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WO2025015406A1 - Formes posologiques d'acide tranexamique et leurs utilisations - Google Patents

Formes posologiques d'acide tranexamique et leurs utilisations Download PDF

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Publication number
WO2025015406A1
WO2025015406A1 PCT/CA2023/050976 CA2023050976W WO2025015406A1 WO 2025015406 A1 WO2025015406 A1 WO 2025015406A1 CA 2023050976 W CA2023050976 W CA 2023050976W WO 2025015406 A1 WO2025015406 A1 WO 2025015406A1
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WO
WIPO (PCT)
Prior art keywords
minutes
dosage form
subject
txa
administration
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/CA2023/050976
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English (en)
Inventor
Tyler DUBETZ
Kelly Mottet
Marc CURIAL
Chris Terriff
Biju KORAVANKUDI
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Mach32 Inc
Original Assignee
Mach32 Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Publication date
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Priority to PCT/CA2023/050976 priority Critical patent/WO2025015406A1/fr
Publication of WO2025015406A1 publication Critical patent/WO2025015406A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner

Definitions

  • the present disclosure generally relates to dosage forms of tranexamic acid (TXA).
  • TXA tranexamic acid
  • the present disclosure also relates to use of dosage forms of TXA for treating hemorrhage in a subject.
  • TXA Tranexamic acid
  • TXA is a synthetic lysine analog that inhibits fibrinolysis, the breakdown of fibrin clots, and therefore reduces bleeding.
  • TXA is considered a first-line medication.
  • TXA dosage forms provide a time to therapeutic TXA concentration ranging between 4 minutes to almost an hour, where the therapeutic concentration ranges between 5 mg/L to 15 mg/L of plasma TXA.
  • maximum serum concentration of TXA (Cmax) and area under the curve (AUC) levels above 65 mg/L and 160 mg*h/L, respectively, have not been achieved in the art.
  • TXA crosses the blood-brain barrier, at approximately 10% of its plasma concentration, and can adversely affect the central nervous system.
  • a dose increase poses various challenges when administered via various routes.
  • TXA is usually administered intravenously and recommended to be slowly injected over the course of 10 minutes.
  • intravenous administration limit accessibility to TXA therapy a higher dose requires further lengthening of an already lengthy injection process.
  • TXA dosage forms that provide better pharmacokinetics in order to reduce bleeding rapidly and durably.
  • the present disclosure provides a dosage form of TXA, wherein upon administration to a subject, the dosage form provides a time to therapeutic concentration of less than about 3 minutes.
  • the present disclosure provides a dosage form of TXA, wherein upon administration to a subject, the dosage form provides a time above 15mg/L of plasma TXA of more than 3 hours.
  • the present disclosure provides a dosage form of TXA formulated for intramuscular administration, wherein upon administration to a subject, the dosage form provides, per 1g of TXA, an AUC above about 170 mg*h/L.
  • the present disclosure provides a dosage form of TXA formulated for intramuscular administration, wherein upon administration to a subject, the dosage form provides a Cmax above about 65 mg/L.
  • the present disclosure provides the use of the dosage form of any one of the embodiments of the invention for reducing or preventing hemorrhage in a subject in need thereof.
  • the present disclosure provides a method for reducing or preventing hemorrhage, comprising administering the dosage form of any one of the embodiments of the invention to a subject in need thereof.
  • FIG. 1A is a cross-sectional view of a delivery device according to one embodiment in a first configuration
  • FIG. IB is a cross-sectional view of the delivery device of FIG. 1A in a second configuration
  • FIG. 1C is a cross-sectional view of the delivery device of FIG. 1A in a third configuration
  • FIG. ID is a cross-section view of the delivery device of FIG. 1 A in a fourth configuration
  • FIG. 2 is an exploded view of a delivery device according to an embodiment of the present disclosure
  • FIG. 3 is a cross-sectional view of the delivery device of FIG. 2 in a first configuration
  • FIG. 4 is a cross-sectional view of the delivery device of FIG. 2 in a second configuration
  • FIG. 5 is a cross-sectional view of the delivery device of FIG. 2 in a third configuration
  • FIG. 6 is a cross-sectional view of the delivery device of FIG. 2 in a fourth configuration.
  • FIG. 7 is a perspective view of the delivery device of FIG. 2 in a first configuration
  • FIGS. 8A-D are perspective views of a delivery device according to an embodiment of the present disclosure.
  • FIGS. 8E and 8F are cross-sectional views of the delivery device of FIGS. 8A-D with the driver at the first driver position;
  • FIG. 8G is a cross-sectional view of the delivery device of FIGS. 8A-D, prior to removal of the safety lock;
  • FIG. 8H is a cross-sectional view of the delivery device of FIGS. 8A-D with the driver at the second driver position;
  • FIG. 9 is a perspective view of the safety lock of the delivery device of FIGS. 8A to 8H.
  • the present disclosure relates to the unexpected discovery of TXA dosage forms that provide pharmacokinetics that has not been achieved previously.
  • the presently disclosed dosage forms of TXA provide for the first time, upon administration to a subject, a time to therapeutic concentration of less than 3 minutes.
  • the presently disclosed dosage forms of TXA also provide for the first time, upon intramuscular administration, an AUC above 170 mg*h/L. Faster time to therapeutic concentration facilitates earlier reduction in bleeding.
  • a higher AUC is an indicator of sustained TXA levels over a longer period of time, which may avoid the need of another dose of TXA, thereby limiting the risk of side effects.
  • a container means one container or more than one container.
  • the phrases “in one embodiment”, “according to one embodiment” and the like generally mean the particular feature, structure, or characteristic following the phrase is included in at least one embodiment of the present disclosure, and may be included in more than one embodiment of the present disclosure. Importantly, such phrases do not necessarily refer to the same aspect. If the specification states a component or feature “may”, “can”, “could”, or “might” be included or have a characteristic, that particular component or feature is not required to be included or have the characteristic.
  • dosage form is defined as the means by which an active pharmaceutical agent is delivered to sites of action within the body of a subject and includes, but is not limited to, a pharmaceutical composition or device, such as an injector or a syringe, comprising the active pharmaceutical agent, and optional pharmacologically inactive ingredients, for example, pharmaceutically acceptable excipients such as polymers, suspending agents, surfactants, disintegrants, dissolution modulating components, binders, diluents, lubricants, stabilizers, antioxidants, osmotic agents, colorants, plasticizers, coatings and the like.
  • a dosage form also includes various routes of administration, such as intravenous, intramuscular, intraosseous, intraoral, subcutaneous, etc.
  • time to therapeutic concentration is defined as the time it takes for plasma concentration of TXA to reach therapeutic concentration in a subject, from the time TXA is first administered to the subject.
  • any numerical value inherently contains certain errors necessarily resulting from the standard deviation found in the respective testing measurements.
  • the term “about” generally means within 10%, 5%, 1%, or 0.5% of a given value or range.
  • the term “about” means within an acceptable standard error of the mean when considered by one of ordinary skill in the art. Unless otherwise indicated, the numerical parameters set forth in the present disclosure and attached claims are approximations that can vary as desired.
  • proximal and distal refer to directions closer to and away from, respectively, the desired position of injection and delivery of fluid of the delivery device.
  • the words “upward”, “downward”, “upper”, “lower”, “right” and “left” are relative terms used to designate components and/or directions for convenience and are not intended to be limiting. For example, an upper part could be located below a lower part depending on the direction of view (and vice versa).
  • the words “inward” and “outward” refer to directions toward and away from, respectively.
  • IM site refers to a position where an injection of a fluid can be administered into any muscle of a subject, such as the deltoid, vastus lateralis, rectus femoris or the ventrogluteal and dorsogluteal areas.
  • movably coupled means that one member is directly or indirectly supported by another member to allow movement of the one member.
  • operatively coupled can refer to a direct or indirect coupling engagement between two or more structural component parts.
  • fluid includes any liquid, such as but not limited to, blood, water, saline solutions, IV solutions or plasma, or any mixture of liquids, particulate matter, medicament, dissolved medicament and/or drugs appropriate for injection into the target site of a subject.
  • container refers to a pharmaceutically acceptable container comprising a chamber suitable to house a fluid.
  • Containers include but are not limited to vials, barrels, ampoules or bottles and in some embodiments are made of glass, plastic, composites, laminates or metal.
  • a “subject” may be a human or non-human mammal.
  • Non-human mammals include, for example, livestock and pets, such as ovine, bovine, porcine, canine and feline mammals.
  • the subj ect is a human, in some embodiments, the operator and the subj ect are the same (i.e., the delivery device is a self-administering delivery device).
  • a dosage form of TXA wherein upon administration to a subject, the dosage form provides a time to therapeutic concentration of less than about 180 seconds, less than about 170 seconds, less than about 160 seconds, less than about 150 seconds, less than about 140 seconds, less than about 130 seconds, less than about 120 seconds, less than about 115 seconds, less than about 110 seconds, less than about 105 seconds, less than about 100 seconds, less than about 95 seconds, less than about 90 seconds, less than about 85 seconds, less than about 80 seconds, less than about 75 seconds, less than about 70 seconds, less than about 65 seconds, less than about 60 seconds, less than about 55 seconds, less than about 50 seconds, less than about 45 seconds, less than about 40 seconds, less than about 35 seconds, less than about 30 seconds, less than about 25 seconds, less than about 20 seconds, or less than about 15 seconds.
  • the therapeutic concentration of plasma TXA is 5 mg/L, 6 mg/L, 7 mg/L, 8 mg/L, 9 mg/L or 10 mg/L.
  • the therapeutic concentration of plasma TXA is 10 mg/L, 11 mg/L, 12, mg/L, 13 mg/L, 14 mg/L or 15 mg/L.
  • the dosage form of TXA wherein upon administration to a subject, further provides, a time above 15 mg/L of plasma TXA of more than about 180 minutes, more than about 190 minutes, more than about 200 minutes, more than about 210 minutes, more than about 220 minutes, more than about 230 minutes, more than about 240 minutes, more than about 250 minutes, more than about 260 minutes, more than about 270 minutes, more than about 280 minutes, more than about 290 minutes, or more than about 300 minutes.
  • the dosage form of TXA wherein upon administration to a subject, further provides, a time to Cmax from about 5 minutes to about 60 minutes, from about 5 minutes to about 55 minutes, from about 5 minutes to about 50 minutes, from about 5 minutes to about 45 minutes, from about 5 minutes to about 40 minutes, from about 5 minutes to about 35 minutes, from about 5 minutes to about 30 minutes, from about 5 minutes to about 25 minutes, from about 5 minutes to about 20 minutes, from about 5 minutes to about 15 minutes, from about 5 minutes to about 10 minutes, from about 10 minutes to about 60 minutes, from about 10 minutes to about 55 minutes, from about 10 minutes to about 50 minutes, from about 10 minutes to about 45 minutes, from about 10 minutes to about 40 minutes, from about 10 minutes to about 35 minutes, from about 10 minutes to about 30 minutes, from about 10 minutes to about 25 minutes, from about 10 minutes to about 20 minutes, from about 10 minutes to about 15 minutes, from about 15 minutes to about 60 minutes, from about 15 minutes to about 55 minutes, from about 15 minutes to about 50 minutes, from about 15 minutes to about 15 minutes, from about 15 minutes
  • the time to Cmax is from about 5 minutes to about 40 minutes, from about 5 minutes to about 35 minutes, from about 5 minutes to about 30 minutes, from about 5 minutes to about 25 minutes, from about 5 minutes to about 20 minutes, from about 5 minutes to about 15 minutes, from about 5 minutes to about 10 minutes, from about 10 minutes to about 40 minutes, from about 10 minutes to about 35 minutes, from about 10 minutes to about 30 minutes, from about 10 minutes to about 25 minutes, from about 10 minutes to about 20 minutes, from about 10 minutes to about 15 minutes, from about 15 minutes to about 40 minutes, from about 15 minutes to about 35 minutes, from about 15 minutes to about 30 minutes, from about 15 minutes to about 25 minutes, from about 15 minutes to about 20 minutes, from about 20 minutes to about 40 minutes, from about 20 minutes to about 35 minutes, from about 20 minutes to about 30 minutes, from about 20 minutes to about 25 minutes, from about 25 minutes to about 40 minutes, from about 25 minutes to about 35 minutes, from about 25 minutes to about 30 minutes, from about 30 minutes to about 40
  • the time to Cmax is from about 5 minutes to about 20 minutes, from about 5 minutes to about 15 minutes, from about 5 minutes to about 13 minutes, from about 5 minutes to about 11 minutes, from about 7 minutes to about 20 minutes, from about 7 minutes to about 15 minutes, from about 7 minutes to about 13 minutes, from about 7 minutes to about 11 minutes, from about 7 minutes to about 9 minutes, from about 9 minutes to about 20 minutes, from about 9 minutes to about 15 minutes, from about 9 minutes to about 13 minutes, from about 9 minutes to about 11 minutes, from about 11 minutes to about 20 minutes, from about 11 minutes to about 15 minutes, from about 11 minutes to about 13 minutes, from about 13 minutes to about 20 minutes, or from about 13 minutes to about 15 minutes.
  • the dosage form of TXA wherein upon administration to a subj ect, further provides, per 1g of TXA, a Cmax from about 10 mg/L to about 80 mg/L, from about 10 mg/L to about 70 mg/L, from about 10 mg/L to about 80 mg/L, from about 10 mg/L to about 60 mg/L, from about 10 mg/L to about 50 mg/L, from about 10 mg/L to about 40 mg/L, from about 10 mg/L to about 30 mg/L, from about 10 mg/L to about 20 mg/L, from about 20 mg/L to about 80 mg/L, from about 20 mg/L to about 70 mg/L, from about 20 mg/L to about 60 mg/L, from about 20 mg/L to about 50 mg/L, from about 20 mg/L to about 40 mg/L, from about 20 mg/L to about 30 mg/L, from about 30 mg/L to about 80 mg/L, from about 30 mg/L to about 70 mg/L, from
  • the Cmax is from about 20 mg/L to about 80 mg/L, from about 20 mg/L to about 70 mg/L, from about 20 mg/L to about 60 mg/L, from about 20 mg/L to about 50 mg/L, from about 20 mg/L to about 40 mg/L, from about 20 mg/L to about 30 mg/L, from about 30 mg/L to about 80 mg/L, from about 30 mg/L to about 70 mg/L, from about 30 mg/L to about 60 mg/L, from about 30 mg/L to about 50 mg/L, from about 30 mg/L to about 40 mg/L, from about 40 mg/L to about 80 mg/L, from about 40 mg/L to about 70 mg/L, from about 40 mg/L to about 60 mg/L, from about 40 mg/L to about 50 mg/L, from about 50 mg/L to about 80 mg/L, from about 50 mg/L to about 70 mg/L, from about 50 mg/L to about 60 mg/L,
  • the Cmax is from about 65 mg/L to about 80 mg/L, from about 65 mg/L to about 75 mg/L, from about 65 mg/L to about 70 mg/L, from about 70 mg/L to about 80 mg/L, or from about 70 mg/L to about 75 mg/L.
  • the dosage form of TXA wherein upon administration to a subject, further provides, per 1g of TXA, an AUC from about 90 mg*h/L to about 250 mg*h/L, from about 90 mg*h/L to about 230 mg*h/L, from about 90 mg*h/L to about 210 mg*h/L, from about 90 mg*h/L to about 190 mg*h/L, from about 90 mg*h/L to about 170 mg*h/L, from about 90 mg*h/L to about 150 mg*h/L, from about from about 90 mg*h/L to about 130 mg*h/L, from about 90 mg*h/L to about 110 mg*h/L, from about 110 mg*h/L to about 250 mg*h/L, from about 110 mg*h/L to about 230 mg*h/L, from about 110 mg*h/L to about 210 mg*h/L, from about 110 mg*h/L to about 190 mg*h/L, from about
  • the AUC is from about from about 90 mg*h/L to about 130 mg*h/L, from about 90 mg*h/L to about 120 mg*h/L, from about 90 mg*h/L to about 110 mg*h/L, from about 90 mg*h/L to about 100 mg*h/L, from about 100 mg*h/L to about 130 mg*h/L, from about 100 mg*h/L to about 120 mg*h/L, from about 100 mg*h/L to about 110 mg*h/L, from about 110 mg*h/L to about 130 mg*h/L, from about 110 mg*h/L to about 120 mg*h/L, or from about 120 mg*h/L to about 130 mg*h.
  • the AUC is from about 170 mg*h/L to about 250 mg*h/L, from about 170 mg*h/L to about 230 mg*h/L, from about 170 mg*h/L to about 210 mg*h/L, from about 170 mg*h/L to about 190 mg*h/L, from about 190 mg*h/L to about 250 mg*h/L, from about 190 mg*h/L to about 230 mg*h/L, from about 190 mg*h/L to about 210 mg*h/L, from about 210 mg*h/L to about 250 mg*h/L, from about 210 mg*h/L to about 230 mg*h/L, or from about 230 mg*h/L to about 250 mg*h/L.
  • the dosage form of TXA wherein upon administration to a subject, further provides a clearance rate from about 4 L/h to about 12 L/h, from about 4 L/h to about 11 L/h, from about 4 L/h to about 10 L/h, from about 4 L/h to about 9 L/h, from about 4 L/h to about 8 L/h, from about 4 L/h to about 7 L/h, from about 4 L/h to about 6 L/h, from about 4 L/h to about
  • 5 L/h from about 5 L/h to about 12 L/h, from about 5 L/h to about 11 L/h, from about 5 L/h to about 10 L/h, from about 5 L/h to about 9 L/h, from about 5 L/h to about 8 L/h, from about 5 L/h to about 7 L/h, from about 5 L/h to about 6 L/h, from about 6 L/h to about 12 L/h, from about 6 L/h to about 11 L/h, from about 6 L/h to about 10 L/h, from about 6 L/h to about 9 L/h, from about
  • 6 L/h to about 8 L/h from about 6 L/h to about 7 L/h, from about 7 L/h to about 12 L/h, from about 7 L/h to about 11 L/h, from about 7 L/h to about 10 L/h, from about 7 L/h to about 9 L/h, from about 7 L/h to about 8 L/h, from about 8 L/h to about 12 L/h, from about 8 L/h to about 11 L/h, from about 8 L/h to about 10 L/h, from about 8 L/h to about 9 L/h, from about 9 L/h to about 12 L/h, from about 9 L/h to about 11 L/h, from about 9 L/h to about 10 L/h, from about 10 L/h to about 12 L/h, from about 10 L/h to about 11 L/h, or from about 11 L/h to about 12 L/h.
  • the clearance rate is from about 6 L/h to about 11 L/h, from about 6 L/h to about 10 L/h, from about 6 L/h to about 9 L/h, from about 6 L/h to about 8 L/h, from about 6 L/h to about 7 L/h, from about 7 L/h to about 11 L/h, from about
  • the clearance rate is from about 4 L/h to about 7 L/h, from about 4 L/h to about 6 L/h, from about 4 L/h to about 5 L/h, from about 5 L/h to about 7 L/h, from about 5 L/h to about 6 L/h, or from about 6 L/h to about 7 L/h.
  • the dosage form of TXA wherein upon administration to a subject, further provides a half life from about 80 minutes to about 200 minutes, 80 minutes to about 180 minutes, 80 minutes to about 160 minutes, 80 minutes to about 140 minutes, 80 minutes to about 120 minutes, 80 minutes to about 100 minutes, 100 minutes to about 200 minutes, 100 minutes to about 180 minutes, 100 minutes to about 160 minutes, 100 minutes to about 140 minutes, 100 minutes to about 120 minutes, 120 minutes to about 200 minutes, 120 minutes to about 180 minutes, 120 minutes to about 160 minutes, 120 minutes to about 140 minutes, 140 minutes to about 200 minutes, 140 minutes to about 180 minutes, 140 minutes to about 160 minutes, 160 minutes to about 200 minutes, 160 minutes to about 180 minutes, or 180 minutes to about 200 minutes.
  • a dosage form of TXA wherein upon administration to a subject, the dosage form provides a time above 15 mg/L of plasma TXA of more than about 180 minutes, more than about 190 minutes, more than about 200 minutes, more than about 210 minutes, more than about 220 minutes, more than about 230 minutes, more than about 240 minutes, more than about 250 minutes, more than about 260 minutes, more than about 280 minutes, more than about 290 minutes, or more than about 300 minutes.
  • the dosage form of TXA wherein upon administration to a subject, further provides, a time to therapeutic concentration of less than about 180 seconds, less than about 170 seconds, less than about 160 seconds, less than about 150 seconds, less than about 140 seconds, less than about 130 seconds, less than about 120 seconds, less than about 115 seconds, less than about 110 seconds, less than about 105 seconds, less than about 100 seconds, less than about 95 seconds, less than about 90 seconds, less than about 85 seconds, less than about 80 seconds, less than about 75 seconds, less than about 70 seconds, less than about 65 seconds, less than about 60 seconds, less than about 55 seconds, less than about 50 seconds, less than about 45 seconds, less than about 40 seconds, less than about 35 seconds, less than about 30 seconds, less than about 25 seconds, less than about 20 seconds, or less than about 15 seconds.
  • the therapeutic concentration of plasma TXA is 5 mg/L, 6 mg/L, 7 mg/L, 8 mg/L, 9 mg/L or 10 mg/L.
  • the therapeutic concentration of plasma TXA is 10 mg/L, 11 mg/L, 12, mg/L, 13 mg/L, 14 mg/L or 15 mg/L.
  • the dosage form of TXA wherein upon administration to a subject, further provides, a time to Cmax from about 5 minutes to about 60 minutes, from about 5 minutes to about 55 minutes, from about 5 minutes to about 50 minutes, from about 5 minutes to about 45 minutes, from about 5 minutes to about 40 minutes, from about 5 minutes to about 35 minutes, from about 5 minutes to about 30 minutes, from about 5 minutes to about 25 minutes, from about 5 minutes to about 20 minutes, from about 5 minutes to about 15 minutes, from about 5 minutes to about 10 minutes, from about 10 minutes to about 60 minutes, from about 10 minutes to about 55 minutes, from about 10 minutes to about 50 minutes, from about 10 minutes to about 45 minutes, from about 10 minutes to about 40 minutes, from about 10 minutes to about 35 minutes, from about 10 minutes to about 30 minutes
  • the time to Cmax is from about 5 minutes to about 40 minutes, from about 5 minutes to about 35 minutes, from about 5 minutes to about 30 minutes, from about 5 minutes to about 25 minutes, from about 5 minutes to about 20 minutes, from about 5 minutes to about 15 minutes, from about 5 minutes to about 10 minutes, from about 10 minutes to about 40 minutes, from about 10 minutes to about 35 minutes, from about 10 minutes to about 30 minutes, from about 10 minutes to about 25 minutes, from about 10 minutes to about 20 minutes, from about 10 minutes to about 15 minutes, from about 15 minutes to about 40 minutes, from about 15 minutes to about 35 minutes, from about 15 minutes to about 30 minutes, from about 15 minutes to about 25 minutes, from about 15 minutes to about 20 minutes, from about 20 minutes to about 40 minutes, from about 20 minutes to about 35 minutes, from about 20 minutes to about 30 minutes, from about 20 minutes to about 25 minutes, from about 25 minutes to about 40 minutes, from about 25 minutes to about 35 minutes, from about 25 minutes to about 30 minutes, from about 30 minutes to about 40
  • the time to Cmax is from about 5 minutes to about 20 minutes, from about 5 minutes to about 15 minutes, from about 5 minutes to about 13 minutes, from about 5 minutes to about 11 minutes, from about 7 minutes to about 20 minutes, from about 7 minutes to about 15 minutes, from about 7 minutes to about 13 minutes, from about 7 minutes to about 11 minutes, from about 7 minutes to about 9 minutes, from about 9 minutes to about 20 minutes, from about 9 minutes to about 15 minutes, from about 9 minutes to about 13 minutes, from about 9 minutes to about 11 minutes, from about 11 minutes to about 20 minutes, from about 11 minutes to about 15 minutes, from about 11 minutes to about 13 minutes, from about 13 minutes to about 20 minutes, or from about 13 minutes to about 15 minutes.
  • the dosage form of TXA wherein upon administration to a subj ect, further provides, per 1g of TXA, a Cmax from about 10 mg/L to about 80 mg/L, from about 10 mg/L to about 70 mg/L, from about 10 mg/L to about 80 mg/L, from about 10 mg/L to about 60 mg/L, from about 10 mg/L to about 50 mg/L, from about 10 mg/L to about 40 mg/L, from about 10 mg/L to about 30 mg/L, from about 10 mg/L to about 20 mg/L, from about 20 mg/L to about 80 mg/L, from about 20 mg/L to about 70 mg/L, from about 20 mg/L to about 60 mg/L, from about 20 mg/L to about 50 mg/L, from about 20 mg/L to about 40 mg/L, from about 20 mg/L to about 30 mg/L, from about 30 mg/L to about 80 mg/L, from about 30 mg/L to about 70 mg/L, from
  • the Cmax is from about 20 mg/L to about 80 mg/L, from about 20 mg/L to about 70 mg/L, from about 20 mg/L to about 60 mg/L, from about 20 mg/L to about 50 mg/L, from about 20 mg/L to about 40 mg/L, from about 20 mg/L to about 30 mg/L, from about 30 mg/L to about 80 mg/L, from about 30 mg/L to about 70 mg/L, from about 30 mg/L to about 60 mg/L, from about 30 mg/L to about 50 mg/L, from about 30 mg/L to about 40 mg/L, from about 40 mg/L to about 80 mg/L, from about 40 mg/L to about 70 mg/L, from about 40 mg/L to about 60 mg/L, from about 40 mg/L to about 50 mg/L, from about 50 mg/L to about 80 mg/L, from about 50 mg/L to about 70 mg/L, from about 50 mg/L to about 60 mg/L,
  • the Cmax is from about 65 mg/L to about 80 mg/L, from about 65 mg/L to about 75 mg/L, from about 65 mg/L to about 70 mg/L, from about 70 mg/L to about 80 mg/L, or from about 70 mg/L to about 75 mg/L.
  • the dosage form of TXA wherein upon administration to a subject, further provides, per 1g of TXA, an AUC from about 90 mg*h/L to about 250 mg*h/L, from about 90 mg*h/L to about 230 mg*h/L, from about 90 mg*h/L to about 210 mg*h/L, from about 90 mg*h/L to about 190 mg*h/L, from about 90 mg*h/L to about 170 mg*h/L, from about 90 mg*h/L to about 150 mg*h/L, from about from about 90 mg*h/L to about 130 mg*h/L, from about 90 mg*h/L to about 110 mg*h/L, from about 110 mg*h/L to about 250 mg*h/L, from about 110 mg*h/L to about 230 mg*h/L, from about 110 mg*h/L to about 210 mg*h/L, from about 110 mg*h/L to about 190 mg*h/L, from about
  • the AUC is from about from about 90 mg*h/L to about 130 mg*h/L, from about 90 mg*h/L to about 120 mg*h/L, from about 90 mg*h/L to about 110 mg*h/L, from about 90 mg*h/L to about 100 mg*h/L, from about 100 mg*h/L to about 130 mg*h/L, from about 100 mg*h/L to about 120 mg*h/L, from about 100 mg*h/L to about 110 mg*h/L, from about 110 mg*h/L to about 130 mg*h/L, from about 110 mg*h/L to about 120 mg*h/L, or from about 120 mg*h/L to about 130 mg*h.
  • the AUC is from about 170 mg*h/L to about 250 mg*h/L, from about 170 mg*h/L to about 230 mg*h/L, from about 170 mg*h/L to about 210 mg*h/L, from about 170 mg*h/L to about 190 mg*h/L, from about 190 mg*h/L to about 250 mg*h/L, from about 190 mg*h/L to about 230 mg*h/L, from about 190 mg*h/L to about 210 mg*h/L, from about 210 mg*h/L to about 250 mg*h/L, from about 210 mg*h/L to about 230 mg*h/L, or from about 230 mg*h/L to about 250 mg*h/L.
  • the dosage form of TXA wherein upon administration to a subject, further provides a clearance rate from about 4 L/h to about 12 L/h, from about 4 L/h to about 11 L/h, from about 4 L/h to about 10 L/h, from about 4 L/h to about 9 L/h, from about 4 L/h to about 8 L/h, from about 4 L/h to about 7 L/h, from about 4 L/h to about 6 L/h, from about 4 L/h to about
  • 5 L/h from about 5 L/h to about 12 L/h, from about 5 L/h to about 11 L/h, from about 5 L/h to about 10 L/h, from about 5 L/h to about 9 L/h, from about 5 L/h to about 8 L/h, from about 5 L/h to about 7 L/h, from about 5 L/h to about 6 L/h, from about 6 L/h to about 12 L/h, from about 6 L/h to about 11 L/h, from about 6 L/h to about 10 L/h, from about 6 L/h to about 9 L/h, from about
  • 6 L/h to about 8 L/h from about 6 L/h to about 7 L/h, from about 7 L/h to about 12 L/h, from about 7 L/h to about 11 L/h, from about 7 L/h to about 10 L/h, from about 7 L/h to about 9 L/h, from about 7 L/h to about 8 L/h, from about 8 L/h to about 12 L/h, from about 8 L/h to about 11 L/h, from about 8 L/h to about 10 L/h, from about 8 L/h to about 9 L/h, from about 9 L/h to about 12 L/h, from about 9 L/h to about 11 L/h, from about 9 L/h to about 10 L/h, from about 10 L/h to about 12 L/h, from about 10 L/h to about 11 L/h, or from about 11 L/h to about 12 L/h.
  • the clearance rate is from about 6 L/h to about 11 L/h, from about 6 L/h to about 10 L/h, from about 6 L/h to about 9 L/h, from about 6 L/h to about 8 L/h, from about 6 L/h to about 7 L/h, from about 7 L/h to about 11 L/h, from about 7 L/h to about 10 L/h, from about 7 L/h to about 9 L/h, from about 7 L/h to about 8 L/h, from about 8 L/h to about 11 L/h, from about 8 L/h to about 10 L/h, from about 8 L/h to about 9 L/h, from about 9 L/h to about 11 L/h, from about 9 L/h to about 10 L/h, or from about 10 L/h to about 11 L/h.
  • the clearance rate is from about 4 L/h to about 7 L/h, from about 4 L/h to about 6 L/h, from about 4 L/h to about 5 L/h, from about 5 L/h to about 7 L/h, from about 5 L/h to about 6 L/h, or from about 6 L/h to about 7 L/h.
  • the dosage form of TXA wherein upon administration to a subject, further provides a half life from about 80 minutes to about 200 minutes, 80 minutes to about 180 minutes, 80 minutes to about 160 minutes, 80 minutes to about 140 minutes, 80 minutes to about 120 minutes, 80 minutes to about 100 minutes, 100 minutes to about 200 minutes, 100 minutes to about 180 minutes, 100 minutes to about 160 minutes, 100 minutes to about 140 minutes, 100 minutes to about 120 minutes, 120 minutes to about 200 minutes, 120 minutes to about 180 minutes, 120 minutes to about 160 minutes, 120 minutes to about 140 minutes, 140 minutes to about 200 minutes, 140 minutes to about 180 minutes, 140 minutes to about 160 minutes, 160 minutes to about 200 minutes, 160 minutes to about 180 minutes, or 180 minutes to about 200 minutes.
  • a dosage form of TXA formulated for intramuscular administration to a subject, wherein the dosage form provides, per 1g of TXA, an AUC above about 170 mg*h/L, above about 180 mg*h/L, above about 190 mg*h/L, or above about 200 mg*h/L.
  • the AUC is from about 170 mg*h/L to about 250 mg*h/L, from about 170 mg*h/L to about 230 mg*h/L, from about 170 mg*h/L to about 210 mg*h/L, from about 170 mg*h/L to about 190 mg*h/L, from about 190 mg*h/L to about 250 mg*h/L, from about 190 mg*h/L to about 230 mg*h/L, from about 190 mg*h/L to about 210 mg*h/L, from about 210 mg*h/L to about 250 mg*h/L, from about 210 mg*h/L to about 230 mg*h/L, or from about 230 mg*h/L to about 250 mg*h/L.
  • the dosage form of TXA wherein upon administration to a subject, further provides, a time to therapeutic concentration of less than about 180 seconds, less than about 170 seconds, less than about 160 seconds, less than about 150 seconds, less than about 140 seconds, less than about 130 seconds, less than about 120 seconds, less than about 115 seconds, less than about 110 seconds, less than about 105 seconds, less than about 100 seconds, less than about 95 seconds, less than about 90 seconds, less than about 85 seconds, less than about 80 seconds, less than about 75 seconds, less than about 70 seconds, less than about 65 seconds, less than about 60 seconds, less than about 55 seconds, less than about 50 seconds, less than about 45 seconds, less than about 40 seconds, less than about 35 seconds, less than about 30 seconds, less than about 25 seconds, less than about 20 seconds, or less than about 15 seconds.
  • the therapeutic concentration of plasma TXA is 5 mg/L, 6 mg/L, 7 mg/L, 8 mg/L, 9 mg/L or 10 mg/L.
  • the therapeutic concentration of plasma TXA is 10 mg/L, 11 mg/L, 12, mg/L, 13 mg/L, 14 mg/L or 15 mg/L.
  • the dosage form of TXA wherein upon administration to a subject, further provides, a time above 15 mg/L of plasma TXA of more than about 180 minutes, more than about 190 minutes, more than about 200 minutes, more than about 210 minutes, more than about 220 minutes, more than about 230 minutes, more than about 240 minutes, more than about 250 minutes, more than about 260 minutes, more than about 280 minutes, more than about 290 minutes, or more than about 300 minutes.
  • the dosage form of TXA wherein upon administration to a subject, further provides, a time to Cmax from about 5 minutes to about 60 minutes, from about 5 minutes to about 55 minutes, from about 5 minutes to about 50 minutes, from about 5 minutes to about 45 minutes, from about 5 minutes to about 40 minutes, from about 5 minutes to about 35 minutes, from about 5 minutes to about 30 minutes, from about 5 minutes to about 25 minutes, from about 5 minutes to about 20 minutes, from about 5 minutes to about 15 minutes, from about 5 minutes to about 10 minutes, from about 10 minutes to about 60 minutes, from about 10 minutes to about 55 minutes, from about 10 minutes to about 50 minutes, from about 10 minutes to about 45 minutes, from about 10 minutes to about 40 minutes, from about 10 minutes to about 35 minutes, from about 10 minutes to about 30 minutes, from about 10 minutes to about 25 minutes, from about 10 minutes to about 20 minutes, from about 10 minutes to about 15 minutes, from about 15 minutes to about 60 minutes, from about 15 minutes to about 55 minutes, from about 15 minutes to about 50 minutes, from about 15 minutes to about 15 minutes, from about 15 minutes
  • the time to Cmax is from about 5 minutes to about 40 minutes, from about 5 minutes to about 35 minutes, from about 5 minutes to about 30 minutes, from about 5 minutes to about 25 minutes, from about 5 minutes to about 20 minutes, from about 5 minutes to about 15 minutes, from about 5 minutes to about 10 minutes, from about 10 minutes to about 40 minutes, from about 10 minutes to about 35 minutes, from about 10 minutes to about 30 minutes, from about 10 minutes to about 25 minutes, from about 10 minutes to about 20 minutes, from about 10 minutes to about 15 minutes, from about 15 minutes to about 40 minutes, from about 15 minutes to about 35 minutes, from about 15 minutes to about 30 minutes, from about 15 minutes to about 25 minutes, from about 15 minutes to about 20 minutes, from about 20 minutes to about 40 minutes, from about 20 minutes to about 35 minutes, from about 20 minutes to about 30 minutes, from about 20 minutes to about 25 minutes, from about 25 minutes to about 40 minutes, from about 25 minutes to about 35 minutes, from about 25 minutes to about 30 minutes, from about 30 minutes to about 40
  • the time to Cmax is from about 5 minutes to about 20 minutes, from about 5 minutes to about 15 minutes, from about 5 minutes to about 13 minutes, from about 5 minutes to about 11 minutes, from about 7 minutes to about 20 minutes, from about 7 minutes to about 15 minutes, from about 7 minutes to about 13 minutes, from about 7 minutes to about 11 minutes, from about 7 minutes to about 9 minutes, from about 9 minutes to about 20 minutes, from about 9 minutes to about 15 minutes, from about 9 minutes to about 13 minutes, from about 9 minutes to about 11 minutes, from about 11 minutes to about 20 minutes, from about 11 minutes to about 15 minutes, from about 11 minutes to about 13 minutes, from about 13 minutes to about 20 minutes, or from about 13 minutes to about 15 minutes.
  • the dosage form of TXA wherein upon administration to a subject, further provides, per 1g of TXA, a Cmax from about 10 mg/L to about 80 mg/L, from about 10 mg/L to about 70 mg/L, from about 10 mg/L to about 80 mg/L, from about 10 mg/L to about 60 mg/L, from about 10 mg/L to about 50 mg/L, from about 10 mg/L to about 40 mg/L, from about 10 mg/L to about 30 mg/L, from about 10 mg/L to about 20 mg/L, from about 20 mg/L to about 80 mg/L, from about 20 mg/L to about 70 mg/L, from about 20 mg/L to about 60 mg/L, from about 20 mg/L to about 50 mg/L, from about 20 mg/L to about 40 mg/L, from about 20 mg/L to about 30 mg/L, from about 30 mg/L to about 80 mg/L, from about 30 mg/L to about 70 mg/L, from about 30 mg/L
  • the Cmax is from about 20 mg/L to about 80 mg/L, from about 20 mg/L to about 70 mg/L, from about 20 mg/L to about 60 mg/L, from about 20 mg/L to about 50 mg/L, from about 20 mg/L to about 40 mg/L, from about 20 mg/L to about 30 mg/L, from about 30 mg/L to about 80 mg/L, from about 30 mg/L to about 70 mg/L, from about 30 mg/L to about 60 mg/L, from about 30 mg/L to about 50 mg/L, from about 30 mg/L to about 40 mg/L, from about 40 mg/L to about 80 mg/L, from about 40 mg/L to about 70 mg/L, from about 40 mg/L to about 60 mg/L, from about 40 mg/L to about 50 mg/L, from about 50 mg/L to about 80 mg/L, from about 50 mg/L to about 70 mg/L, from about 50 mg/L to about 60 mg/L,
  • the Cmax is from about 65 mg/L to about 80 mg/L, from about 65 mg/L to about 75 mg/L, from about 65 mg/L to about 70 mg/L, from about 70 mg/L to about 80 mg/L, or from about 70 mg/L to about 75 mg/L.
  • the dosage form of TXA wherein upon administration to a subject, further provides a clearance rate from about 4 L/h to about 12 L/h, from about 4 L/h to about 11 L/h, from about 4 L/h to about 10 L/h, from about 4 L/h to about 9 L/h, from about 4 L/h to about 8 L/h, from about 4 L/h to about 7 L/h, from about 4 L/h to about 6 L/h, from about 4 L/h to about
  • 5 L/h from about 5 L/h to about 12 L/h, from about 5 L/h to about 11 L/h, from about 5 L/h to about 10 L/h, from about 5 L/h to about 9 L/h, from about 5 L/h to about 8 L/h, from about 5 L/h to about 7 L/h, from about 5 L/h to about 6 L/h, from about 6 L/h to about 12 L/h, from about 6 L/h to about 11 L/h, from about 6 L/h to about 10 L/h, from about 6 L/h to about 9 L/h, from about
  • 6 L/h to about 8 L/h from about 6 L/h to about 7 L/h, from about 7 L/h to about 12 L/h, from about 7 L/h to about 11 L/h, from about 7 L/h to about 10 L/h, from about 7 L/h to about 9 L/h, from about 7 L/h to about 8 L/h, from about 8 L/h to about 12 L/h, from about 8 L/h to about 11 L/h, from about 8 L/h to about 10 L/h, from about 8 L/h to about 9 L/h, from about 9 L/h to about 12 L/h, from about 9 L/h to about 11 L/h, from about 9 L/h to about 10 L/h, from about 10 L/h to about 12 L/h, from about 10 L/h to about 11 L/h, or from about 11 L/h to about 12 L/h.
  • the clearance rate is from about 6 L/h to about 11 L/h, from about 6 L/h to about 10 L/h, from about 6 L/h to about 9 L/h, from about 6 L/h to about 8 L/h, from about 6 L/h to about 7 L/h, from about 7 L/h to about 11 L/h, from about
  • the clearance rate is from about 4 L/h to about 7 L/h, from about 4 L/h to about 6 L/h, from about 4 L/h to about 5 L/h, from about 5 L/h to about 7 L/h, from about 5 L/h to about 6 L/h, or from about 6 L/h to about 7 L/h.
  • the dosage form of TXA wherein upon administration to a subject, further provides a half life from about 80 minutes to about 200 minutes, 80 minutes to about 180 minutes, 80 minutes to about 160 minutes, 80 minutes to about 140 minutes, 80 minutes to about 120 minutes, 80 minutes to about 100 minutes, 100 minutes to about 200 minutes, 100 minutes to about 180 minutes, 100 minutes to about 160 minutes, 100 minutes to about 140 minutes, 100 minutes to about 120 minutes, 120 minutes to about 200 minutes, 120 minutes to about 180 minutes, 120 minutes to about 160 minutes, 120 minutes to about 140 minutes, 140 minutes to about 200 minutes, 140 minutes to about 180 minutes, 140 minutes to about 160 minutes, 160 minutes to about 200 minutes, 160 minutes to about 180 minutes, or 180 minutes to about 200 minutes.
  • a dosage form of TXA formulated for intramuscular administration to a subject wherein the dosage form provides, per 1g of TXA, a Cmax above about 63 mg/L, about 64 mg/L, about 65 mg/L, about 66 mg/L, about 67 mg/L, about 68 mg/L, about 69 mg/L, about 70 mg/L, about 71 mg/L, about 72 mg/L, about 73 mg/L, about 74 mg/L, about 75 mg/L, about 76 mg/L, about 77 mg/L, about 78 mg/L, about 79 mg/L, or about 80 mg/L.
  • the Cmax is from about 65 mg/L to about 80 mg/L, from about 65 mg/L to about 75 mg/L, from about 65 mg/L to about 70 mg/L, from about 70 mg/L to about 80 mg/L, or from about 70 mg/L to about 75 mg/L.
  • the dosage form of TXA wherein upon administration to a subject, further provides, a time to therapeutic concentration of less than about 180 seconds, less than about 170 seconds, less than about 160 seconds, less than about 150 seconds, less than about 140 seconds, less than about 130 seconds, less than about 120 seconds, less than about 115 seconds, less than about 110 seconds, less than about 105 seconds, less than about 100 seconds, less than about 95 seconds, less than about 90 seconds, less than about 85 seconds, less than about 80 seconds, less than about 75 seconds, less than about 70 seconds, less than about 65 seconds, less than about 60 seconds, less than about 55 seconds, less than about 50 seconds, less than about 45 seconds, less than about 40 seconds, less than about 35 seconds, less than about 30 seconds, less than about 25 seconds, less than about 20 seconds, or less than about 15 seconds.
  • the therapeutic concentration of plasma TXA is 5 mg/L, 6 mg/L, 7 mg/L, 8 mg/L, 9 mg/L or 10 mg/L.
  • the therapeutic concentration of plasma TXA is 10 mg/L, 11 mg/L, 12, mg/L, 13 mg/L, 14 mg/L or 15 mg/L.
  • the dosage form of TXA wherein upon administration to a subject, further provides, a time above 15 mg/L of plasma TXA of more than about 180 minutes, more than about 190 minutes, more than about 200 minutes, more than about 210 minutes, more than about 220 minutes, more than about 230 minutes, more than about 240 minutes, more than about 250 minutes, /more than about 260 minutes, more than about 280 minutes, more than about 290 minutes, or more than about 300 minutes.
  • the dosage form of TXA wherein upon administration to a subject, further provides, a time to Cmax from about 5 minutes to about 60 minutes, from about 5 minutes to about 55 minutes, from about 5 minutes to about 50 minutes, from about 5 minutes to about 45 minutes, from about 5 minutes to about 40 minutes, from about 5 minutes to about 35 minutes, from about 5 minutes to about 30 minutes, from about 5 minutes to about 25 minutes, from about 5 minutes to about 20 minutes, from about 5 minutes to about 15 minutes, from about 5 minutes to about 10 minutes, from about 10 minutes to about 60 minutes, from about 10 minutes to about 55 minutes, from about 10 minutes to about 50 minutes, from about 10 minutes to about 45 minutes, from about 10 minutes to about 40 minutes, from about 10 minutes to about 35 minutes, from about 10 minutes to about 30 minutes, from about 10 minutes to about 25 minutes, from about 10 minutes to about 20 minutes, from about 10 minutes to about 15 minutes, from about 15 minutes to about 60 minutes, from about 15 minutes to about 55 minutes, from about 15 minutes to about 50 minutes, from about 15 minutes to about 15 minutes, from about 15 minutes
  • the time to Cmax is from about 5 minutes to about 40 minutes, from about 5 minutes to about 35 minutes, from about 5 minutes to about 30 minutes, from about 5 minutes to about 25 minutes, from about 5 minutes to about 20 minutes, from about 5 minutes to about 15 minutes, from about 5 minutes to about 10 minutes, from about 10 minutes to about 40 minutes, from about 10 minutes to about 35 minutes, from about 10 minutes to about 30 minutes, from about 10 minutes to about 25 minutes, from about 10 minutes to about 20 minutes, from about 10 minutes to about 15 minutes, from about 15 minutes to about 40 minutes, from about 15 minutes to about 35 minutes, from about 15 minutes to about 30 minutes, from about 15 minutes to about 25 minutes, from about 15 minutes to about 20 minutes, from about 20 minutes to about 40 minutes, from about 20 minutes to about 35 minutes, from about 20 minutes to about 30 minutes, from about 20 minutes to about 25 minutes, from about 25 minutes to about 40 minutes, from about 25 minutes to about 35 minutes, from about 25 minutes to about 30 minutes, from about 30 minutes to about 40
  • the time to Cmax is from about 5 minutes to about 20 minutes, from about 5 minutes to about 15 minutes, from about 5 minutes to about 13 minutes, from about 5 minutes to about 11 minutes, from about 7 minutes to about 20 minutes, from about 7 minutes to about 15 minutes, from about 7 minutes to about 13 minutes, from about 7 minutes to about 11 minutes, from about 7 minutes to about 9 minutes, from about 9 minutes to about 20 minutes, from about 9 minutes to about 15 minutes, from about 9 minutes to about 13 minutes, from about 9 minutes to about 11 minutes, from about 11 minutes to about 20 minutes, from about 11 minutes to about 15 minutes, from about 11 minutes to about 13 minutes, from about 13 minutes to about 20 minutes, or from about 13 minutes to about 15 minutes.
  • the dosage form of TXA wherein upon administration to a subject, further provides, per 1g of TXA, an AUC from about 90 mg*h/L to about 250 mg*h/L, from about 90 mg*h/L to about 230 mg*h/L, from about 90 mg*h/L to about 210 mg*h/L, from about 90 mg*h/L to about 190 mg*h/L, from about 90 mg*h/L to about 170 mg*h/L, from about 90 mg*h/L to about 150 mg*h/L, from about from about 90 mg*h/L to about 130 mg*h/L, from about 90 mg*h/L to about 110 mg*h/L, from about 110 mg*h/L to about 250 mg*h/L, from about 110 mg*h/L to about 230 mg*h/L, from about 110 mg*h/L to about 210 mg*h/L, from about 110 mg*h/L to about 190 mg*h/L, from about
  • the AUC is from about from about 90 mg*h/L to about 130 mg*h/L, from about 90 mg*h/L to about 120 mg*h/L, from about 90 mg*h/L to about 110 mg*h/L, from about 90 mg*h/L to about 100 mg*h/L, from about 100 mg*h/L to about 130 mg*h/L, from about 100 mg*h/L to about 120 mg*h/L, from about 100 mg*h/L to about 110 mg*h/L, from about 110 mg*h/L to about 130 mg*h/L, from about 110 mg*h/L to about 120 mg*h/L, or from about 120 mg*h/L to about 130 mg*h.
  • the AUC is from about 170 mg*h/L to about 250 mg*h/L, from about 170 mg*h/L to about 230 mg*h/L, from about 170 mg*h/L to about 210 mg*h/L, from about 170 mg*h/L to about 190 mg*h/L, from about 190 mg*h/L to about 250 mg*h/L, from about 190 mg*h/L to about 230 mg*h/L, from about 190 mg*h/L to about 210 mg*h/L, from about 210 mg*h/L to about 250 mg*h/L, from about 210 mg*h/L to about 230 mg*h/L, or from about 230 mg*h/L to about 250 mg*h/L.
  • the dosage form of TXA wherein upon administration to a subject, further provides a clearance rate from about 4 L/h to about 12 L/h, from about 4 L/h to about 11 L/h, from about 4 L/h to about 10 L/h, from about 4 L/h to about 9 L/h, from about 4 L/h to about 8 L/h, from about 4 L/h to about 7 L/h, from about 4 L/h to about 6 L/h, from about 4 L/h to about
  • 5 L/h from about 5 L/h to about 12 L/h, from about 5 L/h to about 11 L/h, from about 5 L/h to about 10 L/h, from about 5 L/h to about 9 L/h, from about 5 L/h to about 8 L/h, from about 5 L/h to about 7 L/h, from about 5 L/h to about 6 L/h, from about 6 L/h to about 12 L/h, from about 6 L/h to about 11 L/h, from about 6 L/h to about 10 L/h, from about 6 L/h to about 9 L/h, from about
  • 6 L/h to about 8 L/h from about 6 L/h to about 7 L/h, from about 7 L/h to about 12 L/h, from about 7 L/h to about 11 L/h, from about 7 L/h to about 10 L/h, from about 7 L/h to about 9 L/h, from about 7 L/h to about 8 L/h, from about 8 L/h to about 12 L/h, from about 8 L/h to about 11 L/h, from about 8 L/h to about 10 L/h, from about 8 L/h to about 9 L/h, from about 9 L/h to about 12 L/h, from about 9 L/h to about 11 L/h, from about 9 L/h to about 10 L/h, from about 10 L/h to about 12 L/h, from about 10 L/h to about 11 L/h.
  • the clearance rate is from about 6 L/h to about 11 L/h, from about 6 L/h to about 10 L/h, from about 6 L/h to about 9 L/h, from about 6 L/h to about 8 L/h, from about 6 L/h to about 7 L/h, from about 7 L/h to about 11 L/h, from about 7 L/h to about 10 L/h, from about 7 L/h to about 9 L/h, from about 7 L/h to about 8 L/h, from about 8 L/h to about 11 L/h, from about 8 L/h to about 10 L/h, from about 8 L/h to about 9 L/h, from about 9 L/h to about 11 L/h, from about 9 L/h to about 10 L/h, or from about 10 L/h to about 11 L/h.
  • the clearance rate is from about 4 L/h to about 7 L/h, from about 4 L/h to about 6 L/h, from about 4 L/h to about 5 L/h, from about 5 L/h to about 7 L/h, from about 5 L/h to about 6 L/h, or from about 6 L/h to about 7 L/h.
  • the dosage form of TXA wherein upon administration to a subject, further provides a half life from about 80 minutes to about 200 minutes, 80 minutes to about 180 minutes, 80 minutes to about 160 minutes, 80 minutes to about 140 minutes, 80 minutes to about 120 minutes, 80 minutes to about 100 minutes, 100 minutes to about 200 minutes, 100 minutes to about 180 minutes, 100 minutes to about 160 minutes, 100 minutes to about 140 minutes, 100 minutes to about 120 minutes, 120 minutes to about 200 minutes, 120 minutes to about 180 minutes, 120 minutes to about 160 minutes, 120 minutes to about 140 minutes, 140 minutes to about 200 minutes, 140 minutes to about 180 minutes, 140 minutes to about 160 minutes, 160 minutes to about 200 minutes, 160 minutes to about 180 minutes, or 180 minutes to about 200 minutes.
  • TXA may be delivered via a device adapted to automatically inject a dose of TXA into a target site, such as an IM site of a subject.
  • the delivery device is sized to be carried in compact spaces such as, but not limited to, military pouches and tactical vests.
  • FIGS. 1A-1D a cross-sectional view of a delivery device 1 is shown according to one embodiment advancing sequentially from a first configuration to a second configuration, to a third configuration and to a fourth configuration, respectively.
  • the delivery device 1 includes an upper body 4 and a lower body which are both configured to house an injection assembly 2.
  • Injection assembly 2 is configured to inj ect and deliver a fluid to the IM site of the subj ect.
  • the inj ection assembly is configured to inject and deliver at least 1 mL or at least 2 mL or at least 3 mL or at least 4 mL or at least 5 mL of the fluid to the IM site of the subject.
  • the delivery device 1 may include one or more injection assemblies.
  • the delivery device 1 also includes a lower body 3 which is movably coupled to the upper body 4.
  • the upper body 4 is configured to be moveable relative to the lower body 3 in a proximal direction along the longitudinal axis L of delivery device 1 (FIG. 1 A) upon application of a force F to the upper body 4.
  • the injection assembly includes a plunger 8 moveable between a first plunger position and second plunger position, a first releasable retainer member 6 configured to secure the plunger 8 in the first plunger position and release the plunger 8 after activation of the injection assembly 2, a first energy storage member 7 operable to release energy to the plunger 8 and displace the plunger 8 in the proximal direction from the first plunger position to the second plunger position, and a fluid container 9 having a distal end configured to receive the plunger 8 and a proximal end with an orifice or outlet.
  • the orifice or outlet of container 9 may be in fluid communication with a needle 14.
  • the plunger 8 is sized to be movably disposed inside the lower body 3.
  • the injection assembly 2 may include a safety lock to prevent activation of injection assembly 2.
  • the safety lock may be any suitable mechanism, such as a button or a pin.
  • the safety lock is a safety pin 13 which needs to be removed before activating the injection assembly 2.
  • safety pin 13 When in the position shown in FIG. 1A, safety pin 13 may be engaged with upper body 4 and lower body 3, such as by insertion of a portion of safety pin 13 in openings of upper body 4 and lower body 3, to prevent movement of upper body 4 relative lower body 3.
  • safety pin 13 When safety pin 13 is removed, upper body 4 may be free to move relative to lower body 3.
  • the delivery device 1 also includes a driver 11 moveable relative to lower body 3 from a first driver position to a second driver position and having a proximal end and a distal end.
  • the delivery device 1 also includes a second energy storage member 10 operable to release energy to the driver 11 and displace the driver 11 in a proximal direction when the plunger 8 reaches the second plunger position and detaches the driver 11 from lower body 3.
  • the lower body 3 and the driver 11 are releasably coupled by second releasable retainer member 12, which is configured to secure driver 11 to lower body 3 and release driver 11 from lower body 3 when plunger 8 is located at the second plunger position.
  • the delivery device 1 can generally be operated by removing the safety pin 13 in the direction indicated by arrow D in FIG. 1 A.
  • the user may place the proximal end of driver 11 in contact to the target site and apply a force to the upper body 4 in the proximal direction.
  • the upper body 4 moves in a proximal direction over lower body 3, such that a portion of needle 14 (which interconnected to upper body 4) extends from the proximal end of driver 11.
  • the movement of upper body 4 in a proximal direction also activates the actuator 5.
  • Activation of actuator 5 causes an automatic sequence of movements. First, activation of the actuator 5 causes the first releasable retainer member 6 to release plunger 8.
  • the plunger 8 is then displaced in a proximal direction by the first energy storage member 7. Movement of the plunger 8 in the proximal direction will continue until reaching the second plunger position at the proximal end of the fluid container 9 (FIG. 1C). As plunger 8 moves proximally, the liquid is delivered from/urged out of fluid container 9 to needle 14, as will be explained in more detail below.
  • the first energy storage member 7 is operable to continue to apply energy to the plunger 8 that is sufficient for plunger 8 to engage second releasable retainer member 12 such that driver 11 is released from lower body 3.
  • the user may hold the device to the target site for a prescribed time period, which may be a time sufficient for the liquid to be delivered/urged out of the fluid container 9 to and through needle 14 for delivery to the target site.
  • the prescribed time period may be selected based on factors such as the volume of fluid to be delivered and the configuration of device 1.
  • the user reduces the force F applied to the upper body 4.
  • the second energy storage member 10 exerts a force on the lower body 3 in the distal direction (as indicated by arrow C in FIG. ID) which in turn displaces upper body 4 in a distal direction which is sufficient, in combination with the reduced force F applied to the upper body 4 to displace delivery device 1 in a distal direction relative to the target site such that needle 14 is retracted from the target site.
  • driver 11 is displaced proximally by second energy storage member 10 relative to the needle and lower body 3 from its first driver position (FIG. 1C) to a second driver position (FIG. ID).
  • driver 11 is displaced with respect to the lower body 3, the needle 14 is retracted back from the target site and is enclosed within driver 11.
  • the delivery device 1 is shown in a first configuration and a second configuration respectively.
  • the upper body 4 is displaced over the lower body 3 in a proximal direction, as indicated by arrow A in FIGS. 1A and IB, along a longitudinal axis L of the delivery device between a first upper body position (FIG. 1A) and a second upper body position (FIG. IB).
  • a distal portion 3 a of the lower body 3 makes contact with a proximal portion 5a of actuator 5 (FIG. 1A), which activates actuator 5.
  • the actuator 5 may be any suitable device for activating the delivery device 1, such as, for example, a handle, a lever, a push button, lock, a slidable button or a trigger.
  • the plunger 8 Prior to activation of actuator 5, the plunger 8 is held relative to the upper body in the first plunger position by the first releasable retainer member 6.
  • the first releasable retainer member 6 is configured to release the plunger 8 and release the first energy storage member 7 from its first configuration to second configuration wherein the first energy storage member 7 is able to release energy to the plunger 8 to displace plunger 8 when in the second configuration, after actuator 5 has been activated by movement of the upper body 4 in the proximal direction from the first actuator position (FIG. 1A) to the second actuator position (FIG. IB).
  • the first releasable retainer member 6 can be any suitable mechanism for releasably retaining the plunger 8 and releasing the first energy storage member 7, such as, for example, a mechanical linkage, a compressed ring, a spring-loaded rod, interlocking threads, a tensioned latch or tab or the like.
  • the interlocking threads are a helical male and female thread arrangement.
  • the needle 14 which is in fluid communication with the fluid container 9 is housed within the driver 11.
  • the delivery device moves to the second configuration, a portion of needle 14 extends outside the lower body 3 (due to proximal movement of the upper body 4 and the interconnected needle 14 relative to lower body 3) for insertion into the target site of a subject at a desired depth.
  • movement of the delivery device 1 from the first configuration to second configuration will extend the needle 14 outside of the lower body 3 for insertion into, for example, the IM site of the subject.
  • the plunger 8 is displaced in a proximal direction relative to upper body 4, as indicated by arrow B, along a longitudinal axis L of the delivery device 1 between a first plunger position (FIG. IB) and second plunger position (FIG. 1 C) by deployment of the first energy storage member 7.
  • a portion of the proximal end of the plunger 8 is positioned at the distal end of the fluid container 9.
  • the plunger 8 is in fluid communication with the fluid contained within fluid container 9.
  • the plunger 8 When the plunger 8 is displaced (or advanced) to the second plunger position, the plunger 8 is advanced from the distal end of the fluid container 9 to the proximal end of the fluid container 9. In this manner, as the plunger 8 is displaced (or advanced) between the first and second plunger positions, fluid is conveyed/urged out from within fluid container 9 through the needle 14 and into the IM site of the subject. Thus, movement of the delivery device 1 from the second configuration to third configuration delivers fluid into the IM site of the subject.
  • the driver 11 prior to the plunger 8 reaching the second plunger position, the driver 11 is held in a secure position to the lower body 3 by the second releasable retainer member 12.
  • the second releasable retainer member 12 is configured to release the driver 11 once the plunger 8 reaches the second plunger position and release the second energy storage member 10 from its first configuration (FIG. 1C) to its second configuration (FIG. ID), wherein the second energy storage member 10 is able to release energy to the driver 11 to displace the driver 11 when in the second configuration.
  • the second releasable retainer member 12 can be any suitable mechanism for releasably retaining the driver 11 and deploying the second energy storage member 10, such as, for example, a mechanical linkage, a compressed ring, a spring-loaded rod, a tensioned latch or tab or the like.
  • the second energy storage member 10 Upon release of the driver 11 by the second releasable retainer member 12, the second energy storage member 10 is also released from its first configuration to its second configuration. Energy released from the second energy storage member 10 displaces the lower body 3 and the upper body 4 in the distal direction, which is sufficient, in combination with the reduced force F applied to the upper body 4 to displace delivery device 1 in a distal direction relative to the target site such that needle 14 is retracted from the target site. As this happens the driver 11 is displaced by second energy storage member 10 proximally, as indicated by arrow D in FIG. ID, along the longitudinal axis L of delivery device 1 from its first driver position (FIG. 1C) to its second driver position (FIG. ID) where the needle 14 is fully within driver 11.
  • the first and second energy storage members 7 and 10 each independently can be any device for storing energy.
  • one or both of the first and second energy storage members 7 and 10 may be a mechanical energy storage member, such as a spring, a device containing compressed gas, a device containing a vapor pressure-based propellant or something similar or an electrical energy storage member, such as a battery, a capacitor, a magnetic energy storage member or something similar
  • one or more of the first and second energy storage members 7 and 10 can be a chemical energy storage member, such as a container containing two substances that, when mixed, react to produce energy.
  • the first energy storage member 7 moves within the upper body 4 along axis L between a first configuration (FIGS.
  • first energy storage member 7 When the first energy storage member 7 is in its first configuration, it has a first potential energy. When the first energy storage member 7 is in its second configuration, it has a second potential energy that is less than the first potential energy.
  • the first energy storage member 7 is operably coupled to the plunger 8 such that when the first energy storage member 7 moves from its first configuration to its second configuration, it converts at least a portion of its first potential energy into kinetic energy to displace the plunger 8 in the proximal direction from the first plunger position to the second plunger position.
  • the movement of the first energy storage member 7 from its first configuration to its second configuration results in the release of energy that acts upon the plunger 8 to move the plunger 8 from the first plunger position (FIGS. 1 A and IB) to the second plunger position (FIG. 1C) and thereby dispense fluid contained within the fluid container 9.
  • the energy released is also sufficient to activate the second releasable retainer member 12, thereby detaching the driver 11 from lower body 3.
  • the second energy storage member 10 can be moved within the driver 11 and lower body 3 along L between a first configuration (FIG. 1C) and a second configuration (FIG. ID).
  • a first configuration FOG. 1C
  • a second configuration FOG. ID
  • the second energy storage member 10 When the second energy storage member 10 is in its first configuration, it also has a first potential energy.
  • the second energy storage member 10 When the second energy storage member 10 is in its second configuration, it has a second potential energy that is less than the first potential energy.
  • the second energy storage member 10 is operably coupled to the driver 11 such that when the second energy storage member 10 moves from its first configuration to its second configuration, it converts at least a portion of its first potential energy into kinetic energy to displace (in combination with the reduced force F applied to the upper body 4) the lower body 3 and upper body 4 distally and displace the driver 11 in the proximal direction from the first driver position to the second driver position.
  • the needle 14, which is secured to the upper body 4 also moves distally.
  • the delivery device 100 generally includes an upper body 110 and a lower body 120 movably coupled to the upper body 110.
  • the upper body 110 is generally shaped and dimensioned to fit within an operator’s hand and includes a distal end 110a, a proximal end 110b and an exterior surface 111.
  • the upper body 110 may be a unitary structure (i.e., one-piece) that defines the exterior surface 111, or it may include a plurality of layers with different layers defining the exterior surface 111.
  • the upper body 110 may further include a safety pin 112 movably coupled thereto which may be operated by the operator.
  • the safety pin 112 is adapted and configured to prevent the premature or accidental activation of the delivery device 100.
  • the safety pin 112 may be a pull pin arrangement, such as shown in FIG. 2, but may also be a switch, a button, or similar mechanism to prevent accidental activation.
  • safety pin 112 may be inserted into a pair of upper openings 113 and a lower opening 116 (FIG. 7).
  • the upper body 110 may be rigid. According to other embodiments, the upper body 110 may be flexible, whether according to the nature of the material that defines the upper body 110 or according to the nature of the structure of the upper body 110.
  • the upper body 110 may be made of glass, metal, or polymer, for example.
  • polymer versions may be made of polycarbonate, polypropylene, polyethylene (such as high density polyethylene), polytetrafluoroethylene, cyclic olefin polymer, cyclic olefin copolymer, crystal zenith olefinic polymer, nylon, or engineering resins.
  • polyethylene such as high density polyethylene
  • cyclic olefin polymer such as high density polyethylene
  • cyclic olefin copolymer such as high density polyethylene
  • crystal zenith olefinic polymer such as nylon, or engineering resins.
  • the device 100 has a chamber 114 (FIG. 3), sized and configured to receive injection assembly 102.
  • the upper body 110 may include more than one chambers for holding more than one injection assembly if desired.
  • Chamber 114 includes openings at both the distal end 110a and the proximal end 110b of upper body 110. Such openings may include a breakable or removable seal or cover for sterilization purposes prior to use.
  • a plug 118 may be disposed at the distal end 110a of chamber 114.
  • plug 118 may be permanently attached to upper body 110 or formed as an integral part of upper body 110. In other embodiments, plug 118 may be removable from upper body 110.
  • a fluid container 150 may be located within the chamber 114 and secured to and is movable with the upper body 110.
  • fluid container 150 may be secured to upper body by an interference fit; adhesive, fasteners (such as screws, rivets, clips), interlocking structural elements or any suitable means that restricts the relative motion of fluid container 150 relative to upper body 110.
  • fluid container 150 may be secured to upper body 110 through an interference fit in combination with a suitable adhesive.
  • the lower body 120 includes a distal end 120a and a proximal end 120b and is generally shaped and dimensioned such that upper body 110 may move relative to lower body 120 in a proximal direction along a longitudinal axis L of delivery device 100 (FIG. 3) from a first upper body position to a second upper body position upon application of user applied force F at the distal end 110a or along the exterior surface 111 of the upper body 110 directed in a proximal direction, generally towards the target IM site.
  • the lower body 120 includes an exterior surface 121.
  • the lower body 120 may be a unitary structure (i.e. one-piece) that defines the exterior surface 121 or include a plurality of layers with different layers defining the exterior surface 121.
  • the lower body 120 may further include a releasable retainer member 122 releasably coupled to a driver 170.
  • upper body 110 may feature one or more elongated windows sized and configured to allow the operator to view the contents of lower body 120.
  • the windows may be any suitable shape for viewing the contents, such as, but not limited to, an arrow, rectangle or a long oval.
  • the windows may comprise a clear material, such as a translucent or transparent material to maintain the sterility of the delivery device 100 whilst allowing the operator to view the contents of upper body 110.
  • upper body 110 has elongated windows 115a and 115b which are sized and configured to allow the operator to view the contents of fluid container 150 of injection assembly 102 (FIG. 2).
  • Windows 115a and 115b may align with a longitudinally extending slot 125 in the lower body 120 such that at least a portion of fluid container 150 may be in view. This may allow visualization of the fluid prior to delivery and allow a user to confirm that the fluid has been delivered.
  • the delivery device 100 as shown includes only one injection assembly 102 and in some embodiments there may a second injection assembly.
  • the components for additional injection assemblies and their arrangement and operation would be similar to injection assembly 102 and accordingly only one injection assembly 102 will be described below.
  • the injection assembly 102 includes an actuator 130, a first releasable retainer member 132, a first energy storage member 134, a plunger 140, and a fluid container 150.
  • First releasable retainer member 132 may be seated in a collar 136 secured to the upper body 110.
  • the first releasable retainer member 132 includes a generally circular proximal portion 132a, a distal portion 132b and a threaded opening 132c (FIGS. 2 and 3).
  • the collar 136 has a centrally located opening 136a into which the proximal end 132a of the first releasable retainer member 132 is received, such that member 132 may be rotatable relative to collar 136 within the opening 136a.
  • the actuator 130 may be generally ring shaped and includes a centrally located opening 130b for engaging the outer edge of the first releasable retainer member 132 such that actuator 130 interlocks with first releasable retainer member 132.
  • Actuator 130 is moveable relative to the first releasable retainer member 132.
  • actuator 130 When actuator 130 is in the first actuator position, as shown in FIG. 3, actuator 130 is positioned directly above collar 136 and engages distal portion 132b of first releasable retainer member 132 such that rotational movement of first releasable retainer member is prevented.
  • the plunger 140 may include a plunger rod 142.
  • the plunger rod 142 is shown having a cylindrical body 143 with a distal end 143a, a proximal end 143b an inner cavity 143c.
  • the plunger rod 142 may include a plunger piston contact member 143d within cavity 143c (FIG. 3).
  • the plunger rod 142 and first energy storage member 134 are operatively coupled at the distal end 143 a of the plunger rod 142.
  • the plunger rod 142 is configured to be slidably movable within the tower body 120 in a longitudinal axis L shown in FIG. 3.
  • An outwardly projecting tab 143e (FIG. 2) on the outer surface of the cylindrical body 143 is received within the longitudinally extending slot 125 in the tower body 120.
  • the slot 125 may guide plunger rod 142 during longitudinal movement of the plunger rod 142 within the tower body 120.
  • the plunger rod 142 may also include a threaded member 145 extending in a distal direction from the distal end 143a of the cylindrical body 143.
  • a distal portion of the threaded member 145 is received within the threaded opening 132c of the first releasable retainer member 132 and actuator 130 is also in engagement with the first releasable retainer member 132.
  • first energy storage member 134 When first energy storage member 134 is in its first position (FIG. 3) it will be exerting a force upon plunger rod 142 in a proximal direction which, acting through the threaded connection between plunger rod 142 and first releasable retainer member 132, will bias member 132 to rotate. However, rotation of first releasable retainer member 132 is prevented by engagement with actuator 130, which is in turn prevented from rotational movement by engagement of the tab 130a with the longitudinally extending slot (not shown) on the interior surface of the upper body 110. Additionally, plunger rod 142 is prevented from rotational movement by engagement of outwardly projecting tab 143e within the longitudinally extending slot 125 in the tower body 120.
  • plunger rod 142 cannot disengage from first releasable retainer member 132 whilst actuator 130 is in the first actuator position.
  • actuator 130 is lightly restrained from motion in the distal direction by frictional forces with first releasable retainer member 132.
  • the movement of the actuator 130 in the proximal direction is restricted by the distal surface of collar 136 and may only move distally from the first actuator position. This is caused by movement of lower body 120 in a distal direction from the first actuator position (FIG. 3) to the second actuator position (FIG. 4), whereby the distal end 120a of the lower body 120 will contact the proximal surface of the actuator 130, displacing actuator 130 in a distal direction from the first actuator position and thereby disengaging the actuator 130 from the first releasable retainer member 132.
  • the member 132 As actuator 130 disengages with the first releasable retainer member 132, the member 132 is free to rotate about longitudinal axis L relative to collar 136, such that threaded member 145 and thereby plunger rod 142 is released to disengage from member 132 and is able to move in a proximal direction from the first plunger position to the second plunger position.
  • actuator 130 may move distally within chamber 114 from the first actuator position as shown in FIG. 3 to the second actuator position shown in FIG. 4 such that actuator 130 disengages with first releasable retainer member 132.
  • the actuator 130 is advanced in the distal direction by the movement of the lower body 120.
  • the actuator 130 may include a tab 130a on the exterior circumference which engages a longitudinally extending slot (not shown) on the interior surface of the upper body 110, which may act to prevent rotation of actuator (130 about longitudinal axis L) relative to first upper body 110.
  • such movement by the actuator 130 from the first actuator position to the second actuator position activates the delivery device 100 to cause a sequence of movements of the injection assembly 102 that subsequently leads to the injection and delivery of fluid contained within the injection assembly 102.
  • the injection assembly 102 may further include a safety activation mechanism operatively coupled with actuator 130 which prevents the actuator 130 from moving in a distal direction thus preventing the first releasable retainer member 132 being activated and releasing the plunger 140 from engagement until the safety activation mechanism is activated.
  • safety activation mechanism is configured to prevent the premature or accidental deployment of the delivery device 100.
  • the safety activation mechanism can be comprised of any suitable mechanism, such as an energy storage member described above, a button, a pin, or similar mechanism. In such embodiments, regardless of whether the safety pin 112 has been released from engagement, the safety activation mechanism will prevent the actuator 130 from activation.
  • the safety activation mechanism therefore acts as a second safety mechanism and will prevent the premature or accidental activation of the delivery device, irrespective of the release of safety pin 112.
  • the safety pin 112 may also be releasably coupled to the lower body 120 and the upper body 110, preventing movement of the lower body 120 relative to the upper body 110, thus preventing displacement of the actuator 130 from the first actuator position.
  • the injection assembly 102 also includes afluid container 150 and aneedle 160.
  • the fluid container 150 is configured to hold a fluid.
  • the fluid container 150 includes an open distal end 150a and a proximal end 150b comprising an outlet or orifice that is fluidly coupled to needle 160, such as by a luer connector, threads, a snap-fit, a latch, a lock, a friction fit coupling, an adhesive or any other suitable coupling features (not shown).
  • the fluid container 150 may have a length of between about 10 millimeters (mm) to about 100 mm. In an embodiment the fluid container has a length of about 77 mm.
  • the distal end 150a and proximal end 150b may have a diameter of between about 10 mm to about 25 mm.
  • the orifice at the proximal end 150b may have a diameter of between about 0.05 mm to about 1.6 mm.
  • the fluid container 150 defines an internal volume configured to house a fluid. In some embodiments the fluid container 150 may be configured to hold an amount of fluid in the range of about 1 milliliter (mL) to about 20 mL, or about 2 mL to about 15 mL, or about 3 mL to about 10 mL, or about 4 mL to about 6 mL.
  • the injection assembly 102 also includes a first energy storage member 134. In the embodiment shown in FIG.
  • the first energy storage member 134 is a mechanical energy storage member comprising a spring, such as, for example, a helical, compression, extension, torsion, constant, variable, variable stiffness or any other type of spring having a spring constant ranging between about 1 N/m to about 3000 N/m. In some embodiments the spring has a spring constant about 1680 N/m.
  • the first energy storage member 134 is operatively coupled to the plunger 140 and releases energy to the plunger 140 to displace the plunger 140 in the proximal direction when the first energy storage member 134 moves from its first configuration to second configuration after the actuator 130 has been activated.
  • the plunger 140 also includes a plunger piston 144.
  • the plunger 140 may be formed as a single piece or as modular components. The modular components may be affixed to one another or located adjacently but not connected, so as to move together.
  • the plunger 140 is sized and configured to be movably disposed within the fluid container 150 when it moves between the first plunger position and second plunger position.
  • the plunger piston 144 has a distal end 144a and a proximal end 144b which is configured to be in fluid communication with the fluid disposed within the internal volume defined by the fluid container 150. In some embodiments, plunger piston 144 may be supplied with (and installed in) fluid container 150.
  • plunger piston contact member 143d of the plunger rod 142 can be coupled to and/or in contact with the distal end 144a of the plunger tip 144. In other embodiments, there may be a gap between plunger piston contact member 143d and the distal end 144a of the plunger piston 144 (as shown in FIG. 3). In some embodiments, another component may be positioned between the plunger piston contact member 143 d and the distal end 144a of plunger piston 144. The component may be made from a compressible material, such as a foam and may minimize or dampen any forces/shocks between plunger rod 142 and plunger piston 144.
  • the distal end 144a of the plunger piston 144 is configured to be movably displaced within the internal volume defined by the fluid container 150 by the energy released by the first energy storage member 134 when the first energy storage member 134 moves from its first configuration to second configuration. In this manner, the first energy storage member 134 acting on the plunger 140 can displace the plunger piston 144 proximally within fluid container 150 to expel the fluid through the orifice at proximal end 150b of fluid container 150.
  • the sidewalls of the proximal end 144b of the plunger piston 144 may include a piston plunger seal 146 (FIG.
  • the piston plunger seal can be made of an inert and/or biocompatible material. Example materials include rubber, silicone, plastic, polymers, any other suitable material or combination thereof.
  • the piston plunger seal 146 can be monolithically formed with the plunger 140.
  • the plunger 140 may also include one-way bendable tabs (not shown) to prevent movement of the plunger rod 142 in the distal direction once the plunger 140 has advanced to the second plunger position.
  • the delivery device 100 includes a driver 170.
  • the driver 170 is shown as a cylindrical plug having a distal end 170a and a proximal end 170b and is sized and configured to be moveable in a proximal direction from a first driver position to a second driver position relative to lower body 120.
  • the driver 170 further includes an inner cavity 171 sized and configured to support the needle 160.
  • the inner cavity 171 further includes an expanded region 172 sized to accommodate a lower portion of fluid container 150.
  • the delivery device 100 also includes a second energy storage member 152.
  • the second energy storage member 152 is a mechanical energy storage member comprising a spring, such as, for example, a helical, compression, extension, torsion, constant, variable, variable stiffness or any other type of spring having a spring constant ranging between about 1 N/m to about 500 N/m.
  • the second energy storage member is a spring having a spring constant of 370 N/m.
  • the second energy storage member 152 is operatively coupled to the driver 170 and releases energy to the driver 170 to displace the driver 170 from its first driver position to its second driver position relative to lower body 120 when the second energy storage member 152 moves from its first configuration to its second configuration after the second releasable retainer member 122 releases the driver 170.
  • the delivery device 100 also includes a second releasable retainer member 122 which secures the lower body 120 to the driver 170 at a first driver position and is configured to release the driver 170 when the plunger 140 moves to the second plunger position.
  • the second releasable retainer member 122 may be formed by one or more inwardly extending tabs formed in the surface of lower body 120 (FIG. 2), configured to engage corresponding openings 170c in the driver 170 when the second releasable retainer mechanism 122 is at the first position (FIG. 3).
  • the second releasable retainer member 122 which may be what is commonly referred to as a snap (which may encompass a snap fit, snap joint snap lock or plastic clip) is inherently biased inwardly, so as to interferingly engage the opening 170c in the driver 170, such that a lower, inwardly protruding portion 122a of second releasable retainer member 122 engages the upper wall of opening 170c of the driver 170. With this arrangement, movement of the driver 170 relative to lower body 120 in the L direction is prevented.
  • the second releasable retainer member 122 will then move from a first position to a second position, thereby releasing the lower body 120 from engagement with driver 170 (i.e., some of the energy released from the first energy member 134 is translated to the second releasable retainer member 122 when the plunger 140 is displaced to the second plunger position, the energy being sufficient to displace the second releasable retainer member 122 from a first position to a second position).
  • delivery device 100 may further include a needle cover (not shown).
  • the needle cover is configured to prevent needlestick injuries and maintain the sterility of the needle by providing a protective barrier around the needle.
  • the needle cover can be manually removed before operation of the delivery device 100 or may be operable to automatically remove itself during the insertion of needle 160 into the subject then and re-cover the needle 160 after retraction of needle 160.
  • FIGS. 3-6 To illustrate operation of the delivery device 100, a sequence of events illustrating the injection and delivery of fluid by the device 100, as well as the position of the various components, is discussed progressing from FIGS. 3-6.
  • FIG. 3 illustrates the delivery device 100 in an initial position (i.e., first configuration), where the delivery device 100 is ready for use and activation.
  • Upper body 110 is in a first upper body position.
  • Actuator 130 is in the first actuator position.
  • First and second energy storage members 134 and 152 are in their first configurations.
  • the plunger 142 is held in place by the first releasable retainer member 132, the first releasable retainer member 132 being in engagement with the plunger 142 and the actuator 130.
  • the driver 170 is at the first driver position and is cooperatively engaged with lower body 120.
  • the needle 160 is fully within driver 170.
  • FIG. 4 illustrates the delivery device 100 in a second configuration.
  • a 2-step activation mechanism may be required to activate the actuator 130.
  • the safety pin 112 is released from engagement and then the second safety activation mechanism which is configured to oppose the upward motion of the lower body 120 is released from engagement.
  • activation may be a 1-step activation where either the safety pin 112 or safety activation mechanism is present and must be released, while in still other embodiments the delivery device 100 does not include the safety pin 112 or safety activation mechanism.
  • the delivery device 100 can be activated when force is applied at the proximal end 170b of the driver 170. This is typically the reaction force at the IM site as the user holds on to the upper body 110 and exerts force F upon the upper body 110 in the proximal direction.
  • the upper body 110 is moved relative to lower body 120 in the proximal direction from the first upper body position to the second upper body position (as indicated by arrow A in FIG 3).
  • plunger 140, fluid container 150 and needle 160 are coupled to upper body 110 and will also move in the proximal direction relative to lower body 120, such that a portion of needle 160 extends outside of the driver 170 to inject into the target site of the subject at a desired depth.
  • Movement of upper body 110 moves actuator 130 in a distal direction relative to upper body 110 from the first actuator position to the second actuator position through contact of the distal end 120a of lower body 120 with the proximal end of actuator 130.
  • the first releasable retainer member 132 is now able to release from the plunger rod 142.
  • Energy is released from the first energy storage member 134 as it moves from its first configuration to second configuration, causing the plunger rod 142 to begin movement in the proximal direction within the chamber 114 and driving the plunger piston 144 towards proximal end 150b of fluid container 150 (as indicated by arrow B in FIG. 4).
  • movement by the plunger rod 142 in the proximal direction towards second plunger position begins delivery of fluid from the fluid container 150 to the needle 160 and into the subject.
  • FIG. 5 illustrates the delivery device 100 in athird configuration.
  • the plunger rod 142 has moved in the proximal direction to the second plunger position, driving plunger piston 144 to deliver substantially all of the fluid within the fluid container 150 to and through the needle 160 and into the subject.
  • plunger rod 142 has moved over fluid container 150 such that fluid container 150 is partially received in inner cavity 143c of plunger rod 142.
  • the proximal end 143b of the plunger rod 142 is now in cooperative engagement with the second releasable retainer member 122.
  • FIG. 6 illustrates the delivery device 100 in a fourth configuration.
  • the second releasable retainer member 122 is activated and detaches the driver 170 from the lower body 120.
  • the second energy member 152 moves from its first configuration to its second configuration.
  • the distal end of the second energy storage member 152 is in contact with the proximal end 120b of the lower body 120 and the proximal end of the second energy member 152 is in contact with the driver 170.
  • the user may hold the device 100 to the target site for a prescribed time period, and after this prescribed time period, the user reduces the force F applied to the upper body 110.
  • the second energy storage member 152 moving to the second configuration exerts force on the lower body 120 in the distal direction (as indicated by arrow C in FIG. 5) which in turn displaces upper body 110 in a distal direction which is sufficient, in combination with the reduced force F applied to the upper body 110 to displace delivery device 100 in a distal direction relative to the target site such that needle 160 is retracted from the target site.
  • driver 170 is displaced proximally (as indicated by arrow D in FIG. 5) by second energy storage member 152 relative to the needle from its first driver position (FIG. 5) to a second driver position (FIG. 6).
  • the needle 160 is retracted back from the target site and is enclosed within driver 170.
  • Proximal movement of driver 170 may be restricted by the contact of a lip (not shown in FIGS.) on the upper portion of driver 170 contacting the inwardly extending proximal edge (not shown in FIGS, of the lower body 120 which prevents movement of driver 170 further than is shown in FIG. 6.
  • the contact of the lip of driver 170 with the edge of lower body 120 is similar to as illustrated and described below with respect to delivery device 200.
  • the delivery device 100 may also include a component for providing feedback to the operator once the injection and delivery of fluid is complete and the needle 160 is fully enclosed in the driver 170, such as, but not limited to, one or more viewing windows, such as windows 115a and 115b described above indicating that the injection and delivery of fluid has been completed or an audible click.
  • needle 160 (and attached fluid container 150) of delivery device 100 may be driven by a force to drive the needle from a first needle position to a second needle position, whereby movement of the needle from the first needle position to the second needle position inserts the needle into the target site of the subject.
  • the force is an external force applied by a user to the delivery device, such as force F described above for delivery devices 1 and 100.
  • the force is applied by the first energy storage member 134 or the second energy storage member 152.
  • the force is applied by a third energy storage member (which may be similar to first and second energy storage members 134, 152 described above).
  • the force may be applied to needle 160, fluid container 150 or other interconnected components.
  • the third energy storage member comprises a spring.
  • the third energy storage member may cause movement of needle 160 (and attached fluid container 150) in the proximal direction whilst a user holds the delivery device over the target site of a subject in order to drive the needle into target site of the subject.
  • needle 160 (and attached fluid container 150) may be initiated, for example, in response to the pressing of a button or switch on delivery device 100.
  • An example of a suitable mechanism for driving needle 160 and fluid container 150 is disclosed in PCT application Serial No. PCT/CA2022/050057 (filed on 2022-01-14 and published on 2022-07-21 as PCT publication no. WO 2022/150927 Al), the entire contents of which are incorporated by reference herein.
  • a delivery device according to another embodiment is shown and generally designated by reference numeral 200.
  • the delivery device 200 may generally be similar to delivery device 100 described above.
  • delivery device 200 includes an upper body 210 generally shaped and dimensioned to fit within an operator’s hand.
  • Delivery device 200 may also include a safety pin 212, which may operate in a similar manner to safety pin 112 described above.
  • Safety pin 212 shown in isolation in FIG. 9, may include having one or more inwardly extending upper pins 212a and lower pin 212b configured to be inserted into respective openings 213, 216 (which may be similar to openings 113, 116 described above) in the upper body 210, as shown in FIG. 8G.
  • FIG. 8G In FIG.
  • the pins 212a may extend into a chamber 214 of the device 200 and may perform a similar function to the upper portion 112a of the safety pin 112 described above, in this embodiment preventing movement of actuator 230 in a distal direction.
  • Actuator 230 may be similar to actuator 130 described above.
  • the safety pin 212 may be operated by a user gripping the opposed outer sides 212c, 212d of safety pin 212 and removing the safety pin 212 from the upper body 210 in the direction indicated by arrow A in FIG. 8B. This will also extract the pins 212a, 212b of the safety pin 212 through the slot 213, such that movement of the actuator 230 in a distal direction is no longer restricted by the safety pin 212. This will enable operation of the delivery device 200 in a similar manner to the delivery device 100.
  • delivery device 200 is shown with a driver 270 (which may be generally similar to driver 170 described above) in a second driver position, which may be similar to the second driver position of driver 170 described above. In this position, further proximal movement of driver 270 is prevented by engagement of lip 272 at the distal end of driver 270 with the inwardly extending proximal edge of lower body 220.
  • a method for reducing or preventing hemorrhage comprising administering the dosage form of any one of the embodiments of the invention to a subject in need thereof.
  • the hemorrhage is posttraumatic hemorrhage, postpartum hemorrhage, perioperative or postoperative hemorrhage.
  • the hemorrhage is posttraumatic hemorrhage, e.g., hemorrhage caused by a traumatic brain injury.
  • the hemorrhage is postpartum hemorrhage.
  • the hemorrhage is postoperative hemorrhage.
  • the hemorrhage is external.
  • the hemorrhage is internal.
  • the hemorrhage is associated with hemorrhagic shock and/or coagulopathy.
  • the antifibrinolytic agent is administered within 5 hours, within 4 hours, within 3 hours, within 2 hours, within 1 hour, within 45 min, within 30 min, or within 15 min of the onset of the hemorrhage.
  • Particular embodiments include, without limitation, the following:
  • TXA tranexamic acid
  • a dosage form of TXA wherein upon administration to a subj ect, the dosage form provides a time above 15 mg/L of plasma TXA of more than about 3 hours.
  • embodiment 48 The dosage form of embodiment 48 which is an autoinjector.
  • a dosage form of TXA formulated for intramuscular administration wherein upon administration to a subject, the dosage form provides, per 1g of TXA, an AUC above about 170 mg*h/L.
  • a dosage form of TXA formulated for intramuscular administration wherein upon administration to a subject, the dosage form provides a Cmax above about 65 mg/L.
  • the dosage form of embodiment 80 or 81 wherein upon administration to a subject, the dosage form provides a time to therapeutic concentration of less than about 3 minutes.
  • hemorrhage is posttraumatic hemorrhage, postpartum hemorrhage, perioperative hemorrhage, or postoperative hemorrhage.
  • a method for reducing or preventing hemorrhage comprising administering the dosage form of any one of embodiments 1-104 to a subject in need thereof.
  • hemorrhage is posttraumatic hemorrhage, postpartum hemorrhage, perioperative hemorrhage, or postoperative hemorrhage.
  • PK pharmacokinetics
  • IM intramuscular autoinjector
  • Example 1 PK study using a high-volume intramuscular autoinjector on a swine model
  • IMSAFE autoinjectors were fdled with 5 mL of 100 mg/mL commercially available TXA, resulting in 0.5 g of TXA per autoinjector. A total of two autoinjectors were used per animal to deliver a total of 1 g of TXA. TXA was delivered in the following manner: the first autoinjector delivered 0.5 g of TXA into the animal thigh and was held in place for 10 seconds, a second autoinjector was then used to deliver 0.5 g of TXA into the other thigh and held in place for 10 seconds. Immediately following injection, injection sites were closely examined for any signs of blood, tissue damage or leakage of drug product from the administration site.
  • the injection site was reassessed over the course of the experiment for any visible physical signs of tissue damage or bruising.
  • Blood samples were collected in 2 mL EDTA tubes and spun down to collect plasma which was used to determine TXA concentration using LC/MS (liquid chromatography mass spectroscopy). Chromatographic separation was performed on an Agilent 1100/1200 series HPLC with a Zorbax SB-C18 column 4.6x5mm, 3.5um (Agilent Technologies, Mississauga, ON) at flow rate of 0.35 ml/min and temperature of 40 °C. Sample injection volume was 1 pL.
  • the mobile phase consisted of Buffer A (10 mM formic acid in water) and Buffer B (10 mM formic acid in 90% acetonitrile).
  • a linear gradient elution was used with an initial mobile phase composition of 3% Buffer B, changing to 30% Buffer B at 7 min, then at 9 min to 3% Buffer B.
  • the instrument was operated in positive mode using electrospray ionization (ESI) source and following operational settings: Drying gas temperature of 300 °C and flow rate of 9.5 l/min, nebulizer pressure at 45 psi, capillary voltage at 2000 V in positive mode and fragmentor voltage of 40 V.
  • the pharmacokinetic (PK) data was determined using Phoenix (Phoenix WinNonLin, Certara L.P.). The maximum concentration (Cmax), time to reach maximal concentration (Tmax) and area under the curve vs. time curve were calculated. The total injection time was recorded.
  • Results All animals were successfully injected with a total 1 g of TXA using two autoinjectors. No bruising or hematomas were observed at the injection site initially after inj ection or over the entire course of the experimental period. The pharmacokinetics were fit to a 1st order, one compartment model with uniform weighting and Gauss-Newton (Levenberg and Hartley) minimization. Time to maximal concentration was determined to be 10.7 ⁇ 0.7 minutes. Maximal concentration was determined to be 72.4 pg/mL ⁇ 3.3 pg/ml (or 72.4 mg/L ⁇ 3.3 mg/L). The observed area under the curve was 12096 ⁇ 1342 pg*min/ml.

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Abstract

La présente divulgation concerne de manière générale des formes posologiques permettant d'améliorer le profil pharmacocinétique de l'acide tranexamique (TXA). L'invention concerne également l'utilisation de formes posologiques fournies ici pour le traitement d'une hémorragie chez un sujet.
PCT/CA2023/050976 2023-07-20 2023-07-20 Formes posologiques d'acide tranexamique et leurs utilisations Pending WO2025015406A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20190224121A1 (en) * 2018-01-19 2019-07-25 Hyloris Developments Sa Tranexamic acid oral solution
US20200078326A1 (en) * 2018-09-06 2020-03-12 RTU Pharma SA Ready-to-use tranexamic acid intravenous solution
WO2023154750A1 (fr) * 2022-02-09 2023-08-17 Aktivax, Inc. Compositions d'acide tranexamique injectables concentrées et leurs procédés d'utilisation

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20190224121A1 (en) * 2018-01-19 2019-07-25 Hyloris Developments Sa Tranexamic acid oral solution
US20200078326A1 (en) * 2018-09-06 2020-03-12 RTU Pharma SA Ready-to-use tranexamic acid intravenous solution
WO2023154750A1 (fr) * 2022-02-09 2023-08-17 Aktivax, Inc. Compositions d'acide tranexamique injectables concentrées et leurs procédés d'utilisation

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Title
ERDOES G., KOSTER A., ORTMANN E., MEESTERS M. I., BOLLIGER D., BARYSHNIKOVA E., MARTINEZ LOPEZ DE ARROYABE B., AHMED A., LANCE M. : "A European consensus statement on the use of four‐factor prothrombin complex concentrate for cardiac and non‐cardiac surgical patients", ANAESTHESIA., BLACKWELL SCIENCE LTD., GB, vol. 76, no. 3, 1 March 2021 (2021-03-01), GB , pages 381 - 392, XP093268690, ISSN: 0003-2409, DOI: 10.1111/anae.15181 *
GRASSIN-DELYLE STANISLAS, SHAKUR-STILL HALEEMA, PICETTI ROBERTO, FRIMLEY LAUREN, JARMAN HEATHER, DAVENPORT ROSS, MCGUINNESS WILLIA: "Pharmacokinetics of intramuscular tranexamic acid in bleeding trauma patients: a clinical trial", BRITISH JOURNAL OF ANAESTHESIA, ELSEVIER, vol. 126, no. 1, 1 January 2021 (2021-01-01), pages 201 - 209, XP093268684, ISSN: 0007-0912, DOI: 10.1016/j.bja.2020.07.058 *
SRIVANI VENNA: "TXA Autoinjector technology to stop blood loss on battlefield", ARMY-TECHNOLOGY.COM, 18 April 2019 (2019-04-18), pages 1 - 3, XP093268695, Retrieved from the Internet <URL:https://www.army-technology.com/news/txa-autoinjector-blood-loss/> *

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