EP4021420A1 - System und verfahren zur multiwirkstofffreisetzung - Google Patents

System und verfahren zur multiwirkstofffreisetzung

Info

Publication number
EP4021420A1
EP4021420A1 EP20857394.9A EP20857394A EP4021420A1 EP 4021420 A1 EP4021420 A1 EP 4021420A1 EP 20857394 A EP20857394 A EP 20857394A EP 4021420 A1 EP4021420 A1 EP 4021420A1
Authority
EP
European Patent Office
Prior art keywords
tablet
capsule
drug
elagolix
interior
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
EP20857394.9A
Other languages
English (en)
French (fr)
Other versions
EP4021420A4 (de
Inventor
Yihong Qiu
Deliang Zhou
Mohamad SHEBLEY
Juki Wing-Keung NG
Ahmed Mohamed
Jian-Hwa HAN
David Metzger
Alexander RUGGLES
Hui ZU
Xi Shao
Yuchuan Gong
Yisheng Chen
Jian Gong
Min Li
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
AbbVie Inc
Original Assignee
AbbVie 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.)
Filing date
Publication date
Application filed by AbbVie Inc filed Critical AbbVie Inc
Publication of EP4021420A1 publication Critical patent/EP4021420A1/de
Publication of EP4021420A4 publication Critical patent/EP4021420A4/de
Pending legal-status Critical Current

Links

Classifications

    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4808—Preparations in capsules, e.g. of gelatin, of chocolate characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
    • A61J3/00—Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms
    • A61J3/07—Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms into the form of capsules or similar small containers for oral use
    • A61J3/071—Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms into the form of capsules or similar small containers for oral use into the form of telescopically engaged two-piece capsules
    • A61J3/074—Filling capsules; Related operations
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
    • A61J3/00—Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms
    • A61J3/10—Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms into the form of compressed tablets
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A61K31/567—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in position 17 alpha, e.g. mestranol, norethandrolone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
    • A61J1/00—Containers specially adapted for medical or pharmaceutical purposes
    • A61J1/03—Containers specially adapted for medical or pharmaceutical purposes for pills or tablets
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates

Definitions

  • the field of the present disclosure relates generally to medicinal products and, more specifically, to a drug dosage form that enables simultaneous, immediate release of more than one drug enclosed within a capsule upon ingestion by a patient, and a delivery system for the drug dosage that ensures compliance with intake instructions by the patient.
  • a capsule generally includes a hollow shell having an interior for storing powder or liquid-based drugs therein, and a tablet may be fabricated from a compressed powder of the medicinal substance.
  • tablets and capsules may be fabricated to enable administration or intake of two or more drugs to the patient in a single dose or single dosage form.
  • at least some known capsules contain a mixture of drugs in liquid or powder form within the interior of the hollow shell.
  • at least some known tablets include a first drug encapsulated within a second drug. However, encapsulating the first drug within the second drug may hinder dissolution of the first drug, and may reduce the dissolution of the first and second drugs.
  • drugs administered in powder or liquid form may dissolve at a rate unsuitable for a desired efficacy.
  • a multi-drug delivery system includes a first capsule including a first capsule body having a first interior, and a first tablet and a second tablet included within the first interior.
  • the first tablet includes a first drug
  • the second tablet includes at least a second drug different from the first drug.
  • the second tablet may include a second and third drug, each of which are different from the first drug and each other.
  • the first tablet and the second tablet are configured for simultaneous release upon dissolution of the first capsule body within a patient.
  • the system also includes a second capsule, co-packaged with the first capsule, including a second capsule body having a second interior, and a third tablet included within the second interior.
  • the third tablet may include either the first drug, the second drug and/or one or more other drugs. At least 75% ⁇ 10% of the first drug in the first tablet dissolves after 60 minutes and at least 70% ⁇ 10% or 70% ⁇ 20% or 70% ⁇ 30% or 70% ⁇ 40% of the second and third drugs in the second tablet dissolve after 30 minutes when using USP apparatus 2 at 50 rpm, pH 6.8, and 37.5 ⁇ 0.5°C.
  • the first tablet may include a gonadotropin releasing hormone antagonist.
  • the first tablet may include elagolix, relugolix, another gonadotropin-releasing hormone antagonist and/or a combination of gonadotropin-releasing hormone antagonists.
  • the first tablet may include elagolix.
  • the first tablet may include between about 175 mg to about 325 mg of the gonadotropin-releasing hormone antagonist and the second tablet may include between about 0.75 mg and about 1.25 mg of estradiol; the second tablet may further include between about 0.1 mg and about 1 mg of norethindrone acetate; after about 15 minutes, the release of estradiol is equal to or greater than 70% ⁇ 10% or 70% ⁇ 20% or 70% ⁇ 30% or 70% ⁇ 40%.
  • the first capsule may be marked with a first identifier and the second capsule may be marked with a second identifier different from the first identifier such that the first capsule and the second capsule are visually distinguishable;
  • the first identifier may be configured to indicate the first capsule is intended for administration within a first time window in the day, and the second identifier may be configured to indicate the second capsule is intended for administration within a second time window in the day different from the first time window.
  • the first identifier may be configured to indicate the first capsule is intended for administration at the first time window that is before noon, and the second identifier may be configured to indicate the second capsule is intended for administration at the second time window that is after noon;
  • the first identifier may be a first color included on the first capsule, and the second identifier may be a second color included on the second capsule.
  • the system may include a package having a plurality of compartments configured to house the first capsule and the second capsule.
  • the package may include a blister card that defines the plurality of compartments, wherein the first capsule and the second capsule housed in the plurality of compartments are accessible by puncturing a seal in the blister card; the package may have information printed thereon related to when to administer the first capsule and the second capsule to the patient; the blister card may have a first row of the plurality of compartments and a second row of the plurality of compartments, wherein the first capsule is housed in the first row, wherein the second capsule is housed in the second row, and wherein the first row and the second row are visually distinct.
  • a capsule for use in delivering drugs to a patient includes a capsule body having an interior, and at least one first tablet and a second tablet included within the interior.
  • the at least one first tablet includes a first drug
  • the second tablet includes at least a second drug different from the first drug.
  • the at least one first tablet and the second tablet are configured for simultaneous release upon dissolution of the capsule body within the patient.
  • the first tablet may include between about 175 mg and about 325 mg of a gonadotropin-releasing hormone antagonist, such as elagolix, and the second tablet comprises between about 0.75 mg and about
  • the second tablet may further comprise between about 0.1 mg and about 1.0 mg of norethindrone acetate.
  • the capsule body may be oblong to define a longitudinal axis, wherein the at least one first tablet and the second tablet are arranged in a serial relationship along the longitudinal axis within the interior; the at least one first tablet and the second tablet may be distinct tablets that have been formed separately from each other and then secured within the interior; the capsule body may not contain drugs in powder form; the capsule body may not include a barrier extending between the first tablet and the second tablet, and wherein the first tablet and the second tablet are not bonded together within the interior; the first capsule may include gelatin.
  • a method of delivering drugs to a patient includes delivering a first capsule to the patient, wherein the first capsule includes a first capsule body having a first interior, and a first tablet and a second tablet included within the first interior.
  • the first tablet includes a first drug
  • the second tablet includes at least a second drug different from the first drug.
  • the first tablet and the second tablet are configured for simultaneous release upon dissolution of the first capsule body within a patient.
  • the method also includes delivering a second capsule, which is co-packaged with the first capsule, to the patient after a predetermined amount of time has elapsed after administration of the first capsule.
  • the second capsule includes a second capsule body having a second interior, and a third tablet included within the second interior.
  • the third tablet includes the first drug.
  • the first tablet comprises the first tablet comprises between about 175 and 325 mg of gonadotropin-releasing hormone antagonist and the second tablet comprises between about 0.75 mg and 1.25 mg of estradiol and between about 0.1 mg and 1.0 mg of norethindrone; after 20 minutes, the release of estradiol is equal to or greater than 70% ⁇ 10% or 70% ⁇ 20% or 70% ⁇ 30% or 70% ⁇ 40%; delivering a second capsule includes delivering the second capsule at least 5 hours after administration of the first capsule; includes providing a package comprising a plurality of compartments configured to house the first capsule and the second capsule therein; and/or further includes housing a plurality of first capsules and a plurality of second capsules within the package, such that the number of first capsules and the number of second capsules housed within the package are each a multiple of the number of days in a week.
  • a multi-drug tablet includes a first tablet and a second tablet coated on the first tablet; the second tablet may be positioned in the center of the first tablet; and/or the multi-tablet includes crospovidone.
  • a medication container assembly includes a first set of a plurality of compartments each compartment configured to support a first capsule; a second set of a plurality of compartments each compartment configured to support a second capsule; wherein, the first capsule comprises a first interior; a first tablet within the first interior, the first tablet comprising a first drug; and a second tablet within the first interior, the second tablet comprising at least a second drug different from the first drug, wherein the first tablet and the second tablet are configured for simultaneous release upon dissolution of the first capsule body within a patient; and the second capsule comprises a second capsule body comprising a second interior; and a third tablet within the second interior, the third tablet comprising the at least one drug selected from the group consisting of: the first drug, the second drug, or a third drug.
  • a multi-drug capsule includes a first tablet, the first tablet comprising a first drug; a second tablet co-packaged with the first tablet and, the second tablet comprising at least a second drug different from the first drug; and a third drug different from the first and second drug, wherein the first tablet and the second tablet are configured for simultaneous release upon dissolution of the capsule within a patient; wherein using USP apparatus 2 at 50 rpm, pH 6.8, and 37.5 ⁇ 0.5°C, at least 75% ⁇ 10% of the first drug in the first tablet dissolves after 60 minutes and at least 70% ⁇ 10% or 70% ⁇ 20% or 70% ⁇ 30% or 70% ⁇ 40% of the second and third drugs in the second tablet dissolve after 30 minutes.
  • a multi-drug capsule includes a first tablet, the first tablet comprising a first drug; a second tablet co-packaged with the first tablet and, the second tablet comprising at least a second drug different from the first drug; and a third drug different from the first and second drug, wherein the first tablet and the second tablet are configured for simultaneous release upon dissolution of the capsule within a patient; wherein using USP apparatus 1 at 100 rpm, pH 6.8, and 37.5 ⁇ 0.5°C, at least 75% ⁇ 10% of the first drug in the first tablet dissolves after 45 minutes and at least 90% ⁇ 10% or 90% ⁇ 20% or 90% ⁇ 30% or 90% ⁇ 40% of the second and third drugs in the second tablet dissolve after 30 minutes.
  • the first tablet comprises elagolix
  • the first tablet has between about 175 mg to about 325 mg of elagolix
  • the second tablet has between about 0.75 mg and about 1.25 mg of estradiol.
  • an oral multi-drug capsule composition includes 300 mg of free acid equivalent of elagolix; 1 mg of estradiol; and 0.5 mg of norethindrone acetate; and following administration of a single dose of the composition to healthy adult subjects results in a mean peak concentration (Cmax) for said elagolix of about 1218.4 ng/mL to about 2185 ng/mL; a mean peak concentration (Cmax) for said estradiol of about 0.0424 ng/mL to about 0.0775 ng/mL; a mean peak concentration (Cmax) for said norethindrone acetate of about 4.56 ng/mL to about 8.0 ng/mL; a mean Area Under the Curve (AUC/t)) for said elagolix of about 3293.6 ng.hr/mL to about 5892.5 ng.hr/mL; a mean Area Under the Curve (AUC®) for said estradiol of about 0.688
  • a multi-drug capsule composition includes 300 mg of free acid equivalent of elagolix; 1 mg of estradiol; and 0.5 mg of norethindrone acetate; and administration of a single dose of the composition to healthy adult subjects results in a mean peak concentration, Cmax for said elagolix of about 1218.4 ng/ml to about 2185 ng/mL; a mean peak concentration, Cmax for said estradiol of about 0.0424 ng/ml to about 0.0775 ng/ml; and a mean peak concentration, Cmax for said norethindrone acetate of about 4.56 ng/ml to about 8.0 ng/ml.
  • the multi-drug composition has a mean Area Under the Curve, AUC(t) for said elagolix of about 3296.6 ng.hr/mL to about 5892.5 ng.hr/mL; a mean Area Under the Curve, AUC(t) for said estradiol of about 0.688 ng.hr/mL to about 1.1375 ng.hr/mL; and a mean Area Under the Curve, AUC(t) for said norethindrone acetate of about 17.6 ng.hr/mL to about 33.125 ng.hr/mL.
  • multi-drug capsule composition includes 300 mg of free acid equivalent of elagolix; 1 mg of estradiol; and 0.5 mg of norethindrone acetate; and administration of a single dose of the composition to healthy adult subjects results in a mean Area Under the Curve, AUC(t) for said elagolix of about 3293.6 ng.hr/ml_ to about 5892.5 ng.hr/ml_; a mean Area Under the Curve, AUC(t) for said estradiol of about 0.0.688 ng.hr/ml_ to about 1 .1375 ng.hr/ml_; and a mean Area Under the Curve, AUC(t) for said norethindrone acetate of about 17.6 ng.hr/ml_ to about 33.125 ng.hr/ml_.
  • administration of the multi-drug capsule to healthy adult subjects results in a mean peak concentration, Cmax for said elagolix of about 1218.4 ng/mL to about 2185 ng.hr/ml_; a mean peak concentration, Cmax for said estradiol of about 0.0424 ng.hr/ml_ to about 0.0775 ng/mL ng/ml; and a mean peak concentration, Cmax for said norethindrone acetate of about 4.56 ng.hr/mL to about 8.0 ng/ml.
  • an oral multi-drug capsule composition includes 300 mg of free acid equivalent of elagolix; 1 mg of estradiol; and 0.5 mg of norethindrone acetate; and using USP apparatus 2 at 50 rpm, pH 6.8, and 37.5 ⁇ 0.5°C, at least 75% of the first drug in the first tablet dissolves after 60 minutes and at least 70% of the second and third drugs in the second tablet dissolve after 30 minutes.
  • a method of safely treating heavy menstrual bleeding associated with uterine leiomyomas (fibroids) in a pre menopausal female patient is provided.
  • the method comprising once daily oral administration to said patient of: (a) 300 mg of free acid equivalent of elagolix; (b) 1 mg of estradiol; and (c) 0.5 mg of norethindrone acetate, wherein said method results in a mean Cmax for said elagolix of about 1218.4 ng.hr/mL to about 2185 ng/mL; for said estradiol of about 0.0424 ng/mL to about 0.0775 ng/mL; for said norethindrone acetate of about 4.56 ng/mL to about 8.0 ng/mL, and a mean AUC(t) for said elagolix of about 3293.6ng.hr/mL to about 5892.5 ng.hr/mL; for said estradiol of about 0.0.688 ng.hr/ml_ to about 1.1375 ng.hr/ml_; and for said norethindrone acetate of about 17.6 ng.h
  • an oral capsule for use in delivering drugs to a patient comprises: a capsule body comprising an interior; a first tablet within the interior, the at least one first tablet comprising a first drug; and a second tablet within the interior, the second tablet comprising at least a second drug different from the first drug, wherein the first tablet and the second tablet are configured for simultaneous release upon dissolution of the capsule body within the patient, wherein using USP apparatus 1 at 100 rpm, pH 6.8, and 37.5 ⁇ 0.5°C, at least 75% of the first drug in the first tablet dissolves after 45 minutes and at least 90% of the second and third drugs in the second tablet dissolve after 30 minutes.
  • an oral multi-drug capsule composition is provided that is bioequivalent to any of the foregoing compositions.
  • a method of delivering co-packaged drugs to a patient for oral use comprises delivering a first capsule to the patient, wherein the first capsule includes: a first capsule body including a first interior; a first tablet within the first interior, the first tablet including a first drug; and a second tablet within the first interior, the second tablet including at least a second drug different from the first drug, wherein the first tablet and the second tablet are configured for simultaneous release upon dissolution of the first capsule body within the patient; and delivering a second capsule, co-packaged with the first capsule, to the patient after a predetermined amount of time has elapsed after administration of the first capsule, wherein the second capsule includes: a second capsule body including a second interior; and a third tablet within the second interior, the third tablet including the first drug.
  • FIG. 1 is an illustration of an example multi-drug delivery system that includes a first capsule and a second capsule of drugs.
  • FIG. 2 is an internal view of an example capsule housing two tablets.
  • FIG. 3 is an internal view of an example capsule housing a single tablet.
  • FIG. 4A is an internal view of a first example multi-drug tablet having a first tablet encapsulating a second tablet.
  • FIG. 4B is an internal view of a second example multi-drug tablet having a first tablet encapsulating a second tablet.
  • FIG. 5 is internal view of a third example multi-drug tablet having a bilayer, the bilayer having a first layer of a first drug and a second layer of a second and third drug.
  • FIG. 6 is an internal view of a fourth example multi-drug tablet having a first tablet coated with a mixture of a third and fourth drug.
  • FIG. 7 internal view of a fifth example multi-drug tablet having a bilayer, the bilayer having a first layer of a first drug and a second layer of an embedded tablet.
  • FIG. 8 is an internal view of an example capsule according to FIG. 1 having a first tablet, and four mini-tablets.
  • FIG. 9 is an internal view of an example capsule according to FIG. 1 containing melt granules and a tablet.
  • FIG. 10 is a flow chart showing Process of Examples 1 E2/NETA tablet-in-elagolix tablet and Example 2 E2/NETA tablet embedded on the surface of elagolix tablet.
  • FIG. 11 A is a flow chart showing Process of Example 3-1 : bilayer tablet E2/NETA layer: fluid-bed granulation, spraying API solution onto lactose.
  • FIG. 11 B is a flow chart showing the process of Example 3-2: bilayer tablet E2/NETA layer: fluid-bed granulation, spraying binder onto API mixture.
  • FIG. 11 C is a flow chart showing the process of Example 3-3: bilayer tablet, direct blend of E2/NETA layer, with disintegrant.
  • FIG. 11 D is a flow chart showing the process of Example 3-4: bilayer tablet, direct blend of E2/NETA layer without disintegrant.
  • FIG. 12 is a flow chart showing the process of Example 4: Coating of elagolix core tablet with solution of E2/NETA.
  • FIG. 13 is a flow chart showing the process of Example 5: bilayer tablet, E2/NETA embedded in the placebo layer.
  • FIG. 14 is a flow chart showing the process of Example 6: Elagolix tablet and E2/NETA tablet in a capsule.
  • FIG. 15 is a flow chart showing the process of Example 7: minitablets of elagolix and one E2/NETA tablet in a capsule.
  • FIG. 16 is a flow chart showing the process of Example 8: elagolix granules and one E2/NETA tablet filled in a capsule.
  • FIG. 17 is a perspective view of an example package that may be used to house and transport the multi-drug delivery system shown in FIG. 1.
  • FIG. 18 is a diagram illustrating the dissolution rates of drugs administered according to various embodiments of the present disclosure, and according to the multi-drug tablet shown in FIG. 4A and Example 1.
  • FIG. 19 is a diagram illustrating the dissolution rates of drugs administered according to various embodiments of the present disclosure, and according to the multi-drug tablet shown in FIG. 4B and Example 2.
  • FIG. 20A is a diagram illustrating the dissolution rates of drugs administered according to various embodiments of the present disclosure, and according to the multi-drug tablet shown in FIG. 5 and Example 3-1.
  • FIG. 20B is a diagram illustrating the dissolution rates of drugs administered according to various embodiments of the present disclosure, and according to the multi-drug tablet shown in FIG. 5 and Example 3-2.
  • FIG. 20C is a diagram illustrating the dissolution rates of drugs administered according to various embodiments of the present disclosure, and according to the multi-drug tablet shown in FIG. 5 and Example 3-3.
  • FIG. 20D is a diagram illustrating the dissolution rates of drugs administered according to various embodiments of the present disclosure, and according to the multi-drug tablet shown in FIG. 5 and Example 3-4
  • FIG. 21 is a diagram illustrating the dissolution rates of drugs administered according to various embodiments of the present disclosure, and according to the multi-drug tablet shown in FIG. 6 and Example 4
  • FIG. 22 is a diagram illustrating the dissolution rates of drugs administered according to various embodiments of the present disclosure, and according to the multi-drug tablet shown in FIG. 7 and Example 5.
  • FIG. 23 is a diagram illustrating the dissolution rates of drugs administered according to various embodiments of the present disclosure, and according to the capsule shown in FIG. 2 and Example 6.
  • FIG. 24 is a diagram illustrating the dissolution rates of drugs administered according to various embodiments of the present disclosure, and according to the capsule shown in FIG. 8 and Example 7.
  • FIG. 25 is a diagram illustrating the dissolution rates of drugs administered according to various embodiments of the present disclosure, and according to the capsule shown in 9 and Example 8.
  • FIG. 26 is a graphical representation of the percent change from baseline in lumbar spine bone mineral density (BMD) in Women with Uterine Fibroids who received 12 months of the System described in Example 10 and had follow-up BMD 12 months off therapy in studies UF-1, UF-2, UF-3.
  • BMD lumbar spine bone mineral density
  • FIG. 27 is a graphical representation of monthly change from Baseline in MBL Volume in Women with Uterine Fibroids in the UF-1 study.
  • FIG. 28 is a graphical representation of monthly change from Baseline in MBL Volume in Women with Uterine Fibroids in the UF-2 study.
  • FIG. 29A is a diagram illustrating the dissolution rates of elagolix administered according to various embodiments of the present disclosure, and according to the multi-drug tablet shown in FIG. 6 using USP apparatus 1.
  • FIG. 29B is a diagram illustrating the dissolution rates of E2 administered according to various embodiments of the present disclosure, and according to the multi-drug tablet shown in FIG. 6 using USP apparatus 1.
  • FIG. 29C is a diagram illustrating the dissolution rates of NETA administered according to various embodiments of the present disclosure, and according to the multi-drug tablet shown in FIG. 6 using USP apparatus 1.
  • Embodiments of the present disclosure relate to a drug dosage form that enables substantially simultaneous, immediate release of more than one drug enclosed within a capsule upon administration by a patient, and a delivery system for the dosage that facilitates compliance of administration instructions by a patient.
  • the drug delivery system includes a first capsule and also may include a second capsule intended to be administered within different and non-overlapping time windows in the day.
  • the first capsule is intended to be administered during morning hours (e.g., before noon), and the second capsule is intended to be administered at least 5 hours after administration of the first capsule (e.g., during the afternoon or evening hours).
  • the first capsule and the second capsule may contain different drugs, or combinations of drugs, and may be marked with identifiers that facilitate compliance with the administration instructions of a prescription, for example.
  • the surfaces of the first capsule and the second capsule may have distinct identifying colors and/or surface characteristics.
  • the first capsule and the second capsule may also include symbolic and/or textual markings that indicate in which time window the respective capsule should be administered.
  • a plurality of first capsules and a plurality of second capsules may be housed in a package that includes symbolic and/or textual markings that likewise indicate in which time window the respective capsules should be administered.
  • the first capsule and the second capsule are conspicuously and prominently marked or marked and arranged to enable the patient to easily distinguish the capsules.
  • the system co-packages multiple capsules and may include a single capsule containing two or more different drugs, for example, a first tablet containing a first drug and a second tablet containing a second and third drug.
  • the first drug may be elagolix or other gonadotropin-releasing hormone (GnRH) releasing antagonists.
  • Oral dosage size is an important component for patient compliance. Larger oral dose sizes create a reluctance for patients to comply with dosing recommendations.
  • the first capsule contains at least two distinct tablets, with the first tablet including a first drug and the second tablet including a second drug and a third drug different from the first drug.
  • the first, second, and third drugs have different efficacies and, in the example embodiment, the second and third drugs are included in the capsule to at least partially counteract the undesirable adverse effects of the first drug on the patient.
  • the first and second tablets are formed separately from each other and then secured within the first capsule to facilitate simultaneous, immediate release of the drugs in the first tablet and the second tablet upon dissolution of the outer shell of the capsule within the patient. That is, securing the distinct tablets within the capsule enables the tablets to dissolve simultaneously to result in a desirable bioavailability for a patient.
  • the dosage form provided by the first capsule facilitates desirable dissolution of the drugs and bioavailability within the patient.
  • a bioequivalent composition or formulation is one that is bioequivalent as defined by the U.S. Food and Drug Administration (FDA).
  • FDA U.S. Food and Drug Administration
  • co-administration of the tablets in a capsule may provide a presentation that is easy for a patient to swallow and simpler to manufacture.
  • the presentation allows the co-administration of the first, second, and third drugs.
  • This co-administration allows for the desired balance between the therapeutic effect and safety of the first drug in the first tablet with at least the second drug or the third drug in the second tablet.
  • the co administration of the first drug in the first tablet and the second and third drugs in the second tablet facilitates potential reduction of the undesired effects of the first drug.
  • the first drug in the first tablet may be elagolix or another GnRH antagonist
  • the second and third drugs in the second tablet may be a combination of estradiol (E2) and norethindrone (NETA) (e.g. Activella® tablet).
  • E2/NETA facilitate the add-back therapy that counters certain undesirable impact of hormone regulation that is caused by the exogenous introduction of a GnRH antagonist, such as elagolix, relugolix and the like.
  • the first drug may suitably be a GnRH antagonist, such as elagolix, and/or relugolix
  • the second drug may suitably be estradiol
  • the third drug may suitably be norethindrone acetate.
  • Elagolix is commonly available as elagolix sodium.
  • the dissolution rate of the drugs and resulting bioavailability within the patient may be undesirably high and therefore may not be ideal for dosing under certain conditions.
  • the drugs in the first and second tablets do not dissolve together as a result of the second tablet slowing down the release of the drug in the first tablet.
  • the total amount of elagolix contained in the first capsule or the second capsule may suitably be the free acid equivalent of elagolix, administered as a sodium salt.
  • the free acid equivalent of elagolix may be provided as 100 milligrams (mg), 150 mg, 200 mg, 250 mg, 300 mg, 400 mg, 450 mg, or 500 mg, and ranges constructed therefrom, such as about 100 mg to about 500 mg, about 150 mg to about 400 mg, and about 175 mg to about 325 mg.
  • the total amount of estradiol contained in the first capsule may suitably be 0.5 mg, 0.75 mg, 1.0 mg,
  • the total amount of base equivalent of norethindrone, available as norethindrone acetate that is contained in the first capsule may suitably be 0.05 mg, 0.1 mg, 0.25 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.75 mg, or 1.0 mg, and ranges constructed therefrom, such as about 0.1 mg to about 1.0 mg, about 0.25 mg to about 0.75 mg, or about 0.4 mg to about 0.6 mg.
  • Tablets within the scope of the present disclosure comprise the active drug and one or more excipients, including but not limited to, binders, fillers, disintegrants, surfactants, efficacy/bioavailability enhancing agents, glidants, and lubricants.
  • excipients including but not limited to, binders, fillers, disintegrants, surfactants, efficacy/bioavailability enhancing agents, glidants, and lubricants.
  • Binders promote the bonding and cohesiveness of granules and tablets and function to improve hardness.
  • Some non-limiting examples of binders include: pregelatinized starch, hydroxypropyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, copovidone, povidone, crospovidone, and combinations.
  • Other examples include polyethylene glycol, polyvinyl pyrrolidone, and polyvinyl alcohols.
  • the binder is copovidone, povidone, HMP, pregelatinized starch, and combinations thereof.
  • the binder is copovidone.
  • Fillers that may be used, include non-limiting examples such as sugars and sugar alcohols, cellulosics, and other fillers.
  • suitable sugars and sugar alcohols include dextrates, dextrin, dextrose, lactose, maltodextrin, mannitol, isomalt, sorbitol, sucrose, sugars spheres, xylitol, fructose, lactitol, erythritol, maltitol, xylose, glucose, mannose, galactose, maltose, cellobiose, trehalose and raffinose.
  • Non-limiting examples of cellulosics include microcrystalline cellulose (“MCC”) and silicified MCC.
  • Non-limiting examples of other fillers include calcium carbonate, calcium sulphate, calcium silicate, chitin, chitosan, dibasic calcium phosphate dihydrate, glyceryl palmitostearate, hydrogenated vegetable oil, kaolin, magnesium aluminum silicate, magnesium carbonate, magnesium oxide, polymethacrylates, potassium chloride, powdered cellulose, pregelatinized starch, sodium chloride, starch, talc, and di- and tri-basic calcium phosphate. Combinations of the above-listed fillers are within the scope of the present disclosure.
  • Disintegrants that may be used include, non-limiting examples such as modified starches such as sodium carboxymethyl starch (sodium starch glycolate); cross-linked polyvinylpyrrolidones such as crospovidone; modified celluloses such as croscarmellose sodium; cross-linked alginic acid; gums such as gellan gum and xanthan gum; calcium silicate; and combinations thereof.
  • modified starches such as sodium carboxymethyl starch (sodium starch glycolate); cross-linked polyvinylpyrrolidones such as crospovidone; modified celluloses such as croscarmellose sodium; cross-linked alginic acid; gums such as gellan gum and xanthan gum; calcium silicate; and combinations thereof.
  • Surfactants may function to increase the concentration of the drug in the diffusion layer formed at the interface of the drug surface and the aqueous medium after administration and/or increase wettability of the drug/formulation.
  • Non-limiting examples of surfactants include, vitamin E d-alpha tocopheryl polyethyleneglycol succinate, sodium dodecyl sulfate, polysorbate, poloxamer, Tween® type, and combinations thereof.
  • Lubricants that may be used include, non-limiting examples such magnesium stearate, calcium stearate, stearic acid, sodium stearyl fumarate, hydrogenated vegetable oils, polyethylene glycol (4000-6000), sodium lauryl sulfate, and combinations thereof.
  • Glidants that may be used include, non-limiting examples such colloidal silicon dioxide (e.g., highly dispersed silica (Aerosil®)), animal or vegetable fats, waxes, and combinations thereof.
  • Other excipients may be present include an acidifying agent or an alkalizing agent.
  • Acidifying agents may be organic acids for pH adjustment and/or control after administration, such as, for instance and without limitation, fumaric acid, citric acid, and tartaric acid.
  • selection of excipients and weight/weight concentrations or active to excipient ratios thereof in tablets may be made to increase drug solubility in an aqueous medium (e.g., the stomach and/or intestine) and thereby improve dissolution rate and bioavailability. Further, in the case of co-administration of a first tablet having a first drug and a second tablet having a second drug, selection of excipients and weight over weight concentrations or active to excipient ratios thereof may be made to both increase drug bioavailability and minimize any interaction between the first and second tablets that could adversely affect bioavailability of either drug.
  • an aqueous medium e.g., the stomach and/or intestine
  • Tablets of the present disclosure may be formed utilizing pharmaceutical operations, such as, but not limited to, screening, blending, dry granulation, compression, and optional film coating.
  • the excipient may be blended, the blend may be roller compacted and milled, and the resulting material may be tableted by compression in tableting equipment known in the art.
  • the roller compacted, and milled material may be termed “intragranular” and said material may then be blended with one or more additional excipients described above prior to tableting. The one or more additional excipients would be present as an “extragranular” component in the tablet.
  • the uncoated tablets of the present disclosure may be optionally coated with a film-coating to provide for tablets that are predominantly tasteless and odorless and are easy to swallow. Further, film coating prevents dust formation during packaging and ensures robustness during transportation.
  • Commercial coating compositions are suitable for purposes of the present disclosure and include, without limitation, Opadry® YS-1-7003, Opadry® YS-1 -18202, and Opadry® II White 85F18422.
  • Tablets containing elagolix sodium are commercially available as Orilissa®. Manufacturing of different strengths of elagolix is described in AbbVie Inc’s applications US201900540088 and US 20190054027, both of which are incorporated in its entirety by reference. Other manufacturers also provide various manufacturing of elagolix active ingredient and elagolix containing drug product, as described in applications WO2017/221144, WO2018/189213, and WO201 8/224063. Tablets containing varying strengths of E2/NETA are commercially available as Activella®.
  • FIG. 1 is an illustration of an example multi-drug delivery system 100 that includes a first capsule 102 and a second capsule 104 of drugs.
  • First capsule 102 includes a first capsule body 106 including a first body portion 108 and a first cap portion 110
  • second capsule 104 includes a second capsule body 112 including a second body portion 114 and a second cap portion 116.
  • first capsule 102 is marked with a first identifier 118
  • second capsule 104 is marked with a second identifier 120 that is different from first identifier 118 to facilitate rendering first capsule 102 and second capsule 104 visually distinguishable from each other to a patient.
  • First capsule 102 and second capsule 104 may include any suitable identifier that enables multi-drug delivery system 100 to function as described herein.
  • the identifier may include, but is not limited to, shading, coloring, a symbolic marking, and/or a textual marking.
  • first color 122 (as illustrated by a first pattern) is included on first capsule 102
  • second color 124 (as illustrated by a second pattern) is included on second capsule 104.
  • first cap portion 110 is first color 122 and second cap portion 116 is second color 124.
  • First color 122 is different from second color 124.
  • first cap portion 110 is visually distinguishable from first body portion 108, second body portion 114, and second cap portion 116
  • second cap portion 116 is visually distinguishable from first body portion 108, first cap portion 110, and second body portion 114.
  • First identifier 118 and second identifier 120 may also be configured to indicate when a respective capsule is intended to be administered.
  • first identifier 118 includes a first textual marking 126 and second identifier 120 includes a second textual marking 128.
  • First textual marking 126 is configured to indicate that first capsule 102 is intended for administration within a first time window in the day
  • second textual marking 128 is configured to indicate that second capsule 104 is intended for administration within a second time window in the day that is different from the first time window. More specifically, first textual marking 126 (“AM”) indicates that first capsule 102 is intended for administration before noon, and second textual marking 128 (“PM”) indicates that second capsule 104 is intended for administration after noon.
  • first capsule 102 and second capsule 104 may contain different types of drugs. As such, first textual marking 126 and second textual marking 128 facilitate quick and easy identification of the capsules and compliance with administration instructions.
  • FIG. 2 is a cross-sectional views of examples of first capsule 102 that may be used in multi-drug delivery system 100 (shown in FIG. 1)
  • FIG. 8 is a cross-sectional view of an additional first capsule 102 that may be used in multi-drug delivery system 100.
  • FIG. 3 is a cross-sectional view of an example second capsule 104 that may be used in multi-drug delivery system 100 (shown in FIG. 1).
  • second capsule body 112 includes a second interior 140 sized to receive at least one first tablet 132 therein. While illustrated as housing a single first tablet 132, it should be understood that any number of first tablets 132 may be included within second interior 140 that enables multi-drug delivery system 100 to function as described herein.
  • Second capsule body 112 includes second body portion 114 and second cap portion 116.
  • Second body portion 114 includes an open end 142 sized to enable insertion of first tablet 132 therethrough. After insertion of first tablet 132 into second body portion 114, second cap portion 116 may be engaged with second body portion 114 to enclose open end 142, and to define and seal second interior 140.
  • First capsule body 106 (shown in FIGS. 2 and 3) and second capsule body 112 may be fabricated from any material that enables multi-drug delivery system 100 to function as described herein.
  • Example capsule body materials include, but are not limited to, gelatin (in the form of hard gelatin capsules or soft elastic gelatin capsules), starch, carrageenan and hydroxypropylmethylcellulose.
  • First capsule body 106 and second capsule body 112 can additionally be prepared with coatings that ease swallowing, provide a taste barrier, or provide other functions.
  • first capsule 102 and second capsule 104 may each contain a different drug, or a different combination of drugs, such that first capsule 102 and second capsule 104 are intended for administration at different times of the day.
  • second capsule 104 only contains first tablet 132 therein, and does not contain second tablet 134 therein.
  • FIG. 17 is a perspective view of an example package 144 that may be used to house and transport multi-drug delivery system 100 (shown in FIG. 1).
  • package 144 includes a carton 146, and a blister card 148 positioned within carton 146.
  • Carton 146 includes a first wall 150 having an access opening 152 defined therein.
  • Access opening 152 is sized to provide access to blister card 148 and, more specifically, to a plurality of compartments 154 of blister card 148 that are each configured to house an individual first capsule 102 or second capsule 104 therein. As such, a plurality of first capsules 102 and a plurality of second capsules 104 are housed within package 144.
  • first wall 150 includes informational markings 156 thereon that may be either symbolic or textual markings to easily distinguish the capsules 102 and 104 from each other.
  • Informational markings 156 are printed on package 144 and include information related to when to administer first capsule 102 and second capsule 104 to the patient. As such, including compartments 154 as a multiple of the number of days in the week in package 144, and including informational markings 156 on first wall 150, facilitates compliance of administration instructions by a patient.
  • the invention further provides a multi-drug capsule composition
  • a multi-drug capsule composition comprising: (a) 300 mg of free acid equivalent of elagolix which is administered twice daily; (b) 1 mg of estradiol which is administered once daily; and (c) 0.5 mg of norethindrone acetate which is administered once daily.
  • Table A7 provides the mean peak concentration Cmax and mean Area Under the Curve AUC(t) for this formulation when the composition is administered to healthy volunteers.
  • the invention further includes the mean peak concentration Cmax and the mean Area Under the Curve, AUCT that is 80%-125% of the Cmax or AUCT provided in Table A7.
  • mean peak concentration, Cmax for said elagolix is about 80% to about 125% of 1200 ⁇ 45% ng/mL or about 528-2175 ng/mL
  • the mean peak concentration, Cmax for said estradiol is about 80% to about 125% of 0.06 ⁇ 52% ng/ml or 0.023-0.114 ng/mL
  • the mean peak concentration, Cmax for said norethindrone acetate is about 80% to about 125% of 6.1 ⁇ 35% ng/ml or 3.172- 10.294 ng/mL.
  • AUCT for said elagolix is about 80% to about 125% of 2826 ⁇ 44% ng.hr/mL or 1266.0-5086.8 ng.hr/mL.
  • the mean Area Under the Curve, AUCT for said estradiol is about 80% to about the Curve, AUCT for said norethindrone acetate is about 80% to about 125% of 23.8 ⁇ 48% ng.hr/mL or 9.90-44.03 ng.hr/mL.
  • the invention further provides a multi-drug capsule composition
  • a multi-drug capsule composition comprising: (a) 300 mg of free acid equivalent of elagolix which is administered twice daily; (b) 1 mg of estradiol which is administered once daily; and (c) 0.5 mg of norethindrone acetate which is administered once daily.
  • Table A7 provides the mean peak concentration Cmax and mean Area Under the Curve AUC (t) for this formulation when the composition is administered to healthy volunteers.
  • the invention further includes the mean peak concentration Cmax and the mean Area Under the Curve, AUCT that is 80%-125% of the Cmax AUCT provided in Table A7.
  • mean peak concentration, Cmax for said elagolix is about 80% to about 125% of 1200 ng/mL or about 960-1500 ng/mL
  • the mean peak concentration, Cmax for said estradiol is about 80% to about 125% of 0.06 ng/ml or 0.048-0.075 ng/mL
  • the mean peak concentration, Cmax for said norethindrone acetate is about 80% to about 125% of 6.1 ng/ml or 4.88-7.625 ng/mL.
  • the mean Area Under the Curve, AUCT for said elagolix is about 80% to about 125% of 2826 ng.hr/mL or 2260.8-3532.5 ng.hr/mL.
  • AUCT for said estradiol is about 80% to about 125% of 0.86 ng.hr/mL or 0.688-1.075 ng.hr/mL.
  • the mean Area Under the Curve, AUCT for said norethindrone acetate is about 80% to about 125% of 23.8 ng.hr/mL or 19.04-29.75 ng.hr/mL.
  • the invention further provides a multi-drug capsule composition
  • a multi-drug capsule composition comprising: (a) 300 mg of free acid equivalent of elagolix which is administered twice daily; (b) 1 mg of estradiol which is administered once daily; and (c) 0.5 mg of norethindrone acetate which is administered once daily.
  • Table A7 provides the mean peak concentration Cmax and mean Area Under the Curve AUC (t) for this formulation when the composition is administered to healthy volunteers.
  • the invention further includes the mean peak concentration Cmax and the mean Area Under the Curve, AUCT that is 80%-125% of the Cmax AUCT provided in Table A7.
  • mean peak concentration, Cmax for said elagolix is about 80% to about 125% of 629-1770 ng/mL or about 503-2212.5 ng/mL.
  • the mean peak concentration, Cmax for said estradiol is about 80% to about 125% of 0.053-0.062 ng/ml or 0.0424-0.0775 ng/mL.
  • the mean peak concentration, Cmax for said norethindrone acetate is about 80% to about 125% of 5.7-6.4 ng/ml or 4.56-8.0 ng/mL.
  • the mean Area Under the Curve, AUCT for said elagolix is about 80% to about 125% of 1534-4118 ng.hr/mL or 1227.2-5147.5 ng.hr/mL.
  • AUCT for said estradiol is about 80% to about 125% of 0.81-0.91 ng.hr/mL or 0.688-1.1375 ng.hr/mL.
  • the mean Area Under the Curve, AUCT for said norethindrone acetate is about 80% to about 125% of 22- 26.3 ng.hr/mL or 17.6-33.125 ng.hr/mL.
  • the current invention provides an oral multi-drug capsule composition comprising: (a) 300 mg of free acid equivalent of elagolix; (b) 1 mg of estradiol; and (c) 0.5 mg of norethindrone acetate.
  • composition When the composition is administered as depicted on Table 7 (d) to healthy adult subjects, it results in a steady state concentration Cmaxss for said elagolix of about 503-2212.5 ng/mL; mean peak concentration Cmax for said estradiol of about 0.0424-0.0775 ng/mL ng/ml; mean peak concentration Cmax for said norethindrone acetate of about 4.56-8.0 ng/ml; a mean Area Under the Curve, (AUCT) for said elagolix of about 1227.2-5147.5 ng.hr/mL; a mean Area Under the Curve AUC(t) for said estradiol of about 0.0.688-1.1375 ng.hr/mL; and AUC(t) for said norethindrone acetate of about 17.6-33.125 ng.hr/mL.
  • AUCT Mean Area Under the Curve,
  • AUC(t) for said estradiol of about 0.0.688-1.1375 ng.hr
  • composition when administered as depicted on Table 7 (d) to healthy adult subjects, it results in a mean peak concentration Cmax for said elagolix of about 1218.4-2185 ng/mL; Cmax for said estradiol of about 0.0424- 0.0775 ng/mL ng/ml; Cmax for said norethindrone acetate of about 4.56-8.0 ng/ml; a mean Area Under the Curve, (AUC(t)) for said elagolix of about 3293.6- 5892.5 ng.hr/ml_; AUC(t) for said estradiol of about 0.0.688-1.1375 ng.hr/ml_; and AUC(t) for said norethindrone acetate of about 17.6-33.125 ng.hr/ml_.
  • AUC(t) Average Area Under the Curve
  • the current invention provides an oral multi drug capsule composition
  • an oral multi drug capsule composition comprising: (a) 300 mg of free acid equivalent of elagolix; (b) 1 mg of estradiol; and (c) 0.5 mg of norethindrone acetate.
  • the composition When the composition is administered based on Table A7(c) or Table A7(d), to healthy adult subjects, it results in a mean steady state concentration, Cmaxss for said elagolix of about 503-2212.5 ng/mL; mean peak concentration Cmax for said estradiol of about 0.0424-0.0775 ng/mL; and mean peak concentration, Cmax for said norethindrone acetate of about 4.56-8.0 ng/ml.
  • the oral multi-drug capsule composition has a steady state Area Under the Curve, AUCT for said elagolix of about 1227.2-5147.5 ng.hr/ml_; AUCT for said estradiol of about 0.0.688-1.1375 ng.hr/ml_; and AUCT for said norethindrone acetate of about 17.6-33.125 ng.hr/ml_.
  • the current invention provides an oral multi drug capsule composition
  • an oral multi drug capsule composition comprising: (a) 300 mg of free acid equivalent of elagolix; (b) 1 mg of estradiol; and (c) 0.5 mg of norethindrone acetate.
  • the composition is administered based on Table A7(c) or Table A7(d), to healthy adult subjects, it results in a mean peak concentration, Cmax for said elagolix of about 1218.4-2185 ng/mL; mean peak concentration Cmax for said estradiol of about 0.0424-0.0775 ng/ml; and mean peak concentration, Cmax for said norethindrone acetate of about 4.56-8.0 ng/ml.
  • the oral multi-drug capsule composition has a mean Area Under the Curve, AUC(t) for said elagolix of about 3293.6-5892.5 ng.hr/ml_; AUC(t) for said estradiol of about 0.0.688-1.1375 ng.hr/ml_; and AUC(t) for said norethindrone acetate of about 17.6-33.125 ng.hr/ml_.
  • the current invention provides an oral multi-drug capsule composition
  • an oral multi-drug capsule composition comprising: (a) 300 mg of free acid equivalent of elagolix; (b) 1 mg of estradiol; and (c) 0.5 mg of norethindrone acetate; further when the composition is administered as shown in Table A7(c) and Table A7(d) to healthy adult subjects, it results in a mean Area Under the Curve, AUCT for said elagolix of about 1227.2-5147.5 ng.hr/ml_; AUCT for said estradiol of about 0.0.688-1.1375 ng.hr/ml_; and AUCT for said norethindrone acetate of about 17.6- 33.125 ng.hr/ml_.
  • the oral multi-drug capsule composition results in a steady state peak concentration, Cmaxss for said elagolix of about 503-2212.5 ng/mL; mean peak concentration, Cmaxss for said estradiol of about 0.0424-0.0775 ng/mL ng/ml; and mean peak concentration, Cmaxss for said norethindrone acetate of about 4.56-8.0 ng/ml
  • the current invention provides an oral multi-drug capsule composition
  • an oral multi-drug capsule composition comprising: (a) 300 mg of free acid equivalent of elagolix; (b) 1 mg of estradiol; and (c) 0.5 mg of norethindrone acetate; further when the composition is administered as shown in Table A7(c) and Table A7(d) to healthy adult subjects, it results in a mean Area Under the Curve, AUC(t) for said elagolix of about 3293.6-5892.5 ng.hr/mL; AUC(t) for said estradiol of about 0.0.688-1.1375 ng.hr/mL; and AUC(t) for said norethindrone acetate of about 17.6-33.125 ng.hr/mL.
  • the oral multi-drug capsule composition results in a mean peak concentration, Cmax for said elagolix of about 1218.4- 2185 ng/mL; mean peak concentration, Cmax for said estradiol of about 0.0424- 0.0775 ng/mL ng/ml; and mean peak concentration, Cmax for said norethindrone acetate of about 4.56-8.0 ng/ml.
  • an oral multi-drug capsule composition includes 300 mg of free acid equivalent of elagolix which is administered twice daily; 1 mg of estradiol which is administered once daily; and 0.5 mg of norethidrone acetate which is administered once daily; administration of the composition to healthy subject results is shown in Table A7 (a) or Table A7 (b).
  • hr/ml a mean Area Under the Curve, AUCT for said estradiol of about 0.4266-1 .4835 ng.hr/mL; and a mean Area Under the Curve, AUCT for said norethindrone acetate of about 9.90-44.03 ng.hr/mL.
  • an oral multi-drug capsule composition includes 300 mg of free acid equivalent of elagolix which is administered twice daily; 1 mg of estradiol which is administered once daily; and 0.5 mg of norethidrone acetate which is administered once daily; further wherein administration of the composition to healthy subject results in a mean steady state concentration, Cmaxss for said elagolix of about 960-1500 ng/mL; a mean peak concentration, Cmaxss for said estradiol of about 0.048-0.075 ng/mL; a mean peak concentration, Cmaxss for said norethindrone acetate of about 4.88-7.625 ng/ml; a mean Area Under the Curve, AUCT for said elagolix of about 2260.8-3532.5 ng.
  • AUCT for said estradiol of about 0.688-1 .075 ng.hr/mL; and a mean Area Under the Curve, AUCT for said norethindrone acetate of about 19.04-29.75 ng.hr/mL.
  • the oral multi-drug capsule may have a mean Area Under the Curve, AUCT for said elagolix of about 1266.0-5086.8 ng.hr/mL; a mean Area Under the Curve, AUCT for said estradiol of about 0.4266-1 .4835 ng.hr/ml_; and a mean Area Under the Curve, AUCT for said norethindrone acetate of about 9.90-44.03 1.4835 ng.hr/ml_.
  • an oral multi-drug capsule composition includes 300 mg of free acid equivalent of elagolix which is administered twice daily; 1 mg of estradiol which is administered once daily; and 0.5 mg of norethindrone acetate which is administered once daily; further wherein administration of the composition to healthy adult subjects results in a mean Area Under the Curve, AUCT for said estradiol of about 0.4266-1.4835 ng.hr/ml_; and a mean Area Under the Curve, AUCT for said norethindrone acetate of about 9.90-44.03 ng.hr/ml_.
  • administration of the multi-drug capsule composition to healthy adult subjects may further result in a mean steady state concentration, Cmaxss for said elagolix of about 528-2175 ng/mL; a mean peak concentration, Cmaxss for said estradiol of about 0.023-0.114 ng/mL; and a mean peak concentration, Cmaxss for said norethindrone acetate of about 3.172-10.294 ng/ml.
  • an oral multi-drug capsule composition comprising: (a) 300 mg of free acid equivalent of elagolix which is administered twice daily; (b) 1 mg of estradiol which is administered once daily; and (c) 0.5 mg of norethindrone acetate which is administered once daily; wherein using USP apparatus 2 at 50 rpm, pH 6.8, and 37.5 ⁇ 0.5°C, at least 75% of the first drug in the first tablet dissolves after 60 minutes and at least 70% of the second and third drugs in the second tablet dissolve after 30 minutes.
  • an oral multi-drug capsule composition comprising: (a) 200 mg of free acid equivalent of elagolix which is administered twice daily; (b) 1 mg of estradiol which is administered once daily; and (c) 0.5 mg of norethindrone acetate which is administered once daily; wherein using USP apparatus 2 at 50 rpm, pH 6.8, and 37.5 ⁇ 0.5°C, at least 75% of the first drug in the first tablet dissolves after 60 minutes and at least 70% of the second and third drugs in the second tablet dissolve after 30 minutes.
  • an oral multi-drug capsule composition includes 300 mg of free acid equivalent of elagolix; 1 mg of estradiol; and 0.5 mg of norethindrone acetate; and following administration of a single dose of the composition to healthy adult subjects results in a mean peak concentration (Cmax) for said elagolix of about1218.4 ng/mL to about 2185 ng/mL; a mean peak concentration (Cmax) for said estradiol of about 0.0424 ng/mL to about 0.0775 ng/mL; a mean peak concentration (Cmax) for said norethindrone acetate of about 4.56 ng/mL to about 8.0 ng/mL; a mean Area Under the Curve (AUC®) for said elagolix of about 3293.6 ng.hr/mL to about 5892.5 ng.hr/mL; a mean Area Under the Curve (AUC®) for said estradiol of about 0.688 ng
  • a multi-drug capsule composition includes 300 mg of free acid equivalent of elagolix; 1 mg of estradiol; and 0.5 mg of norethindrone acetate; and administration of a single dose of the composition to healthy adult subjects results in a mean peak concentration, Cmax for said elagolix of about 1218.4 ng/ml to about 2185 ng/mL; a mean peak concentration, Cmax for said estradiol of about 0.0424 ng/ml to about 0.0775 ng/ml; and a mean peak concentration, Cmax for said norethindrone acetate of about 4.56 ng/ml to about 8.0 ng/ml.
  • the multi-drug composition has a mean Area Under the Curve, AUC(t) for said elagolix of about 3296.6 ng.hr/mL to about 5892.5 ng.hr/mL; a mean Area Under the Curve, AUC(t) for said estradiol of about 0.688 ng.hr/mL to about 1.1375 ng.hr/mL; and a mean Area Under the Curve, AUC(t) for said norethindrone acetate of about 17.6 ng.hr/mL to about 33.125 ng.hr/mL.
  • multi-drug capsule composition includes 300 mg of free acid equivalent of elagolix; 1 mg of estradiol; and 0.5 mg of norethindrone acetate; and administration of a single dose of the composition to healthy adult subjects results in a mean Area Under the Curve, AUC(t) for said elagolix of about 3293.6 ng.hr/ml_ to about 5892.5 ng.hr/ml_; a mean Area Under the Curve, AUC(t) for said estradiol of about 0.0.688 ng.hr/ml_ to about 1 .1375 ng.hr/ml_; and a mean Area Under the Curve, AUC(t) for said norethindrone acetate of about 17.6 ng.hr/ml_ to about 33.125 ng.hr/ml_.
  • administration of the multi-drug capsule to healthy adult subjects results in a mean peak concentration, Cmax for said elagolix of about 1218.4 ng/mL to about 2185 ng.hr/ml_; a mean peak concentration, Cmax for said estradiol of about 0.0424 ng.hr/ml_ to about 0.0775 ng/mL ng/ml; and a mean peak concentration, Cmax for said norethindrone acetate of about 4.56 ng.hr/ml_ to about 8.0 ng/ml.
  • an oral multi-drug capsule composition includes 300 mg of free acid equivalent of elagolix; 1 mg of estradiol; and 0.5 mg of norethindrone acetate; and using USP apparatus 2 at 50 rpm, pH 6.8, and 37.5 ⁇ 0.5°C, at least 75% of the first drug in the first tablet dissolves after 60 minutes and at least 70% of the second and third drugs in the second tablet dissolve after 30 minutes.
  • the invention further provides an oral multi-drug capsule composition that is bioequivalent to any of the multi-drug capsules described herein.
  • an oral multi-drug capsule composition includes 300 mg of free acid equivalent of elagolix; 1 mg of free acid equivalent estradiol; and 0.5 mg of free acid equivalent norethindrone acetate may be useful for reducing uterine fibroid volume prior to surgery (pre-surgery) for removal of uterine fibroids.
  • certain doses of elagolix plus estradiol and norethindrone acetate therapy may be useful for treating pain associated with endometriosis.
  • 200 mg of free acid equivalent of elagolix plus 1 mg free acid equivalent of estradiol, and 0.5 mg free acid equivalent of norethindrone may be useful for treating pain associated with endometriosis.
  • a method of treating heavy menstrual bleeding associated with uterine leiomyomas includes once daily oral administration to an adult human female patient suffering from uterine leiomyomas (fibroids) of a capsule comprising 300 mg of free acid equivalent of elagolix; 1 mg of estradiol; and 0.5 mg of norethindrone acetate, and the method results in a mean Cmax for the elagolix of about 1218.4 ng.hr/ml_ to about 2185 ng/mL; for the estradiol of about 0.0424 ng/mL to about 0.0775 ng/mL; for the norethindrone acetate of about 4.56 ng/mL to about 8.0 ng/mL, and a mean AUC(t) for the elagolix of about 3293.6ng.hr/mL to about 5892.5 ng.hr/mL; for the estradiol of about 0.0.688
  • Example 1 Estradiol (E2) and norethindrone (NETA) tablet with elagolix compression overcoat. As shown in FIG. 4A
  • Elagolix/E2/NETA tablets 400 were prepared by coating commercially sourced E2/NETA tablets 403 with compression coating using elagolix granules 401 as shown in FIG. 4A.
  • the composition of the tablets 400 is provided in Table 1 and the granule composition is in Table 2 and the process is shown in FIG. 10.
  • Example 2 Elagolix tablets containing E2/NETA tablets. As shown in FIG.
  • the Elagolix/E2/NETA tablets were prepared according to the process shown in FIG. 10.
  • the tablets 410 of Example 2 were prepared by first loading of the final blend and subsequently placing the Activella® tablets 403 on the surface of the powder bed followed by compression manually.
  • the composition of the tablets 410 is provided in Table 4 and the tablet 410 is shown in FIG. 4B.
  • Example 3 Elagolix and E2/NETA bilayer tablets. As shown in FIG. 5.
  • bilayer tablets 500 consisting of elagolix 501 and E2/NETA layers 503 as shown in FIG. 3 were prepared using following examples:
  • Elagolix/E2/NETA tablets 500 were prepared according to the process shown in FIG. 11 A.
  • Example 3-1 Tablet Composition of Example 3-1 Tablet. a: (200 mg of free acid elagolix is equivalent to about 207.0 mg elagolix sodium)
  • Example 3-2 Composition of Example 3-1 Tablet. a: (200 mg of free acid elagolix is equivalent to about 207.0 mg elagolix sodium)
  • Example 3-2 Composition of Example 3-1 Tablet. a: (200 mg of free acid elagolix is equivalent to about 207.0 mg elagolix sodium)
  • composition of the tablets 500 is provided in Table 7.
  • Elagolix/E2/NETA tablets 500 were prepared according to the process shown in FIG. 11 C. [131 ] The composition of the tablets 500 is provided in Table 8.
  • Table 8 Composition of Example 3-3 Tablet.
  • composition of the tablets is provided in Table 9.
  • Table 8 Composition of Example 3-4 Tablet.
  • Example 4 Elagolix tablets with E2/NETA overcoat. As shown in FIG. 6.
  • Elagolix/E2/NETA tablets were prepared by coating elagolix tablets 601 using layering of E2/NETA formulation as shown in FIG. 4. elagolix tablets 601 were first compressed using the final blend described in Example 3-1 on a tablet press with the target tablet weight of 352.7 mg. The tablets were prepared using the process shown in FIG. 12. The composition of the tablets 600 is provided in Table 9. Table 9: Composition of Example 4 Tablet.
  • Example 5 Elagolix and E2/NETA bilayer tablets. As shown in FIG. 7.
  • Bilayer tablets consist of one layer of elagolix formulation 701 and a rapidly disintegrating layer 705 with embedded E2/NETA tablets 703, as shown in FIG. 7, were prepared for dissolution test.
  • the compositions of each layer are provided in Table 10 and prepared according to the process shown in FIG. 13.
  • the rapidly disintegrating layer 705 contains commercially sourced excipient composite of Prosolv EASYtab (JRS Pharma) and one commercially sourced E2/NETA tablet 703 (Breckenridge Pharmaceutical Inc.).
  • the bilayer tablet 700 was prepared individually by sequential filling into the die of tooling A2310: (1) 80 mg EASYtab, (2) one E2/NETA tablet, (3) 80 mg EASYtab and (3) 529 mg Elagolix granules, followed by compression into the final tablet.
  • Table 11 Extruder temperature setup for melt granules used in Example 5.
  • Example 6 Elagolix and E2/NETA Capsules. As shown in FIG. 2 [138] The capsule of example 6, as shown in FIG. 2, provides a presentation that is easy for a patient to swallow and simpler to manufacture. The capsule was prepared according to the process shown in FIG. 14. This formulation allows for desirable co-administration of Elagolix/E2/NETA, which in turn provides the desired balance between the therapeutic and safety effect of elagolix E2 and NETA. Exogenous addition of a GnRFI antagonist, such as elagolix regulates the hormones that may create certain adverse effects.
  • a GnRFI antagonist such as elagolix regulates the hormones that may create certain adverse effects.
  • Table 12 Composition of Example 6 Capsules.
  • Example 7 Elagolix tablets in capsules. As shown in FIG. 8.
  • Example 7 Elagolix Tablets. a: (75 mg of free acid elagolix is equivalent to about 77.9 mg elagolix sodium)
  • Example 8 Elagolix Melt Granules and E2/NETA Tablet in capsules. As shown in FIG. 9.
  • the capsules 900 containing elagolix melt granules 901 and E2/NETA tablets 903 were prepared according to the process shown in FIG. 16.
  • the capsule 900 may include air, or any other suitable filler in interior space 910.
  • the elagolix melt granules 901 and E2/NETA tablets 903 may be mixed/placed together in the capsule 900.
  • Example 9A Dissolution test of Examples 1-8
  • Table 15 Dissolution Data for Example 1 (mean ⁇ SD). As shown in FIG. 4A.
  • Table 16 Dissolution Data of Example 2 (mean ⁇ SD). As shown in FIG. 4B.
  • Table 17 Dissolution Data of Example 3-1 (mean ⁇ SD). As shown in FIG. 5.
  • Table 18 Dissolution Data for Example 3-2 (mean ⁇ SD). As shown in FIG. 5.
  • Table 19 Dissolution Data of Example 3-3 (mean ⁇ SD). As shown in FIG. 5.
  • Table 20 Dissolution Data for Example 3-4 (mean ⁇ SD). As shown in FIG. 5.
  • Table 21 Dissolution Data for Example 4 (mean ⁇ SD). As shown in FIG. 6.
  • Example 9B Dissolution test of Example 6
  • the drug delivery system 100 includes a morning capsule 102 labelled “AM” 126.
  • Capsule 102 is white and yellow and includes additional identifying labelling “EL300.”
  • Capsule 102 includes about 300 mg elagolix, about 1 mg estradiol, and about 0.5 mg norethindrone acetate.
  • Capsule 104 is labelled “PM” is white and light blue, and also is labelled “EL300.” In some examples, capsule 104 may include about 300 mg elagolix.
  • Each capsule 102, 104 should be administered orally daily at approximately the same time each day (e.g. 102 taken in the morning and capsule 104 taken in the evening).
  • each of the capsules may be taken with or without food and the capsules may be administered daily for about 48 months. In another embodiment, each of the capsules may be taken with or without food and the capsules may be administered daily for about 60 months. In another embodiment, each of the capsules may be taken with or without food and the capsules may be administered daily for about 72 months. In another embodiment, each of the capsules may be taken with or without food and the capsules may be administered daily for about 6 months, for about 12 months, for about 12-24 months, for about 24-36 months, for about 36-48 months, for about 48-60 months, or for about 60-72 months.
  • Duration of treatment may be extended based on assessment of bone mineral density loss or any other adverse effect, for example, if a woman is treated for a duration of 24 months, and continues to have a positive benefit-risk profile, the duration of treatment may be extended to 36 months or longer.
  • the bone mineral density loss may be assessed using any suitable methods, including radiographic techniques e.g. DXA scan for continued treatment. If a patient has missed a dose, the patient should be instructed to take the missed dose within 4 hours of the time the dose was supposed to be taken and them the next dose may be taken and the usual time. If, however, more than 4 hours have passed since the missed dose would have usually been taken, the patient should not take the missed dose and take the next dose at the usual time. Only one morning and one evening capsule should be taken per day.
  • Example 10 The safety of system of Example 10 was evaluated in two randomized, double-blind, placebo-controlled studies [UF-1 (NCT02654054) and UF-2 (NCT02691494)] in which 790 premenopausal women received elagolix, elagolix 300 mg twice daily, or placebo for 6 months. Elagolix 300 mg twice daily was included as a reference arm to characterize the impact of estradiol/norethindrone acetate (E2/NETA) on safety and efficacy.
  • E2/NETA estradiol/norethindrone acetate
  • Table A1 Adverse Reactions Occurring in at Least 5% of Women with Uterine Fibroids Receiving the System of Example 10 in Studies UF-1 and UF-2 and at a Greater incidence Than Placebo
  • Elagolix is a weak to moderate inducer of cytochrome P450 (CYP) 3A). Coadministration with the System of Example 10 may decrease plasma concentrations of drugs that are substrates of CYP3A. Elagolix is a weak inhibitor of CYP2C19. Co-administration with the System of Example 10 may increase plasma concentrations of drugs that are substrates of CYP2C19 (e.g., omeprazole and esomeprazole) ([see Table A5)]
  • CYP2C19 e.g., omeprazole and esomeprazole
  • Elagolix is an inhibitor of efflux transporter P-glycoprotein (P-gp).
  • Co-administration with the System of Example 10 may increase plasma concentrations of drugs that are substrates of P-gp (e.g., digoxin) ([see Table A5]).
  • Exposure to the System of Example 10 early in pregnancy may increase the risk of early pregnancy loss.
  • Use of the System of Example 10 is contraindicated in pregnant women.
  • the System of Example 10 should be discontinued if pregnancy occurs during treatment.
  • MRHD maximum recommended human dose
  • Spontaneous abortion and total litter loss were observed in rabbits at doses 4 and 7 times the MRHD.
  • Embryofetal development studies were conducted in the rat and rabbit. Elagolix was administered by oral gavage to pregnant rats (25 animals/dose) at doses of 0, 300, 600 and 1200 mg/kg/day and to rabbits (20 animals/dose) at doses of 0, 100, 150, and 200 mg/kg/day, during the period of organogenesis (gestation day 6-17 in the rat and gestation day 7-20 in the rabbit). In rats, maternal toxicity was present at all doses and included six deaths and decreases in body weight gain and food consumption. Increased post implantation losses were present in the mid dose group, which was 12 times the MRHD based on AUC.
  • the System of Example 10 is not recommended during lactation. There is limited information on the presence of the System of Example 10 in human milk, the effects on the breastfed child, or the effects on milk production.
  • the System of Example 10 combines elagolix, a GnRH receptor antagonist, and estradiol/norethindrone acetate (E2/NETA), an exogenous combination of estrogen and progestin.
  • Elagolix inhibits endogenous GnRH signaling by binding competitively to GnRH receptors in the pituitary gland.
  • Estrogens such as E2 act through binding to nuclear receptors in estrogen- responsive tissues.
  • Progestins such as NETA enhance cellular differentiation and generally oppose the actions of estrogens by decreasing estrogen receptor levels, increasing local metabolism of estrogens to less active metabolites, or inducing gene products that blunt cellular responses to estrogen.
  • Progestins exert their effects in target cells by binding to specific progesterone receptors that interact with progesterone response elements in target genes.
  • LH and FSH were approximately 0.40 to 0.70 mlll/mL and 1.8 to 2.5 mlll/mL respectively, resulting in median concentrations of estradiol of approximately 42 to 51 pg/mL, and progesterone of approximately 0.37 to 0.38 nM.
  • elagolix 150 mg QD or 100, 200, 300, or 400 mg BID or placebo was administered for 21 days.
  • Dose-dependent suppression of sex hormones was achieved rapidly within hours after administration of the first dose on day 1 and continued through day 21, with maximum E2 suppression achieved with elagolix doses of 200 mg BID or higher.
  • P concentrations remained at anovulatory levels throughout 21 days of dosing.
  • Dose-dependent suppression of FSH and LH was also observed, with maximal or near-maximal suppression achieved at elagolix doses of 300 mg BID and 200 mg BID, respectively.
  • Table A7 (b): Mean ( ⁇ SD) Pharmacokinetic Parameters of the System of Example 10 with 90% confidence intervals around the mean Cmax or AUC ratios of 0.8-1.25.
  • Elagolix exposures were not altered by renal impairment.
  • the elagolix mean plasma exposures were similar for women with moderate to severe or end stage renal disease (including women on dialysis) compared to women with normal renal function.
  • the effect of renal impairment on the pharmacokinetics of E2/NETA has not been studied.
  • Body weight or body mass index does not affect the pharmacokinetics of elagolix.
  • the effect of body weight/body mass index on the pharmacokinetics of E2/NETA has not been studied.
  • Disposition Hepatic uptakedate of elagolix involves the OATP 1 B1 transporter protein. Higher plasma concentrations of elagolix have been observed in groups of patients who have two reduced function alleles of the gene that encodes OATP 1B1 (SLC01B1 521T>C) (these patients are likely to have reduced hepatic uptake of elagolix; and thus, higher plasma elagolix concentrations).
  • the frequency of this SLC01B1 521 C/C genotype is generally less than 5% in most racial/ethnic groups. WomenPatients with this genotype are expected to have approximately 2-fold higher elagolix mean concentrations compared to women with normal transporter function (i.e.
  • the dose of elagolix may be reduced to about 50% of the original dose in order to achieve once daily mean concentration of elagolix.
  • the elagolix dose may be reduced to half the original dose, the dosing interval may be reduced from twice a day to once a day, or the dosing may be reduced from daily dosing to every other day dosing.
  • Example 15 Nonclinical Toxicology
  • mice 50, 150, or 500 mg/kg/day
  • rats 150, 300, or 800 mg/kg/day
  • elagolix by the dietary route revealed no increase in tumors in mice at up to 11.9-fold the MRHD based on AUC.
  • the rat there was an increase in thyroid (male and female) and liver (males only) tumors at the high dose (7.7 to 8.1 -fold the MRHD).
  • the rat tumors were likely species-specific and of negligible relevance to humans.
  • Elagolix was not genotoxic or mutagenic in a battery of tests, including the in vitro bacterial reverse mutation assay, the in vitro mammalian cell forward mutation assay at the thymidine kinase (TK+/-) locus in L5178Y mouse lymphoma cells, and the in vivo mouse micronucleus assay.
  • TK+/- thymidine kinase
  • UF-1 and UF-2 the median age was 43 years (ranging from 25 to 53 years); 68% of the women were Black or African American, 29% were White, and 3% were other races; 16% of women had uterine fibroids and coexisting adenomyosis at baseline as evaluated by transvaginal and transabdominal ultrasound (TVU/ TAU) and/or MRI; MBL at baseline ranged from 83.8 mL to 1207.1 mL; uterine volume by TVU/TAU ranged from 71.6 cm3 to 3347.9 cm3; and primary fibroid volume by TVU/TAU ranged from 1 cm3 to 1081.5 cm3.
  • TVU/ TAU transvaginal and transabdominal ultrasound
  • MBL at baseline ranged from 83.8 mL to 1207.1 mL
  • uterine volume by TVU/TAU ranged from 71.6 cm3 to 3347.9 cm3
  • primary fibroid volume by TVU/TAU ranged from 1 cm3 to 1081.5 cm3.
  • MBL at baseline was defined as the mean of total MBL volume from at least 2 screening menstrual cycles that are >80 mL.
  • Final month is defined as the last 28 days before and including the last treatment visit date or the last dose date.
  • Elagolix is approved at doses of 150 mg once daily and 200 mg twice daily for the management of moderate to severe pain associated with endometriosis, with roller compacted (RC2) tablets being used as the commercial formulation.
  • RC2 roller compacted
  • a combination product of elagolix 200 mg and estradiol (E2) 1 mg/norethindrone acetate (NETA) 0.5 mg is being evaluated in endometriosis Phase 3 trials.
  • phase 3 investigational product consisted of elagolix 200 mg tablet co-administered with E2/NETA tablet, while the proposed commercial product consists of elagolix 200 mg melt granulated (MG) tablet and E2/NETA tablet as a fixed-dose combination (FDC) morning capsule and elagolix 200 mg MG evening capsule.
  • Dissolution tests performed using USP I (basket) apparatus showed dissimilar in vitro dissolution profiles for the Phase 3 and the to-be- marketed (TBM) capsules, thus requiring the evaluation of bioequivalence (BE) with respect to in vivo exposures.
  • Physiologically based pharmacokinetic (PBPK) modeling was used along with in vitro dissolution data for various formulations to conduct virtual BE simulations in order to demonstrate simulated bioequivalent exposures without conducting clinical BE studies.
  • the PBPK model with in vitro data incorporated was externally validated using clinical data from two clinical bioequivalence studies, where the elagolix capsules at 300 mg dose were evaluated against the reference RC2 tablet for a different indication.
  • Model predicted exposures (Cmax and AUC) in a virtual healthy, female population were compared to clinical observations for each formulation from the BE studies.
  • Model predicted exposure ratios for Cmax and AUC of the test capsule formulations to the reference (RC2) tablet were also compared to clinical observations.
  • the clinically validated PBPK model was used to simulate virtual bioequivalence trials in a cross-over fashion to compare elagolix 200 mg capsules to 200 mg RC2 tablets.
  • the virtual BE trials were conducted 100 times with different virtual subjects to evaluate the effect of inter-occasion or inter trial variability on bioequivalence of the formulations.
  • PBPK model predicted exposures for the 300 mg tablet (RC2) and mg capsules formulations compared well with clinical observations from BE studies with less than 25% predictions errors. Model predictions of relative BE ratios comparing test to reference formulations also compared well with clinical data from the BE studies. These BE study results were not used in model calibration or verification and thus were used as external validation of the PBPK model predictions. This provided confidence in using the PBPK model to predict exposures for clinically untested formulations using their in vitro dissolution data as inputs. Based on results of the virtual BE trials simulations, both capsule formulations at the 200 mg dose met the bioequivalence criteria of 0.80 - 1.25 when compared to the reference RC2 formulation.
  • Elagolix is being developed for the management of heavy menstrual bleeding (HMB) associated with uterine fibroids (UF).
  • the investigational drug product being studied in the UF phase 3 trials is elagolix 300 mg twice daily roller compaction 2 (RC2) tablets co-administered with estradiol/norethindrone acetate (E2/NETA) 1 mg/0.5 mg once daily tablet.
  • RC2 roller compaction 2
  • E2/NETA estradiol/norethindrone acetate
  • TBM proposed to-be-marketed
  • FDC fixed dose combination capsule consisting of elagolix/E2/NETA 300/1/0.5 mg for the morning dose, and an elagolix 300 mg capsule for the evening dose.
  • the two formulations exhibited dissimilar for in vitro dissolution profiles, indicating potential different release characteristics in vivo.
  • the purpose of the studies was to assess (1 ) BE of the TBM elagolix FDC morning capsule formulation compared to elagolix RC2 tablet co-administered with E2/NETA tablet in postmenopausal healthy women; (2) BE of the TBM elagolix evening capsule formulation compared to elagolix RC2 tablet in premenopausal healthy women; and (3) the effect of food (high-fat meal) on bioavailability of elagolix capsules.
  • the present research included two separate large phase 1 BE studies.
  • the first one is a randomized, single-center, single dose, four sequence, two/three-period, crossover, phase 1 BE study.
  • Serial blood samples for assay of elagolix were collected prior to dosing and up to 24 hours after dosing on study days.
  • NCA non-compartmental analysis

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JP2022546496A (ja) 2022-11-04
CN114650810A (zh) 2022-06-21
EP4021420A4 (de) 2023-11-22
AU2020336093A1 (en) 2022-03-31

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