WO2006023001A1 - Formules d’acide tranéxamique - Google Patents

Formules d’acide tranéxamique Download PDF

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Publication number
WO2006023001A1
WO2006023001A1 PCT/US2005/020563 US2005020563W WO2006023001A1 WO 2006023001 A1 WO2006023001 A1 WO 2006023001A1 US 2005020563 W US2005020563 W US 2005020563W WO 2006023001 A1 WO2006023001 A1 WO 2006023001A1
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Prior art keywords
tranexamic acid
pharmaceutically acceptable
dosage form
acceptable salt
oral dosage
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PCT/US2005/020563
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English (en)
Inventor
Keith A. Moore
Ralph A. Heasley
Jeffrey S. Greiwe
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Xanodyne Pharmaceuticals, Inc.
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Priority to JP2007523556A priority Critical patent/JP5000504B2/ja
Publication of WO2006023001A1 publication Critical patent/WO2006023001A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/16—Otologicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • the invention is directed to oral tranexamic acid formulations and methods of treatment with these formulations.
  • Tranexamic acid (trans-4-(aminomethyl) cyclohexanecarboxylic acid, Cyklokapron® (Pfizer) is an antifibrinolytic agent. That is, it helps to prevent lysis or dissolution of a fibrin clot which forms in the normal physiologic process of hemostasis. Its mechanism of action is as a competitive inhibitor of plasminogen activation, and as a noncompetitive inhibitor of plasmin; both plasminogen and plasmin are activators of fibrinolysis and active clot-lysing agents. Tranexamic acid thus helps to stabilize fibrin clots, which in turn maintains coagulation and helps to control bleeding.
  • Tranexamic acid is used to control excess bleeding, for example, excess bleeding that occurs during dental procedures in hemophiliacs and for heavy bleeding during menstruation (menorrhagia). Women suffering from menorrhagia are typically treated orally with 500 mg tranexamic acid tablets administered three or four times daily with a total daily dose ranging from 3 grams/day (two tablets every eight hours) to 6 grams/day (three tablets every six hours). However, this treatment may cause adverse gastrointestinal reactions, including nausea, vomiting, diarrhea, and cramping, etc.
  • the above advantages and objects and others can be achieved by virtue of the present invention which is directed in part to a method of treating a patient in need of tranexamic acid therapy comprising administering to the patient about 1300 mg of tranexamic acid or pharmaceutically acceptable salt thereof in one or more oral dosage forms including the tranexamic acid or pharmaceutically acceptable salt thereof such that the dose administered provides a mean maximum plasma concentration (C max ) of tranexamic acid of from about 9 to about 15 mcg/ml, preferably from about 10 to about 14 mcg/ml, more preferably about 12 mcg/ml after single dose oral administration to humans.
  • C max mean maximum plasma concentration
  • the invention is directed to an oral dosage form comprising 650 mg of tranexamic acid or pharmaceutically acceptable salt thereof which provides a mean maximum plasma concentration (C max ) of tranexamic acid of from about 9 to about 15 mcg/ml, preferably from about 10 to about 14 mcg/ml, more preferably about 12 mcg/ml per 1300 mg of tranexamic acid after single dose oral administration to humans.
  • C max mean maximum plasma concentration
  • the invention is directed to an oral dosage form comprising 650 mg of tranexamic acid or pharmaceutically acceptable salt thereof which provides a mean T max of tranexamic acid at from about 2 to about 4 hours, preferably at about 3 hours after oral administration to humans.
  • the invention is directed to an oral dosage form comprising about 650 mg of tranexamic acid or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient; said dosage form providing an in-vitro dissolution release rate of the tranexamic acid, when measured by a USP 27 Apparatus Type II Paddle Method @ 50 RPM in 900 ml water at 37 ⁇ 0.5°C, of at least about 70% by weight tranexamic acid or pharmaceutically acceptable salt thereof or released at about 45 minutes, and preferably 100% by weight tranexamic. acid or pharmaceutically acceptable salt thereof release by about 45 minutes.
  • the invention is directed to an oral dosage form comprising about 650 mg of tranexamic acid or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, said dosage form providing an in-vitro dissolution release rate of the tranexamic acid or pharmaceutically acceptable salt thereof from the dosage form, when measured by the USP 27 Apparatus Type II Paddle Method @ 50 RPM in 900 ml water at 37 ⁇ 0.5°C of about 0% to about 95% by weight tranexamic acid or pharmaceutically acceptable salt thereof released at about 15 minutes, from about 30% to about 100% by weight tranexamic acid or pharmaceutically acceptable salt thereof released at about 30 minutes, from about 70% to about 100% by weight tranexamic acid or pharmaceutically acceptable salt thereof released at about 45 minutes, about 100% by weight tranexamic acid or pharmaceutically acceptable salt thereof released at about 60 minutes.
  • the invention is directed to an oral dosage form comprising about 650 mg of tranexamic acid or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, said dosage form providing an in-vitro dissolution release rate of the tranexamic acid or pharmaceutically acceptable salt thereof from the dosage form, when measured by the USP 27 Apparatus Type II Paddle Method @ 50 RPM in 900 ml water at 37 ⁇ 0.5°C of about 50% to about 95% by weight tranexamic acid or pharmaceutically acceptable salt thereof released at about 15 minutes, from about 70% to about 100% by weight tranexamic acid or pharmaceutically acceptable salt thereof released at about 30 minutes, from about 80% to about 100% by weight tranexamic acid or pharmaceutically acceptable salt thereof released at about 45 minutes, about 100% by weight tranexamic acid or pharmaceutically acceptable salt thereof released at about 60 minutes.
  • the invention is further directed to an oral dosage form comprising tranexamic acid (preferably in an amount of about 650 mg) or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, which provides for a bioavailability of tranexamic acid of greater than 40%, from about 41% to about 60%, preferably from about 42% to about 50%, more preferably about 46% after oral administration to humans.
  • the invention is further directed to an oral dosage form comprising about 650 mg of tranexamic acid or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, the dosage form being suitable for oral administration on a twice a day basis, and the dosage form providing a mean maximum plasma concentration (C max ) of tranexamic acid of from about 13.5 to about 22.5 mcg/ml, preferably from about 15 to about 21 mcg/ml, more preferably about 18 mcg/ml per 1950 mg tranexamic acid after single dose oral administration to humans.
  • C max mean maximum plasma concentration
  • the invention is further directed to a method of treating a patient with a therapeutically effective amount of tranexamic acid or pharmaceutically acceptable salt thereof comprising administering to the patient two or three dosage forms of the present invention, each dosage form comprising from about 585 mg to about 715 mg of tranexamic acid or pharmaceutically acceptable salt thereof, preferably about 650 mg tranexamic acid or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • the invention is directed to a dose of tranexamic acid or pharmaceutically acceptable salt thereof comprising two oral dosage forms, each oral dosage form comprising from about 585 mg to about 715 mg, preferably about 650 mg of tranexamic acid or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, the dose providing a therapeutic effect when administered three times a day.
  • the invention is directed to a dose of tranexamic acid or pharmaceutically acceptable salt thereof comprising three oral dosage forms, each oral dosage form comprising from about 585 mg to about 715 mg, preferably about 650 mg of tranexamic acid or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, the dose providing a therapeutic effect when administered twice a day.
  • the oral dosage form of the invention further provides a mean transit time of said tranexamic acid of 7.21 ⁇ 1.01 hours when administered across a patient population.
  • the oral dosage form of the invention further provides a mean absorption time of said tranexamic acid of 3.70 ⁇ 0.94 hours when administered across a patient population.
  • the invention is further directed to an oral dosage form comprising tranexamic acid or pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient which provides less than about 20 percent incidence of nausea, less than about 15 percent incidence of nausea, preferably less than about 10 percent incidence of nausea as a side effect after single dose oral administration across a patient population.
  • the dosage form provides less CNS side effects (e.g., headache), less GI side effects (e.g., nausea), or combination thereof in comparison to a therapeutically equivalent amount of tranexamic acid administered intravenously in five minutes or less when administered across a patient population.
  • CNS side effects e.g., headache
  • GI side effects e.g., nausea
  • the therapeutically effective dose of the tranexamic acid is provided via the administration of two or more dosage units.
  • the dosage unit comprises 650 mg of tranexamic acid and the dose for administration is about 1300 mg then two dosage units would be administered to a patient in need of such treatment, or for example, when the dose for administration is 1950 mg, three dosage units would be administered.
  • the invention is further directed to a method of treating a patient with one or more oral dosage forms comprising tranexamic acid or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, wherein the oral dosage form provides a therapeutically effective plasma level of tranexamic acid in accordance with a three times a day (TID) dosing schedule, and the therapeutically effective dose administered comprises about 1300 mg of tranexamic acid.
  • TID three times a day
  • the invention is further directed to a method of treating a patient with one or more oral dosage forms comprising tranexamic acid or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, wherein the oral dosage form provides a therapeutically effective plasma level of tranexamic acid in accordance with a twice a day (BID) dosing schedule, and the therapeutically effective dose administered comprises about 1950 mg of tranexamic acid.
  • the tranexamic acid for use in the methods and formulations of the present invention is in the form of a pharmaceutically acceptable salt thereof.
  • Such salt forms include for example and without limitation the sodium salt, potassium salt, calcium salt, magnesium salt and the like; as well as the hydrochloride, hydrobromide, sulfate, phosphate, formate, acetate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate, p-toluenesulfonatemethanesulfonate salt forms, and the like.
  • the active ingredient for use in accordance with the present invention is tranexamic acid.
  • C ma ⁇ unless otherwise indicated is meant for purposes of the present invention to mean the maximum plasma concentration of a medicament achieved after single dose administration of a dosage form, or the maximum plasma concentration of a medicament achieved over a dosing interval from multiple-doses at steady-state in accordance with the present invention.
  • T max is meant for purposes of the present invention to mean the elapsed time from administration of a dosage form to the time the C max of the medicament is achieved.
  • steady state means that the amount of the drug reaching the system is approximately the same as the amount of the drug leaving the system. Thus, at “steady- state", the patient's body eliminates the drug at approximately the same rate that the drug becomes available to the patient's system through absorption into the blood stream.
  • mean for purposes of the present invention, when used to define a pharmacokinetic value (e.g., T max ), unless specified otherwise, represents the arithmetic mean value measured across a patient or subject population.
  • TID basis means that the dosage regimen is to be administered three times a day, preferably on a schedule of every 8 hours.
  • mean transit time is understood by those skilled in the art and means the time-point where 63.2% of the total AUC is attained after oral administration, or 63.2% of the IV dose is eliminated, as described in Applied Pharmacokinetics, Principles of Therapeutic Drug Monitoring, Second Edition (1986), edited by William E. Evans, et al., the disclosure of which is hereby incorporated by reference in its entirety.
  • mean absorption time is understood by those skilled in the art and means a quantitative parameter which summarizes how long, on average, the drug molecule remains unabsorbed, i.e.
  • Figure 1 depicts mean plasma concentration-time profiles on a semi-log scale over 36 hours for the study of Example 3.
  • Figure 2 depicts mean plasma concentration-time profiles on a linear scale over 36 hours for the study of Example 3.
  • the dosage regimen typically listed for tranexamic acid in HMB (Heavy Menstrual Bleeding) therapy is 1 — 1.5 g per dose administered three - four times a day at the onset of copious menstrual bleeding and continued for the first 3 — 5 days of the menstrual cycle.
  • the most frequently reported dosage regimen of tranexamic acid is an immediate release oral formulation in which 1 g tranexamic acid is administered four times a day (4 g per day) for HMB therapy outside of the US.
  • tranexamic acid serum concentrations are 9, 41, 73, 88 percent (with food), and 22, 63, 85, and 98 percent (fasting) of maximal absorption at 0.5, 1, 1.5 and 2 hours after a 2 g oral dose, respectively.
  • tranexamic acid oral absorption appears to be controlled by a non-dissolution rate limited process, i.e. the rate and extent of oral absorption is a function of a transmembrane passage-limited process, in order to explain the disparity between the time of product dissolution and relatively prolonged tmax (time to achieve the peak serum concentration).
  • the goal of the formulation, dose strength and dosage regimen of the invention is to provide HMB therapy which achieves from about 20% to 100% reduction in menstrual blood loss per menstrual cycle.
  • an oral dosage form comprising about 650 mg of tranexamic acid is disclosed.
  • the oral dosage form contains at least one pharmaceutically acceptable excipient.
  • the oral dosage form of the present invention provides for an increased bioavailability as compared to other immediate release oral dosage forms currently available (e.g., Cyclokapron).
  • the increased bioavailability allows therapeutic plasma levels of tranexamic acid to be reached with a lower dose of drug.
  • the increased bioavailability also decreases the amount of tranexamic acid that remains unabsorbed in the gastrointestinal which leads to decreased incidence of side effects that are typically associated with formulations that provide higher levels of unabsorbed tranexamic acid and prolonged exposure of the gastrointestinal tract to the higher tranexamic acid levels.
  • the oral dosage form of the present invention provides for a bioavailability of tranexamic acid of greater than 40%, from about 41% to about 60%, preferably from about 42% to about 50%, more preferably about 46% after oral administration to humans.
  • the invention is directed to a method of providing a tranexamic acid plasma concentration within the range of about 5 mcg/mL to about 15 mcg/mL by administration of at least one formulation of the present invention comprising tranexamic acid and pharmaceutically acceptable excipient on a three times a day basis to a patient in need of tranexamic acid treatment
  • the invention is further directed to a method of treating a human patient with heavy menstrual bleeding (e.g., menorrhagia) comprising administering about 1300 mg of tranexamic acid on a three times a day basis to the human patient to provide a tranexamic acid plasma concentration within the range of about 5 mcg/mL to about 15 mcg/mL after steady state oral administration to a human patient.
  • heavy menstrual bleeding e.g., menorrhagia
  • the invention is directed to a method of treating a patient suffering from menorrhagia, conization of the cervix, epistaxis, hyphema, hereditary angioneurotic edema, a patient with a blood coagulation disorder undergoing dental surgery, combinations, thereof, and the like, by administering at least one dosage form of the present invention to the patient in need in tranexamic acid therapy.
  • the invention is directed to a method of treating heavy menstrual bleeding with a therapeutically effective dose of at least one oral formulation of the present invention comprising tranexamic acid and a pharmaceutically acceptable excipient wherein the menstrual blood loss 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 a most preferred embodiment the menstrual blood loss per menstrual cycle is reduced by greater than or equal to about 50 ml.
  • the invention is directed to a method of treating heavy menstrual bleeding with a therapeutically effective dose of at least one oral formulation of the present invention comprising tranexamic acid and a pharmaceutically acceptable excipient which upon oral administration to a human female reduces the blood loss per menstrual cycle by about 35 ml to about 200 ml, preferably about 40 ml to about 175 ml, more preferably from about 50 ml to about 150 ml.
  • the invention is further directed to a method of treating heavy menstrual bleeding with a therapeutically effective dose of at least one oral formulation of the present invention comprising tranexamic acid and a pharmaceutically acceptable excipient which upon oral administration to a human female reduces the blood loss per menstrual cycle by about 20% to 100%, preferably from about 20% to about 70%.
  • the menstrual blood loss can be measured by procedures known in the art.
  • the menstrual blood loss can be determined by a procedure described by (i) L. Hallbert, et al. in "Determination of Menstrual Blood Loss", Scandinav. J. Clin. & Lab. Investigation, 244-248, 16, 1964, wherein the procedure is performed by extracting the menstrual blood from vaginal tampons and towels with a sodium hydroxide solution, converting heme chromogens to alkaline hematin, which is determined spectrophotometrically; or (U) the menstrual blood loss can be determined by a procedure described by J.
  • the oral dosage forms of the present invention may be prepared as tablets, capsules, granules, pellets, powders, pellets, dragees, troches, non-pariels, pills or encapsulated suspension, and may be packaged into capsules, sachets, etc.
  • Tranexamic acid oral dosage forms of the present invention are formulated to provide about a 650 mg dose of tranexamic acid. Typically, two oral dosage forms are administered to a patient in need of tranexamic acid therapy to provide a total dose of about 1300 mg. In addition, at least one pharmaceutically acceptable excipient is included in the oral dosage form.
  • the pharmaceutically acceptable excipient may include, for example and without limitation, preservatives, diluents (e.g., microcrystalline cellulose), lubricants (e.g., stearic acid, magnesium stearate, and the like), binders (e.g., povidone, starch, and the like), disintegrants (e.g, croscarmellose sodium, corn starch, and the like), glidants (e.g., talc, colloidal silicon dioxide, and the like), granulating aids, colorants, and flavorants that are conventional in the pharmaceutical art.
  • diluents e.g., microcrystalline cellulose
  • lubricants e.g., stearic acid, magnesium stearate, and the like
  • binders e.g., povidone, starch, and the like
  • disintegrants e.g, croscarmellose sodium, corn starch, and the like
  • glidants e.g.
  • diluents include dextrose, sucrose, starch, powdered cellulose, lactose, mannitol, microcrystalline cellulose, combinations thereof, and the like.
  • Examples of lubricants include magnesium stearate, calcium stearate, oleic acid, caprylic acid, stearic acid, magnesium isovalerate, calcium laurate, magnesium palmitate, behenic acid, glyceryl behenate, glyceryl stearate, sodium stearyl fumarate, potassium stearyl fumarate, zinc stearate, combinations thereof and the like.
  • Examples of disintegrants include crospovidone, alginates, cellulose and its derivatives, clays, polyvinylpyrrolidone, polysaccharides, such as corn and potato starch, dextrins, croscarmellose sodium, sugars, combinations thereof, and the like.
  • Binders when added to the formulation, promote granulation and/or promote cohesive compact during the direct compression into tablets.
  • binders include povidone, acacia, cellulose derivatives, gelatin, glucose, polyvinylpyrrolidone, sodium alginate and alginate derivatives, sorbitol, starch, combinations thereof, and the like.
  • alleviation of adverse effects using these formulations indicates any relief in one or more symptoms, such as decrease in incidence, severity, or duration of symptoms, and is not limited to absence of symptoms or elimination of symptoms.
  • treatment includes any decrease in incidence, duration, intensity, frequency, etc.
  • adverse gastrointestinal symptoms including, but not limited to, headache, nausea, vomiting, diarrhea, constipation, cramping, bloating, and combinations thereof.
  • the formulations may reduce symptoms at any time during tranexamic acid therapy, but minimized adverse effects are particularly noted immediately or shortly after dosing, that is, within the first few hours after dosing.
  • adverse gastrointestinal effects and side effects are used interchangeably to indicate. nontherapeutic effects (i.e., not relating to any possible beneficial effects due to tranexamic acid), ranging from unpleasant but tolerable sensations to severe gastrointestinal symptoms.
  • oral formulations As used herein, the terms oral formulations, ingestable formulations, and orally administered formulations are used interchangeably and include any dosage forms which are ingested by mouth, including, but not limited to, tablets, pills, liquids, gelcaps, dragees, capsules, powders, granules, pellets, etc.
  • the formulation includes tranexamic acid in the range of about 50% by weight to about 95% or more by weight of the formulation. In other embodiments, tranexamic acid is in the range of about 60% by weight to about 90% by weight, or about 60% by weight to about 80% by weight of the formulation. The remaining weight may be made-up of the pharmaceutically acceptable excipient.
  • the pharmaceutically acceptable excipient may be incorporated into e.g., a tablet matrix with the tranexamic acid or coated onto e.g., the tranexamic acid or both.
  • tablet formulations prepared are formulated by granulating a blend of powders of the pharmaceutically acceptable excipient and the tranexamic acid.
  • the powder blend is formed by combining portions of the powdered components that make up the tablet. These powders are intimately mixed by dry-blending.
  • the dry blended mixture is granulated by wet mixing of a solution of a binding agent with the powder blend. Following granulation, the particles are removed from the granulator and placed in a fluid bed dryer, a vacuum dryer, a microwave dryer, or a tray dryer for drying. Drying conditions are sufficient to remove unwanted granulating solvent, typically water, or to reduce the amount of granulating solvent to an acceptable level.
  • Drying conditions in a fluid bed dryer or tray dryer are typically about 50 to 7O 0 C.
  • the granulate is dried, screened, mixed with additional excipients such as disintegrating agents, flow agents, or compression aids and lubricants such as talc, stearic acid, or magnesium stearate, and compressed into tablets.
  • the tablet may be coated with an optional film-forming agent. This applied film may aid in identification, mask an unpleasant taste, allow desired colors and surface appearance, provide enhanced elegance, aid in swallowing, etc.
  • the amount of film-forming agent may be in the range of about 2% tablet weight to about 4% tablet weight.
  • Suitable film-forming agents are known to one skilled in the art and include hydroxypropyl cellulose, cellulose ester, cellulose ether, one or more acrylic polymer(s), hydroxypropyl methylcellulose, cationic methacrylate copolymers (diethylaminoethyl) methacrylate/methyl-butyl-methacrylate copolymers such as Eudragit E® (Rohm Pharma) and the like.
  • the film-forming agents may optionally contain colorants, plasticizers, fillers, etc. including, but not limited to, propylene glycol, sorbitan monooleate, sorbic acid, titanium dioxide, and one or more pharmaceutically acceptable dye(s).
  • tranexamic acid tablets are formulated by dry blending, rotary compacting, or wet granulating powders composed of tranexamic acid and tablet excipients. These powders are compressed into a tablet.
  • the tranexamic acid formulations may be administered by pellets or granules in e.g., a sachet or capsule.
  • Tranexamic acid pellets or granules may be prepared by using the pharmaceutically acceptable excipient to form a granule or pellet matrix.
  • U.S. Patent Nos. 5,650,174; and 5,229,135 each of which is expressly incorporated by reference herein in its entirety, disclose variations on fabricating a pellet or nonpareil dosage form. Spheres are filled into packets, termed sachets, or capsules which are filled by weight to contain the prescribed dose of drug.
  • the tranexamic acid formulations of the present invention may be used for additional indications other than monorrhagia, such as conization of the cervix, epistaxis, hyphema, hereditary angioneurotic edema, a patient with a blood coagulation disorder undergoing dental surgery, combinations thereof, and the like.
  • monorrhagia such as conization of the cervix, epistaxis, hyphema, hereditary angioneurotic edema, a patient with a blood coagulation disorder undergoing dental surgery, combinations thereof, and the like.
  • Example 1 immediate release 650 mg tranexamic acid tablets were prepared having the ingredients listed in Table 1 below:
  • Example 1 The formulation of Example 1 was prepared as follows:
  • Modified release 650 mg tranexamic acid tablets were prepared having the ingredients listed in the Table 2 below:
  • Example 2 Purified water is removed during processing
  • the formulation of Example 2 was prepared as follows:
  • Example 3 a comparative, randomized, single dose, 4- way Crossover Absolute Bioavailability (BA) and Bioequivalence (BE) study of Tranexamic Acid Tablet Formulations prepared in accordance with Examples 1 and 2 in Healthy Adult Women Volunteers under Fasting Conditions was performed. The objective was to assess the bioequivalence of a 650 mg immediate release tablet formulation prepared in accordance with Example 1 compared to the modified release tablet formulation of tranexamic acid prepared in accordance with Example 2, and to determine the bioavailability of the tablet formulations to the approved IV (1 g) formulation Cyklokapron ® by Pharmacia & Upjohn. The design was a randomized, 4-way crossover, comparative BE and BA determination. All oral doses administered were 1.3 g.
  • AUC 0-t is the area under the plasma concentration versus time curve, from time 0 to the last measurable concentration, as calculated by the linear trapezoidal method.
  • MRT The mean residence time (MRT) after intravenous administration of tranexamic acid was determined using the equation, AUMC/ AUC + infusion time/2, where the AUMC is the area under the moment-time curve.
  • the mean transit time (MTT) of tranexamic acid was calculated by dividing the AUMC by the AUC.
  • MAT The mean abso rption time (MAT) for the two formulations was derived by subtracting the MRT from the MTT.
  • the mean transit time (MTT) and mean absorption time (MAT) of the Modified Release formulation of tranexamic acid was approximately 30 minutes longer than that observed for the Immediate Release formulation.

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Abstract

Formules d’acide tranéxamique orales et procédés de traitement avec celles-ci.
PCT/US2005/020563 2004-07-30 2005-06-13 Formules d’acide tranéxamique WO2006023001A1 (fr)

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US7947739B2 (en) 2004-03-04 2011-05-24 Ferring B.V. Tranexamic acid formulations
US8022106B2 (en) 2004-03-04 2011-09-20 Ferring B.V. Tranexamic acid formulations
US8273795B2 (en) 2004-03-04 2012-09-25 Ferring B.V. Tranexamic acid formulations
US8957113B2 (en) 2004-03-04 2015-02-17 Ferring B.V. Tranexamic acid formulations
US8968777B2 (en) 2003-07-31 2015-03-03 Ferring B.V. Tranexamic acid formulations with reduced adverse effects

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BR112017009207A2 (pt) 2014-11-03 2019-10-01 Bayer Pharma AG piperidinilpirazolopirimidinonas e seu uso
WO2016173948A1 (fr) 2015-04-30 2016-11-03 Bayer Pharma Aktiengesellschaft Indazolopyrimidinones comme inhibiteurs de la fibrinolyse
WO2023233422A1 (fr) * 2022-05-30 2023-12-07 Syri Research Private Limited Formulation liquide orale d'acide tranexamique ou de son sel pharmaceutiquement acceptable

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Publication number Priority date Publication date Assignee Title
US8968777B2 (en) 2003-07-31 2015-03-03 Ferring B.V. Tranexamic acid formulations with reduced adverse effects
US7947739B2 (en) 2004-03-04 2011-05-24 Ferring B.V. Tranexamic acid formulations
US8022106B2 (en) 2004-03-04 2011-09-20 Ferring B.V. Tranexamic acid formulations
US8273795B2 (en) 2004-03-04 2012-09-25 Ferring B.V. Tranexamic acid formulations
US8487005B2 (en) 2004-03-04 2013-07-16 Ferring B.V. Tranexamic acid formulations
US8791160B2 (en) 2004-03-04 2014-07-29 Ferring B.V. Tranexamic acid formulations
US8809394B2 (en) 2004-03-04 2014-08-19 Ferring B.V. Tranexamic acid formulations
US8957113B2 (en) 2004-03-04 2015-02-17 Ferring B.V. Tranexamic acid formulations
US9060939B2 (en) 2004-03-04 2015-06-23 Ferring B.V. Tranexamic acid formulations

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JP2011168596A (ja) 2011-09-01
JP2008508276A (ja) 2008-03-21
WO2006023000A1 (fr) 2006-03-02
JP5000504B2 (ja) 2012-08-15
JP2014193878A (ja) 2014-10-09
JP5205053B2 (ja) 2013-06-05

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