some embodiments, the present application provides a sustained release dosage form comprising about 150 mg of milvexian.

[0026] In some embodiments, the present application provides a sustained release dosage form comprising about 200 mg of milvexian.

[0027] In some embodiments, the present application provides a sustained release dosage form comprising about 250 mg of milvexian.

[0028] In some embodiments, the present application provides a sustained release dosage form comprising about 300 mg of milvexian.

[0029] The present application provides sustained release formulation comprising milvexian and a sustained release matrix former.

[0030] In some embodiments, the present application provides sustained release formulation comprising: a) milvexian in an amount of 25 mg to 200 mg, b) a sustained release matrix former, and c) one or more pharmaceutically acceptable excipients.

[0031] The phrase “sustained release matrix former” as used herein refers to an agent or material which helps in achieving the desired modified release of the composition and includes one or more of a release modifying polymer.

[0032] In some embodiments, the release modifying polymer may be selected from hydrophilic polymers which include both water soluble and water swellable polymers, hydrophobic polymers, enteric polymers, delayed-release polymers, and mixtures thereof.

[0033] In some embodiments, the hydrophilic polymers include, but are not limited to, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxymethyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, carboxymethyl cellulose calcium, polyvinylpyrrolidone, polyethylene oxide, polyvinyl alcohol, and mixtures thereof.

[0034] In some embodiments, the hydrophobic polymers include, but are not limited to, methyl cellulose, ethyl cellulose, propyl cellulose, ethylmethyl cellulose, isopropyl cellulose, ethylpropyl cellulose, butyl cellulose, benzyl cellulose; cellulose esters such as cellulose acetate, cellulose butyrate, cellulose propionate, cellulose butyrate, and cellulose acetate propionate; cellulose cyanoalkyl ethers such as cyanoethyl cellulose, cyanomethyl cellulose, cyanoethylmethyl cellulose, cyanopropyl cellulose, methacrylic acid-acrylic acid copolymers (e.g., Eudragit® RS, Eudragit® RL, Eudragit® NE, Eudragit® RSPO, and Eudragit® RLPO) and mixtures thereof.

[0035] In some embodiments, the enteric polymers or delayed-release polymers include, but are not limited to, methacrylic acid copolymers, ammonio methacrylate copolymer, hydroxypropylmethyl cellulosephthalate, hydroxypropylmethyl celluloseacetate succinate, cellulose acetate phthalate, and mixtures thereof.

[0036] In some embodiments, the present application provides sustained release formulation comprising: a) milvexian in an amount of 25 mg to 200 mg, b) a sustained release matrix former, and c) one or more pharmaceutically acceptable excipients; wherein the sustained release matrix former is a cellulosic ether.

[0037] In some embodiments, cellulosic ether includes one or more of sodium carboxymethyl cellulose, methylcellulose, methylhydroxyethyl cellulose, ethylhydroxylethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose or combinations thereof.

[0038] In some embodiments, cellulosic ether includes hydroxypropyl methylcellulose.

[0039] In some embodiments, hydroxypropyl methylcelluloses include Methocel K15M, Methocel K4M, Methcel K100M, and / or Methocel K100LV.

[0040] In some embodiments, the sustained release formulation has from about 10% to about 40%, about 15% to about 25%, or about 18% to about 24% by weight of one or more sustained release matrix former.

[0041] In some embodiments, the sustained release formulation has from about 15% to about 30% by weight of one or more sustained release matrix former.

[0042] In some embodiments, the sustained release formulation has about 20% by weight of one or more sustained release matrix former.

[0043] In some embodiments, the sustained release formulation has from about 10% to about 40%, about 15% to about 25%, or about 18% to about 24% by weight of one or more cellulosic ethers.

[0044] In some embodiments, the sustained release formulation has from about 15% to about 30% by weight of one or more cellulosic ethers.

[0045] In some embodiments, the sustained release formulation has about 20% by weight of one or more cellulosic ethers.

[0046] In some embodiments, the f sustained release formulation has about 20% by weight of one or more hydroxypropyl methylcelluloses. In further embodiments, the formulation has about 22% by weight of one or more hydroxypropyl methyl celluloses.

[0047] In some embodiments, the sustained release formulation includes one or more pharmaceutically acceptable excipients selected from fillers, glidants, disintegrants, binders, or lubricants.

[0048] In some embodiments, the sustained release formulation includes one or more pharmaceutically acceptable excipient which can have multi-functionality and serve a variety of purposes within the formulation.

[0049] In some embodiments, the pharmaceutically acceptable excipient is a filler selected from disaccharides such as sucrose, lactose anhydrous and lactose monohydrate, polysaccharides such as starches and cellulose derivatives, for example, starch 1500, microcrystalline cellulose and hydroxypropyl cellulose (HPC), sugar alcohols such as mannitol, xylitol, sorbitol or maltitol, proteins such as gelatine and synthetic polymers such as polyethylene glycol (PEG) or combinations thereof.

[0050] In some embodiments, the filler comprises microcrystalline cellulose, lactose monohydrate, or both.

[0051] In some embodiments, the filler can be present in an amount of about 5% to about 60% by weight.

[0052] In some embodiments, the filler can be present in an amount of about 20% to about 60% by weight.

[0053] In some embodiments, the filler can be present in an amount of about 10% to about 50%, about 20 to about 40%, or about 25% to about 35% by weight.

[0054] In some embodiments, the pharmaceutically acceptable excipient is a binder selected from starch, pregelatinized starch, microcrystalline cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, carboxymethylcellulose sodium, maltodextrin, copovidone, polyvinylpyrrolidone, saccharose, maltodextrin or combination thereof.

[0055] In some embodiments, the binder can be present in an amount of about 0.5% to about 10% by weight.

[0056] In some embodiments, the pharmaceutically acceptable excipient is a lubricant selected from magnesium stearate, stearic acid, hydrogenated oil, polyethylene glycol, sodium stearyl fumarate, and glyceryl behenate.

[0057] In some embodiments, the lubricant can be present in an amount of about 0.1% to about 5% by weight.

[0058] In some embodiments, the pharmaceutically acceptable excipient is a glidant selected from talc, colloidal silicon dioxide, and cornstarch. In some embodiments, the glidant is colloidal silicon dioxide.

[0059] In some embodiments, the glidant can be present in an amount of about 2% to about 10 % by weight.

[0060] In some embodiments, the pharmaceutically acceptable excipient is a disintegrant selected from croscarmellose sodium, crospovidone, starch, cellulose, and low substituted hydroxypropyl cellulose.

[0061] In some embodiments, the disintegrant can be present in an amount of about 0.1% to about 5% by weight.

[0062] In some embodiments, the sustained release formulation of the present invention can be prepared by dry granulation or direct compression, or wet granulation of the formulation disclosed herein.

[0063] In some embodiments, the formulations provided herein are suitable for making solid oral dosage forms.

[0064] In some embodiments, the dosage form provided herein can be tablet.

[0065] In some embodiments, the tablet further comprises a film coating. The filmcoating can comprise one or more film-forming substances, plasticizers, intestinal lubricants, colorants, or pigments.

[0066] In some embodiments, the dosage form may optionally be coated with a functional coat.

[0067] In some embodiments, the present application provides sustained release dosage form of milvexian comprising:(a) about 10% to about 40 % by weight of sustained-release matrix former,(b) about 5% to about 60% by weight of filler,(c) about 0.5% to about 10% by weight of binder,(d) about 0.1% to about 5% by weight of lubricant, and(e) optionally, about 2% to about 10 % by weight of glidant.

[0068] In some embodiments, the present application provides sustained release dosage form of milvexian comprising:(a) about 10% to about 40 % by weight of sustained-release matrix former selected from the group consisting of sodium carboxymethyl cellulose, methylcellulose, methylhydroxyethyl cellulose, ethylhydroxylethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, and mixtures thereof,(b) about 5% to about 60% by weight of filler selected from the group consisting of microcrystalline cellulose, lactose monohydrate, and mixtures thereof,(c) about 0.5% to about 10% by weight of binder selected from the group consisting of pregelatinized starch, microcrystalline cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, carboxymethylcellulose sodium, maltodextrin, copovidone, polyvinylpyrrolidone, saccharose, maltodextrin and mixtures thereof,(d) about 0.1% to about 5% by weight of lubricant selected from the group consisting of magnesium stearate, stearic acid, hydrogenated oil, polyethylene glycol, sodium stearyl fumarate, glyceryl behenate and mixtures thereof, and(e) optionally, about 2% to about 10 % by weight of glidant selected from the group consisting of talc, colloidal silicon dioxide, cornstarch, and mixtures thereof.

[0069] In some embodiments, the present application provides sustained release dosage form comprising:(a) about 10% to about 40% by weight of milvexian in an amount from about 25 mg to about 200 mg,(b) about 10% to about 40 % by weight of sustained-release matrix former,(c) about 5% to about 60% by weight of filler,(d) about 0.5% to about 10% by weight of binder,(e) about 0.1% to about 5% by weight of lubricant, and(f) optionally, about 2% to about 10 % by weight of glidant.

[0070] In some embodiments, the present application provides sustained release dosage form comprising:(a) about 10% to about 40% by weight of milvexian in an amount from about 25 mg to about 200 mg,(b) about 10% to about 40 % by weight of sustained-release matrix former selected from the group consisting of sodium carboxymethyl cellulose, methylcellulose, methylhydroxyethyl cellulose, ethylhydroxylethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, and mixtures thereof,(c) about 5% to about 60% by weight of filler,(d) about 0.5% to about 10% by weight of binder, and(e) about 0.1% to about 5% by weight of lubricant.

[0071] In some embodiments, the present application provides sustained release dosage form comprising:(a) about 10% to about 40% by weight of milvexian,(b) about 10% to about 40 % by weight of sustained-release matrix former which is hydroxypropyl methylcellulose,(c) about 5% to about 60% by weight of lactose, and(d) about 0.1% to about 5% by weight of magnesium stearate.

[0072] In some embodiments, the present application provides sustained release dosage form comprising:(a) about 10% to about 40% by weight of milvexian in an amount from about 25 mg to about 200 mg,(b) about 10% to about 40 % by weight of sustained-release matrix former which is hydroxypropyl methylcellulose,(c) about 5% to about 60% by weight of lactose, and(d) about 0.1% to about 5% by weight of magnesium stearate.

[0073] In some embodiments, the sustained release dosage forms as disclosed herein results in the relatively slow release of milvexian once administered, characterized byparticular pharmacokinetic parameters different from those of an immediate- release formulation.

[0074] In some embodiments, the sustained release dosage forms of the invention can minimize potentially harmful spikes in milvexian plasma concentrations that are associated with immediate-release formulations, and can help provide continuous, steady, and therapeutically effective plasma levels of milvexian.

[0075] In some embodiments, the sustained release dosage forms of the invention include a reduction in unwanted side effects while maintaining therapeutic efficacy comparable with an immediate-release dosing regimen.

[0076] In the present invention provides sustained release dosage form comprising milvexian, wherein milvexian is released from said dosage form at a rate effective to increase the time it takes to reach maximum therapeutic concentration (i.e., Tmax) as compared to the Tmax of an instant or immediate release formulation. For example, the Tmaxof the sustained release dosage formulation is longer by 1.5 to 4.5 times as that of the Tmax of an instant or immediate release formulation.

[0077] In some embodiments, administration of the sustained release dosage form of the invention to a human result in a mean time to peak plasma concentration (Tmax) of milvexian of about 3 hours or more.

[0078] In some embodiments, administration of the sustained release dosage form of the invention to a human result in a mean time to peak plasma concentration (Tmax) of milvexian of about 3 hours to about 12 hours.

[0079] In some embodiments, administration of the sustained release dosage form of the invention to a human result in a mean time to peak plasma concentration (Tmax) of milvexian of about 5 hours to about 7 hours.

[0080] The present invention provides sustained release dosage form comprising milvexian, wherein milvexian is released from said dosage form at a rate effective to decrease the maximum therapeutic concentration of milvexian (i.e., Cmax) compared to the Cmaxof an instant release formulation. For example, the Cmax of the sustained release dosage form is in the range of 0.75 to 1.15 times the Cmaxof an instant release formulation. For example, the Cmaxof the sustained release dosage form is in the range of 0.9 to 1.1 times the Cmaxof an instant release formulation.

[0081] In some embodiments, administration of the sustained release dosage form of the invention to a human result in a mean peak plasma concentration (Cmax) of milvexian of about 161-248 ng / mL.

[0082] In some embodiments, administration of the sustained release dosage form of the invention to a human result in a mean peak plasma concentration (Cmax) of milvexian of about 222 ng / mL.

[0083] In some embodiments, administration of the sustained release dosage form of the invention to a human result in a mean peak plasma concentration (Cmax) of milvexian of about 300 to about 500 nM.

[0084] In some embodiments, administration of the sustained release dosage form of the invention to a human result in a mean peak plasma concentration (Cmax) of milvexian of about 300 to about 400 nM.

[0085] In some embodiments, administration of the sustained release dosage form of the invention results in a mean peak plasma concentration (Cmax) of milvexian of about 350 nM or less.

[0086] In some embodiments, administration of the sustained release dosage form of the invention to a human result in a ratio of mean peak plasma concentration (Cmax) to mean concentration at the end of dosing interval plasma concentration (Ctrough) of milvexian of less than about 10.

[0087] In some embodiments, administration of the sustained release dosage form of the invention to a human result in a ratio of mean peak plasma concentration (Cmax) to mean concentration at the end of dosing interval (Ctrough) of milvexian of less than about 6.

[0088] In some embodiments, administration of the sustained release dosage form of the invention to a human result in a ratio of mean peak plasma concentration (Cmax) to mean concentration at the end of dosing interval (Ctrough) of milvexian of about 5.

[0089] In some embodiments, administration of the sustained release dosage form of the invention to a human result in a ratio of mean peak plasma concentration (Cmax) to mean concentration at the end of dosing interval (Ctrough) of milvexian of about 4 or less.

[0090] The present invention provides sustained release dosage forms comprising milvexian, wherein milvexian is released from the dosage form at a rate effective to increase the pharmaceutically effective concentration of the compound in a mammal over a time period(i.e., area under the plasma (serum or blood) concentration versus time curve, AUC, such as AUC0-24) relative to an instant release formulation, for example, so that the AUC0-72 of the controlled release dosage formulation is at least about 0.8 to 1.25 times the AUCo-24 of the instant release formulation.

[0091] In some embodiments, administration of the sustained release dosage form of the invention to a human result in a mean half-life (ti / 2) of from about 4 hours to about 8 hours.

[0092] In some embodiments, administration of the sustained release dosage form of the invention to a human result in a mean half-life (ti / 2) of from about 3 to about 7 hours.

[0093] In some embodiments, administration of the sustained release dosage form of the invention to a human result in a mean half-life (ti / 2) of about 5.5 hours.

[0094] As used herein, “Cmax” means the maximum observed plasma concentration. As used herein, “Ctrough” refers to the plasma concentration measured at end of dosing interval. As used herein, “Tmax” refers to the time at which the maximum blood plasma concentration is observed. As used herein, “T1 / 2” refers to the time at which the plasma concentration is half of the observed maximum. As used herein, “AUC” refers to the area under the plasma concentration-time curve which is a measure of total bioavailability. As used herein, “AUCo- □o” refers to the area under the plasma concentration-time curve extrapolated to infinity. As used herein, “AUCo-t” refers to the area under the plasma concentration-time curve from time 0 to the last time point with a quantifiable plasma concentration, usually about 12-72 hours. As used herein, “AUCO-T” refers to the area under the plasma concentration-time curve from time 0 to the time of the next dose.

[0095] The sustained release dosage forms of the invention have certain advantages over immediate-release dosage forms. The maintenance of steady, therapeutically effective plasma levels of milvexian afforded by the sustained release dosage forms of the invention allows for reduced dosing, such as doing only once per day, as opposed to twice or more for immediate- release forms. The reduced dosing can help with patient compliance in their treatment regimen.

[0096] In some embodiments, administration of the sustained release dosage form of the invention to a human result in increased a PTT (time, sec) at least about 1.1-2 times as compared to instant release formulation. In some embodiments, administration of sustained release dosage form of the invention to human results in decreased %FXI activity at least by 1.1-2 times as compared to instant release formulation.

[0097] In some embodiments, the sustained release dosage forms of the invention when administered once daily results in a similar pharmacokinetic profile of a twice daily immediate release formulation. For example, 50 mg sustained release dosage forms of the invention when administered once daily results in a similar pharmacokinetic profile of a 25 mg twice daily immediate release formulation.

[0098] In some embodiments, the sustained release dosage form of the invention maintains a plasma level between about 75 and about 500 nM for at least about 8 hours, at least about 12 hours, or at least about 18 hours.

[0099] In some embodiments, the sustained release dosage form of the invention maintains a plasma level between about 100 and about 400 nM for at least about 6 hours or at least about 8 hours.

[0100] In some embodiments, the present invention provides sustained release dosage form for oral administration comprising milvexian and a pharmaceutically acceptable carrier, wherein said sustained release dosage form when added to a test medium comprising 900 mL of 0.05M pH 6.8 potassium phosphate buffer at 37 °C in a standard USP rotating paddle apparatus and the paddles are rotated at 50 rpm, dissolves not more than 30% of the milvexian in about 1 hour.

[0101] In some embodiments, the present invention provides sustained release dosage form for oral administration comprising milvexian and a pharmaceutically acceptable carrier, wherein said sustained release dosage form when added to a test medium comprising 900 mL of 0.05M pH 6.8 potassium phosphate buffer at 37 °C in a standard USP rotating paddle apparatus and the paddles are rotated at 50 rpm, dissolves not more than 60% of the milvexian in about 4 hour.

[0102] In some embodiments, the present invention provides the sustained release dosage form for oral administration comprising milvexian and a pharmaceutically acceptable carrier, wherein said sustained release dosage form when added to a test medium comprising 900 mL of 0.05M pH 6.8 potassium phosphate buffer at 37 °C in a standard USP rotating paddle apparatus and the paddles are rotated at 50 rpm, dissolves not less than 25% and not more than 55% of the milvexian in about 4 hours.

[0103] In some embodiments, the present invention provides the sustained release dosage form for oral administration comprising milvexian and a pharmaceutically acceptable carrier, wherein said sustained release dosage form when added to a test medium comprising 900 mLof 0.05M pH 6.8 potassium phosphate buffer at 37 °C in a standard USP rotating paddle apparatus and the paddles are rotated at 50 rpm, dissolves not less than 65% of the milvexian in about 8 hours.

[0104] In some embodiments, the present invention provides the sustained release dosage form for oral administration comprising milvexian and a pharmaceutically acceptable carrier, wherein said sustained release dosage form when added to a test medium comprising 900 mL of 0.05M pH 6.8 potassium phosphate buffer at 37 °C in a standard USP rotating paddle apparatus and the paddles are rotated at 50 rpm, dissolves more than about 80% of the milvexian in about 8 hours.

[0105] In some embodiments, the present invention provides the sustained release dosage form for oral administration comprising milvexian and a pharmaceutically acceptable carrier, wherein said sustained release dosage form when added to a test medium comprising 900 mL of 0.05M pH 6.8 potassium phosphate buffer at 37 C in a standard USP rotating paddle apparatus and the paddles are rotated at 50 rpm, dissolves not more than 30% of the milvexian in about 1 hour, and not less than 25% and not more than 55% of the milvexian in about 4 hours and not less than 65% of the milvexian in about 8 hours.

[0106] In some embodiments, the present invention provides sustained release dosage form for oral administration comprising milvexian in an amount of 25 to 200 mg, and a sustained-release matrix former, wherein the sustained-release dosage form when added to a test medium comprising 900 ml of 0.05M pH 6.8 potassium phosphate buffer at 37° C in a standard USP rotating paddle apparatus and the paddles are rotated at 50 rpm, dissolves not more than 30% of the milvexian in 1 hour, and not less than 25% and not more than 55% of the milvexian in 4 hours and not less than 65% of the milvexian in about 8 hours.

[0107] In some embodiments, the presentation invention provides sustained release dosage form for oral administration comprising milvexian in an amount of 25 to 200 mg, and a sustained-release matrix former selected from the group consisting of one or more of sodium carboxymethyl cellulose, methylcellulose, methylhydroxyethyl cellulose, ethylhydroxylethyl cellulose, , hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, wherein the sustained-release dosage form when added to a test medium comprising 900 ml of 0.05M pH 6.8 potassium phosphate buffer at 37° C in a standard USP rotating paddle apparatus and the paddles are rotated at 50 rpm, dissolves notmore than 30% of the milvexian in about 1 hour, and not less than 25% and not more than 55% of the milvexian in about 4 hours and not less than 65% of milvexian in about 8 hours.

[0108] In some embodiments, the presentation invention provides sustained release dosage form for oral administration comprising(a) milvexian, and(b) about 10% to about 40 % by weight of sustained-release matrix former; wherein administration of the dosage form to a patient result in a ratio of mean peak plasma concentration (Cmax) to mean 24-hour plasma concentration (C24h) of milvexian is about 5.

[0109] In some embodiments, the presentation invention provides sustained release dosage form for oral administration comprising(a) milvexian in an amount from about 25 mg to about 200 mg, and(b) about 10% to about 40 % by weight of sustained-release matrix former; wherein administration of the dosage form to a patient result in a ratio of mean peak plasma concentration (Cmax) to mean 24-hour plasma concentration (C24h) of milvexian is about 5.

[0110] In some embodiments, the presentation invention provides sustained release dosage form for oral administration comprising(a) milvexian, and(b) about 10% to about 40 % by weight of sustained-release matrix former which is hydroxypropyl methylcellulose; wherein administration of the dosage form to a patient result in a ratio of mean peak plasma concentration (Cmax) to mean 24-hour plasma concentration (C24h) of milvexian is about 5.[OHl] In some embodiments, the presentation invention provides sustained release dosage form for oral administration comprising(a) milvexian, and(b) about 10% to about 40 % by weight of sustained-release matrix former;wherein administration of the dosage form to a human result in a mean half-life (ti / 2) of about 5 to about 6 hours.

[0112] In some embodiments, the presentation invention provides sustained release dosage form for oral administration comprising(a) milvexian, and(b) about 10% to about 40 % by weight of sustained-release matrix former; wherein administration of the dosage form to a human result in a mean half-life (ti / 2) of about 5 to about 6 hours.

[0113] In some embodiments, the presentation invention provides sustained release dosage form for oral administration comprising(a) milvexian in an amount from about 25 mg to about 200 mg, and(b) about 10% to about 40 % by weight of sustained-release matrix former; wherein administration of the dosage form to a human result in a mean half-life (ti / 2) of about 5 to about 6 hours.

[0114] In some embodiments, the presentation invention provides sustained release dosage form for oral administration comprising(a) milvexian, and(b) about 10% to about 40 % by weight of sustained-release matrix former, which is hydroxypropyl methylcellulose; wherein administration of the dosage form to a human result in a mean half-life (ti / 2) of about 5 to about 6 hours.

[0115] In some embodiments, the presentation invention provides sustained release dosage form for oral administration comprising(a) milvexian, and(b) about 10% to about 40 % by weight of sustained-release matrix former, which is hydroxypropyl methylcellulose, wherein administration of the dosage form to a patient result in a ratio of mean peak plasma concentration (Cmax) to to mean 24-hour plasma concentration (C2411) of milvexian is about 5; andwherein administration of the dosage form to a human result in a mean half-life (ti / 2) of about 5 to about 6 hours.

[0116] In some embodiments, the present application provides sustained release formulation comprising:(a) about 10% to about 40% by weight of milvexian in an amount from about 25 mg to about 200 mg,(b) about 10% to about 40 % by weight of hydroxypropyl methylcellulose,(c) about 5% to about 60% by weight of lactose, and(d) about 0.1% to about 5% by weight of magnesium stearate; wherein administration of the dosage form to a patient result in a ratio of mean peak plasma concentration (Cmax) to mean 24-hour plasma concentration (C24h) of milvexian is about 5; and wherein administration of the dosage form to a human result in a mean half-life (ti / 2) of about 5 to about 6 hours.

[0117] In some embodiments, the present application provides a method of treatment or prevention of a venous thromboembolic disorder in a human patient, comprising administering an oral sustained-release dosage form of the present invention.

[0118] In some embodiments, the present application provides a method of treatment or prevention of a venous thromboembolic disorder in a human patient, comprising administering an oral sustained-release dosage form of the present invention once daily.

[0119] In some embodiments, the thromboembolic disorder is unstable angina, an acute coronary syndrome, atrial fibrillation, myocardial infarction, cerebrovascular ischemic attacks, transient ischemic attack, stroke, atherosclerosis, peripheral occlusive arterial disease, venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary arterial thrombosis, cerebral arterial thrombosis, cerebral embolism, kidney embolism, pulmonary embolism, or thrombosis resulting from medical implants, devices, or procedures in which blood is exposed to an artificial surface that promotes thrombosis.EXAMPLES

[0120] Example 1: 50 mg sustained release formulation prepared by wet granulation (NB1-42)

[0121] Example 1 describes a 250 mg solid oral tablet dosage form, prepared by using a crystalline form of milvexian and by a wet granulation process. Milvexian and the specified intragranular excipients were dispensed separately, followed by sifting each component through a suitable screen to segregate cohesive particles and improve content uniformity. The excipients and milvexian were then mixed in a blender and granulated by adding a suitable amount of water. The wet granules were dried in a drying oven until the desired moisture content is achieved and milled to reduce the particle size and ensure uniformity. The extra granular excipients were dispensed, sifted individually and mixed with the granules. A lubricant and the resulting lubricated blend was then compressed into tablets using a suitable tablet press.Dissolution profile of the tablet prepared according to Example 1:

[0122] Example 2: 50 mg sustained release formulation prepared by dry granulation (NB1-46)

[0123] Example 2 describes a 500 mg solid oral tablet dosage form, prepared by using an amorphous solid dispersion of milvexian in a 1 :2 ratio with polymer (Milvexian ASD) and by a dry granulation process. Milvexian ASD and the specified intragranular excipients were dispensed separately, followed by sifting each component through a suitable screen to segregate cohesive particles and improve content uniformity. Milvexian ASD and excipients were then blended together, optionally including lubricant in an additional blending cycle. The resulting mixture was compacted using a roller compactor and subsequently milled into granules. The extra granular excipients were dispensed, sifted individually and mixed with thegranules. Lubricant was added to this step and the final blend was compressed into tablet using a suitable table press.Dissolution profile of the tablet prepared according to Example 2:

[0124] Example 3: 50 mg sustained release formulation prepared by dry granulation method (NB1-48)

[0125] Example 3 describes a 350 mg solid oral tablet dosage form, prepared by using an amorphous solid dispersion of milvexian in a 1 :2 ratio with polymer (Milvexian ASD) and by a dry granulation process similar to as described in Example 2.Dissolution profile of the tablet prepared according to Example 3:

[0126] Example 4: 50 mg Sustained release formulation prepared by Blending / dry granulation / direct blending method (NB1-50)

[0127] Example 4 describes a 350 mg solid oral tablet dosage form, prepared by using an amorphous solid dispersion of milvexian in a 1 :2 ratio with polymer (Milvexian ASD) and by a dry granulation process similar to as described in Example 2.

[0128] Example 5: 25 mg immediate release formulation (NB1-52)

[0129] Example 5 describes a 200 mg solid oral tablet dosage form, prepared by using an amorphous solid dispersion of milvexian in a 1 :2 ratio with polymer (Milvexian ASD) and by a dry granulation process similar to as described in Example 2, with the distinction being weight percentage (w / w %) of the ingredients and inclusion of a disintegrant.

[0130] Example 6: Comparative drug release profile of 50 mg sustained release formulation prepared according to Example 4 and 25 mg immediate release formulation prepared according to Example 5.

[0131] Example 7: Drug release profile of 25 mg immediate release formulation prepared according to Example 5.

[0132] Example 8: Predicted T / R Values of once daily 50 mg sustained release formulation of Example 4 and twice daily 25 mg immediate release formulation of Example 5.

[0133] Example 9: Predicted T / R Values of once daily 50 mg sustained release formulation of Example 4 and twice daily 25 mg immediate release formulation of Example 5

Claims

CLAIMSWhat is claimed:

1. A sustained release dosage form comprising:(a) milvexian,(b) about 10% to about 40 % by weight of sustained release matrix former,(c) about 5% to about 60% by weight of filler, and(d) about 0.1% to about 5% by weight of lubricant.

2. The sustained release dosage form of claim 1, wherein milvexian is present in the sustained dosage form in an amount from about 10% to about 40% by weight.

3. The sustained release dosage form of claim 1, wherein milvexian is present in an amount from about 25 mg to about 200 mg.

4. The sustained release dosage form of claim 1, wherein sustained-release matrix former is selected from the group consisting of sodium carboxymethyl cellulose, methylcellulose, methylhydroxyethyl cellulose, ethylhydroxylethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, and mixtures thereof.

5. The sustained release dosage form of claim 1, wherein sustained-release matrix former is hydroxypropyl methylcellulose.

6. The sustained release dosage form of claim 1, wherein the filler is selected from the group consisting of sucrose, lactose anhydrous, lactose monohydrate, starch 1500, microcrystalline cellulose and hydroxypropyl cellulose, mannitol, xylitol, sorbitol, maltitol and mixtures thereof.

7. The sustained release dosage form of claim 1, wherein the filler is selected from the group consisting of microcrystalline cellulose, lactose and mixtures thereof.

8. The sustained release dosage form of claim 1, wherein the binder is selected from the group consisting of pregelatinized starch, microcrystalline cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, carboxymethylcellulose sodium, maltodextrin, copovidone, polyvinylpyrrolidone, saccharose, maltodextrin and mixtures thereof,9. The sustained release dosage form of claim 1, wherein the lubricant is selected from the group consisting of magnesium stearate, stearic acid, hydrogenated oil, polyethylene glycol, sodium stearyl fumarate, glyceryl behenate and mixtures thereof.

10. The sustained release dosage form of claim 1, wherein the dosage form further comprising a glidant selected from the group consisting of talc, colloidal silicon dioxide, cornstarch, and mixtures thereof11. The sustained release dosage form of claim 1, wherein the dosage form is a tablet or capsule.

12. The sustained release dosage form of claim 1, wherein the dosage form is a film coated tablet13. The sustained-release dosage form of claim 1, wherein administration of said dosage form to a human result in a mean peak plasma concentration (Cmax) of milvexian of about 500 nM or less.

14. The sustained-release dosage form of claim 1, wherein administration of said dosage form to a human result in a mean peak plasma concentration (Cmax) of milvexian of about 400 nM or less.

15. The sustained-release dosage form of claim 1, wherein administration of said dosage form to a human result in a mean peak plasma concentration (Cmax) of milvexian of about 350 nM.

16. The sustained-release dosage form of claim 1, wherein administration of said dosage form to a human result in a mean peak plasma concentration (Cmax) of milvexian of about 220 ng / mL.

17. A method of treatment or prevention of a venous thromboembolic disorder in a human patient, comprising administering to the human patient once daily a sustained-release dosage form of claim 1.

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