JP2011168596A - Tranexamic acid formulation - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide modified release oral tranexamic acid formulations that preferably minimize or eliminate undesirable side effects. <P>SOLUTION: The modified release oral formulations of tranexamic acid include a modified release material which is selected from the group consisting of a gel-forming polymer, a hydratable polymer, a water soluble polymer, a water swellable polymer, or mixtures thereof. When measured by a USP 27 Apparatus Type II Paddle Method (50 RPM) in 900 ml water at 37±0.5°C, less than about 70 wt.% tranexamic acid or pharmaceutically acceptable salt thereof is released at about 45 minutes and about 100 wt.% of the tranexamic acid or pharmaceutically acceptable salt thereof is released by about 120 minutes. <P>COPYRIGHT: (C)2011,JPO&INPIT

Description

  The present invention relates to modified release oral tranexamic acid formulations that preferably minimize or eliminate unwanted side effects, and methods of treatment using such formulations.

  Tranexamic acid (trans-4- (aminomethyl) cyclohexanecarboxylic acid, Cyklokapron® (Pfizer)) is an antifibrinolytic agent. That is, it helps to prevent dissolution of fibrin clots formed during the normal physiological process of hemostasis. Its mechanism of action is as a competitive inhibitor of plasminogen activation and as a non-competitive inhibitor of plasmin. Plasminogen and plasmin are both activators of fibrinolysis and are effective clot lysing agents. Thus, tranexamic acid helps stabilize the fibrin clot, which helps maintain blood coagulation and suppress bleeding.

  Tranexamic acid is used to control excessive bleeding, where excessive bleeding is, for example, excessive bleeding that occurs during dental procedures in hemophilia patients or heavy bleeding during menstruation (menorrhagia) Excessive bleeding that occurs with respect to. Women with menorrhagia are typically treated by oral administration of 500 mg tranexamic acid tablets 3 or 4 times per day, for a total daily dose of 3 grams / day (every 8 hours 2 tablets) to 6 grams / day (3 tablets every 6 hours). However, this treatment can cause gastrointestinal side effects such as nausea, vomiting, diarrhea and convulsions. These gastrointestinal side effects are due to the amount of tranexamic acid at each dose and / or the fast release rate of tranexamic acid into the stomach, and the large amounts of excipients used in tablets and brought into the stomach Also due to. In addition to convulsions, bloating, pain and other symptoms that can accompany menstruation, such side effects are undesirable and a tranexamic acid formulation that reduces or eliminates these side effects is needed.

  Disclosed is a tranexamic acid formulation that minimizes or eliminates undesirable gastrointestinal side effects in patients undergoing oral tranexamic acid treatment, e.g., women undergoing menorrhagia (severe menstrual bleeding). ing. The present invention relates, in part, to a modified release formulation, wherein the formulation contains tranexamic acid from the formulation to prevent a bolus of tranexamic acid from entering the stomach and dissolving in the stomach contents. Is formulated to be released systematically. Such modified release formulations, for example, prevent large boluss of tranexamic acid from being introduced into the stomach and reduce the concentration of tranexamic acid dissolved in the stomach contents. The beneficial effect of this reduced tranexamic acid concentration is to reduce the amount of tranexamic acid in the stomach contents, resulting in fewer side effects associated with tranexamic acid therapy. This reduction in side effects preferably improves patient compliance with treatment. This is preferably because the patient does not deliberately take to avoid the side effects. Physicians will also preferably have a greater tendency to initiate and continue tranexamic acid treatment for their patients by reducing patient dissatisfaction.

  The object of the present invention is to provide a tranexamic acid-containing oral formulation suitable for administration to humans twice or three times per day.

  A further object of the present invention is to provide a modified release oral formulation (dosage form) suitable for administration twice or three times per day comprising tranexamic acid and a modified release substance that modulates the release of tranexamic acid. Is to provide.

  A further object of certain embodiments of the present invention is to provide a release modifier and tranexamic acid that minimizes or eliminates undesirable gastrointestinal side effects of patients in oral tranexamic acid therapy while maintaining or improving the therapeutic effect of tranexamic acid. It is to provide a modified release oral formulation comprising.

  A further object of certain embodiments of the invention is to provide a method for treating a patient suffering from severe menstrual bleeding (menorrhagia), wherein the method is performed twice or three times per day. By orally administering to the patient one or more formulations comprising a modified release substance and tranexamic acid that provide a therapeutically effective level of tranexamic acid suitable for a single administration.

  The advantages and objectives described above, etc., can be achieved in part by the present invention relating to a modified release oral formulation comprising tranexamic acid or a pharmaceutically acceptable salt thereof and a modified release agent, wherein The controlled release agent is one that modulates the release of tranexamic acid or a pharmaceutically acceptable salt thereof from the formulation such that the formulation is suitable for administration twice or three times per day, The formulation is less than about 70% by weight in about 45 minutes when measured at 37 ± 0.5 ° C. in 900 mL of water by the US Pharmacopeia (USP 27) Type II Paddle Method (50 RPM). In vitro of tranexamic acid or a pharmaceutically acceptable salt thereof, wherein tranexamic acid or a pharmaceutically acceptable salt thereof is released and about 100% by weight of tranexamic acid or a pharmaceutically acceptable salt thereof is released in about 120 minutes. Has a dissolution release rate .

In certain embodiments, the invention relates to a method of treating a patient in need of treatment with tranexamic acid or a pharmaceutically acceptable salt thereof, wherein the method comprises tranexamic acid or a pharmaceutically acceptable salt thereof. And about 1300 mg of tranexamic acid or a pharmaceutically acceptable salt thereof in at least one oral dosage form comprising a modified release substance, wherein the dosage form is about 1 mg after oral administration to a human. An average maximum plasma concentration (C _max ) of tranexamic acid of 5 to about 17.5 mcg / mL, preferably about 6.5 to about 15 mcg / mL, more preferably about 9 to about 14.5 mcg / mL is provided.

In certain embodiments, the invention further relates to a method of treating a patient in need of treatment with tranexamic acid or a pharmaceutically acceptable salt thereof, wherein the method comprises tranexamic acid or a pharmaceutically acceptable salt thereof. Administering to the patient about 1300 mg of tranexamic acid or a pharmaceutically acceptable salt thereof in at least one oral formulation comprising a salt and a modified release agent, wherein the formulation is steady state for humans After oral administration, about 5 to about 25 mcg / mL, preferably about 10 to about 20 mcg / mL, more preferably about 12.5 to about 17.5 mcg / mL, most preferably about 15 to about 17 mcg / mL tranexamic acid Provides the mean maximum plasma concentration (C _max ).

In certain embodiments, the modified release oral formulation of the present invention is about 1 to about 5.5 hours, preferably about 2 to about 4 hours, more preferably about 2 to about 4 hours after the formulation is orally administered to a human. Provides an average T _max of tranexamic acid of 3.5 hours.

  In certain embodiments, the present invention further relates to a modified release oral formulation comprising tranexamic acid or a pharmaceutically acceptable salt thereof and a modified release agent, wherein the modified release agent is administered twice daily per formulation. Or when the formulation is measured at 37 ± 0.5 ° C. in 900 mL of water by the United States Pharmacopeia (USP 27) Type II paddle method (50 RPM), so that it is suitable for three doses, Less than about 40% by weight of tranexamic acid or a pharmaceutically acceptable salt thereof is released in about 15 minutes, and less than about 70% by weight of tranexamic acid or a pharmaceutically acceptable salt thereof is released in about 45 minutes. Tranexamic acid or a pharmaceutical thereof from the formulation so as to have an in vitro dissolution rate of tranexamic acid or a pharmaceutically acceptable salt thereof that releases at least 50% by weight of tranexamic acid or a pharmaceutically acceptable salt thereof in minutes. Adjust top acceptable salt release .

  In certain embodiments, the present invention further relates to a modified release oral formulation comprising tranexamic acid or a pharmaceutically acceptable salt thereof and a modified release agent, wherein the modified release agent is administered twice daily per formulation. Or when the formulation is measured at 37 ± 0.5 ° C. in 900 mL of water by the United States Pharmacopeia (USP 27) Type II paddle method (50 RPM), so that it is suitable for three doses, About 0% to about 40% by weight of tranexamic acid or a pharmaceutically acceptable salt thereof is released in about 15 minutes, and about 20% to about 60% by weight of tranexamic acid or a pharmaceutically acceptable salt thereof in about 30 minutes. From about 40% to about 65% by weight of tranexamic acid or a pharmaceutically acceptable salt thereof in about 45 minutes, and from about 50% to about 90% by weight of tranexamic acid or a pharmaceutical thereof in about 60 minutes. An acceptable salt is released and at least 60% by weight of tranexamic acid or a pharmaceutically acceptable salt thereof in about 90 minutes Released, so as to have a tranexamic acid or in vitro dissolution rate of a pharmaceutically acceptable salt thereof, to modulate the release of tranexamic acid or pharmaceutically acceptable salt thereof from the formulation.

  In certain embodiments, the invention further relates to a modified release oral formulation comprising tranexamic acid or a pharmaceutically acceptable salt thereof and a modified release agent, wherein the formulation is 40% after oral administration to a human. More than about 41% to about 60%, preferably about 42% to about 50%, and more preferably about 45% of bioavailability of tranexamic acid.

  In certain embodiments, the invention further comprises about 585 to about 715 mg of tranexamic acid or a pharmaceutically acceptable salt thereof, preferably about 650 mg of tranexamic acid or a pharmaceutically acceptable salt thereof and a release modifier. For a modified release oral formulation comprising wherein the modified release material is tranexamic acid or a pharmaceutically acceptable salt thereof from the formulation such that the formulation is suitable for administration twice or three times per day Control the release of.

  In certain embodiments, the present invention relates to a modified release oral formulation comprising tranexamic acid or a pharmaceutically acceptable salt thereof and a modified release agent, wherein the modified release agent is administered twice or 3 times a day. The release of tranexamic acid or a pharmaceutically acceptable salt thereof from the formulation is adjusted to be suitable for a single administration, and the formulation is an immediate release oral when administered to all of the patient population. At least one selected from the group consisting of headache, nausea, vomiting, diarrhea, constipation, convulsions, bloating and combinations thereof as compared to the same amount of tranexamic acid or a pharmaceutically acceptable salt thereof in the formulation Reduce side effects.

  In certain embodiments, the invention relates to a modified release oral formulation comprising tranexamic acid or a pharmaceutically acceptable salt thereof and a modified release excipient, wherein the formulation comprises 2 modified release oral formulations per day. It provides a release of tranexamic acid or a pharmaceutically acceptable salt thereof that is slower than an immediate release oral formulation and faster than a controlled release oral formulation to be suitable for single or triple administration.

In certain embodiments, the present invention further relates to a modified release oral formulation comprising about 650 mg tranexamic acid or a pharmaceutically acceptable salt thereof and a modified release agent, wherein the formulation is administered orally 3 times daily. Also suitable for administration, and the formulation is about 5 to about 17.5 mcg / mL, preferably about 6.5 to about 15 mcg / mL, more preferably about 1300 mg of tranexamic acid after a single oral administration to humans. Providing an average maximum plasma concentration (C _max ) of tranexamic acid of about 9 to about 14.5 mcg / mL.

In certain embodiments, the present invention further relates to a modified release oral formulation comprising about 650 mg of tranexamic acid or a pharmaceutically acceptable salt thereof and a modified release agent, wherein the formulation is administered orally twice daily. Also suitable for administration, and the formulation is an average of about 5 to about 40 mcg / mL, preferably about 10 to about 30 mcg / mL tranexamic acid per 1950 mg tranexamic acid after a single oral administration to humans. Provides the maximum plasma concentration (C _max ).

  In certain embodiments, the present invention further relates to a modified release oral formulation comprising about 650 mg tranexamic acid or a pharmaceutically acceptable salt thereof and a modified release agent, wherein the formulation is administered orally 3 times daily. Also suitable for administration, and the formulation is about 5 to about 25 mcg / mL, preferably about 7.5 to about 15 mcg / mL, more preferably about 1300 mg of tranexamic acid after steady state oral administration to humans. An average plasma concentration of tranexamic acid of about 8 to about 10 mcg / mL, most preferably about 9 mcg / mL is provided.

In certain embodiments, the invention further relates to a modified release oral formulation comprising about 650 mg of tranexamic acid or a pharmaceutically acceptable salt thereof and a modified release agent, wherein the formulation is administered 3 times per day. And the formulation is about 5 to about 25 mcg / mL, preferably about 10 to about 20 mcg / mL, more preferably about 1300 mg of tranexamic acid after steady state oral administration to humans. An average maximum plasma concentration (C _max ) of tranexamic acid of 12.5 to about 17.5 mcg / mL, most preferably about 15 to about 17 mcg / mL is provided.

  In certain embodiments, the invention further relates to a modified release oral formulation comprising about 650 mg of tranexamic acid or a pharmaceutically acceptable salt thereof and a modified release agent, wherein the formulation is administered 3 times per day. And the formulation is about 2 to about 10 mcg / mL, preferably about 3 to about 7.5 mcg / mL, more preferably about 1300 mg of tranexamic acid after steady state oral administration to humans. An average plasma trough concentration of tranexamic acid or a pharmaceutically acceptable salt thereof of about 4 to about 7 mcg / mL, most preferably about 5 to about 6 mcg / mL is provided.

  In certain embodiments, the invention further relates to a method of treating a patient with a therapeutically effective amount of tranexamic acid or a pharmaceutically acceptable salt thereof, wherein the method comprises Each formulation comprising from about 585 mg to about 715 mg tranexamic acid or a pharmaceutically acceptable salt thereof, preferably such that the formulation is suitable for oral administration three times per day Contains about 650 mg of tranexamic acid or a pharmaceutically acceptable salt thereof and a modified release substance.

  In certain embodiments, the present invention further relates to a method of treating a patient with a therapeutically effective amount of tranexamic acid or a pharmaceutically acceptable salt thereof, wherein said method comprises Each formulation comprising about 585 mg to about 715 mg of tranexamic acid or a pharmaceutically acceptable salt thereof, preferably such that the formulation is suitable for oral administration twice a day Contains about 650 mg of tranexamic acid or a pharmaceutically acceptable salt thereof and a modified release substance.

  In certain embodiments, the present invention relates to a dose of tranexamic acid or a pharmaceutically acceptable salt thereof comprising two unit dosage forms, wherein the modified release formulation Each unit formulation comprises about 585 mg to about 715 mg of tranexamic acid or a pharmaceutically acceptable salt thereof (preferably about 650 mg of tranexamic acid or a pharmaceutically acceptable salt thereof) and a controlled release substance. The substance provides for the release of tranexamic acid or a pharmaceutically acceptable salt thereof from the formulation such that the dose shows a therapeutic effect when administered three times per day.

  In certain embodiments, the invention relates to a dose of tranexamic acid comprising three unit dosage forms of the modified release formulation, wherein each unit formulation of the modified release formulation is from about 585 mg to about 715 mg. Of tranexamic acid or a pharmaceutically acceptable salt thereof (preferably about 650 mg of tranexamic acid or a pharmaceutically acceptable salt thereof) and a modified release substance, wherein the modified release substance is administered twice a day Providing release of tranexamic acid or a pharmaceutically acceptable salt thereof from the formulation such that the dose exhibits a therapeutic effect.

  In certain preferred embodiments, the present invention further relates to a modified release oral formulation comprising tranexamic acid or a pharmaceutically acceptable salt thereof and a modified release agent, wherein the modified release agent comprises 2 formulations per day. When the formulation is measured at 37 ± 0.5 ° C. in 900 mL of water by the United States Pharmacopeia (USP 27) Type II device paddle method (50 RPM) so that it is suitable for single or triple administration From about 0% to about 40% by weight of tranexamic acid or a pharmaceutically acceptable salt thereof in about 15 minutes, and from about 20% to about 60% by weight of tranexamic acid or a pharmaceutically acceptable salt in about 30 minutes. Salt is released, about 40% to about 80% by weight of tranexamic acid or a pharmaceutically acceptable salt thereof is released in about 45 minutes, and about 50% to about 95% by weight of tranexamic acid or a pharmaceutical thereof in about 60 minutes A top acceptable salt is released and at least about 60% by weight of tranexamic acid or its pharmaceutically acceptable in about 90 minutes. Salt is released, so as to have an in vitro dissolution rate of tranexamic acid or pharmaceutically acceptable salts, to modulate the release of tranexamic acid or pharmaceutically acceptable salt thereof from the formulation.

  In certain preferred embodiments, the present invention further relates to a modified release oral formulation comprising tranexamic acid or a pharmaceutically acceptable salt thereof and a modified release agent, wherein the modified release agent comprises 2 formulations per day. When the formulation is measured at 37 ± 0.5 ° C. in 900 mL of water by the United States Pharmacopeia (USP 27) Type II device paddle method (50 RPM) so that it is suitable for single or triple administration From about 14% to about 22% by weight of tranexamic acid or a pharmaceutically acceptable salt thereof in about 15 minutes, and from about 32% to about 50% by weight of tranexamic acid or a pharmaceutically acceptable salt thereof in about 30 minutes. The salt is released, about 47% to about 71% by weight of tranexamic acid or a pharmaceutically acceptable salt thereof is released in about 45 minutes, and about 61% to about 92% by weight of tranexamic acid or the pharmaceutical thereof in about 60 minutes. From about 79% to about 100% by weight of tranexamic acid or its pharmaceutically acceptable in about 90 minutes. The release of tranexamic acid or its pharmaceutically acceptable salt from the formulation is adjusted to have an in vitro dissolution rate of tranexamic acid or its pharmaceutically acceptable salt that is released.

  In certain embodiments, the invention relates to modified release oral formulations, wherein the modified release oral formulation is 37 ± 0.5 ° C. in 900 mL of water according to the United States Pharmacopeia (USP 27) Type II device paddle method (50 RPM). Tranexamic acid or a pharmaceutically acceptable salt thereof such that the formulation releases about 10% to about 25% by weight of tranexamic acid or a pharmaceutically acceptable salt thereof every 15 minutes when measured in vitro. And an effective amount of a modified release excipient. In certain preferred embodiments, the formulation is about 18% every 15 minutes as measured in vitro at 37 ± 0.5 ° C. in 900 mL of water by the United States Pharmacopeia (USP 27) Type II device paddle method (50 RPM). Releases about 23% by weight of tranexamic acid or a pharmaceutically acceptable salt thereof. Most preferably, the formulation is about 100% tranexam within about 120 minutes as measured in vitro at 37 ± 0.5 ° C. in 900 mL of water by the United States Pharmacopeia (USP 27) Type II device paddle method (50 RPM). Releases acid or pharmaceutically acceptable salt thereof. In certain embodiments, the formulation is about 1% per minute as measured in vitro at 37 ± 0.5 ° C. in 900 mL of water by the United States Pharmacopeia (USP 27) Type II paddle method (50 RPM). Releases tranexamic acid or a pharmaceutically acceptable salt thereof.

  In certain preferred embodiments, the modified release oral formulation of the present invention further provides an average transit time of tranexamic acid of 7.70 ± 0.72 hours when administered to all patient populations.

  In certain preferred embodiments, the modified release oral formulations of the present invention further provide an average absorption time of tranexamic acid of 4.18 ± 0.70 hours when administered to all patient populations.

In certain further embodiments, the modified release oral formulations of the invention comprise In converted pharmacokinetic parameters “AUC _0-t ”, “AUC; _n f” and “C _max for tranexamic acid in plasma. Provides a confidence interval that is within 80-125% of an immediate release formulation containing the same amount of tranexamic acid when administered to all of the patient population under fasting conditions .

  In certain embodiments, the present invention further relates to a modified release oral formulation comprising tranexamic acid or a pharmaceutically acceptable salt thereof and a modified release agent, wherein the modified release agent is administered twice daily per formulation. Or the formulation so that the incidence of headache as a side effect of the formulation is less than about 20% after a single oral administration to all of the patient population. The release of tranexamic acid or a pharmaceutically acceptable salt thereof.

  In certain embodiments, the present invention further relates to a modified release oral formulation comprising tranexamic acid or a pharmaceutically acceptable salt thereof and a modified release agent, wherein the modified release agent is administered twice daily per formulation. Or administered to the entire patient population so that the incidence of nausea as a side effect of the product when administered to the entire patient population is less than about 10% The incidence of nausea as a side effect due to the preparation when administered to all patient populations is preferably less than about 5% so that the incidence of nausea as a side effect due to the preparation is less than about 7%. More preferably, tranexamic acid from the formulation or a pharmaceutically acceptable product thereof is such that the incidence of nausea as a side effect from the formulation after a single oral administration to all patient populations is less than about 2%. Control the release of salt To.

  In certain embodiments, the modified release oral formulation of the present invention has CNS side effects (when administered to the entire patient population compared to the same amount of tranexamic acid or a pharmaceutically acceptable salt thereof in the immediate release formulation. For example, there are few headaches, few GI side effects (eg nausea), or few combinations. In addition or in the alternative, in certain embodiments, the formulation has CNS side effects (e.g., headaches) compared to a therapeutically equivalent amount of tranexamic acid administered intravenously within 5 minutes to the entire patient population. ), GI side effects (eg nausea), or combinations thereof.

  In certain embodiments, a modified release oral formulation of the invention comprises an immediate release oral formulation comprising the same amount of tranexamic acid or a pharmaceutically acceptable salt thereof in the same or different patient population as the modified release formulation. Compared to the immediate release formulation when administered to all, at least one side effect is reduced. Here, the immediate release oral formulation was obtained within about 45 minutes when measured in vitro at 37 ± 0.5 ° C. in 900 mL of water by the United States Pharmacopeia (USP 27) type II device paddle method (50 RPM). Releases all of the acid or its pharmaceutically acceptable salt. Such side effects can be, for example, headache, nausea, vomiting, diarrhea, constipation, convulsions, bloating and combinations thereof.

  In certain embodiments, the modified release oral formulation of the present invention, when administered to the entire patient population, is at least about 20 minutes, preferably about 30 minutes longer than the immediate release formulation comprising the same amount of tranexamic acid. Provides the average transit time of the acid.

  In certain embodiments, the formulation of the present invention has an average of tranexamic acid that is at least about 20 minutes, preferably about 30 minutes longer than an immediate release formulation comprising the same amount of tranexamic acid when administered to the entire patient population. Provides absorption time.

  In certain preferred embodiments, a therapeutically effective dose of tranexamic acid or a pharmaceutically acceptable salt thereof is provided by administering two or more dosage units. For example, if the dosage unit contains 650 mg tranexamic acid or a pharmaceutically acceptable salt thereof and the dose for administration is about 1300 mg, two doses are administered to a patient in need of such treatment. A unit is administered or, for example, if the dose for administration is about 1950 mg, 3 dosage units are administered.

  In certain preferred embodiments, the present invention further relates to a method of treating a patient with one or more modified release oral formulations comprising tranexamic acid or a pharmaceutically acceptable salt thereof and a modified release agent, wherein The oral formulation provides a therapeutically effective plasma level of tranexamic acid or a pharmaceutically acceptable salt thereof according to a three times daily (TID) dosing schedule, and the therapeutically effective dose administered is about Contains 1300 mg of tranexamic acid or a pharmaceutically acceptable salt thereof.

  In certain preferred embodiments, the present invention further relates to a method of treating a patient with one or more modified release oral formulations comprising tranexamic acid or a pharmaceutically acceptable salt thereof and a modified release agent, wherein The oral formulation provides a therapeutically effective plasma level of tranexamic acid or a pharmaceutically acceptable salt thereof according to a twice daily (BID) dosing schedule, and the therapeutically effective dose administered is about Contains 1950 mg tranexamic acid or a pharmaceutically acceptable salt thereof.

  In certain embodiments, the present invention provides a modified release formulation of the invention comprising tranexamic acid or a pharmaceutically acceptable salt thereof and a controlled release agent in a patient in need of treatment with tranexamic acid or a pharmaceutically acceptable salt thereof. Of tranexamic acid in the range of about 5 mcg / mL to about 15 mcg / mL by administering 3 times daily.

  In certain embodiments, the invention further relates to a method of treating a human patient suffering from severe menstrual bleeding (menorrhea), wherein the method comprises about 1300 mg of tranexamic acid or The pharmaceutically acceptable salt is administered three times a day to produce tranexamic acid or a pharmaceutically acceptable salt thereof in the range of about 5 mcg / mL to about 15 mcg / mL after steady state oral administration to a human patient. Providing a plasma concentration.

  In certain embodiments, the present invention provides polymenorrhea, cervical colectomy by administering at least one formulation of the present invention to a patient in need of treatment with tranexamic acid or a pharmaceutically acceptable salt thereof. Treat patients with nasal bleeding, anterior chamber bleeding or hereditary angioedema, patients undergoing oral surgery and suffering from blood coagulation disorders, or a combination thereof Regarding the method.

  In certain embodiments, the invention relates to a method of treating severe menstrual bleeding with a therapeutically effective dose of at least one oral formulation of the invention comprising tranexamic acid or a pharmaceutically acceptable salt thereof and a modified release substance. Here, the menstrual blood flow per menstrual cycle is reduced by at least about 10 mL, preferably at least about 20 mL, more preferably at least about 40 mL. In the most preferred embodiment, the amount of menstrual blood per menstrual cycle is reduced by about 50 mL or more.

  In certain embodiments, the invention relates to a method of treating severe menstrual bleeding with a therapeutically effective dose of at least one oral formulation of the invention comprising tranexamic acid or a pharmaceutically acceptable salt thereof and a modified release substance. Wherein the modified release substance has a menstrual blood flow rate of from about 35 mL to about 200 mL, preferably from about 40 mL to about 175 mL, more preferably from about 50 mL when administered orally to a human female. Reduce by about 150 mL.

  In certain embodiments, the present invention further treats severe menstrual bleeding with a therapeutically effective dose of at least one oral formulation of the present invention comprising tranexamic acid or a pharmaceutically acceptable salt thereof and a controlled release agent. With respect to the method, wherein the modified release agent reduces the blood flow per menstrual cycle by about 20% to 100%, preferably about 20% to about 70% when administered orally to a human female.

The amount of menstrual blood can be measured by a method known in the art. For example, in certain embodiments, the menstrual blood volume is (i) L. Hallbert, et al. ("Determination of Menstrual Blood Loss", Scandinav. J. Clin. & Lab. Investigation , 244-248, 16, 1964. (Where the method extracts menstrual blood from vaginal tampon and sanitary napkin with sodium hydroxide solution, converts heme pigment source to alkaline hematin and measures it spectrophotometrically) The blood flow can be measured by (ii) J. Newton, MD, et al. ("A Rapid Method for Measuring Menstrual Blood Loss Using Automatic Extraction.", Contraception , 269- 282, September 1977, Vol. 16, No. 3) where the formation of alkaline hematin after extraction of blood from vaginal tampon and sanitary napkin by automated Stomacher Lab-Blender Based on). The disclosure of the above article is incorporated herein by reference in its entirety.

  In certain embodiments, the modified release material can be incorporated into a coating applied to the surface of a tablet comprising, for example, tranexamic acid or a pharmaceutically acceptable salt thereof, or tranexamic acid or a pharmaceutically acceptable salt thereof. Can be incorporated into a matrix containing the resulting salts, or can be incorporated into a combination thereof. For example, in certain preferred embodiments, the modified release material is a controlled release material such as a gel-forming or hydratable polymer added to a matrix composition comprising, for example, tranexamic acid or a pharmaceutically acceptable salt thereof. It is.

  In certain embodiments, tranexamic acid for use in the methods and formulations of the present invention is in the form of its pharmaceutically acceptable salt. Examples of such salt forms include, but are not limited to, sodium salts, potassium salts, calcium salts, magnesium salts, and the like, and hydrochloride forms, hydrobromide forms, sulfate salts, and the like. Form, phosphate form, formate form, acetate form, trifluoroacetate form, maleate form, tartrate form, methanesulfonate form, benzenesulfonate form, p-toluenesulfonate form methanesulfonate form And so on. Preferably, the active ingredient for use according to the present invention is tranexamic acid.

  For the purposes of the present invention, an “immediate release oral dosage form” is measured in vitro at 37 ± 0.5 ° C. in 900 mL of water according to the US Pharmacopeia (USP 27) Type II device paddle method (50 RPM). A formulation that releases all of the active ingredient (eg, tranexamic acid) contained therein within about 45 minutes.

  For the purposes of the present invention, a “modified release oral dosage form” refers to an active ingredient (e.g., tranexamic acid) contained therein that contains the same amount of active ingredient as the modified release oral dosage form. An oral formulation that releases slower than an immediate release oral formulation when included and releases faster than a controlled release oral formulation. As used in this application, one definition for the terms `` slower '' and `` faster '' is that each measurement at 15-minute intervals is statistically It shows a significant difference. In certain preferred embodiments, the modified release oral dosage form of the invention is about 45 minutes when measured at 37 ± 0.5 ° C. in 900 mL of water by the United States Pharmacopeia (USP 27) Type II device paddle method (50 RPM). Less than about 70% by weight of tranexamic acid or a pharmaceutically acceptable salt thereof is released, and about 100% by weight of tranexamic acid or a pharmaceutically acceptable salt thereof is released in about 120 minutes. Has an in vitro dissolution rate of acceptable salts.

  For the purposes of the present invention, a “controlled release oral dosage form” was measured in vitro in 900 mL of water at 37 ± 0.5 ° C. according to the US Pharmacopeia (USP 27) Type II device paddle method (50 RPM). Sometimes the formulation releases all of the active ingredient (eg, tranexamic acid) contained therein after about 4 hours or more.

For the purposes of the present invention, the term “C _max ” means the maximum plasma concentration of a drug achieved after a single dose of a formulation, unless otherwise indicated, or By steady state according to the invention is meant the maximum plasma concentration of the drug achieved over the entire dosing interval by multiple doses.

For the purposes of the present invention, the term “T _max ” is intended to mean the elapsed time from administration of a formulation to the point at which the C _max of the drug is reached.

  The term “steady state” means that the amount of the drug reaching the system is approximately equal to the amount of the drug leaving the system. Thus, in “steady state”, the patient's body excretes the drug at approximately the same rate that the drug becomes available to the patient's entire body via absorption into the bloodstream.

For the purposes of the present invention, the term “mean”, when used to define a pharmacokinetic value (eg, T _max ), unless otherwise specified, is the patient or subject. Represents the arithmetic mean value measured for all members of the group.

  For the purposes of the present invention, the term "three times a day (TID) basis" means that the dosage is 3 doses per day, preferably on an 8 hour schedule. To do.

The term `` mean transit time '' is understood by those skilled in the art and the document `` Applied Pharmacokinetics, Principles of Therapeutic Drug Monitoring , Second Edition (1986), edited by William E. Evans, et al. '' (The disclosure of this document is incorporated herein by reference in its entirety) When 63.2% of the total AUC is reached after oral administration, or 63.2% of the IV dose is excreted. Means the point in time.

The term “mean absorption time” is understood by those skilled in the art and is also the document “ Applied Pharmacokinetics, Principles of Therapeutic Drug Monitoring , Second Edition (1986), edited by William E. Evans, et al. Means a quantitative parameter that briefly describes the average time that a drug molecule remains unabsorbed (i.e., the average time that the drug molecule remains in the gastrointestinal tract as it is in the formulation). To do. Unlike the absorption rate constant (ka), which can distort the fact, the average absorption time is the inadequate release of drug from its formulation, irregular absorption, lag time, mixed zero-order dissolution rate (mixed Zero-order dissolution rate), changing GI motility, GI blood flow, and first-pass effects.

The concentration-time profile when 1.3 g of the tranexamic acid release-regulating formulation of Example 1 was dosed on a 6:00 AM, 2:00 PM and 10:00 PM Q8H (every 8 hours) dosing schedule was determined as 1 g Q8H. It is a figure showing comparing with administration. The concentration-time profile when 1.3 g of the tranexamic acid release-regulating formulation of Example 1 was administered on a TID (3 times per day) dosing schedule at 8:00 AM, 2:00 PM and 8:00 PM was shown as 1 g TID. FIG. FIG. 6 represents the mean plasma concentration-time profile on a semi-log scale over 36 hours for the test of Example 4. FIG. 5 represents mean plasma concentration-time profiles on an equal scale over 36 hours for the test of Example 4.

  In the treatment of HMB (Heavy Menstrual Bleeding), the usage typically described for tranexamic acid is 1 to 1.5 g per dose on the day that a large amount of menstrual bleeding begins. It is administered 3-4 times a day and continues for the first 3-5 days of the menstrual cycle. However, the most frequently reported use for tranexamic acid is an immediate-release oral formulation that administers 1 g of tranexamic acid 4 times per day (4 g per day) to treat HMB outside the United States. Knowledge of this general usage can be found in randomized controlled trials published in the medical literature, product labeling by regulatory authorities in other countries with products approved for HMB treatment, Sweden (Rybo 1991) Is supported by a careful review of round-trip letters and interviews with non-US clinicians who have experience with the product. The regimen is currently a dosage studied by the US Centers for Disease Control (CDC) in women suffering from HMB associated with bleeding abnormalities.

The absolute bioavailability of tranexamic acid observed in male subjects when administered in Europe (Cyklokapron, Kabi AB, Sweden Batch 90288; assay 499 mgm / tablet) is approximately 35%. Yes, its excretion correlates with renal creatinine clearance. Serum tranexamic acid peak concentration is reached approximately 3 hours after oral administration of European immediate release tablets (over 85% dissolved in 15 minutes) (Pilbrant, et al., Eur. J. Clin. Pharmacol , (1981) -20: 65-72). In comparison, the in vivo absorption profile observed with European immediate release formulations is slow and very gradual over 3 hours. Specifically, tranexamic acid serum concentrations were 9%, 41%, 73% and 88% of maximum absorption at 0.5 hours, 1 hour, 1.5 hours and 2 hours, respectively, after oral administration of 2 g. % (With food and drink) and 22%, 63%, 85% and 98% (fasted state). While not wishing to be bound by any particular theory, at present, to explain the discrepancy between product dissolution time and relatively long T _max (time to reach peak serum concentration), oral The absorption of tranexamic acid appears to be controlled by a non-dissolution rate limited process, i.e. the rate and extent of oral absorption correlates with a process that is restricted by membrane passage. It is assumed that there is a relationship.

Preferably, the goal of the formulations, dose strength and usage of the present invention is to provide an HMB treatment that reduces menstrual blood flow per menstrual cycle by about 20% to 100%. According to certain embodiments of the invention, a preferred dose of tranexamic acid of 1.3 g every 8 hours is at an average serum tranexamic acid concentration (ie 12.4 mcg / mL) obtained with a 1 g dosing regime every 6 hours. It is expected to produce comparable mean serum tranexamic acid concentrations, with related peaks and troughs approximately within the therapeutic antifibrinolysis range (5-15 mcg / mL; Cyklokapron NDA 19-280). In certain embodiments, a two-compartment oral absorption and elimination simulation model combined with pharmacokinetic data (Pilbrant, et al., Eur. J. Clin. Pharmacol , (1981)- 20: 65-72) as well as information on the dissolution capacity of tablets with controlled release, the preferred main usage was determined.

  In an immediate release formulation, the total dose and soluble components in the formulation dissolve in the gastrointestinal fluid and provide a high concentration of solute to be absorbed. The most frequently reported side effects are mainly restricted to the proximal gastrointestinal tract (nausea and vomiting). The symptoms of these side effects appear to be related to the amount of drug that has reached the gastric mucosa, because this action reduces the dose of the immediate release oral formulation or the product. This is because it can be minimized by slow administration by intravenous route. In certain embodiments, preferred oral modified release formulations of the invention (e.g., 1.3 g administered every 8 hours) reduce the incidence of proximal gastrointestinal side effects, which include, for example, the drug This is due to the modified release characteristics of the formulation.

  In certain embodiments, the oral formulations of the present invention provide increased bioavailability as compared to currently available immediate release oral formulations (eg, Cyclokapron). In certain preferred embodiments, its increased bioavailability makes it possible to reach plasma levels with the therapeutic effect of tranexamic acid at low dosages. Preferably, its increased bioavailability further reduces the amount of tranexamic acid that is not absorbed and remains in the gastrointestinal tract, resulting in high levels of tranexamic acid that are not absorbed, resulting in high levels of the gastrointestinal tract. The incidence of side effects typically associated with long-term exposure to tranexamic acid is reduced. Preferably, the oral formulation of the present invention has greater than 40% bioactivity of tranexamic acid, about 41% to about 60% bioavailability of tranexamic acid after oral administration to humans, preferably About 42% to about 50%, more preferably, about 45% of tranexamic acid bioavailability is provided.

  The tranexamic acid modified release oral formulation of the present invention provides a slower drug release than the immediate release 500 mg Cyklokapron product currently marketed in Canada. Here, the immediate-release 500 mg Cyklokapron product contains 100% by weight of tranexam in about 15 minutes when measured at 37 ± 0.5 ° C. in 900 mL of water by the US Pharmacopoeia (USP 27) Type II device paddle method (50 RPM). It provided the average release rate at which the acid was released.

  In certain embodiments, the modified release oral formulation may be described as providing an average transit time through the proximal gastrointestinal mucosa that is about 30 minutes longer than the immediate release formulation. In another preferred embodiment, the modified release formulation of the present invention is about 20%, about 40%, about 60%, about 60%, about 0.25 hours, 0.5 hours, 0.75 hours, 1 hour, and 1.5 hours, respectively. Provides a release rate of (dissolved) tranexamic acid from the formulation in vitro of 80% and about 100%. In certain preferred embodiments, such a release rate in vitro is such that the formulation of the present invention is in close proximity to dissolved tranexamic acid at 0.25 hours, 0.5 hours, 0.75 hours, 1 hour and 1.5 hours, respectively, following oral administration. Demonstrate that the amount and rate of reaching the distal gastric mucosa is reduced to about 20%, about 40%, about 60%, about 80% and about 100%.

  In certain embodiments, the majority of tranexamic acid absorption appears to occur slowly distal to the stomach and, assuming linear pharmacokinetics, the modified release formulation is currently used outside the United States. An absorption profile comparable to that achieved with available oral immediate release formulations is achieved.

  In accordance with the present invention, a modified release tranexamic acid tablet for oral administration is disclosed. Preferably, the tablet comprises at least one substance (herein described) that minimizes or eliminates gastrointestinal side effects in patients (e.g. women who have been orally administered tranexamic acid to treat menorrhagia). The document includes any active substance (ie, defined as any substance other than tranexamic acid).

  Such modified release oral formulations of tranexamic acid for the purposes of the present invention are known in the art as extended release formulations, sustained release formulations and controlled release formulations. The formulation ingredients and / or shapes typically used in certain formulations are adjusted to provide a desired release rate consistent with the teachings of the present invention. The modified release formulation is preferably by controllably releasing tranexamic acid over a period of time after administration, as opposed to an immediate release formulation that releases all doses of tranexamic acid at once. Reduce the concentration of tranexamic acid and other substances that dissolve in the gastric juice. The modified release formulations of the present invention thus minimize or prevent gastrointestinal reactions and side effects that occur when a particular dose of tranexamic acid is ingested and reaches the stomach immediately.

  The modified release formulations of the present invention can be prepared as tablets, capsules, granules, pellets, powders, dragees, troches, non-pareils, pills or encapsulated suspensions. Yes, it can be put in a capsule or sachet. Such formulations can be prepared by any formulation technique that regulates the release of the active substance (tranexamic acid) from the formulation to occur at a rate that is slower than the rate of release from the immediate release product. In such a formulation, tranexamic acid is released in the stomach and / or intestine, but the dissolved drug bolus does not reach the surface in the stomach and does not cause side effects or tranexamic acid. Is released at a slower rate so that the intensity and frequency of side effects can be reduced by lowering the concentration of. Thus, side effects are preferably reduced or minimized or eliminated.

  Methods for preparing modified release formulations are described in `` Modified Release Drug Delivery Technology, Rathbone, Hadgraft, and Roberts, Eds., Drugs and the Pharmaceutical Sciences, Vol. 126, Marcel Dekker Inc., New York, 2003 '', `` Modern Pharmaceutics, Third Edition, Banker and Rhodes, Eds.Drugs and the Pharmaceutical Sciences, Vol. 72, Marcel Dekker Inc., New York, 1996 '', `` Sustained and Controlled Release Drug Delivery Systems, Robinson, Ed., Drugs and the Pharmaceutical Sciences, Vol. 6, Marcel Dekker Inc., NY 1978, Sustained Release Medications, Chemical Technology Review No. 177, Johnson, Ed., Noyes Data Corporation 1980, and Controlled Drug Delivery, Fundamentals and Applications, Second Edition, Robinson and Lee, Eds., Marcel Dekker Inc., New York, 1987 ”and in US Pat. No. 6,548,084. Each of these references is specifically incorporated herein by reference.

Preferably, due to the modified release form, tranexamic acid is effective over a long period after ingestion. The modified release formulation is coupled with the digestive and absorption processes in the gastrointestinal tract, compared to the administration of tranexamic acid provided as a conventional formulation (e.g., as a solution or as an immediate release formulation). The amount of tranexamic acid in the solution state is reduced. The modified release formulation is in accordance with Food and Drug Administration standards (for example, as described in “ www.fda.gov. 21 CFR §314, 320” and “USP 23 NF 18 §711,724”). Can be demonstrated by evidence support for in vivo bioequivalence and in vitro dissolution tests. Confirm release of tranexamic acid from the formulation using, for example, an in vitro dissolution test such as the United States Pharmacopeia (USP 27) Type II Device Paddle Method (50 RPM) performed at 37 ± 0.5 ° C in 900 mL of water be able to.

  Formulating a tranexamic acid modified-release tablet to provide a specific dose of tranexamic acid (typically about 500 mg to about 2 g per 1-2 tablets) within the first 1-2 hours after taking the tablet Can do. Thus, over a predetermined period of time (eg, about 60 minutes to about 120 minutes), tranexamic acid is released at a planned rate. The release rate of tranexamic acid over that period is planned so that tranexamic acid can be absorbed in the gastrointestinal tract while simultaneously reducing the concentration of tranexamic acid in the stomach. Absorption of tranexamic acid typically begins as soon as tranexamic acid is released from the formulation and dissolves in gastrointestinal fluid in contact with the membrane lining the gastrointestinal tract. The release rate of tranexamic acid from the formulation and the absorption of the drug by the gastrointestinal mucosa contributes to keeping the concentration of the drug in the gastrointestinal fluid low. Lower concentrations preferably reduce the intensity of gastrointestinal side effects, less frequent, and / or reduce severity. The planned release rate of tranexamic acid from the formulation in the stomach and upper small intestine, the spontaneous elimination of gastric fluid from the stomach with little dissolved tranexamic acid, and from a larger part of the gastrointestinal tract (i.e. longer release times). Absorption of tranexamic acid, preferably from the stomach and the small intestine, but not from the stomach alone or from the lower part of the small intestine, preferably proximal or distal gastrointestinal The level of dissolved tranexamic acid at the site of the tube is reduced. Reducing the concentration of tranexamic acid along the gastrointestinal tract preferably reduces the gastrointestinal side effects associated with oral tranexamic acid therapy.

  As used herein, reducing side effects using the above formulation means some reduction in one or more symptoms, such as reduced incidence, reduced severity, or reduced symptom duration, etc. And is not limited to the absence of symptoms or the removal of symptoms. Thus, treatment includes the incidence, duration, and duration of adverse gastrointestinal symptoms (such as, but not limited to, headache, nausea, vomiting, diarrhea, constipation, convulsions, bloating and combinations thereof) Reductions in strength, frequency, etc. are included. The formulation may reduce symptoms at any point during the course of tranexamic acid therapy, but minimally controlled side effects may occur immediately or shortly after administration, i.e. within the first hours after administration. Especially recognized. As used herein, adverse gastrointestinal effects and side effects are exchanged to indicate non-therapeutic effects (i.e., effects not related to any possible beneficial effects caused by tranexamic acid). The range of use ranges from unpleasant but tolerable sensations to severe gastrointestinal symptoms. As used herein, the terms "oral formulation", "ingestable formulation" and "orally administered formulation" are used interchangeably and are taken by mouth. Includes all formulations, including but not limited to tablets, pills, solutions, gel cups, soft gels, dragees, capsules, powders, granules, pellets, etc. Can be mentioned.

  Tranexamic acid modified release formulations include tablets, pellets, granules, capsules, or other oral formulations prepared to release tranexamic acid in a planned manner. In certain embodiments, the modified release material is a gel-forming polymer, a hydratable polymer, a water-soluble polymer, a water-swellable polymer, or a mixture thereof.

In certain embodiments, modified release tranexamic acid tablets are prepared by adding a modified release material comprising a gel-forming polymer or a hydratable polymer to the tranexamic acid tablet composition. Suitable gel-forming polymers or hydratable polymers include, but are not limited to, hydroxypropylcellulose, hydroxypropylmethylcellulose (or hypromellose), carboxymethylcellulose and polyvinyl alcohol. This gives a compressed tablet, which may or may not be film coated. The tablets release tranexamic acid by diffusion of tranexamic acid through the tablet matrix, by erosion of the tablet matrix, or by a combination of diffusion from the tablet matrix and erosion of the tablet matrix. Tablets formed with water-swellable polymers release tranexamic acid by diffusion of tranexamic acid through the tablet matrix, by erosion of the tablet matrix, or by a combination of diffusion from the tablet matrix and erosion of the tablet matrix To do. One or more water-soluble hydrophilic polymers can also be used. Such as polyvinylpyrrolidone, hydroxypropylcellulose, hydroxypropylmethylcellulose (which is now referred to as hypromellose (e.g. MethocelTM, Dow Chemical Company)), methylcellulose, vinyl acetate / crotonic acid copolymer, methacrylic acid. Mention may be made of acid copolymers, maleic anhydride / methyl vinyl ether copolymers, derivatives thereof and mixtures thereof. In various embodiments, the polymer is hydroxypropylcellulose or hydroxypropylmethylcellulose. The polymer can be hydroxypropyl-methylcellulose having a viscosity in the range of about 50 cps to about 200 cps. The polymer can be 100 cps hydroxypropyl-methylcellulose, a clay marketed as Methocel ^™ K 100 LV (Dow Chemical Company). The amount of polymer in the composition can range from about 5% to about 50% by weight of the composition. In various embodiments, the polymer ranges from about 10% to about 35% by weight of the composition, or ranges from about 10% to about 30% by weight of the composition.

  In certain embodiments, the modified release material is a vinyl polymer, a phthalic acid derivative of a vinyl copolymer, a hydroxyalkyl cellulose, an alkyl cellulose (eg, ethyl cellulose), cellulose acetate, hydroxyalkyl cellulose acetate, cellulose ether, alkyl cellulose acetate and the like As well as lower alkyl acrylic acid and lower alkyl acrylate polymers and copolymers and their partial esters, or combinations thereof. In a preferred embodiment, the modified release material is hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, methylcellulose, vinyl acetate / crotonic acid copolymer, methacrylic acid copolymer, maleic anhydride / methyl vinyl ether copolymer, they Derivatives thereof, and mixtures thereof. In a preferred further embodiment, the modified release material comprises a polymer such as a methacrylic acid copolymer. They are neutral acrylic acid esters or copolymers of methacrylic acid and methacrylic acid, such as ethyl acrylate or methyl methacrylate.

  In certain embodiments, the release modifier is a pH independent binder or film former, such as hydroxypropyl methylcellulose, hydroxypropylcellulose, methylcellulose, polyvinylpyrrolidone, neutral poly (meth) acrylate (e.g., Diluents such as lactose, such as methyl methacrylate / ethyl acrylate copolymer sold as Eudragit® (Rohm Pharma), starch, gelatin, sugars (e.g. glucose, sucrose and mannitol), silicic acid, carboxymethylcellulose, etc. , Mannitol, dry starch, microcrystalline cellulose, etc., surfactants such as polyoxyethylene sorbitan esters, sorbitan ethers, coloring agents, flavoring agents, lubricants such as talc, calcium stearate and Magnesium phosphate, solid polyethylene glycols, sodium lauryl sulfate, and other tableting aids including (tableting aid). Any combination of the binders or film formers described above can be included in the modified release material. The modified release material can be combined with tranexamic acid to form a modified release formulation.

  In certain embodiments, the formulation comprises tranexamic acid in the range of about 50% to about 95% or more by weight of the formulation. In another embodiment, tranexamic acid is in the range of about 60% to about 90%, or in the range of about 60% to about 80% by weight of the formulation. The remaining weight is composed of the modified release material and additional excipients.

  To prepare a modified release tablet, an agent that slows the release rate of tranexamic acid or a modified release agent can be incorporated into the tablet matrix and / or coated on the tablet surface. Can be implemented. In certain embodiments, prepared tablets are formulated by granulating a powder blend of the modified release material. A powder blend is formed by combining some of the powdered ingredients that make up the tablet. The powders are intimately mixed by dry mixing. The dry blended mixture is granulated by wet mixing the binder solution and the powder mixture. By controlling the time of the wet mixing, the dissolution rate of the resulting formulation can be influenced. For example, the total powder mixing time, i.e., the time to granulate the powder, can range from about 1 minute to about 10 minutes, or can range from about 2 minutes to about 5 minutes. Subsequent to granulation, the particles are removed from the granulator and placed in a fluid bed dryer, vacuum dryer, microwave dryer or box dryer for drying. The drying conditions are sufficient to remove unwanted granulation solvent (typically water) or to reduce the amount of granulation solvent to an acceptable level. The drying conditions for fluid bed dryers or box dryers are typically about 50-70 ° C. The granulate is dried, sieved, mixed with additional excipients such as disintegrants, fluidizers, or compression aids and lubricants such as talc, stearic acid or magnesium stearate and compressed. Use tablets.

  In certain embodiments, tablets containing a modified release material within the tablet matrix may be coated with any film forming agent. This applied coating can, for example, aid in identification, mask unpleasant flavors, allow for a desired color and appearance, enhance elegance, and aid in swallowing Can also be an enteric coating. The amount of such film former may range from about 2% to about 4% of the tablet weight. Suitable film formers are known to those skilled in the art and include, for example, hydroxypropylcellulose, cellulose esters, cellulose ethers, one or more acrylic polymers, hydroxypropylmethylcellulose, cationic methacrylate copolymers, (diethylaminoethyl) methacrylate / methyl- There are butyl-methacrylate copolymers such as Eudragit E® (Rohm Pharma). The film-forming agent may optionally contain a colorant, a plasticizer, a bulking agent, etc., such as, but not limited to, propylene glycol, sorbitan monooleate, sorbic acid , Titanium dioxide, and one or more pharmaceutically acceptable dyes.

  In certain embodiments, the tranexamic acid tablets of the present invention are coated with a modified release material. In certain embodiments, tranexamic acid tablets are formulated by dry mixing, rotary compacting, or wet granulating a powder composed of tranexamic acid and tablet excipients. Such powder is compressed into immediate release tablets. The immediate release tablet is coated with a controlled release material as described herein to make the tranexamic acid tablet a controlled release tablet.

  In addition to the modified release material, the formulations of the present invention include appropriate amounts of other materials, such as preservatives, diluents (eg, microcrystalline cellulose), lubricants conventional in the pharmaceutical arts. (E.g., stearic acid, magnesium stearate, etc.), binders (e.g., povidone, starch, etc.), disintegrants (e.g., croscarmellose sodium, corn starch, etc.), glidants (e.g., talc, colloids, etc.) , Etc.), granulation aids, colorants, flavoring agents, and the like. A specific example of a pharmaceutically acceptable excipient that can be used to formulate an oral formulation is "Handbook of Pharmaceutical Excipients, American Pharmaceutical Association (2003)", which is incorporated herein by reference. It is described in.

  The release process can be adjusted to obtain the desired dissolution profile by varying the type, amount and ratio of the ingredients, as is known to those skilled in the art. The coating is a partially neutralized pH-dependent that controls the dissolution rate of tranexamic acid in aqueous media in the full range of pH inside the stomach (pH about 2) and inside the small intestine (upper pH about 5.5) It can be a sex binder. In certain embodiments, the one or more pH dependent binders are used so that tranexamic acid is released slowly and continuously as the formulation passes through the stomach and / or intestine. The dissolution profile can be adjusted.

  In one embodiment, the modified release compressed tablet is formulated to meet US Pharmacopoeia standards and to have a size and shape that can be easily swallowed. The tablet dimensions are determined by the specific excipients selected to provide the tranexamic acid dosage required to provide sufficient therapy and the physical properties required for tableting and controlled release. Depends on the formulation. In various embodiments, the modified release compressed tablet comprises about 500 mg to about 1 g tranexamic acid, or comprises about 600 mg to about 750 mg tranexamic acid. A daily dose of tranexamic acid can be achieved by taking one or two tablets at each administration.

  In certain embodiments, the tranexamic acid contained in the formulation is from about 375 mg to about 1500 mg, preferably from about 375 mg to about 1000 mg. In one embodiment, the dosage of tranexamic acid per tablet ranges from about 500 mg to about 1000 mg for tablets and about 500 mg to about 1500 mg for sachets packed with granules. In another embodiment, the dose of tranexamic acid is about 3 g / day to about 6 g / day, administered in two or three divided doses. As an example, 3 grams of tranexamic acid as a total daily dose can be divided into 3 doses, each time each tablet containing 1 g of tranexamic acid can be administered, or divided into 4 doses. Each time, each tablet can contain one tablet containing 0.75 g of tranexamic acid. As another example, 4 grams of tranexamic acid as a total daily dose can be divided into 3 doses, each time each tablet can contain 2 tablets containing 0.666 g of tranexamic acid, or in 4 doses. Separately, each time one tablet can be administered, each tablet containing 1 g of tranexamic acid. As another example, 5 grams of tranexamic acid as a total daily dose can be administered in 3 divided doses, each time one tablet containing 1.66 g of tranexamic acid, or 4 times Separately, each time, two tablets each containing 0.625 g of tranexamic acid may be administered. As another example, 6 grams of tranexamic acid as a total daily dose can be divided into 3 doses, each time, each tablet can receive 2 tablets containing 1 g of tranexamic acid, or divided into 4 doses Each time, two tablets each containing 0.75 g of tranexamic acid can be administered. To facilitate swallowing, the dose of tranexamic acid taken at each administration may be delivered by taking multiple tablets. For example, a daily dose of 4 grams may be delivered by taking two 666.67 mg tablets three times a day, or taking two 500 mg tablets four times a day. Similarly, a daily dose of 3 grams can be delivered by taking two 550 mg tablets three times per day or taking two 375 mg tablets four times per day. Alternatively, a dosage of 600 mg, 650 mg or 700 mg tranexamic acid per tablet may be used for ease of reference. In a preferred embodiment, the total daily dose of 3900 mg / day is divided into three, and for each administration, 2 tablets (where each tablet contains 650 mg tranexamic acid) is administered 1300 mg. Alternatively, each dose can be delivered by taking a provided amount of granules containing a prescribed amount of tranexamic acid in a conventional package. The above examples are non-limiting and those skilled in the art will appreciate other doses within the above ranges.

  Alternatively, the modified release tranexamic acid formulation can be administered by pellets or granules, for example in sachets or capsules. Modified release tranexamic acid pellets or granules can be prepared using substances that modulate the release of tranexamic acid from the granule matrix or pellet matrix. Modified release preparations can also be formulated with a coating that modulates the release of tranexamic acid from granules or pellets. US Pat. No. 5,650,174 and US Pat. No. 5,229,135, each of which is specifically incorporated herein by reference in its entirety, disclose variations in the manufacture of pellets or nonpareil formulations. The spheres are placed in a package or capsule called a sachet, which is packed on a weight basis to contain a predetermined dose of drug. The multiparticulate can be coated with a modified release coating, as disclosed in US Pat. No. 6,066,339, which is specifically incorporated herein by reference in its entirety. The coated multiparticulates can be placed in capsules or sachets. The formulation of granules or pellets for controlled release is described in "Multiparticulate Oral Drug Delivery, Ghebre-Sellassie, Ed. In Drugs and the Pharmaceutical Sciences, Vol. 65 Marcel Dekker Inc. NY, 1994". And in the relevant part of the references cited above for modified release formulations. This relevant part is incorporated herein by reference.

  In certain embodiments, the tranexamic acid formulations of the present invention may be used for additional indications other than menorrhagia, such as cervical conectomy, nasal bleeding, anterior chamber bleeding and hereditary angioedema, and oral surgery. It can be used for patients who are suffering from blood coagulation disorders and combinations thereof.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS The invention will be further understood with reference to the following non-limiting examples. Other variations or embodiments of the invention will be apparent to those skilled in the art based on the above description and examples. Therefore, the above embodiments should not be construed as limiting the scope of the present invention.

Example 1
A modified release 650 mg tranexamic acid tablet having the ingredients listed in Table 1 below was prepared.

  The formulation of Example 1 was prepared as follows.

  1. Weigh all ingredients and keep in moisture-proof container until ready for use.

  2. Weigh water into a container. Mix povidone at medium speed until completely dissolved.

  3. Add tranexamic acid, microcrystalline cellulose (MCC), pregelatinized corn starch and colloidal silicon dioxide to the high shear mixer.

  4. Mix using impeller only.

  5. Mix further for a specified time (impeller only). All of the povidone solution is added during this mixing step.

  6. Mix until fully granulated (impeller and chopper). Only when the desired granules are obtained, proceed to the next step. If necessary, add more water.

  7. Dry the granules until the water content is 1.2% NMT.

  8. Pass the granules through a vibrating granulator equipped with a # 30 mesh screen. Weigh the granules. Add the granules to the V-blender.

  9. Add hypromellose (USP Methocel K3 Premium) to the V-blender. Mix.

  10. Pass magnesium stearate and stearic acid through a vibrating granulator equipped with a # 40 mesh screen. Magnesium stearate and stearic acid are added to the V-blender and mixed.

  11. Perform specified physical property tests. Proceed to the compression process.

  12. Compress the tablets to the desired weight.

Example 2
In Example 2, an immediate release 650 mg tranexamic acid tablet having the ingredients listed in Table 2 below was prepared.

  The formulation of Example 2 was prepared as follows.

  1. Weigh all ingredients and keep in moisture-proof container until ready for use.

  2. Weigh water into a container. Mix povidone at medium speed until completely dissolved.

  3. Add tranexamic acid, microcrystalline cellulose (MCC), pregelatinized corn starch and colloidal silicon dioxide to the high shear mixer.

  4. Mix using impeller only.

  5. Mix further for a specified time (impeller only). All of the povidone solution is added during this mixing step.

  6. Mix until fully granulated (impeller and chopper). Only when the desired granules are obtained, proceed to the next step. If necessary, add more water.

  7. Dry the granules until the water content is 1.2% NMT.

  8. Pass the granules through a vibrating granulator equipped with a # 30 mesh screen. Weigh the granules. Add the granules to the V-blender.

  9. Add croscarmellose sodium and MCC to the V-blender and mix.

  10. Pass magnesium stearate and stearic acid through a vibrating granulator equipped with a # 40 mesh screen. Magnesium stearate and stearic acid are added to the V-blender and mixed.

  11. Perform specified physical property tests. Proceed to the compression process.

  12. Compress the tablets.

  12. After compression, spray-coat the compressed formulation with Opadry White in water.

Example 3
In Example 3, a modified release 650 mg tranexamic acid tablet was prepared in the same manner as in Example 1, and film coating was applied in the same manner as the immediate release tablet of Example 2. The ingredients are listed in Table 3 below.

Example 4
Evaluation for bioavailability and bioequivalence In Example 4, in healthy adult female volunteers under fasting conditions, tranexamic acid tablets prepared according to Example 1 and Example 2 Comparison, randomization, single dose, 4-way crossover absolute bioavailability (BA) and bioequivalence (BE) studies were performed. Its purpose is to evaluate and approve the bioequivalence of the 650 mg modified release tablet prepared according to Example 1 compared to the immediate release reference tablet of tranexamic acid prepared according to Example 2. Was to determine the bioavailability of the modified release tablet for the IV (1 g) formulation “Cyklokapron®” from Pharmacia & Upjohn. The study design was a randomized 4-way crossover comparative BE and BA measurement. All oral doses administered were 1.3 g. Twenty-eight healthy non-smoking adult female volunteer subjects enrolled in this study. Sample size was calculated assuming 25% CV in AUCi _nf. The endpoint of this study was the pharmacokinetic parameters AUC _0-t , AUQ _n f and C _max of the modified release formulation based on serum concentration-time data obtained up to 36 hours after a single dose of drug. There was a 90% confidence interval for the ratio of least square mean to immediate release formulation. In addition, the bioavailability of the tablets was calculated. Smokers, oral contraceptive users, thromboembolic events and a history of altered vision were excluded from this study. ECG monitoring was performed before, during and after the estimated time of exposure to the serum tranexamic acid peak concentration. Harmful events were captured and recorded throughout the test period.

  In this study, subjects were randomly administered a single oral dose of 1.3 g (2 × 650 mg tablets) of tranexamic acid in tablet form. The tablet contained a modified release formulation and an immediate release formulation. The subject also received a single dose of 1 g- (H) ml) rV solution (concentration 100 mg / mL) of tranexamic acid.

A summary of the pharmacokinetic results obtained from the study of Example 4 is provided in the table below.

  Concentration-time profiles for the test of Example 4 are provided in semi-logarithmic and aliquot scales over 36 hours and are represented in FIGS.

  The following pharmacokinetic parameters in the table below were calculated for plasma tranexamic acid for the study of Example 4.

MRT: Mean residence time (MRT) after intravenous administration of tranexamic acid was determined using the following formula:
AUMC / AUC + injection time / 2
[Where AUMC is the area under the moment-time curve]
MTT: After oral administration of a controlled release formulation and an immediate release formulation, the mean transit time (MTT) of tranexamic acid was calculated by dividing AUMC by AUC.
MAT: The mean absorption time (MAT) for the above two formulations was obtained by subtracting MRT from MTT.

The following table shows the results of average values (± SD).

  The mean transit time (MTT) and mean absorption time (MAT) of the tranexamic acid modified release formulation was approximately 30 minutes longer than that observed for the immediate release formulation.

The side effects reported most frequently in the study of Example 4 are listed in the table below. The table lists the number of subjects who reported adverse events, and the percentage (%) of subjects is shown in parentheses.

Based on United States Pharmacopeia (USP 27) Type II device paddle method (50 RPM) for immediate release and modified release preparations prepared according to Example 2 and Example 1, respectively, used in the test of Example 4 The results of dissolution tested at 37 ± 0.5 ° C. in 900 mL of water are listed in the table below.

Conclusion :
The ratio of least mean squares and 90% confidence interval obtained by analyzing the In converted pharmacokinetic parameters `` AUC <sub>0-t</sub> '', `` AUQ _nf '' and `` C _max '' for tranexamic acid in plasma are: The controlled release formulation for the immediate release formulation under fasting conditions was within the range of 80-125% (acceptable by the Food and Drug Administration (FDA)).

  The absolute bioavailability of the modified release tablet and the immediate release tablet was 44.93% and 46.04%, respectively.

  Based on these results, modified release tranexamic acid tablets and immediate release tranexamic acid formulations are bioequivalent under fasting conditions.

実施例５
実施例５では、単回投与薬物動態パラメータに基づいて、血清濃度の薬物動態シミュレーションを実施して、実施例４の放出調節製剤の8時間毎の投与(Q8H： 6:00AM、2:00PM、10:00PM)と8時間毎ではない1日3回投与(TID： 8:00AM、2:00PM、及び10:00PM)を比較した。その結果は、下記表１１〜表１４に示してある。

Example 4A (Comparative Example)
In Comparative Example 4A, a 500 mg immediate-release tranexamic acid tablet (trade name Cyklokapron, approved and sold in Canada) was obtained and based on the United States Pharmacopeia (USP 27) Type II device paddle method (50 RPM) Then, the dissolution test was performed at 37 ± 0.5 ° C. in 900 mL of water. The results for the elution are listed in Table 10A below.

Example 5
In Example 5, based on single-dose pharmacokinetic parameters, a serum concentration pharmacokinetic simulation was performed to administer the modified release formulation of Example 4 every 8 hours (Q8H: 6:00 AM, 2:00 PM, 10:00 PM) and 3 times daily administration (TID: 8:00 AM, 2:00 PM, and 10:00 PM) not every 8 hours were compared. The results are shown in Tables 11 to 14 below.

The concentration-time profile over 120 hours for the modified release formulation is shown in Table 12 and is shown in FIG. For comparison, the 1g formulation administered at q8h is also shown.

The concentration-time profile over 120 hours for the modified release formulation is shown in Table 14 and shown in FIG. For comparison, a 1 g formulation administered with TID is also shown.

Example 6
In Example 6, using a modified release formulation prepared according to Example 1, a single dose followed by repeated dose study was conducted on 20 healthy non-smoking adult female volunteers. Following an overnight fast, subjects received a single oral dose of tranexamic acid (1.3 g) on day 1. Blood samples were collected before administration and up to 36 hours after administration. The subject received a single oral dose of tranexamic acid (1.3 g) once again in the evening of the second day, and started on the third day until the last dose on the seventh day until 1 Received 3 doses per day (every 8 hours). To determine C _min , blood samples were taken before the 6th, 9th, 12th and 15th (last dose) doses, and the drug in steady state To determine the concentration, blood samples were collected until 8 hours after the last dose. The subjects were housed indoors from at least 10 hours before the first dose on day 1 until 8 hours after the 15th dose (day 7).

  Tranexamic acid exhibits minimal binding (about 3%) to plasma proteins (mainly plasminogen) at about 5-15 mg / L, a plasma concentration with a “typical” therapeutic effect. The main route by which tranexamic acid is excreted is glomerular filtration of the kidney. After oral administration of tranexamic acid (250 or 500 mg) to healthy adults, 40-70% of the dose administered is excreted unchanged in the urine within 24 hours. After IV administration (1 g), 30% of the dose is excreted unchanged in the urine within 1 hour, 45-55% is excreted within 2-3 hours, and 90% is excreted within 24 hours The

The beta elimination half-life of tranexamic acid is 2 hours. Based on the published data, the average C _max and AUC _0-6 pharmacokinetic parameters after single oral administration of tranexamic acid 1.3g, the average C _max and AUC _0-6 is achieved at 2g dose Expected to be about 65% of the pharmacokinetic parameters (ie, -10 mg / L and -40 mg-h / L, C _max and AUC _0-6 under fasting conditions, respectively).

However, “Pilbrant, et al., Eur. J. Clin. Pharmacol, (1981) -20: 65-72” did not fully characterize the pharmacokinetics of tranexamic acid. This is because blood samples were collected only up to 6 hours after administration. Furthermore, the plasma concentration-time curve after IV administration showed three log phases with a gamma elimination half-life of about 7 hours. For that reason, the concentration-time profile of tranexamic acid was estimated by simulating data over 36 hours with NONMEM after oral administration of a 1.3 g dose under fasting conditions. Based on the results of the above simulations, it may be appropriate to take blood samples for up to 36 hours to characterize AUC, C _max , T _max , t 1/2 and F.

  The purpose of this study in Example 6 was to determine the linearity of the pharmacokinetics of a test tablet of tranexamic acid (modified release) after a single oral administration (Day 1) under fasting conditions (8 hours). It was to be evaluated in comparison with 1.3 g) usage (day 2 to day 7).

In the test of Example 6, blood samples (1 × 5 mL) were collected on day 0 at day 0 (before administration), as well as 0.5 hours, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 3.5 hours after administration. Samples were collected in blood collection tubes containing lithium heparin at time 4, 4 hours, 5 hours, 6 hours, 8 hours, 10 hours, 14 hours, 24 hours, 28 hours, 32 hours and 36 hours. Blood samples for C _min measurement were also taken immediately before the 6th, 9th, 12th and 15th administrations on the 4th, 5th, 6th and 7th days respectively. The samples were collected 0.5 hours, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 5 hours, 6 hours and 8 hours after the 15th administration. Plasma samples were separated by centrifugation and then frozen at −20 ° C. ± 10 ° C. and kept frozen until assay at AAI Development Services in New-Ulm, Germany.

Non-compartmental pharmacokinetic parameters The calculated values of plasma tranexamic acid were calculated by the non-compartmental method using the following pharmacokinetic parameters of Table 15 and Table 16.

No kel, AUCinf or t1 / 4 values were recorded for cases where the terminal log-linear phase was not shown in the concentration versus time profile.

Compartment Pharmacokinetic Parameters Compartment analysis was performed on tranexamic acid data after single and multiple oral doses of modified release (MR) tablets. A multi-compartment model was constructed and their performance matching the plasma concentration of tranexamic acid was tested using a standard two-stage (STS) approach using ADAPT-II (maximum likelihood analysis). Evaluated. This identification process can be accomplished by computing the Akaike's Information Criterion (AIC) and the minimum objective function (OBJ), and also by displaying a suitable graphical representation of the goodness of fit (e.g., adapted and observed concentration vs. time). ) Was considered.

Final analysis was performed using an iterative two-step approach using IT2S® software. This software uses a population methodology that makes it possible to provide robust PK parameter estimates based on individual subjects and populations. All relevant pharmacokinetic parameters were calculated and recorded. The concentration was modeled using a weighting procedure of W _j = I / S _j ² , where the variance σj ² is expressed by the equation `` σj ² = (a + b * Y _j ) ² '' (where a And b are the intercept and slope of each dispersion model) and calculated for each observation. The slope is the residual variation associated with each concentration (which includes the intra-individual variation and the sum of all experimental errors), and the intercept is related to the detection limit of the analytical assay. All PK parameter estimates were updated repeatedly until stable values were found during the population PK analysis (VARUP, IT2S®). The analysis included quantitative estimates of population PK parameters and intra-individual variation of plasma tranexamic acid.

  For MR formulations, individual profiles of observed plasma concentrations of tranexamic acid versus matched plasma concentrations were provided.

Statistical analysis Descriptive statistics Descriptive statistics including arithmetic mean, standard deviation and coefficient of variation were calculated for individual concentration and pharmacokinetic data. Furthermore, the geometric mean was calculated for the parameters “AUC _0-t ”, “AUCi _nf ” and “C _max ” for the first day, and the parameters “AUCτ”, “C _max ” and “C _min ” for the seventh day. .

Time-dependent analysis of variance with respect to In transformed values for pharmacokinetic linearity tranexamic acid using (ANOVA), pharmacokinetic parameters AUCτ the (day 7) were compared with AUCi _n f (first day). The ANOVA model included “group”, “day” (Day 1 (AUC _inf ) and Day 7 (AUCτ)) and interaction “Day * Group” as fixed effects. All interaction terms were not statistically significant at the 5% level and were excluded from the final model. The ANOVA included the calculation of the least mean square (LSM), the difference between Day LSMs and the standard error associated with that difference. The statistical analysis was performed using the SAS® GLM procedure.

The LSM ratio was calculated using the Day LSM power method obtained from the analysis of the In transformed response. The ratio was expressed as a percentage of AUQ _nf (Day 1).

The 90% confidence interval for the above ratio was obtained by raising the confidence interval obtained for the difference between Day LSMs obtained from analysis of the In transformed response. The confidence interval was expressed as a percentage of AUQ _nf (Day 1).

Steady state analysis
-72 h, -48 h, the C _min levels before administration, which is In the conversion at the time of -24 hours and 0 time were steady state analysis using the Helmert contrasts (Helmert's contrast). The ANOVA model included “group”, “time” and interaction “time * group” as fixed effects. To model the correlations within all subjects, Akaike's Burnham and Anderson criterion (AICC) was used to select the appropriate variance-covariance matrix from the following: unstructured (UN ), Compound symmetry (CS), compound symmetry heterogeneous (CSH), variance component (VC), autoregressive (AR (1)), autoregressive heterogeneous (ARH (1 )) And autoregressive moving average (ARMA (1,1)). All interaction terms were not statistically significant at the 5% level and were excluded from the final model. The ANOVA also included a least mean square (LSM) calculation for each pre-dose C _min concentration. Helmart contrasts were constructed such that each time point was compared to the average of subsequent time points. There are three controls associated with the four predose concentration time points. They are described in Table 17 below.

  The statistical analysis was performed using the SAS® Mixed procedure.

official
The following formula in Table 18 was used to calculate the ratio of least mean squares derived from ANOVA and 90% confidence intervals for In-transformed pharmacokinetic parameters.

Examination of pharmacokinetic results Time-dependent pharmacokinetic linearity The ANOVA model has fixed effects as `` group '', `` day '' (day 1 (AUC _inf ) and day 7 (AUCτ)) and mutual Included the action “day * group”. All interaction terms were not statistically significant at the 5% level and were excluded from the final model. The ANOVA model includes `` Group '', `` Day '' (Day 1 (AUC _inf ) and Day 7 (AUCτ)) as a fixed effect and interaction `` Group * Day '', and `` Subject '' as a random effect. Pharmacokinetic linearity was calculated for the formulation using the same approach as described above except that it was nested within a “group”.

The results for pharmacokinetic linearity are summarized in the table below.

The above results for pharmacokinetic linearity indicate that the ratio of the least mean square of AUCτ (day 7) to AUC _inf (day 1) and the 90% confidence interval for MR products are acceptable between 80 and 125% Indicates that it was within range. Based on these results, the 650 mg tranexamic acid modified release tablet showed linear pharmacokinetics after repeated administration (7 days) of a 1.3 g dose under fasting conditions.

Steady state analysis For steady state analysis, the CS variance-covariance matrix was chosen to model the correlation within all subjects. Overall, the interaction term (ie time * group) was not statistically significant and was excluded from the final ANOVA model. For each formulation, the same approach was used, except that the ANOVA model included “group”, “time” and interaction “time * group” as fixed effects.

定常状態解析に関する統計的比較についての概要を、下記表２０Ｂに要約する。

上記結果に基づいて、最初の対比についてのp値は5%αエラーで統計的に有意ではなかったので、トラネキサム酸の定常状態血漿濃度は、第4日(-72-時間)に達した。ここで留意すべきことは、第二の比較 [第5日の投与前と(第6日と第7日の平均)の比較] が統計的に有意であると認められたことである。 A summary of LSM results for steady state analysis is summarized in Table 20A below.

A summary of the statistical comparison for steady state analysis is summarized in Table 20B below.

Based on the above results, the steady state plasma concentration of tranexamic acid reached day 4 (−72-hour) because the p-value for the first contrast was not statistically significant with a 5% α error. It should be noted here that the second comparison [comparison between pre-day 5 administration (average of day 6 and day 7)] was found to be statistically significant.

  The largest difference in pre-dose plasma concentration of tranexamic acid observed between LSMs prior to Day 5 compared to Day 6 and Day 7 was less than 10%. This is not considered clinically relevant. Furthermore, the last contrast was not statistically significant, and the observed difference between LSM before administration on day 6 and day 7 was less than 2%.

Compartment Pharmacokinetic Analysis The average apparent oral clearance (CL / F) of the MR preparation calculated by the compartment method was 17.7 L / hour (295 mL / min). Based on previous data reported in the literature, the Pilbrant et al group confirmed that tranexamic acid recovered in the urine exceeded 95% of the dose administered. Considering the bioavailability of MR products (mean F: 44.9%; see Table 5), systemic clearance (CL) of tranexamic acid (295 mL / min x 0.449 = 123 mL / min) is healthy It will be close to the glomerular filtration rate in the subject (125 mL / min) 5.

  When the compartment method was used, the T1 / 2γ average for the MR formulation was 16.6 hours. Similar values for the final elimination half-life have already been reported in the literature. Pilbrant A., et al., Eur. J. Clin. Pharmacol (1981), 20: 65-72.

  The mean plasma concentrations of tranexamic acid observed at 28 hours, 32 hours, and 36 hours after a single oral dose of 1.3 g MR formulation were 0.19724 mcg / mL, 0.15672 mcg / mL, and 0.13624 mcg / mL, respectively. there were. Considering the effective blood concentration range of tranexamic acid (5-15 mcg / mL) and the extremely low plasma concentration levels observed at those time points, the terminal elimination half-life characterized by a slow decrease in plasma concentration (T1 / 2γ) should not play a clinically important role in the frequency of drug administration.

Pharmacokinetic Conclusions The above results for pharmacokinetic linearity show that the ratio of the least mean square of AUCτ (day 7) to AUC _inf (day 1) and the 90% confidence interval for MR products are 80-125 It indicates that it was within the allowable range of%. Based on these results, the 650 mg tranexamic acid modified release tablet showed linear pharmacokinetics after repeated administration (7 days) of a 1.3 g dose under fasting conditions.

  The steady state plasma concentration of tranexamic acid for the modified release tablet reached day 4 (-72-hour) because the p-value for the first contrast was not statistically significant at 5% alpha error.

  The pharmacokinetics of tranexamic acid was adequately described using three compartmental PK models showing linear elimination. The absorption kinetics of single dose (day 1) data of tranexamic acid for MR formulations was described earlier using the mixed-order rate constant of absorption.

The plasma pharmacokinetic parameters for the modified release (MR) formulation of tranexamic acid on day 1 are listed in Table 21 below.

The plasma pharmacokinetic parameters for the tranexamic acid modified release (MR) formulation on day 7 are listed in Table 22 below.

CONCLUSION Although the invention disclosed herein has been described using specific embodiments and applications thereof, those skilled in the art will recognize many of them without departing from the spirit and scope of the invention. Modifications and changes could be made. Such modifications are understood to fall within the scope of the appended claims.

Claims (45)

  A modified release oral formulation comprising tranexamic acid or a pharmaceutically acceptable salt thereof and a modified release agent, such that the modified release agent is suitable for administration twice or three times per day Resulting in a controlled release of tranexamic acid or a pharmaceutically acceptable salt thereof from the formulation, which can be obtained in 900 mL of water according to the United States Pharmacopeia (USP 27) Type II device paddle method (50 RPM). When measured at 37 ± 0.5 ° C., less than about 70% by weight of tranexamic acid or a pharmaceutically acceptable salt thereof is released in about 45 minutes, and about 100% by weight of tranexamic acid or its pharmaceutically acceptable in about 120 minutes. Said modified release oral dosage form having an in vitro dissolution rate of tranexamic acid or a pharmaceutically acceptable salt thereof from which said salt is released.   About 0% to about 40% by weight of tranexamic acid or its pharmaceutically acceptable in about 15 minutes when measured at 37 ± 0.5 ° C in 900 mL of water by the US Pharmacopoeia (USP 27) type II paddle method (50 RPM) From about 20% to about 60% by weight of tranexamic acid or a pharmaceutically acceptable salt thereof in about 30 minutes, and from about 40% to about 65% by weight of tranexamic acid in about 45 minutes or The pharmaceutically acceptable salt is released and about 50% to about 95% by weight of tranexamic acid or its pharmaceutically acceptable salt is released in about 60 minutes and at least about 60% by weight of tranexamic acid in about 90 minutes. 2. The modified release oral dosage form of claim 1 having an in vitro dissolution rate of tranexamic acid or a pharmaceutically acceptable salt thereof from which or a pharmaceutically acceptable salt thereof is released.   About 10% to about 25% by weight of tranexamic acid or its pharmaceutical every 15 minutes when measured in vitro at 37 ± 0.5 ° C in 900 mL of water by the US Pharmacopeia (USP 27) Type II device paddle method (50 RPM) 2. The modified release oral dosage form of claim 1 that releases a top acceptable salt.   About 1% tranexamic acid or a pharmaceutically acceptable salt thereof per minute when measured in vitro at 37 ± 0.5 ° C in 900 mL of water by the United States Pharmacopeia (USP 27) Type II device paddle method (50 RPM) 2. The modified release oral dosage form of claim 1 that releases. The average maximum of about 9 to about 14.5 mcg / mL tranexamic acid after a single oral dose to humans containing about 1300 mg of tranexamic acid or a pharmaceutically acceptable salt thereof in one or more of the modified release oral formulations The modified release oral dosage form of claim 1, which provides plasma concentration (C _max ). About 1300 mg of tranexamic acid or a pharmaceutically acceptable salt thereof in one or more of the modified release oral dosage forms after steady state oral administration to humans, followed by an average maximum plasma of about 5 to about 25 mcg / mL tranexamic acid The _modified release oral dosage form of claim 1, which provides a concentration (C _max ). Average maximum plasma of about 10 to about 20 mcg / mL tranexamic acid after steady state oral administration to a human containing about 1300 mg of tranexamic acid or a pharmaceutically acceptable salt thereof in one or more of the modified release oral formulations The _modified release oral dosage form of claim 1, which provides a concentration (C _max ). The modified release oral dosage form according to claim 1, which provides an average time (T _max ) to reach a maximum plasma concentration of about 1.0 to about 5.5 hours after oral administration of one or more of the modified release oral formulation to a human. Formulation.   2. The modified release oral dosage form of claim 1, which provides an average transit time of tranexamic acid of 7.70 ± 0.72 hours when administered orally to all patient populations.   The modified release oral dosage form of claim 1, which provides an average absorption time of tranexamic acid of 4.18 ± 0.70 hours when administered orally to all patient populations.   The same amount of tranexamic acid or a pharmaceutically acceptable salt thereof, and about 45 when measured in vitro at 37 ± 0.5 ° C. in 900 mL of water by the United States Pharmacopeia (USP 27) Type II paddle method (50 RPM) Headache, as compared to administering an immediate release oral formulation that releases all of tranexamic acid or its pharmaceutically acceptable salt within minutes to the same or different patient population as the modified release formulation, The modified release oral dosage form according to claim 1, which reduces at least one side effect selected from the group consisting of nausea, vomiting, diarrhea, constipation, convulsions, bloating and combinations thereof.   The modified release oral dosage form of claim 1, which provides an average transit time for tranexamic acid that is at least about 20 minutes longer than the immediate release formulation when administered to all patient populations.   The modified release oral dosage form of claim 1, which provides an average absorption time of tranexamic acid that is at least about 20 minutes longer than the immediate release formulation when administered to all patient populations.   Reduces headache, nausea or combinations thereof when administered to all patient populations compared to a therapeutically equivalent amount of tranexamic acid or a pharmaceutically acceptable salt thereof administered intravenously within 5 minutes The modified release oral formulation according to claim 1.   The modified release oral dosage form of claim 1, wherein tranexamic acid or a pharmaceutically acceptable salt thereof is included in an amount of about 375 mg to about 1 g.   The modified release oral dosage form of claim 1, wherein tranexamic acid or a pharmaceutically acceptable salt thereof is included in an amount of about 650 mg.   The modified release oral dosage according to claim 1, selected from the group consisting of one or more tablets, capsules, granules, powders, pellets, dragees, troches, non-pareils and pills. Formulation.   2. The modified release oral dosage form of claim 1, which provides greater than 40% tranexamic acid bioavailability when administered to a human.   A method for treating a human patient in need of treatment with tranexamic acid, comprising a menorrhagia, cervical conectomy, nasal bleeding, anterior chamber bleeding or hereditary angioedema, oral cavity 2. The method comprising administering to a patient undergoing surgery and suffering from a blood coagulation disorder, or a patient suffering from a combination thereof, at least one oral formulation of claim 1. A method of treating a patient in need of treatment with tranexamic acid, comprising about 1300 mg of tranexamic acid or a pharmaceutically acceptable salt thereof comprising at least one of said tranexamic acid or a pharmaceutically acceptable salt thereof and a release modifier. Orally administered to the patient as one oral formulation, wherein the modified release agent has an average maximum plasma concentration (C _max ) of tranexamic acid of about 5 to about 17.5 mcg / mL after a single oral administration to a human. Providing said method. 21. The method of claim 20, wherein the at least one oral formulation provides an average maximum plasma concentration ( _Cmax ) of tranexamic acid of about 9 to about 14.5 mcg / mL after a single oral administration to a human. 21. The method of claim 20, wherein the at least one oral formulation provides an average maximum plasma concentration ( _Cmax ) of tranexamic acid of about 5 to about 25 mcg / mL after steady state oral administration to a human. 21. The method of claim 20, wherein the at least one oral formulation provides a mean maximum plasma concentration ( _Cmax ) of tranexamic acid of about 10 to about 20 mcg / mL after steady state oral administration to a human. 21. The method of claim 20, wherein the at least one oral formulation provides an average time ( _Tmax ) to reach a maximum plasma concentration of about 1.0 to about 5.5 hours after oral administration to a human.   21. The method of claim 20, wherein the at least one oral formulation is two oral formulations.   A dose of tranexamic acid comprising two or three unit dosage forms of a modified release formulation, each unit dosage form of the modified release formulation comprising about 585 to about 715 mg of tranexamic acid or a pharmaceutically acceptable salt thereof and a modified release The release-modifying substance provides release of tranexamic acid or a pharmaceutically acceptable salt thereof from the formulation such that the unit formulation is suitable for administration twice or three times per day Said dose.   27. The dose of claim 26, wherein each unit dosage comprises about 650 mg tranexamic acid or a pharmaceutically acceptable salt thereof.   The modified release substance is vinyl polymer, phthalic acid derivative of vinyl copolymer, hydroxyalkyl cellulose, alkyl cellulose, cellulose acetate, hydroxyalkyl cellulose acetate, cellulose ether, alkyl cellulose acetate, and partial esters thereof, lower alkyl acrylic acid and acrylic 27. The dose of claim 26, selected from the group consisting of polymers and copolymers of lower alkyl acids, and partial esters thereof, and mixtures thereof.   27. The dose of claim 26, wherein the modified release material is selected from the group consisting of a gel-forming polymer, a hydratable polymer, a water-soluble polymer, a water-swellable polymer, and mixtures thereof.   The release modifier is hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, methylcellulose, vinyl acetate / crotonic acid copolymer, methacrylic acid copolymer, maleic anhydride / methyl vinyl ether copolymer, derivatives thereof, and 27. A dose according to claim 26, selected from the group consisting of: 27. The dose of claim 26, which provides a mean maximum plasma concentration ( _Cmax ) of tranexamic acid of about 5 to about 17.5 mcg / mL after a single oral administration to a human. 27. The dose of claim 26, which provides a mean maximum plasma concentration ( _Cmax ) of tranexamic acid of about 9.0 to about 14.5 mcg / mL after a single oral administration to a human. 27. The dose of claim 26, which provides a mean maximum plasma concentration ( _Cmax ) of tranexamic acid of about 5 to about 25 mcg / mL after steady state oral administration to a human. 27. The dose of claim 26, which provides a mean maximum plasma concentration ( _Cmax ) of tranexamic acid from about 10 mcg / mL to about 20 mcg / mL after steady state oral administration to a human. 27. The dose of claim 26, which provides an average time ( _Tmax ) to reach a maximum plasma concentration of tranexamic acid from about 1.0 to about 5.5 hours after oral administration to a human.   27. The dose of claim 26, which reduces menstrual blood volume by about 20% to 100% per menstrual cycle after oral administration to a human patient suffering from severe menstrual bleeding.   When the unit dosage form is measured at 37 ± 0.5 ° C. in 900 mL of water by the United States Pharmacopeia (USP 27) type II device paddle method (50 RPM), less than about 70% by weight of tranexamic acid is released in about 45 minutes. 27. The dose of claim 26 having an in vitro dissolution rate of tranexamic acid or a pharmaceutically acceptable salt thereof.   A modified release oral dosage form comprising tranexamic acid and a modified release substance, wherein the modified release substance releases tranexamic acid from the dosage form such that the dosage form is suitable for administration twice or three times per day When administered to the entire patient population, compared to the same amount of tranexamic acid in immediate-release oral preparations, headache, nausea, vomiting, diarrhea, constipation, convulsions, bloating and those The modified release oral preparation that reduces at least one side effect selected from the group consisting of:   40. The modified release oral formulation of claim 38, wherein the side effect is headache or nausea.   40. The modified release oral dosage form of claim 38, which provides an average transit time for tranexamic acid that is at least about 20 minutes longer than the immediate release dosage form.   40. The modified release oral dosage form of claim 38, which provides an average absorption time of tranexamic acid that is at least about 20 minutes longer than the immediate release dosage form.   A controlled-release oral formulation comprising tranexamic acid or a pharmaceutically acceptable salt thereof and a modified-release excipient, suitable for administration twice or three times a day Said modified release oral formulation providing a slower and faster release of tranexamic acid or a pharmaceutically acceptable salt thereof than a controlled release oral formulation.   43. The modified release oral dosage form of claim 42, wherein tranexamic acid is included in an amount of about 375 mg to about 1 g.   The modified release substance is vinyl polymer, phthalic acid derivative of vinyl copolymer, hydroxyalkyl cellulose, alkyl cellulose, cellulose acetate, hydroxyalkyl cellulose acetate, cellulose ether, alkyl cellulose acetate, and partial esters thereof, lower alkyl acrylic acid and acrylic 43. The modified release oral formulation of claim 42, selected from the group consisting of polymers and copolymers of lower alkyl acids, and partial esters thereof, and mixtures thereof.   The release modifier is hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, methylcellulose, vinyl acetate / crotonic acid copolymer, methacrylic acid copolymer, maleic anhydride / methyl vinyl ether copolymer, derivatives thereof, and 43. The modified release oral dosage form of claim 42, selected from the group consisting of:

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