JP2022546496A - Systems and methods for multi-drug delivery - Google Patents

Abstract

The multiple drug delivery system includes a first capsule body including a first interior and a first capsule including a first tablet and a second tablet within the first interior. The first tablet contains a first drug and the second tablet contains at least a second drug different from the first drug. The first tablet and the second tablet are configured to be released simultaneously upon dissolution of the first capsule body within the patient's body. The system also includes a second capsule body including a second interior, and a second capsule including a third tablet within the second interior. A third tablet contains the first drug.

Description

The field of the present disclosure is generally pharmaceutical products, and more specifically drug dosage forms that allow simultaneous, immediate release of more than one drug entrapped within a capsule upon oral ingestion by a patient; and to delivery systems for drug administration that ensure compliance with patient intake.

Oral administration of pharmaceuticals such as drugs, supplements and other nutritional or therapeutic agents is typically done in tablet and capsule forms. Capsules generally include a hollow shell having an interior for storing a powder or liquid base drug therein, and tablets may be manufactured from a compacted powder of medicinal substance. For at least some known ailments, it may be beneficial to administer more than one type of medication to a patient. Thus, tablets and capsules can be manufactured to permit administration or ingestion of more than one drug to a patient in a single dose or dosage form. For example, at least some known capsules contain a mixture of drugs in liquid or powder form within the interior of a hollow shell. Additionally, at least some known tablets contain a first drug encapsulated within a second drug. However, encapsulating a first drug within a second drug can interfere with the dissolution of the first drug and can reduce the dissolution of the first and second drugs. Additionally, drugs administered in powder or liquid form may dissolve at a rate that is not suitable for desired efficacy.

Additionally, many known prescription drugs have complex instructions and dosing regimens. For example, some prescriptions require oral administration of multiple drug forms containing different types of drugs and/or require administration at different times of the day. Other drugs are to be taken in the morning, afternoon or evening, some with or without food, some with or without specific types of food, and in specific amounts. Thus, patients may have difficulty remembering and adhering to dosing instructions for a drug or group of drugs. Failure to comply with such dosing instructions may result in inadequate efficacy.

(Gist of invention)
In one aspect, a multi-drug delivery system is provided. The system includes a first capsule body having a first interior and a first capsule comprising a first tablet and a second tablet contained within the first interior. The first tablet contains a first drug and the second tablet contains at least a second drug different from the first drug. For example, a second tablet may contain a second and third drug, each different from the first drug and from each other. The first tablet and the second tablet are configured to be released simultaneously upon dissolution of the first capsule body within the patient's body. The system also includes a second capsule packaged with the first capsule and including a second capsule body having a second interior and a third tablet contained within the second interior. A third tablet may contain the first drug, the second drug and/or one or more other drugs. 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 dissolved 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.

In some embodiments, the first tablet may contain a gonadotropin releasing hormone antagonist. For example, a first tablet may contain elagolix, relugolix, another gonadotropin-releasing hormone antagonist and/or a combination of gonadotropin-releasing hormone antagonists. In some embodiments, the first tablet may contain elagolix.

In some embodiments, the first tablet may contain from about 175 mg to about 325 mg of the gonadotropin releasing hormone antagonist, the second tablet may contain from about 0.75 mg to about 1.25 mg of estradiol, the second tablet may contain from about 0.75 mg to about 1.25 mg of estradiol, may further comprise from about 0.1 mg to about 1 mg of norethindrone acetate, and after about 15 minutes the release of estradiol is 70% ± 10% or 70% ± 20% or 70% ± 30% or 70% ± 40% or more.

In some examples, a first capsule may be marked with a first identifier and a second capsule to make the first and second capsules visually distinguishable. , with a second identifier different from the first identifier, the first identifier configured to indicate that the first capsule is intended for administration within a first time period of the day. and the second identifier may be configured to indicate that the second capsule is intended for administration within a second timeframe of the day, different from the first timeframe. In some examples, the first identifier may be configured to indicate that the first capsule is intended for administration at a first time slot in the morning, and the second capsule is The second identifier may be configured to indicate that administration is intended for a second time slot in the afternoon, the first identifier being a first color contained on the first capsule. Possibly, the second identifier can be a second color included on the second capsule.

In some examples, the system can include a package having multiple compartments configured to house the first capsule and the second capsule. The package may include a blister card defining multiple compartments, wherein the first capsule and the second capsule contained in the multiple compartments are accessible by piercing the seal of the blister card. , the package may have printed thereon information related to when to administer the first capsule and the second capsule to the patient, and the blister card may have a first row of compartments and a There may be a second row of multiple compartments, a first capsule contained in the first row, a second capsule contained in the second row, the first row and the second row columns are visually distinct.

In another aspect, a capsule is provided for use in delivering a drug to a patient. The capsule comprises a capsule body having an interior and at least one first tablet and a second tablet contained within the interior. At least one first tablet contains a first drug and a second tablet contains 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's body.

In some embodiments, the first tablet may contain from about 175 mg to about 325 mg of the gonadotropin releasing hormone antagonist, such as elagolix, the second tablet may contain from about 0.75 mg to about 1.25 mg of estradiol, A second tablet may further comprise from about 0.1 mg to about 1.0 mg of norethindrone acetate. In some examples, after 16 minutes, the release of estradiol is 70% ± 10% or 70% ± 20% or 70% ± 30% or 70% ± 40% or more, and the capsule body defines the long axis can be elliptical, wherein the at least one first tablet and the second tablet are disposed within the interior along a longitudinal axis in a serial relationship, and the at least one first tablet and the second tablet The tablets may be separate tablets formed separately from each other and then secured within the interior, the capsule body may not contain the drug in powder form, and the capsule body may contain the first tablet and the second tablet. There may be no extended barrier between the tablets, the first tablet and the second tablet may not be internally bound to each other, and the first capsule may comprise gelatin.

In yet another aspect, a method of delivering a drug to a patient is provided. The method comprises delivering a first capsule to a patient, the first capsule comprising a first capsule body having a first interior and a first tablet contained within the first interior. and a second tablet. The first tablet contains a first drug and the second tablet contains at least a second drug different from the first drug. The first tablet and the second tablet are configured to be released simultaneously upon dissolution of the first capsule body within the patient's body. The method also includes delivering a second capsule packaged with the first capsule to the patient a predetermined amount of time after administration of the first capsule. The second capsule includes a second capsule body having a second interior and a third tablet contained within the second interior. A third tablet contains the first drug.

In some embodiments, the first tablet comprises about 175-325 mg of the gonadotropin-releasing hormone antagonist and the second tablet comprises about 0.75-1.25 mg of estradiol and about 0.1-1.0 mg of estradiol. of norethindrone and after 20 minutes the release of estradiol is 70% ± 10% or 70% ± 20% or 70% ± 30% or 70% ± 40% or more, and delivering a second capsule comprises , delivering a second capsule at least 5 hours after administration of the first capsule; a plurality of compartments configured to house the first capsule and the second capsule therein; and/or the package such that the number of first capsules and the number of second capsules contained in the package are each a multiple of the number of days in a week Further comprising receiving a plurality of first capsules and a plurality of second capsules within.

In some embodiments, the multi-drug tablet comprises a first tablet and a second tablet coated on the first tablet, the second tablet centered on the first tablet. and/or multiple tablets comprising crospovidone.

In some embodiments, the medicament container assembly is a first set of multiple compartments, each compartment configured to support a first capsule; a second set of multiple compartments, each compartment configured to support a second capsule, the first capsule comprising a second set of compartments configured to support a second capsule; an interior; a first tablet within the first interior, the first tablet comprising a first drug; and a second tablet within the first interior, the first tablet comprising at least the first drug a second tablet comprising a different second drug, the first tablet and the second tablet configured for simultaneous release upon dissolution of the first capsule body in the patient; The agent is a second capsule body including a second interior, and a third tablet within the second interior, wherein the agent is selected from the group consisting of a first drug, a second drug, or a third drug. a third tablet containing at least one drug that

In some embodiments, the multi-drug capsule is a first tablet, a first tablet comprising a first drug; a second tablet packaged with the first tablet, comprising: at least a second tablet comprising a second drug that is different from the first drug; and a third drug that is different from the first and second drugs, the first tablet and the second tablet comprising: at least 75% ± 10% of the first of the first drug in the tablet dissolves after 60 minutes and at least 70% ± 10% or 70% ± 20% or 70% ± 30% or 70% ± 40% of the second and second drugs in the second tablet Drug 3 dissolves after 30 minutes.

In some embodiments, the multi-drug capsule is a first tablet, a first tablet comprising a first drug; a second tablet packaged with the first tablet, comprising: at least a second tablet comprising a second drug that is different from the first drug; and a third drug that is different from the first and second drugs, the first tablet and the second tablet comprising: of at least 75% ± 10% using USP apparatus 1 at 100 rpm, pH 6.8 and 37.5 ± 0.5°C, at The first drug in one tablet dissolves after 45 minutes and at least 90% ± 10% or 90% ± 20% or 90% ± 30% or 90% ± 40% of the second and The third drug dissolves after 30 minutes.

In some examples, the first tablet comprises elagolix, the first tablet has from about 175 mg to about 325 mg of elagolix, and the second tablet has from about 0.75 mg to about 1.25 mg of estradiol have

In another aspect, the oral multi-drug capsule composition comprises 300 mg free acid equivalents of elagolix, 1 mg estradiol and 0.5 mg norethindrone acetate for administration of a single dose of the composition to a healthy adult subject. followed by an average peak concentration (Cmax) for said Elagolix of about 1218.4 ng/mL to about 2185 ng/mL; an average peak concentration (Cmax) for said estradiol of about 0.0424 ng/mL to about 0.0775 ng/mL; Mean peak concentration (Cmax) for said norethindrone acetate from about 4.56 ng/mL to about 8.0 ng/mL, about 3293.6 ng. hr/mL to about 5892.5 ng. hr/mL mean area under the curve (AUC _(t) ) for the Elagolix, about 0.688 ng. hr/mL to about 1.1375 ng. hr/mL of mean area under the curve (AUC _(t) ) for the estradiol, and about 17.6 ng. hr/mL to about 33.125 ng. An average area under the curve (AUC _(t) ) for the norethindrone acetate of hr/mL is produced.

In another aspect, the multi-drug capsule composition comprises 300 mg free acid equivalents of elagolix, 1 mg estradiol, and 0.5 mg norethindrone acetate by administration of a single dose of the composition to a healthy adult subject. , a mean peak concentration, Cmax, for said ellagolix, from about 1218.4 ng/ml to about 2185 ng/ml; a mean peak concentration, Cmax, for said estradiol, from about 0.0424 ng/ml to about 0.0775 ng/ml; An average peak concentration, Cmax, for the norethindrone acetate of 0.56 ng/ml to about 8.0 ng/ml results.

In one example, the multi-drug composition contains about 3296.6 ng. hr/mL to about 5892.5 ng. hr/mL mean area under the curve for the Elagolix, AUC _(t) , about 0.688 ng. hr/mL to about 1.1375 ng. hr/mL mean area under the curve for the estradiol, AUC _(t) , and about 17.6 ng. hr/mL to about 33.125 ng. It has an average area under the curve, AUC _(t) , for the norethindrone acetate of hr/mL.

In one aspect, the multi-drug capsule composition comprises 300 mg free acid equivalents of elagolix, 1 mg estradiol and 0.5 mg norethindrone acetate, wherein administration of a single dose of the composition to a healthy adult subject: about 3293.6 ng. hr/mL to about 5892.5 ng. hr/mL mean area under the curve for the Elagolix, AUC _(t) , about 0.0.688 ng. hr/mL to about 1.1375 ng. hr/mL mean area under the curve for the estradiol, AUC _(t) , and about 17.6 ng. hr/mL to about 33.125 ng. An average area under the curve, AUC _(t) , for the norethindrone acetate in hr/mL is generated.

In one example, administration of a multi-drug capsule to healthy adult subjects resulted in about 1218.4 ng/mL to about 2185 ng. hr/mL mean peak concentration for the ellagorix, Cmax, about 0.0424 ng. hr/mL to about 0.0775 ng/mL ng/ml mean peak concentration for the estradiol, Cmax, and about 4.56 ng. An average peak concentration, Cmax, for the norethindrone acetate of hr/mL to about 8.0 ng/ml occurs.

In another aspect, the oral multi-drug capsule composition comprises 300 mg free acid equivalents of elagolix, 1 mg estradiol and 0.5 mg norethindrone acetate 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 dissolves after 30 minutes using USP Apparatus 2 at Dissolve later. In another aspect, a method is provided for safely treating heavy menstrual bleeding associated with uterine leiomyoma (fibroids) in a pre-menopausal female patient. The method comprises oral administration of (a) 300 mg free acid equivalent of elagolix, (b) 1 mg estradiol and (c) 0.5 mg norethindrone acetate to said patient once daily, said method comprising: about 1218.4 ng. about 4.56 ng/mL to about 8.0 ng/mL of the acetic acid to the estradiol, from about 0.0424 ng/mL to about 0.0775 ng/mL for the ellagorix, from about 4.56 ng/mL to about 8.0 ng/mL for the elagolix, hr/mL to about 2185 ng/mL; mean Cmax for norethindrone, and about 3293.6 ng. hr/mL to about 5892.5 ng. hr/mL of about 0.0.688 ng. hr/mL to about 1.1375 ng. hr/mL of said estradiol, and about 17.6 ng. hr/mL to about 33.125 ng. A mean AUC _(t) for the norethindrone acetate of hr/mL occurred, and after a treatment duration of approximately 6 months, the patient had a hemoglobin of approximately Achieve an increase of 2 g/dL or greater.

In another aspect, an oral capsule for use in delivering a drug to a patient comprises a capsule body comprising an interior; a first tablet within the interior, wherein at least one first tablet comprises a first a first tablet comprising a drug; and a second tablet within the interior, the second tablet comprising at least a second drug different from the first drug, the first tablet and the second tablet are configured to be released simultaneously with dissolution of the capsule body in the patient's body, using USP Apparatus 1 at 100 rpm, pH 6.8 and 37.5±0.5° C., the first tablet At least 75% of the first drug in the second tablet dissolves after 45 minutes, and at least 90% of the second and third drugs in the second tablet dissolve after 30 minutes.

In another aspect, an oral multi-drug capsule composition is provided that is bioequivalent to any of the foregoing compositions.

In another aspect, a method of delivering a co-packaged drug to a patient for oral use is provided. A method comprises delivering a first capsule to a patient, the first capsule comprising a first capsule body including a first interior; a first tablet within the first interior; , a 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 the patient; and a second tablet packaged with the first capsule. delivering the capsule to the patient a predetermined amount of time after administration of the first capsule, wherein the second capsule comprises a second capsule body comprising a second interior; and A third tablet within the second interior, the third tablet containing the first drug.

1 illustrates an exemplary multi-drug delivery system comprising a first capsule and a second capsule of drug; FIG. FIG. 2 is an internal view of an exemplary capsule containing two tablets; FIG. 1 is an internal view of an exemplary capsule containing a single tablet; FIG. 4B is an internal view of a first exemplary multi-drug tablet having a first tablet enclosing a second tablet; FIG. 4B is an internal view of a second exemplary multi-drug tablet having a first tablet enclosing a second tablet; FIG. 11 is an internal view of a third exemplary 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; be. FIG. 10 is an internal view of a fourth exemplary multi-drug tablet having the first tablet coated with a mixture of third and fourth drugs; FIG. 10 is an internal view of a fifth exemplary multi-drug tablet having a bilayer, the bilayer having a first layer of a first drug and a second layer of embedded tablets; FIG. 2 is an internal view of an exemplary capsule according to FIG. 1 with a first tablet and four sub-tablets; 2 is an internal view of an exemplary capsule according to FIG. 1 containing molten granules and tablets; FIG. 1 is a flow chart showing the processing steps of Example 1, an E2/NETA tablet in an elagolix tablet and Example 2, an E2/NETA tablet embedded in the surface of an elagolix tablet. Example 3-1: Flow chart showing processing steps for bilayer tablet E2/NETA layer: fluidized bed granulation, spraying API solution onto lactose. Example 3-2: Flow chart showing processing steps for bilayer tablet E2/NETA layer: fluid bed granulation, spraying binder onto API mixture. Example 3-3: Flowchart showing processing steps for bilayer tablets, direct blending of E2/NETA layer and disintegrant. Examples 3-4: Flowchart showing processing steps for bilayer tablets, direct blending of E2/NETA layer without disintegrant. 4 is a flow chart showing the process steps of Example 4: coating ellagorix core tablets with a solution of E2/NETA. Example 5: Flowchart showing process steps for E2/NETA embedded in bilayer tablet, placebo layer. Example 6: Flowchart showing processing steps for elagolix tablets and E2/NETA tablets in capsules. Example 7: Flowchart showing the processing steps for elagolix mini-tablets and one E2/NETA tablet in a capsule. Example 8: Flowchart showing the processing steps for encapsulated Elagolix granules and one E2/NETA tablet. 2 is a perspective view of an exemplary package that can be used to contain and carry the multi-drug delivery system shown in FIG. 1; FIG. 4B is a diagram illustrating dissolution rates of administered drugs according to various embodiments of the present disclosure and according to the multi-drug tablets shown in FIG. 4A and Example 1. FIG. 4B is a diagram illustrating dissolution rates of administered drugs according to various embodiments of the present disclosure and according to the multi-drug tablets shown in FIG. 4B and Example 2. FIG. 5 is a diagram illustrating dissolution rates of administered drugs according to various embodiments of the present disclosure and according to the multi-drug tablets shown in FIG. 5 and Example 3-1. 5 is a diagram illustrating dissolution rates of administered drugs according to various embodiments of the present disclosure and according to the multi-drug tablets shown in FIG. 5 and Example 3-2. 5 is a diagram illustrating dissolution rates of administered drugs according to various embodiments of the present disclosure and according to the multi-drug tablets shown in FIG. 5 and Example 3-3. 5 is a diagram illustrating dissolution rates of administered drugs according to various embodiments of the present disclosure and according to the multi-drug tablets shown in FIG. 5 and Examples 3-4. 7 is a diagram illustrating dissolution rates of administered drugs according to various embodiments of the present disclosure and according to the multi-drug tablets shown in FIG. 6 and Example 4. FIG. 8 is a diagram illustrating dissolution rates of administered drugs according to various embodiments of the present disclosure and according to the multi-drug tablets shown in FIG. 7 and Example 5. FIG. 3 is a diagram illustrating the dissolution rate of administered drug according to various embodiments of the present disclosure and according to capsules shown in FIG. 2 and Example 6. FIG. 9 is a diagram illustrating the dissolution rate of administered drug according to various embodiments of the present disclosure and according to capsules shown in FIG. 8 and Example 7. FIG. 8 is a diagram illustrating the dissolution rate of administered drug according to various embodiments of the present disclosure and according to capsules shown in Example 9 and Example 8. FIG. Lumbar spine bone mineral density in women with uterine fibroids who received the system described in Example 10 for 12 months and who underwent follow-up BMD during a 12-month off-treatment in studies UF-1, UF-2, UF-3. (BMD) is a graphical representation of percent change from baseline. FIG. 10 is a graphical representation of monthly change from baseline in MBL volume in women with uterine fibroids in the UF-1 study. FIG. 10 is a graphical representation of monthly change from baseline in MBL volume in women with uterine fibroids in the UF-2 study. 7 is a diagram illustrating the dissolution rate 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. 7 is a diagram illustrating the dissolution rate 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. 7 is a diagram illustrating the dissolution rate of administered NETA according to various embodiments of the present disclosure and according to the multi-drug tablet shown in FIG. 6 using USP Apparatus 1. FIG.

The following detailed description illustrates the present disclosure by way of illustration and not by way of limitation. The description enables those skilled in the art to make and use the disclosure and describes several embodiments, adaptations, variations, substitutions and uses of the disclosure.

Embodiments of the present disclosure provide drug dosage forms that allow substantially simultaneous, immediate release of more than one drug entrapped within a capsule when administered by a patient, facilitating patient compliance with dosing. It relates to delivery systems for medication. The drug delivery system contains a first capsule and may also contain a second capsule that is intended to be administered at different, non-overlapping time frames during the day. For example, in one embodiment, the first capsule is intended to be administered during the morning hours (eg, mid-morning) and the second capsule is at least It is intended to be administered after 5 hours (eg, during the afternoon or evening hours). The first capsule and the second capsule may contain different drugs or drug combinations and may be marked, for example, with an identifier to facilitate compliance with prescription administration. The surfaces of the first capsule and the second capsule may have distinct distinguishing colors and/or surface properties. The first capsule and the second capsule may also include symbols and/or letter markings that indicate the time frame during which the respective capsule should be administered. Additionally, the plurality of first capsules and the plurality of second capsules may be contained in a package that includes symbols and/or letter markings that also indicate the timeframes in which each capsule is to be administered. Accordingly, the first capsule and the second capsule are clearly and conspicuously marked, or marked or arranged to allow the patient to easily distinguish the capsules.

In some embodiments, the system packages multiple capsules together to contain two or more different drugs, e.g., a first tablet containing a first drug and a second and third drug. It may comprise a single capsule containing a second tablet containing. In some examples, the first drug can be elagolix or other gonadotropin releasing hormone (GnRH) releasing antagonist. Oral dosage size is an important component of patient compliance. A large oral dose size makes patients reluctant to follow dosing recommendations. In one embodiment, the first capsule comprises at least two separate tablets, a first tablet comprising a first drug and a second tablet comprising a second drug and a third drug different from the first drug. Contains 2 tablets. The first, second and third drugs have different efficacies, and in exemplary embodiments the second and third drugs at least partially inhibit the undesired adverse effects of the first drug on the patient. included in the capsule to Thus, the first and second tablets are formed separately from each other, and then dissolution of the outer shell of the capsule in the patient's body facilitates simultaneous, immediate release of the drug in the first and second tablets. is secured within the first capsule so as to That is, securing separate tablets within a capsule allows for simultaneous dissolution of the tablets to produce the desired bioavailability for the patient. Thus, the dosage form provided by the first capsule promotes desirable dissolution and bioavailability of the drug within the patient's body.

As used herein, a bioequivalent composition or formulation is a bioequivalent as defined by the US Food and Drug Administration (FDA).

Furthermore, co-administration of tablets in capsules can provide an easy format for patients to swallow and can be simple to manufacture. Furthermore, this format allows for simultaneous administration of the first, second and third drugs. This co-administration allows for a desired balance between therapeutic efficacy and safety of the first drug in the first tablet and at least the second or third drug in the second tablet. Thus, co-administration of a first drug in a first tablet and a second and third drug in a second tablet facilitates potential suppression of unwanted effects of the first drug. In one example, the first drug in the first tablet can be Elagolix or another GnRH antagonist and the second and third drugs in the second tablet are a combination of estradiol (E2) and norethindrone (NETA) ( For example, Activella® tablets). E2/NETA therefore facilitates add-back therapy to reverse certain undesirable effects of hormone regulation caused by exogenous introduction of GnRH antagonists, eg, ellagorix, relugolix, and the like.

In any of the various aspects of the present disclosure, the first drug may suitably be a GnRH antagonist such as elagolix and/or relugolix, the second drug may suitably be estradiol, and the third The drug may suitably be norethindrone acetate. Elagolix is commonly available as Elagolix Sodium. For these particular drugs, it is important that a delivery mechanism is used that facilitates improved and desirable dissolution of the drug and achievement of desirable bioavailability in the patient's body. For example, drug dissolution may be enhanced if the drug is administered in powder form, or if the drug is embedded, having a first tablet embedded within a second tablet. We have found that multi-drug tablet form may be attenuated. In powder form, the dissolution rate and resulting bioavailability of the drug in the patient's body can be undesirably high and thus not ideal for administration under certain conditions. In the case of embedded multi-drug tablet forms, it was found that the drugs in the first and second tablets do not dissolve together as a result of the second tablet slowing the release of the drug in the first tablet. rice field.

The total amount of elagolix contained in the first capsule or the second capsule may be the free acid equivalent of elagolix, preferably administered as the sodium salt. The free acid equivalent of elagolix is 100 milligrams (mg), 150 mg, 200 mg, 250 mg, 300 mg, 400 mg, 450 mg or 500 mg and ranges constructed therefrom, such as from about 100 mg to about 500 mg, from about 150 mg to about 400 mg and from about 175 mg. May be provided as approximately 325 mg. The total amount of estradiol contained in the first capsule is preferably 0.5 mg, 0.75 mg, 1.0 mg, 1.25 mg or 1.5 mg and ranges constructed therefrom, such as about 0.5 mg. can be from about 1.5 mg, from about 0.5 mg to about 1.25 mg, from about 0.75 mg to about 1.5 mg, or from about 0.75 mg to about 1.25 mg. The total base equivalent amount of norethindrone available as norethindrone acetate contained in the first capsule is preferably 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 from about 0.1 mg to about 1.0 mg, from about 0.25 mg to about 0.75 mg, or from about 0.4 mg to about 0.6 mg.

Tablets within the scope of this disclosure include, but are not limited to, active drug and one of binders, fillers, disintegrants, surfactants, potency/bioavailability enhancers, glidants and lubricants. Contains the above excipients.

Binders serve to increase the cohesiveness and cohesiveness of granules and tablets and improve their hardness. Some non-limiting examples of binders include pregelatinized starch, hydroxypropylcellulose, methylcellulose, hydroxypropylmethylcellulose, copovidone, povidone, crospovidone and combinations. Other examples include polyethylene glycol, polyvinylpyrrolidone and polyvinyl alcohol. In some aspects, the binder is copovidone, povidone, HMP, pregelatinized starch, and combinations thereof. In some further aspects, the binding agent is copovidone.

Fillers that may be used include non-limiting examples such as sugars and sugar alcohols, cellulosic materials and other fillers. Non-limiting examples of suitable sugars and sugar alcohols include dextrates, dextrin, dextrose, lactose, maltodextrin, mannitol, isomalt, sorbitol, sucrose, sugar spheres, xylitol, fructose, lactitol, erythritol, maltitol, xylose, Includes glucose, mannose, galactose, maltose, cellobiose, trehalose and raffinose. Non-limiting examples of cellulosic materials include microcrystalline cellulose (“MCC”) and silicified MCC. Non-limiting examples of other fillers are calcium carbonate, calcium sulfate, calcium silicate, chitin, chitosan, dicalcium phosphate dihydrate, glyceryl palmitostearate, hydrogenated vegetable oils, kaolin, aluminum silicate. Contains magnesium, magnesium carbonate, magnesium oxide, polymethacrylate, potassium chloride, powdered cellulose, pregelatinized starch, sodium chloride, starch, talc, and dibasic and tribasic calcium phosphates. Combinations of the above listed fillers are within the scope of this disclosure.

Disintegrants that may be used include, but are not limited to, modified starches such as sodium carboxymethyl starch (sodium starch glycolate); cross-linked polyvinylpyrrolidone such as crospovidone; modified celluloses such as croscarmellose sodium; crosslinked alginic acid; gums such as gellan gum and xanthan gum; calcium silicate; and combinations thereof.

Surfactants may serve to increase the concentration of the drug and/or increase the wettability of the drug/formulation at the diffusion layer formed at the interface of the drug surface and the aqueous medium after administration. Non-limiting examples of surfactants include vitamin E d-alpha tocopheryl polyethylene glycol succinate, sodium dodecyl sulfate, polysorbates, poloxamers, Tween® types and combinations thereof.

Lubricants that may be used include non-limiting examples such as magnesium stearate, calcium stearate, stearic acid, sodium stearyl fumarate, hydrogenated vegetable oils, polyethylene glycol (4000-6000), sodium lauryl sulfate and combinations thereof. include.

Glidants that may be used include non-limiting examples such as colloidal silicon dioxide (eg, highly dispersed silica (Aerosil®)), animal or vegetable fats, waxes, and combinations thereof.

Other excipients that may be present include acidifying or alkalinizing agents. Acidifying agents can be organic acids such as, but not limited to, fumaric acid, citric acid and tartaric acid for pH adjustment and/or control after administration.

The excipients in the tablet and the weight/weight concentration, or ratio of active agent to excipient, are selected to increase drug solubility in aqueous media (e.g., stomach and/or intestines), thereby reducing dissolution. Speed and bioavailability can be improved. Furthermore, in the case of co-administration of a first tablet with a first drug and a second tablet with a second drug, the excipients and weight-to-weight concentration or the excipients of the active agent The ratio can also be selected to increase drug bioavailability and to minimize any interaction between the first and second tablets that can adversely affect drug bioavailability.

Tablets of the present disclosure may be formed using pharmaceutical operations such as, but not limited to, screening, blending, dry granulation, compression and, optionally, film coating. In some aspects, the excipients can be blended, the blend can be roller compacted and milled, and the resulting material can be compressed into tablets on tableting equipment known in the art. In some such embodiments, the roller-compacted, milled material may be referred to as "intragranular", said material then being subjected to one or more additional excipients as described above prior to tabletting. It can be blended with excipients. One or more additional excipients may be present as an "extragranular" component in the tablet.

Uncoated tablets (eg, tablet cores) of the present disclosure may optionally be coated with a film coating to obtain tablets that are largely tasteless and odorless and are easy to swallow. Additionally, the film coating prevents dust formation during packaging and ensures robustness during shipping. Commercial coating compositions are suitable for the purposes of this disclosure and include Opadry® YS-1-7003, Opadry® YS-1-18202 and Opadry® II White 85F18422, but not limited to them.

A tablet containing elagolix sodium is marketed as Orilissa®. The manufacture of ellagoryx of different strengths is described in AbbVie Inc applications US201900540088 and US20190054027, both of which are incorporated by reference in their entireties. Other manufacturers also provide various productions of Elagolix active ingredients and Elagolix-containing drugs, as described in applications WO2017/221144, WO2018/189213 and WO2018/224063. Tablets containing various strengths of E2/NETA are marketed as Activella®.

Referring now to the Figures, FIG. 1 is an illustration of an exemplary multi-drug delivery system 100 including a first capsule 102 and a second capsule 104 of drug. The first capsule 102 includes a first capsule body 106 including a first body portion 108 and a first cap portion 110, and the second capsule 104 includes a second body portion 114 and a second cap portion 114. It includes a second capsule body 112 including a cap portion 116 . In an exemplary embodiment, the first capsule 102 is marked with a first identifier 118 and the second capsule 104 is marked with a second identifier 120 that differs from the first identifier 118 to provide a patient-friendly , facilitates making the first capsule 102 and the second capsule 104 visually distinguishable from each other. First capsule 102 and second capsule 104 may include any suitable identifier that enables multi-drug delivery system 100 to work as described herein. Identifiers may include, but are not limited to, shades, colors, symbolic markings and/or textual markings.

For example, in the exemplary embodiment, a first color 122 (illustrated by the first pattern) is included on the first capsule 102 and a second color 124 (illustrated by the second pattern) is included on the first capsule. ) is contained on the second capsule 104 . More specifically, first cap portion 110 is a first color 122 and second cap portion 116 is a second color 124 . First color 122 is different from second color 124 . Thus, first cap portion 110 is visually distinguishable from first body portion 108, second body portion 114, and second cap portion 116, and second cap portion 116 is similar to first cap portion 116. It is visually distinguishable from 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 the respective capsule is intended to be administered. For example, in the exemplary embodiment, first identifier 118 includes first character markings 126 and second identifier 120 includes second character markings 128 . A first letter marking 126 is configured to indicate that the first capsule 102 is intended for administration within a first time frame of a day, and a second letter marking 128 is configured to indicate a second Capsule 104 is configured to indicate that it is intended for administration within a second timeframe of the day, different than the first timeframe. More specifically, a first letter marking 126 (“AM”) indicates that the first capsule 102 is intended for morning administration, and a second letter marking 128 (“PM”). indicates that the second capsule 104 is intended for afternoon administration. As described in more detail below, first capsule 102 and second capsule 104 may contain different types of drugs. Accordingly, the first letter marking 126 and the second letter marking 128 facilitate quick and easy identification and compliance with dosing instructions of the capsule.

FIG. 2 is a cross-sectional view of an example of a first capsule 102 that may be used in multi-drug delivery system 100 (shown in FIG. 1), and FIG. 102 is a cross-sectional view of an additional first capsule 102 that may be used.

FIG. 3 is a cross-sectional view of an exemplary second capsule 104 that may be used in multi-drug delivery system 100 (shown in FIG. 1). In the exemplary embodiment, the second capsule body 112 includes a second interior 140 that is sized to receive at least one first tablet 132 therein. Although illustrated to house a single first tablet 132, within the second interior 140 that enables the multi-drug delivery system 100 to work as described herein, It should be appreciated that any number of first tablets 132 may be included. Second capsule body 112 includes a second body portion 114 and a second cap portion 116 . Second body portion 114 includes an open end 142 that is sized to permit insertion of first tablet 132 therethrough. After insertion of the first tablet 132 into the second body portion 114 , the second cap portion 116 engages the two body portions 114 to enclose the open end 142 and the second interior 140 . Can be defined and sealed.

First capsule body 106 (shown in FIGS. 2 and 3) and second capsule body 112 enable multi-drug delivery system 100 to operate as described herein. can be made from any material that Exemplary 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 hydroxypropyl methylcellulose. The first capsule body 106 and the second capsule body 112 may further be prepared with coatings that facilitate swallowing, provide taste barriers, or provide other functions.

As noted above, the first capsule 102 and the second capsule 104 are each different in that the first capsule 102 and the second capsule 104 are intended for administration at different times of the day. It may contain drugs or different combinations of drugs. Thus, the second capsule 104 contains only the first tablet 132 therein and does not contain the second tablet 134 therein.

FIG. 17 is a perspective view of an exemplary package 144 that can be used to contain and carry multi-drug delivery system 100 (shown in FIG. 1). In the exemplary embodiment, package 144 includes a carton 146 and a blister card 148 located within carton 146 . Carton 146 includes a first wall 150 having a contact opening 152 defined therein. The contact openings 152 represent a plurality of compartments of the blister card 148 and, more particularly, a plurality of compartments of the blister card 148 each configured to receive an individual first capsule 102 or second capsule 104 therein. It is sized to touch 154. Thus, a plurality of first capsules 102 and a plurality of second capsules 104 are contained within package 144 . In one embodiment, the number of first capsules 102 and the number of second capsules 104 contained within package 144 in compartment 154 are each a multiple of the number of days in a week (eg, 7, 14 or 21) and each compartment 154 or group of compartments 154 is labeled according to each day of the week. In addition, first wall 150 includes information markings 156 thereon, which may be symbols or letter markings that readily distinguish capsules 102 and 104 from each other. Informational markings 156 are printed on package 144 and contain information relating to when to administer first capsule 102 and second capsule 104 to the patient. Thus, including compartments 154 as multiples of the number of days in a week and including informational markings 156 on first wall 150 in package 144 facilitates patient compliance with dosing instructions.

The present invention provides (a) 300 mg free acid equivalent of elagolix administered twice daily; (b) 1 mg estradiol administered once daily; and (c) 0.5 mg administered once daily. of norethindrone acetate. Table A7 shows 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 present invention further includes average peak concentration Cmax and average area under the curve, AUCτ, ie, 80% to 125% of Cmax or AUCτ shown in Table A7. Thus, the average peak concentration, Cmax, for said ellagorix is about 80% to about 125% of 1200±45% ng/mL or about 528 to 2175 ng/mL. The mean peak concentration, Cmax, for the estradiol is about 80% to about 125% of 0.06±52% ng/ml or 0.023 to 0.114 ng/mL. The mean peak concentration, Cmax, for norethindrone acetate is about 80% to about 125% of 6.1±35% ng/ml or 3.172 to 10.294 ng/mL. Furthermore, the mean area under the curve, AUCτ, for the ellagoryx was 2826±44% ng. about 80% to about 125% of hr/mL or 1266.0 to 5086.8 ng. hr/mL. The mean area under the curve, AUCτ, for the estradiol was 0.86±38% ng. about 80% to about 125% of hr/mL or 0.4266 to 1.4835 ng. hr/mL. The mean area under the curve, AUCτ, for norethindrone acetate was 23.8±48% ng. about 80% to about 125% of hr/mL or 9.90 to 44.03 ng. hr/mL.

The present invention provides (a) 300 mg free acid equivalent of elagolix administered twice daily, (b) 1 mg estradiol administered once daily; and (c) 0.5 mg administered once daily. of norethindrone acetate. Table A7 shows 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 present invention further includes average peak concentration Cmax and average area under the curve, AUCτ, ie, 80% to 125% of Cmax, AUCτ shown in Table A7. Thus, the average peak concentration, Cmax, for said ellagorix is about 80% to about 125% of 1200 ng/mL or about 960-1500 ng/mL. The average peak concentration, Cmax, for the estradiol is about 80% to about 125% of 0.06 ng/ml or 0.048 to 0.075 ng/mL. The mean peak concentration, Cmax, for norethindrone acetate is about 80% to about 125% of 6.1 ng/ml or 4.88 to 7.625 ng/mL. Furthermore, the mean area under the curve, AUCτ, for the Elagoryx was 2826 ng. about 80% to about 125% of hr/mL or 2260.8 to 3532.5 ng. hr/mL. The mean area under the curve, AUCτ, for the estradiol was 0.86 ng. from about 80% to about 125% of hr/mL or from 0.688 to 1.075 ng. hr/mL. The mean area under the curve, AUCτ, for norethindrone acetate was 23.8 ng. about 80% to about 125% of hr/mL or 19.04 to 29.75 ng. hr/mL.

The present invention provides (a) 300 mg free acid equivalent of elagolix administered twice daily, (b) 1 mg estradiol administered once daily, and (c) 0.5 mg administered once daily. of norethindrone acetate. Table A7 shows 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 present invention further includes average peak concentration Cmax and average area under the curve, AUCτ, ie, 80% to 125% of Cmax, AUCτ shown in Table A7. Thus, the average peak concentration, Cmax, for said ellagorix is about 80% to about 125% of 629-1770 ng/mL or about 503-2212.5 ng/mL. The average peak concentration, Cmax, for the estradiol is about 80% to about 125% of 0.053 to 0.062 ng/ml or 0.0424 to 0.0775 ng/mL. The mean peak concentration, Cmax, for norethindrone acetate is about 80% to about 125% of 5.7-6.4 ng/ml or 4.56-8.0 ng/mL. Furthermore, the mean area under the curve, AUCτ, for the ellagoryx ranged from 1534 to 4118 ng. about 80% to about 125% of hr/mL or 1227.2 to 5147.5 ng. hr/mL. The mean area under the curve, AUCτ, for the estradiol ranged from 0.81 to 0.91 ng. about 80% to about 125% of hr/mL or 0.688 to 1.1375 ng. hr/mL. The mean area under the curve, AUCτ, for norethindrone acetate ranged from 22 to 26.3 ng. about 80% to about 125% of hr/mL or 17.6 to 33.125 ng. hr/mL.

In some examples, the invention provides an oral multi-drug capsule composition comprising (a) 300 mg free acid equivalents of elagolix, (b) 1 mg estradiol, and (c) 0.5 mg norethindrone acetate. do.

When the composition is administered to healthy adult subjects as depicted in Table 7(d), the steady-state concentration Cmax _ss for said Elagolix of about 503-2212.5 ng/mL, from about 0.0424 mean peak concentration Cmax for said estradiol of 0.0775 ng/mL ng/ml, mean peak concentration Cmax for said norethindrone acetate of about 4.56-8.0 ng/ml, about 1227.2-5147.5 ng. hr/mL mean area under the curve (AUCτ) for the Elagolix, about 0.0.688-1.1375 ng. hr/mL of mean area under the curve AUC(t) for the estradiol, and from about 17.6 to 33.125 ng. An AUC(t) for the norethindrone acetate of hr/mL is produced. In another embodiment, a mean peak concentration Cmax for said Elagolix of about 1218.4-2185 ng/mL when the composition is administered to a healthy adult subject as depicted in Table 7(d); 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, about 3293.6-5892.5 ng. hr/mL mean area under the curve (AUC(t)) for the Elagolix, approximately 0.0.688-1.1375 ng. hr/mL of AUC(t) for the estradiol, and about 17.6-33.125 ng. An AUC(t) for the norethindrone acetate of hr/mL is produced.

In another embodiment, the present invention provides an oral multi-drug capsule composition comprising (a) 300 mg free acid equivalents of elagolix, (b) 1 mg estradiol, and (c) 0.5 mg norethindrone acetate. do. When the composition is administered to healthy adult subjects according to Table A7(c) or Table A7(d), the mean steady state concentration, Cmax _ss , for said ellagorix of about 503-2212.5 ng/mL, about A mean peak concentration Cmax for the estradiol of 0.0424-0.0775 ng/mL and a mean peak concentration Cmax for the norethindrone acetate of about 4.56-8.0 ng/ml results.

In one example, the oral multiple drug capsule composition contains about 1227.2-5147.5 ng. hr/mL of area under the steady-state curve for the Elagolix, AUCτ, about 0.0.688-1.1375 ng. hr/mL of AUCτ for the estradiol, and about 17.6-33.125 ng. It has an AUCτ for the norethindrone acetate of hr/mL.

In another embodiment, the present invention provides an oral multi-drug capsule composition comprising (a) 300 mg free acid equivalents of elagolix, (b) 1 mg estradiol, and (c) 0.5 mg norethindrone acetate. do. When the composition is administered to healthy adult subjects according to Table A7(c) or Table A7(d), the mean peak concentration, Cmax, for said ellagorix of about 1218.4-2185 ng/mL, about 0.5 ng/mL. A mean peak concentration Cmax for the estradiol of 0424-0.0775 ng/ml and a mean peak concentration Cmax for the norethindrone acetate of about 4.56-8.0 ng/ml occur.

In one example, the oral multiple drug capsule composition contains about 3293.6-5892.5 ng. hr/mL mean area under the curve for the Elagolix, AUC(t), about 0.0.688-1.1375 ng. hr/mL of AUC(t) for the estradiol, and about 17.6-33.125 ng. It has an AUC(t) for the norethindrone acetate of hr/mL.

In another embodiment, the present invention provides an oral multi-drug capsule composition comprising (a) 300 mg free acid equivalents of elagolix, (b) 1 mg estradiol, and (c) 0.5 mg norethindrone acetate. and, in addition, about 1227.2 to 5147.5 ng.o in healthy adult subjects when the compositions are administered as shown in Tables A7(c) and A7(d). hr/mL mean area under the curve for the Elagolix, AUCτ, about 0.0.688-1.1375 ng. hr/mL of AUCτ for the estradiol, and about 17.6-33.125 ng. An AUCτ for the norethindrone acetate of hr/mL is produced.

In another example, the oral multi-drug capsule composition has a steady state peak concentration, Cmax _ss , for said Elagolix of about 503-2212.5 ng/mL, of about 0.0424-0.0775 ng/mL ng/ml , yielding a mean peak concentration, Cmax _ss , for the estradiol, and a mean peak concentration, Cmax _ss , for the norethindrone acetate of about 4.56-8.0 ng/ml.

In another embodiment, the present invention provides an oral multi-drug capsule composition comprising (a) 300 mg free acid equivalents of elagolix, (b) 1 mg estradiol, and (c) 0.5 mg norethindrone acetate. and, in addition, about 3293.6 to 5892.5 ng.o in healthy adult subjects when the compositions are administered as shown in Tables A7(c) and A7(d). hr/mL mean area under the curve for the Elagolix, AUC(t), about 0.0.688-1.1375 ng. hr/mL of AUC(t) for the estradiol, and about 17.6-33.125 ng. An AUC(t) for the norethindrone acetate of hr/mL is produced.

In another example, the oral multi-drug capsule composition provides an average peak concentration, Cmax, of about 0.0424-0.0775 ng/mL for said Elagolix of about 1218.4-2185 ng/mL; A mean peak concentration, Cmax, for estradiol and a mean peak concentration, Cmax for the norethindrone acetate of about 4.56-8.0 ng/ml occur.

In another aspect, the oral multi-drug capsule composition comprises 300 mg of free acid equivalents of elagolix administered twice daily, 1 mg of estradiol administered once daily, and 0 mg of estradiol administered once daily. The results of administering a composition containing .5 mg norethidrone acetate to healthy subjects are shown in Table A7(a) or Table A7(b). This administration produced a steady state concentration, Cmax _ss , for the elagolix of about 528-2175 ng/mL and a mean peak concentration, Cmax, for the estradiol of about 0.023-0.114 ng/mL, about 3.172-10. The mean peak concentration for said norethindrone acetate of 294 ng/ml, Cmax, about 1266.0-5086.8 ng. hr/ml mean area under the curve for the ellagorix, AUCτ, about 0.4266-1.4835 ng. hr/mL mean area under the curve for the estradiol, AUCτ, and about 9.90-44.03 ng. Mean area under the curve, AUCτ, for the norethindrone acetate in hr/mL.

In another aspect, the oral multi-drug capsule composition comprises 300 mg of free acid equivalents of elagolix administered twice daily, 1 mg of estradiol administered once daily, and 0 mg of estradiol administered once daily. .5 mg norethidrone acetate, and further administration of the composition to healthy subjects resulted in a mean steady-state concentration, Cmax _ss , for said ellagorix of about 960-1500 ng/mL, of about 0.048-0.075 ng/mL. , the mean peak concentration for the estradiol, Cmax _ss , about 4.88-7.625 ng/ml, the mean peak concentration for the norethindrone acetate, Cmax _ss , about 2260.8-3532.5 ng/ml. hr/ml mean area under the curve for the Elagolix, AUCτ, about 0.688-1.075 ng. hr/mL mean area under the curve for the estradiol, AUCτ, and about 19.04-29.75 ng. An average area under the curve, AUCτ, for the norethindrone acetate in hr/mL is produced.

In one example, an oral multi-drug capsule contains about 1266.0-5086.8 ng. hr/mL mean area under the curve for the Elagolix, AUCτ, about 0.4266-1.4835 ng. hr/mL mean area under the curve for the estradiol, AUCτ, and about 9.90-44.03 1.4835 ng. It may have an average area under the curve, AUCτ, for said norethindrone acetate in hr/mL.

In another aspect, the oral multi-drug capsule composition comprises 300 mg of free acid equivalents of elagolix administered twice daily, 1 mg of estradiol administered once daily, and 0 mg of estradiol administered once daily. .5 mg of norethindrone acetate, and further administration of the composition to healthy adult subjects produced approximately 0.4266-1.4835 ng. hr/mL mean area under the curve for the estradiol, AUCτ, and about 9.90-44.03 ng. An average area under the curve, AUCτ, for the norethindrone acetate in hr/mL is produced.

In one example, administration of a multi-drug capsule composition to healthy adult subjects resulted in a mean steady state concentration, Cmax _ss , for said Elagolix of about 528-2175 ng/mL, of about 0.023-0.114 ng/mL. _{. _}

In one example, (a) 300 mg free acid equivalent of elagolix administered twice daily; (b) 1 mg estradiol administered once daily; and (c) 0.5 mg elagolix administered once daily. Using USP Apparatus 2 at 50 rpm, pH 6.8 and 37.5±0.5° C. with norethindrone acetate, at least 75% of the first drug in the first tablet is dissolved after 60 minutes; An oral multi-drug capsule composition is provided wherein at least 70% of the second and third drugs in two tablets dissolve after 30 minutes.

In one example, (a) 200 mg free acid equivalent of elagolix administered twice daily, (b) 1 mg estradiol administered once daily, and (c) 0.5 mg Using USP Apparatus 2 at 50 rpm, pH 6.8 and 37.5±0.5° C. with norethindrone acetate, at least 75% of the first drug in the first tablet is dissolved after 60 minutes; An oral multi-drug capsule composition is provided wherein at least 70% of the second and third drugs in two tablets dissolve after 30 minutes.

In another aspect, the oral multi-drug capsule composition comprises 300 mg free acid equivalents of elagolix, 1 mg estradiol, and 0.5 mg norethindrone acetate, wherein a single dose of the composition is administered to a healthy adult subject. after administration, 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; Mean peak concentration (Cmax) for said norethindrone acetate from about 4.56 ng/mL to about 8.0 ng/mL, about 3293.6 ng. hr/mL to about 5892.5 ng. hr/mL mean area under the curve (AUC _(t) ) for the Elagolix, about 0.688 ng. hr/mL to about 1.1375 ng. hr/mL of mean area under the curve (AUC _(t) ) for the estradiol, and about 17.6 ng. hr/mL to about 33.125 ng. An average area under the curve (AUC _(t) ) for the norethindrone acetate of hr/mL is produced.

In another aspect, the multi-drug capsule composition comprises 300 mg free acid equivalents of elagolix, 1 mg estradiol, and 0.5 mg norethindrone acetate for administration of a single dose of the composition to a healthy adult subject. a mean peak concentration, Cmax, for said ellagorix of about 1218.4 ng/ml to about 2185 ng/ml; A mean peak concentration, Cmax, for the norethindrone acetate of 4.56 ng/ml to about 8.0 ng/ml results.

In one example, the multi-drug composition contains about 3296.6 ng. hr/mL to about 5892.5 ng. hr/mL mean area under the curve for the Elagolix, AUC _(t) , about 0.688 ng. hr/mL to about 1.1375 ng. hr/mL mean area under the curve for the estradiol, AUC _(t) , and about 17.6 ng. hr/mL to about 33.125 ng. It has an average area under the curve, AUC _(t) , for the norethindrone acetate of hr/mL.

In one aspect, the multi-drug capsule composition comprises 300 mg free acid equivalents of elagolix, 1 mg estradiol, and 0.5 mg norethindrone acetate by administration of a single dose of the composition to a healthy adult subject. , about 3293.6 ng. hr/mL to about 5892.5 ng. hr/mL mean area under the curve for the Elagolix, AUC _(t) , about 0.0.688 ng. hr/mL to about 1.1375 ng. hr/mL mean area under the curve for the estradiol, AUC _(t) , and about 17.6 ng. hr/mL to about 33.125 ng. An average area under the curve, AUC _(t) , for the norethindrone acetate in hr/mL is generated.

In one example, administration of a multi-drug capsule to healthy adult subjects resulted in about 1218.4 ng/mL to about 2185 ng. hr/mL mean peak concentration for the ellagorix, Cmax, about 0.0424 ng. hr/mL to about 0.0775 ng/mL ng/ml mean peak concentration for the estradiol, Cmax, and about 4.56 ng. An average peak concentration, Cmax, for the norethindrone acetate of hr/mL to about 8.0 ng/ml occurs.

In another aspect, the oral multi-drug capsule composition comprises 300 mg free acid equivalent elagolix, 1 mg estradiol, and 0.5 mg norethindrone acetate at 50 rpm, pH 6.8 and 37.5±0.5 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 dissolves after 30 minutes using USP Apparatus 2 at °C. Dissolves after minutes.

The present invention further provides oral multi-drug capsule compositions that are bioequivalent to any of the multi-drug capsules described herein.

In another aspect, the oral multi-drug capsule composition has a free acid equivalent of 300 mg, which can be useful for reducing the volume of uterine fibroids prior to surgery to remove them (preoperatively). elagolix, 1 mg free acid equivalent estradiol, and 0.5 mg free acid equivalent norethindrone acetate.

In another aspect, estradiol and norethindrone acetate therapy plus a dose of elagolix may be useful for treating pain associated with endometriosis. For example, in one embodiment, 200 mg free acid equivalent elagolix added to 1 mg free acid equivalent estradiol and 0.5 mg free acid equivalent norethindrone may be useful for treating pain associated with endometriosis. .

In another aspect, a method of treating heavy menstrual bleeding associated with uterine leiomyoma (fibroids) is a method of treating uterine leiomyoma in capsules comprising 300 mg free acid equivalents of elagolix, 1 mg estradiol, and 0.5 mg norethindrone acetate. (fibroids) to an adult female patient suffering from fibroids once daily oral administration, according to the method, about 1218.4 ng. mean Cmax for elagolix from about 0.0424 ng/mL to about 0.0775 ng/mL; for norethindrone acetate from about 4.56 ng/mL to about 8.0 ng/mL; , about 3293.6 ng. hr/mL to about 5892.5 ng. hr/mL for Elagolix; about 0.0.688 ng. hr/mL to about 1.1375 ng. hr/mL of estradiol; and about 17.6 ng. hr/mL to about 33.125 ng. Mean AUC(t) for hr/mL norethindrone acetate is produced.

[Example 1]
Estradiol (E2) and norethindrone (NETA) tablet compression overcoat with elagolix. It is shown in FIG. 4A.

Elagolix/E2/NETA tablets 400 were prepared by coating commercially supplied E2/NETA tablets 403 with a compression coating using Elagolix granules 401 as shown in FIG. 4A. The composition of tablet 400 is shown in Table 1, the composition of granules in Table 2, and the processing steps in FIG.

[Example 2]
Elagolix tablets containing E2/NETA tablets. It is shown in FIG. 4B.

Elagolix/E2/NETA tablets were prepared according to the process steps shown in FIG. Tablets 410 of Example 2 were prepared by first loading the final blend and then placing Activella® tablets 403 on the surface of the powder bed followed by hand compression. The composition of tablet 410 is shown in Table 4 and tablet 410 is shown in FIG. 4B.

[Example 3]
Elagolix and E2/NETA bilayer tablets. It is shown in FIG.

A bilayer tablet 500 consisting of Elagolix 501 and E2/NETA layer 503 shown in Figure 3 was prepared using the following example.

[Example 3-1]
Elagolix/E2/NETA tablets 500 were prepared according to the processing steps shown in FIG. 11A.

(Tablet composition is shown in Table 6.

[Example 3-2]
Elagolix/E2/NETA tablets 500 were prepared according to the process steps shown in FIG. 11B.

The composition of tablet 500 is shown in Table 7.

[Example 3-3]
Elagolix/E2/NETA tablets 500 were prepared according to the processing steps shown in FIG. 11C.

The composition of tablet 500 is shown in Table 8.

[Example 3-4]
Elagolix/E2/NETA tablets were prepared according to the processing steps shown in FIG. 11D.

The tablet composition is shown in Table 9.

[Example 4]
Elagolix tablet with E2/NETA overcoat. It is shown in FIG.

Elagolix/E2/NETA tablets were prepared by coating Elagolix Tablet 601 using the layering of the E2/NETA formulation shown in FIG. Elagolix Tablets 601 were first compressed on a tablet press at a target tablet weight of 352.7 mg using the final blend described in Example 3-1. Tablets were prepared using the process steps shown in FIG. The composition of tablet 600 is shown in Table 9.

[Example 5]
Elagolix and E2/NETA bilayer tablets. It is shown in FIG.

The bilayer tablet consisted of one layer of Elagolix formulation 701 and a rapid disintegration layer 705 with embedded E2/NETA tablets 703, as shown in Figure 7, for dissolution testing. prepared. The composition of each layer is shown in Table 10 and was prepared according to the processing steps shown in FIG.

Further barrel temperature settings are shown in Table 11.

Rapidly disintegrating layer 705 contains a commercially supplied excipient complex of Prosolv EASYtab (JRS Pharma) and one commercially supplied E2/NETA tablet 703 (Breckenridge Pharmaceutical Inc.). The bilayer tablets 700 were individually packed by successively packing (1) 80 mg EASYtab, (2) one E2/NETA tablet, (3) 80 mg EASYtab and (3) 529 mg Elagolix granules into the die of a tooling A2310. prepared and subsequently compressed into final tablets.

[Example 6]
Elagolix and E2/NETA Capsules. shown in FIG.

The capsule of Example 6 shown in FIG. 2 has a format that is easy for the patient to swallow and simple to manufacture. Capsules were prepared according to the process steps shown in FIG. This formulation allows desirable co-administration of ellagorix/E2/NETA, which in turn provides a desirable balance of therapeutic and safety effects of ellagorix, E2 and NETA. Exogenous addition of GnRH antagonists, such as elagolix, modulates hormones that can produce certain adverse effects. These adverse effects can be effectively offset by administration at appropriate dosages and formulations of E2/NETA with elagolix so that patients are not adversely affected by competitive antagonism of elagolix administration. The composition of this capsule is shown in Table 12. By using preformed E2/NETA tablets 134 in the capsules of Example 6, additional handling of the estradiol (E2) hormone is avoided.

[Example 7]
Elagolix tablets in capsule form. It is shown in FIG.

Elagolix granules were manufactured as previously described (see Example 1). Additionally, capsules were prepared according to the process steps shown in FIG.

[Example 8]
Elagolix melt granules and E2/NETA tablets in capsules. It is shown in FIG.

Capsules 900 containing Elagolix melt granules 901 and E2/NETA tablets 903 were prepared according to the processing steps shown in FIG. Example 6 and one E2/NETA tablet (Activella®) 903 in size 00 capsule 901, as shown in Figure 9, for dissolution testing. Capsule 900 may contain air or any other suitable filler in interior space 910 . In some examples, Elagolix melt granules 901 and E2/NETA tablets 903 may be mixed/put together in capsule 900 .

[Example 9A]
Dissolution Testing of Examples 1-8 The gelling nature of amorphous elagolix creates unpredictability in formulations containing both elagolix and E2/NETA. It is unclear how ellagorix interacts with E2/NETA in the presence of anti-gelling agents such as sodium carbonate.

In vitro dissolution of Elagolix dosage forms for Examples 1-8 was tested using USP Apparatus 2 at 50 rpm in 900 mL of 0.05 M pH 6.8 phosphate buffer at 37.5±0.5° C. Shown in Tables 15-25. The filtrate was analyzed by HPLC. Elagoryx, E2 and NETA were determined by multiple wavelength detectors at 310, 220 or 241 nm, respectively.

[Example 9B]
Dissolution Test for Example 6 In vitro dissolution of the Elagolix dosage form for Example 6 was performed using USP Apparatus 1 with 900 mL of 0.05 M sodium phosphate buffer, pH 6.8, maintained at 37° C., at 100 rpm. and tested. The indicated dissolution release was measured and the release at various time intervals is shown in Table 26, Figures 29A (Elagolix release), 29B (E2 release) and 29C (NETA release). The filtrate was analyzed by HPLC. Elagoryx, E2 and NETA were determined by multiple wavelength detectors at 310, 220 or 241 nm, respectively.

[Example 10]
Dosage Forms and Administration Drug delivery system 100 includes a morning capsule 102 labeled “AM” 126 . Capsule 102 is white and yellow and contains an additional identifying mark "EL300." Capsule 102 contains about 300 mg elagolix, about 1 mg estradiol and about 0.5 mg norethindrone acetate. The capsule 104 is labeled "PM" which is white and light blue, and is also labeled "EL300". In some examples, capsule 104 may contain about 300 mg elagolix. Each capsule 102, 104 should be orally administered daily at about the same time each day (eg, take 102 in the morning and take capsule 104 in the evening). In one embodiment, each of the capsules can be taken with or without food, and the capsules can be administered daily for about 48 months. In another embodiment, each of the capsules can be taken with or without food, and the capsules can be administered daily for about 60 months. In another embodiment, each of the capsules can be taken with or without food, and the capsules can be administered daily for about 72 months. In another embodiment, each of the capsules can be taken with or without food and the capsules are about 6 months, about 12 months, about 12-24 months, about 24-36 months, about It can be administered daily for 36-48 months, about 48-60 months, or about 60-72 months. The duration of treatment can be extended based on assessment of bone mineral loss or any other adverse effect, e.g., if a woman has been treated for a duration of 24 months and continues to have a positive benefit-risk profile, treatment The duration of can extend to 36 months or more. Bone mineral loss may be assessed using any suitable method, including radiographic techniques, such as DXA scans, for continued treatment. If a patient misses a dose, the patient should be instructed to take the missing dose within 4 hours of the time the dose was supposed to be taken, followed by the next dose at the usual time. can be taken. However, if more than 4 hours have passed since the missing dose was taken as usual, the patient should not take the missing dose and should take the next dose at the usual time. Only one capsule should be taken in the morning and one in the evening per day.

[Example 11]
Adverse Reactions, Clinical Trial Experiments The safety of the system of Example 10 was assessed in two randomized, double-blind, placebo-controlled studies [UF-1 (NCT02654054) and UF-2 (NCT02691494)], here , 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 treatment arm to characterize the impact on safety and efficacy of estradiol/norethindrone acetate (E2/NETA). Women who completed a 6-month treatment period with UF-1 or UF-2 and met the inclusion criteria will receive Elagolix or Elagolix 300 mg twice daily for the entire treatment duration up to 12 months, uncontrolled A blinded 6-month extension study [UF-EXTEND (NCT02925494)] was entered.

Common Adverse Reactions In UF-1 and UF-2, the most commonly reported adverse reactions (at least 10% incidence) in women treated with the system of Example 10 were hot flashes and/or night sweats ( See Table A1). In UF-1 and UF-2, 9.6% (n=38) of women treated with elagolix and 6.6% (n=13) of women receiving placebo discontinued treatment due to any adverse event There has occurred. Adverse reactions reported in >5% of women receiving the system of Example 10 and more frequent than placebo are shown in Table A1.

In studies UF-1 and UF-2, 9.6% (n=38) of women treated with the system of Example 10 and 6.6% (n=13) of women receiving placebo had any adverse effects. Discontinuation of treatment due to a reaction occurred.

Less Common Adverse Reactions In Studies UF-1 and UF-2, adverse reactions reported at ≧3% and <5% in the Example 10 system group and more frequently than in the placebo group were: Included were decreased libido, joint pain, hypertension, hair loss, mood swings, bloating, menorrhagia, influenza, upper respiratory tract infections, vomiting and weight gain. The most commonly reported adverse reactions in the extension trial (Study UF-EXTEND) were similar to those in the placebo-controlled trial.

Bone Loss The effect of the system of Example 10 on BMD was evaluated by dual-energy X-ray absorptiometry (DXA). Studies UF-1 and UF-2 showed a significant reduction in BMD in women treated with the system of Example 10 compared to placebo. The mean changes from baseline in lumbar spine BMD at Months 6 and 12 in women who received the system of Example 10 were -0.6% and -1, respectively, compared to women who received placebo. .5% and is presented in Table A2.

In the extension study UF-EXTEND, 12 months of continuous treatment with the system of Example 10, continued bone loss was observed. Proportion of women experiencing greater than 8% BMD reduction in lumbar spine, total hip or femoral neck at 6 months of treatment in Studies UF-1 and UF-2 and at 12 months of treatment in Study UF-EXTEND are presented in Table A3.

To assess recovery, changes in lumbar spine BMD were analyzed over time in women who received continuous treatment with the system of Example 10 for up to 12 months and then another 12 months after treatment cessation. (Fig. 19). After 12 months of resting the system of Example 10, continued bone loss was observed in 24%, 32% and 38% of women in the spine, total hip and femoral neck, respectively. Of these women, all but one showed a <3% reduction in BMD in the lumbar spine, and all showed a <5% reduction in the gluteal region. Complete recovery of bone loss was observed in 31%, 36% and 24% of women with bone loss in the spine, entire hip and femoral neck, respectively, after 12 months of treatment with the system of Example 10. The remaining women showed partial recovery and the time to full recovery in these women is unknown.

Overall, the presence of E2/NETA in the current 300 mg BID ellagorix formulation (system of Example 10) reduces BMD reduction compared to 300 mg BID elagolix alone without E2/NETA.

Worsening of Suicidal Idea, Suicidal Behavior and Mood Disorders In placebo-controlled trials (studies UF-1 and UF2), the system of Example 10 was associated with adverse mood changes. Depression, depressed mood and/or tearfulness were reported in 3% of women receiving the Example 10 system compared to 1% in the placebo group.

Hepatic Transaminase Elevation In studies UF-1 and UF-2, 1.1% (4/379) of women who received the system of Example 10 and 2.2% (4/379) of women who received Elagolix 300 mg twice daily ( 4/184), subclinical serum ALT elevations occurred to at least 3 times the upper limit of the reference interval (ULN) and were not observed in placebo-naive women. Elevations in ALT were reported up to 8-fold over ULN. No concomitant elevation of bilirubin was reported.

Changes in Lipid Parameters Elevations in total cholesterol, low-density lipoprotein cholesterol (LDL-C), serum triglycerides and apolipoprotein B were recorded during treatment of the system of Example 10 in UF-1 and UF-2. In UF-1 and UF-2, 16.7% and 0% of female subjects with moderately elevated LDL-C at baseline (130-159 mg/dL) were treated with the system of Example 10 and placebo, respectively. During the treatment with which women showed an increase in LDL-C levels greater than or equal to 190 mg/dL, women receiving placebo did not show such an increase in LDL-C. In UF-1 and UF-2, 1.5% and 5.6% of subjects with moderately elevated serum triglycerides (150-300 mg/dL) at baseline were treated with the system of Example 10 and placebo, respectively. It showed an elevation of serum triglycerides to over 500 mg/dL during the treatment used. The highest serum triglyceride concentration measured during treatment with the system of Example 10 was 852 mg/dL. In women who received the system of Example 10, the lipid changes were reversible, with elevated lipid levels returning to near baseline levels within 3 months after cessation of treatment. No cases of pancreatitis were reported in clinical trials.

After 6 months of cessation of treatment with the system of Example 10, 39.0%, 687.8% and 732.9% of women with UF-1 had resumption of menstruation within 1, 2 and 6 months, respectively. and UF-2 by 39.0%, 84.75% and 91.52% of women within 1, 2 and 6 months, respectively. After 12 months of treatment with the system of Example 10 (UF-1 or UF2, then UF-EXTEND), the incidence of amenorrhea during the second 6 months of treatment with UF-EXTEND was systems ranged from 60.0% to 71.6% monthly, and resumption of menstruation was 40.8X%, 79.3X% and 40.8X% in women within 1, 2 and 6 months, respectively, and reported by 89.7X%. It is unknown whether subjects who have not resumed menses are transitioning from the peri-menopausal to the post-menopausal state.

Endometrial Effects Endometrial biopsies were performed at 6 months for UF-1, UF-2 and UF-EXTEND. There were no abnormal biopsy findings, including no endometrial thickening or cancer in women treated with the system of Example 10. Based on ultrasound, treatment of the system of Example 10 in UF-1 and UF-2 resulted in a reduction in mean endometrial thickness from baseline to 6 months (-1.65 mm).

[Example 12]
Drug Interactions Possibility of System of Example 10 Affecting Other Drugs Elagolix is a weak to moderate inducer of cytochrome P450 (CYP) 3A). Co-administration with the system of Example 10 can reduce plasma concentrations of drugs that are substrates of CYP3A. Elagolix is a weak inhibitor of CYP2C19. Co-administration with the system of Example 10 can increase plasma concentrations of drugs that are substrates of CYP2C19 (eg, omeprazole and esomeprazole) (see Table A5)].

Elagolix is an inhibitor of the efflux transporter P-glycoprotein (P-gp). Co-administration with the system of Example 10 can increase plasma concentrations of drugs that are substrates of P-gp, such as digoxin (see Table A5).

Drug Interactions - Examples and Clinical Management Effect of co-administering the system of Example 10 on the concentration of the concomitant drug, and the effect of the concomitant drug on the system of Example 10. Clinical recommendations for these interactions are: , summarized in Table A5.

[Example 13]
Use in Specific Populations Exposure to the system of Example 10 during early 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. When pregnant rats and rabbits were orally administered elagolix during the period of organogenesis, post-implantation loss was observed in pregnant rats at doses 12 times the maximum recommended human dose (MRHD). In rabbits, spontaneous abortions and loss of whole litters were observed at doses 4 and 7 times MRHD. In rats and rabbits, no structural abnormalities were observed in the fetuses at exposures up to 25x and 7x MRHD, respectively.

Human Data Of the 453 women who received the system of Example 10, 1 pregnancy was reported in a Phase 3 uterine fibroids clinical trial. Pregnancy resulted in spontaneous abortion and it was estimated that exposure of the fetus to the system of Example 10 occurred during the first 18 days of pregnancy.

Animal data Embryo-fetal development studies were performed in rats and rabbits. Elagolix at doses of 0, 300, 600 and 1200 mg/kg/day in pregnant rats (25 animals/dose) and 0, 100, 150 and 200 mg/kg/day in rabbits (20 animals/dose). was administered by oral gavage during the period of organogenesis (6-17 gestation days in rats and 7-20 gestation days in rabbits). In rats, all doses exhibited maternal toxicity, which included 6 deaths and decreases in body weight gain and food consumption. An increased post-implantation loss was presented in the mid-dose group that was 12-fold the MRHD-based AUC. In rabbits, 3 spontaneous abortions and 1 full litter loss were observed at the highest non-maternally toxic dose of 7 times the MRHD-based AUC. Loss of one whole litter also occurred at the lower maternal non-toxic dose of 150 mg/kg/day, four times the MRHD. No fetal malformations were exhibited at any dose level tested in either species, even in the presence of maternal toxicity.

At the highest dose tested, the exposure margins were 25 and 7 times MRHD in rats and rabbits, respectively. However, because elagolix binds weakly to the rat gonadotropin-releasing hormone (GnRH) receptor (approximately 1000-fold less than the human GnRH receptor), rat studies do not support pharmacologically mediated effects of elagolix on embryo-fetal development. It is difficult to identify the effect of The rat study is still expected to provide information regarding potential non-target-related effects of ellagorix. In prenatal and postnatal developmental studies in rats, elagolix was given in the diet from day 6 of gestation to day 20 of lactation to achieve doses of 0, 100 and 300 mg/kg/day (25 animals per treatment group). was taken. No evidence of maternal toxicity was observed. At the highest dose, 2 dams showed total litter loss and 1 failed to give birth. The survival rate of pups from birth to 4 days postnatal was reduced. Pups exhibited lower birth weights and at 300 mg/kg/day less weight gain was observed throughout the pre-weaning period. A small effect on body size and startle response is associated with a decrease in pup weight at 300 mg/kg/day. Growth, development and behavioral endpoints in the pre-weaning period were unaffected. At 100 and 300 mg/kg/day (47 and 125 ng/mL), maternal plasma concentrations in 21-day-lactating rats were 0.04 and 0.1 times the maximum elagolix concentration (Cmax) of MRHD in humans. there were. The exposure achieved in rats was much lower than in humans for MRHD, so this study does not predict potentially higher lactational exposures in humans.

Lactation Risk Summary The system of Example 10 is not recommended during lactation. There is limited information regarding the presence of the system of Example 10 in human breast milk, its effect on breastfed infants, or its effect on milk production.

Data No information is available regarding the presence of elagolix or its metabolites in human milk, its effect on breastfed infants, or its effect on milk production. Estrogen administration to lactating women has been shown to reduce the quantity and quality of breast milk. Detectable amounts of estrogen and progestin were found in the breast milk of women who received the combination of estrogen and progestin. Adequate animal data are not available regarding the excretion of Elagolix in breast milk. The incidence and health benefits of breastfeeding depend on the clinical need of the mother for the system of Example 10 and any potential for the system of Example 10 or underlying maternal conditions on the breastfed child. should be considered in conjunction with clinical adverse effects.

[Example 14]
Clinical Pharmacological Mechanism of Action The system of Example 10 combines elagolix, a GnRH receptor antagonist and an exogenous combination of estradiol/norethindrone acetate (E2/NETA), an estrogen and a progestin. Elagolix inhibits endogenous GnRH signaling by competitively binding to GnRH receptors in the pituitary. Estrogens, such as E2, act through binding to nuclear receptors in estrogen-responsive tissues. Progestins, such as NETA, enhance cell differentiation and generally lower estrogen receptor levels, increase local metabolism of estrogen resulting in fewer active metabolites, or dampen the cellular response to estrogen. It interferes with the action of estrogen by inducing gene products. Progestins exert their effects on target cells by binding to specific progesterone receptors that interact with progesterone-responsive elements in target genes.

Pharmacokinetics Effects on gonadotropins and ovarian hormones. Administration of elagolix produces a dose-dependent suppression of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), and causes a decrease in blood levels of ovarian sex hormones, estradiol and progesterone. The E2/NETA component replenishes endogenous estrogen and progesterone. In a Phase 3 trial, LH and FSH were approximately 0.40-0.70 mIU/mL and 1.8-2.5 mIU/mL, respectively, in women with uterine fibroids administered the system of Example 10 for 6 months. , yielded median concentrations of estradiol of approximately 42-51 pg/mL and progesterone of approximately 0.37-0.38 nM.

In a multiple escalating dose study in premenopausal healthy female subjects, 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 rapidly achieved on day 1 within hours after administration of the first dose and lasted for 21 days, with maximal E2 suppression achieved at elagolix doses of 200 mg BID and above. At elagolix doses >100 mg BID, 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 300 mg BID and 200 mg BID doses of Elagolix, respectively. LH and FSH were suppressed compared to placebo, but suppression of LH was more pronounced than that of FSH in all groups except the 150 mg QD group. When elagolix administration was discontinued, LH and FSH levels rose within 24 hours after the last dose and E2 levels began to rise 24 hours after the last dose was administered. The effects of different doses and dosing regimens of elagolix alone or with hormone add-back therapeutic doses of Activella® (E2/norethindrone acetate, 1/0.5 mg) on ovulation, ovarian activity and ovarian reserve It was assessed in an open-label study in healthy adult women.

Suppression of gonadotropins and ovarian hormones was observed in a dose-dependent manner by hormone sampling three times per week during the 3-month treatment phase. Mean E2 levels observed at the 150 mg QD dose were approximately 40-50 pg/mL, consistent with partial E2 suppression. On the other hand, also consistent with previous studies, we observed near-maximal suppression with the 200 mg BID and 300 mg BID regimens, with mean E2 levels of approximately 20-40 pg/mL. However, when said dose of Activella is administered with the elagolix 300 mg BID regimen, the mean E2 levels appear to rise slightly above those observed with the 150 mg QD regimen with the exogenous E2 administration.

Effect on Ovulation In a three-cycle study of the system of Example 10 in healthy women, approximately 10% ovulated.

Cardiac Electrophysiology The effect of elagolix on the QTc interval was assessed in a randomized, placebo- and positive-controlled, open-label, single-dose, cross-over, in-depth QTc study in 48 healthy premenopausal adult women. did. Elagolix concentrations in women given a single dose of 1200 mg were 9-fold higher than those in women who received 300 mg ellagorix twice daily. No clinically relevant QTc interval prolongation was observed.

Pharmacokinetics Pharmacokinetic properties of the system of Example 10 in healthy subjects are summarized in Table A6. Steady-state pharmacokinetic parameters under fasting conditions are summarized in Table A7.

Specific Population Renal Injury Elagolix exposure (Cmax and AUC) was not altered by renal injury. Elagolix mean plasma exposure was similar in 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 E2/NETA pharmacokinetics has not been studied.

Patients with Liver Impairment Elagolix exposure (Cmax and AUC) was similar between women with normal liver function and those with mild liver damage. Elagolix exposures in women with moderate and severe liver damage were approximately 3-fold and 7-fold higher than those in women with normal liver function, respectively. The effect of liver damage on E2/NETA pharmacokinetics has not been studied.

Racial or/Ethnic Populations No clinically significant differences in the pharmacokinetics of Elagolix were observed between Caucasian and Black subjects, or between Hispanics and others. There were no clinically significant differences in the pharmacokinetics of elagolix between Japanese and Han subjects. The effect of race/ethnicity on E2/NETA pharmacokinetics has not been studied.

Body Weight/Body Mass Index 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.

Drug Interaction Studies Drug interaction studies were conducted with Elagolix and other drugs that are susceptible to co-administration and drugs that are commonly used as probes for pharmacokinetic interactions. Tables 8 and 9 summarize the pharmacokinetic effects when elagolix is co-administered with these drugs.

No clinically significant changes in elagolix exposure were observed when elagolix 300 mg was co-administered with rosuvastatin (20 mg once daily), sertraline (25 mg once daily) or fluconazole (200 mg, single dose). it wasn't. The effects of co-administered rosuvastatin, sertraline or fluconazole on E2/NETA have not been studied.

No clinically significant changes in exposure to sertraline, fluconazole, bupropion or transdermal patch E2/NETA 0.51/4.8 mg were observed when co-administered with elagolix 300 mg twice daily.

Pharmacogenomics Disposition Hepatic uptakedate of Elagoricus involves the OATP 1B1 transporter protein. Higher plasma levels of elagolix were observed in a group of patients with reduced two functional alleles of the gene encoding OATP 1B1 (SLCO1B1 521T>C) (these patients had reduced hepatic uptake of elagolix). easier, resulting in higher plasma ellagorix concentrations.). The frequency of this SLCO1B1 521 C/C genotype was generally less than 5% in most racial/ethnic populations. Female patients with this genotype are expected to have approximately 2-fold higher mean ellagorix concentrations compared to females with normal transporter function (ie, SLCO1B1 521T/T genotype). The adverse effects of Elagolix have not been fully evaluated in subjects with reduced two functional alleles of the gene encoding OATP 1B1 (SLCO1B1 521T>C). In one embodiment, in the clinical management of patients with reduced two functional alleles of the gene encoding OATP 1B1 (SLCO1B1 521T>C), the dose of ellagorix achieves an average concentration of ellagorix once daily. Therefore, it can be reduced to about 50% of the original dose. Thus, clinical management of patients with reduced two functional alleles of the gene encoding OATP 1B1 can reduce the dose of ellagorix to half of the original dose, with dosing intervals ranging from twice daily to The dose can be decreased to once daily, or the dosing interval can be decreased from daily administration to every other day administration.

[Example 15]
Nonclinical Toxicology Elagolix From a 2-year carcinogenicity study conducted in mice (50, 150 or 500 mg/kg/day) and rats (150, 300 or 800 mg/kg/day) administered elagolix by the dietary route, AUC It was found that there was no tumor growth in mice up to 11.9 times the MRHD based on . In rats, at high doses (7.7-8.1 times MRHD), an increase was observed in thyroid (males and females) and liver (males only) tumors. Rat tumors were likely species-specific and had negligible relevance to humans. Elagolix has been tested for genotoxicity or mutation in a battery of tests including an in vitro bacterial reverse mutation assay, an in vitro mammalian cell forward mutation assay at the thymidine kinase (TK+/-) locus in L5178Y mouse lymphoma cells and an in vivo mouse micronucleus assay. It was not mutagenic. In a fertility study performed in rats, no effect of elagolix on fertility was observed at any dose (50, 150 or 300 mg/kg/day). Based on AUC, the fold exposure to MRHD in females is approximately 2.9-fold compared to the highest dose of 300 mg/kg/day in female rats. However, because elagolix has a low affinity for the GnRH receptor in rats, and because its effects on fertility are highly likely to be mediated via the GnRH receptor, these data are not relevant to humans. low sex.

E2/NETA
Long-term continuous administration of natural and synthetic estrogens in certain animal species increases the frequency of breast, uterine, cervical, vaginal, testicular and liver cancers.

[Example 16]
Clinical Studies The efficacy of the system of Example 10 in the management of heavy menstrual bleeding (HMB) with uterine fibroids was evaluated in two randomized, double-blind, placebo-controlled studies [UF-1 (NCT02654054) and UF-2 (HMB). NCT02691494)], in which menstrual periods have at least two menstrual cycles and are assessed by the alkaline hematin (AH) method, an objective and validated measure that quantifies MBL volume in sanitary products. 790 premenopausal women with blood loss (MBL) greater than 80 mL received the system of Example 10 or placebo for 6 months. Each study also included a reference treatment arm of Elagolix 300 mg twice daily, which characterizes the impact of E2/NETA on efficacy and safety. In 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, 3% were of other race; 16% of women had fibroids and comorbid adenomyosis at baseline, as assessed by transvaginal and transabdominal ultrasound (TVU/TAU) and/or MRI baseline MBL ranged from 83.8 mL to 1207.1 mL; uterine volume ranged from 71.6 cm to 3347.9 cm by TVU/TAU; The volumes of primary fibroids ranged from 1 cm3 to 1081.5 cm3.

Menstrual Bleedage The primary endpoint in both studies was defined as achieving both 1) an MBL volume of less than 80 mL at the final month and 2) an MBL volume reduction of ≥50% from baseline to the final month. It was the proportion of women who achieved successful treatment. MBL at baseline was defined as the mean total MBL volume from at least two screening menstrual cycles that was >80 mL. The final month is defined as the last 28 days preceding and including the date of the last treatment visit or the date of the last dose. Women treated with the system of Example 10 achieved a higher rate of successful treatment compared to placebo (see Table A10).

Change in MBL Volume Compared to placebo, the system of Example 10 reduced mean MBL volume from baseline from 1 month to 6 months (see Figures 20 and 21). In Study UF-1, the mean baseline MBL was 238.0 mL for the Example 10 system and 255.3 mL for the placebo. In Study UF-2, the mean baseline MBL was 2298.5 mL for the Example 10 system and 254.3 mL for the placebo. Women who took the system of Example 10 showed a significant mean reduction in MBL volume from baseline to final month in both studies UF-1 and UF-2 compared to women who took placebo ( Study UF-1; −176.7 mL for system of Example 10 and 0.81 mL for placebo; Study UF-2, −168.89 mL for system of Example 10 and −4.3 mL for placebo).

Bleeding control In studies UF-1 and UF-2, a higher proportion of women receiving the system of Example 10 compared to 4% and 5%, respectively, of women receiving placebo (57% and 61%, respectively). and in the final month experienced controlled bleeding defined as no bleeding (but spotting was observed).

Hemoglobin (Hgb)
More than 90% of the women had a baseline Hgb < 10.5 g/dL and were taking supplemental iron. In studies UF-1 and UF-2, anemic women with baseline Hgb < 10.5 g/dL treated with the system of Example 10 had a higher proportion of An increase of Hgb≧2 g/dL from baseline to month 6 was achieved (see Table A11).

[Example B1]
Virtual Bioequivalence Evaluation of Various Elagolix Formulations Based on the PBPK Model and roller-compressed (RC2) tablets are used as commercial formulations. A combination product of elagolix 200 mg and estradiol (E2) 1 mg/norethindrone acetate (NETA) 0.5 mg is evaluated in a phase 3 trial for endometriosis. The Phase 3 investigational product consists of elagolix 200 mg tablets co-administered with E2/NETA tablets, while the commercial products of interest are as fixed dose combination (FDC) morning capsules and elagolix 200 mg MG evening capsules. , Elagolix 200 mg melt granulation (MG) tablets and E2/NETA tablets. Dissolution testing performed using the USP I (basket) apparatus showed different in vitro dissolution profiles for phase 3 and marketed (TBM) capsules, thus bioequivalence (BE) with respect to in vivo exposure. ). Physiologically-based pharmacokinetic (PBPK) models are used with in vitro dissolution data for various formulations to demonstrate simulated bioequivalence exposure without performing clinical BE studies For this purpose, a virtual BE simulation was performed.

Methods A previously developed PBPK model for Elagolix (Simcyp V17), validated with clinical PK and drug-drug interaction (DDI) data, served as a base model (Chiney et al., 2019; See Clinical Pharmacokinetics.). The PBPK model was updated by incorporating in vitro dissolution data of Elagolix formulations using the mechanistic ADAM (Advanced Dissolution & Absorption Modeling) module that captures drug dissolution and absorption in different regions of the GI tract. Dissolution testing of relevant formulations was performed using a USP-I apparatus at 100 RPM in 900 mL of 0.05 M sodium phosphate, pH 6.8. The PBPK model with incorporated in vitro data was externally validated using clinical data from two clinical bioequivalence studies, with different indications that elagolix capsules at the 300 mg dose were: Rated against the reference RC2 tablet. Model-predicted exposures (Cmax and AUC) in a hypothetical healthy female population were compared from the BE study to clinical observations for each formulation. The exposure ratios in Cmax and AUC of the model-predicted test capsule formulation and the reference (RC2) tablet were also compared with clinical observations. Using a clinically valid PBPK model, a virtual bioequivalence trial was simulated in a crossover format to compare Elagolix 200 mg capsules and 200 mg RC2 tablets. A virtual BE trial was conducted 100 times with different virtual subjects to assess the effect of situation interval or trial interval variability on formulation bioequivalence.

Results The PBPK model-predicted exposures for the 300 mg tablet (RC2) and 300 mg capsule formulations compared well with clinical observations from the BE study with prediction errors of less than 25%. Model predictions for BE ratios comparing tests to reference formulations also compared well with clinical data from BE studies. The results of these BE studies were not used for model calibration or validation and were therefore used as an external validation of the PBPK model predictions. This lends credibility to the use of PBPK models to predict exposure to clinically untested formulations using in vitro dissolution data as information. Based on the results of the hypothetical BE trial simulation, at the 200 mg dose both capsule formulations met the bioequivalence criteria of 0.80-1.25 when compared to the reference RC2 formulation. Both the Cmax and AUC ratios of the tests to the reference formulation were bioequivalent with the geometric mean of the predicted Cmax and AUC ratios of 0.9 and 0.95, respectively. The 90% prediction interval for the exposure ratio was also within the BE criteria. Results from multiple trial simulations using different virtual subjects also confirmed that the geometric mean and 90% confidence interval of the exposure ratios for all virtual trials met the BE criteria.

Conclusions This novel study used PBPK modeling to combine in vitro and clinical data for different formulations to perform virtual BE simulations instead of clinical trials. The results of virtual BE simulations from a clinically valid PBPK model show that Elagolix's TBM formulation has exposures similar to those of formulations that have been clinically tested and justify the in vivo bioequivalence Weber requirement. Used to justify what is likely to happen. This analysis also showed that permeability, but not solubility, was the determinant of elagolix absorption, suggesting that bioequivalent in vivo exposure was possible despite dissimilar in vitro dissolution profiles. occur. This study demonstrated the combined value of in vitro and in silico data in the development and evaluation of new formulations.

[Example B2]
Clinical pharmacological challenges in assessing bioequivalence for elagolix fixed-dose combination products Elagolix is being developed for the management of heavy menstrual bleeding (HMB) associated with uterine fibroids (UF). The investigational product studied in the UF Phase 3 trial was Elagolix 300 mg roller-compressed twice daily co-administered with once-daily estradiol/norethindrone acetate (E2/NETA) 1 mg/0.5 mg tablet ( RC2) is a tablet. For patient compliance and convenience, the formulation intended to be marketed (TBM) consists of Elagolix/E2/NETA 300/1/0.5 mg for morning dosing and Elagolix 300 mg capsules for evening dosing. Fixed dose combination (FDC) capsules. The two formulations exhibited dissimilar in vitro dissolution profiles, indicating potentially different release profiles in vivo. The purpose of the research is
(1) BE of TBM elagolix FDC morning capsule formulation compared with elagolix RC2 tablets co-administered with E2/NETA tablets in healthy postmenopausal women; To evaluate the effect of the BE of the compared TBM ellagorix evening capsule formulations; and (3) food (high-fat diet) on the bioavailability of ellagorix capsules.

Methods This research included two separate large phase 1 BE studies. The first study is a randomized, single-center, single-dose, 4-sequence, 2/3 period, crossover Phase 1 BE study. This study was conducted in healthy premenopausal women (N=57) to determine the BE between elagolix 300 mg capsule (test product; T) and elagolix 300 mg RC2 tablet (reference product; R) and food was evaluated for its effect on the bioavailability of ellagorix capsules. Serial blood samples for the ellagorix assay were collected pre-dose and up to 24 hours post-dose on study days.

A separate randomized, multicenter, single-dose, four-sequence, period 2/3, crossover phase 1 BE study was conducted in healthy postmenopausal women (N=67) to BE was evaluated between NETA 300/1/0.5 mg FDC capsules (T) and Elagolix 300 mg RC2 tablets co-administered with E2/NETA 1/0.5 mg tablets (R). The effect of food on the bioavailability of Elagolix FDC capsules was also evaluated. Serial blood samples for the Elagolix assay, total estrone and norethindrone, were collected pre-dose and up to 72 hours post-dose on study days.

In both BE studies, non-compartmental analysis (NCA) was performed using SAS software (Certara, Princeton, NJ, USA). For BE assessment, the maximum observed plasma concentration (Cmax) and the geometric mean ratio (GMR) of T/R (90% confidence interval [CI]) was calculated. Food effects were evaluated by assessing the relative bioavailability (90% confidence interval) of elagolix capsules (both elagolix capsules and FDC capsules) under fasting and fed conditions.

Results In the study of elagolix alone, the GMR (90% CI) of T/R at elagolix Cmax and AUC0-inf under fasting conditions were 0.87 (0.81-0.94) and 0.97 (0.94), respectively. .93-1.01), indicating that elagolix 300 mg capsules are bioequivalent to elagolix 300 mg RC2 tablets. Following administration of elagolix 300 mg capsules after a high-fat breakfast, elagolix Cmax and AUC0-inf were 40% and 28% lower, respectively. Tmax was delayed by approximately 1 hour compared to fasting conditions. The effect of food on the relative bioavailability of ellagorix was not clinically relevant based on exposure-response analyses.

In the elagolix FDC study, the T/R GMR (90% CI) at Cmax for elagolix, baseline-adjusted total estrone and norethindrone was 0.91 (0.87-0.95), 1.02 ( 0.96-1.08), 1.12 (1.08-1.15), while the GMR of T/R at AUC0-inf for elagolix, baseline-adjusted total estrone and norethindrone (90 % CI) were 0.97 (0.95-1.00), 0.93 (0.87-1.00), 0.96 (0.94-0.98) under fasting conditions, respectively. rice field. Additional hormone specimens also achieved BE criteria. These findings indicate that elagolix/E2/NETA 300/1/0.5 mg FDC capsules are bioequivalent to elagolix 300 mg RC2 tablets co-administered with 1/0.5 mg E2/NETA tablets. pointed out. Following administration of elagolix/E2/NETA 300/1/0.5 mg FDC capsules after a high-fat breakfast, elagolix Cmax and AUC0-inf were 36% and 25%, respectively, when compared to exposure under fasting conditions. % was low.

Conclusions The results of the BE study indicate that TBM elagolix FDC (elagolix/E2/NETA 300/1/0.5 mg) morning capsule and elagolix 300 mg evening capsule formulations are , was demonstrated to be bioequivalent to the UF Phase 3 clinical trial formulations (elagolix 300 mg tablet and E2/NETA 1/0.5 mg tablet co-administered). The effect of food (high-fat diet) on TBM product components was similar to that previously observed with Elagolix's commercial tablet Orilissa™ and expected with E2/NETA (Activella® USPI). It was just like that. Thus, FDC 300/1/0.5 mg for morning and Elagolix 300 mg capsule for evening can be taken with or without food.

It is understood that the foregoing detailed description and accompanying examples are illustrative only and should not be taken as limiting the scope of the invention, which is defined solely by the appended claims and equivalents thereof. be done.

Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art. Such changes and modifications, including but not limited to those relating to chemical structures, substituents, derivatives, intermediates, syntheses, compositions, formulations or methods of use of this invention, may be modified from its spirit and scope. can be done without deviation.

Claims (47)

A multi-drug delivery system comprising:
a first capsule body including 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 tablet being at least a second tablet different from the first drug. a second tablet comprising two drugs and a third drug different from the first and second drugs, wherein the first tablet and the second tablet are in contact with the first capsule body in the patient's body; a first capsule configured for simultaneous release upon dissolution;
a second capsule body including a second interior;
a third tablet within a second interior, a second capsule packaged with the first capsule containing a third tablet containing the first drug, at 50 rpm, pH 6.0; Using USP Apparatus 2 at 8 and 37.5±0.5° C., at least 75% of the first drug in the first tablet dissolved after 60 minutes, the second and third of the drug dissolves after 30 minutes. 2. The multi-drug delivery system of claim 1, wherein the first tablet comprises elagolix. 3. The multi-drug delivery system of claim 1 or 2, wherein the first tablet comprises from about 175 mg to about 325 mg of elagolix and the second tablet comprises from about 0.75 mg to about 1.25 mg of estradiol. 4. The multiple drug delivery system of Claim 3, wherein the second tablet further comprises about 0.1 mg to about 1 mg of norethindrone acetate. 4. The multi-drug delivery system of claim 3, wherein after about 15 minutes the estradiol release is 70% or greater. The first capsule is marked with a first identifier and the second capsule is different from the first identifier such that the first capsule and the second capsule are visually distinguishable 2. The multi-drug delivery system of claim 1, marked with a second identifier. The first identifier is configured to indicate that the first capsule is intended for administration within a first timeframe of the day and the second capsule is different from the first timeframe 7. The multi-drug delivery system of claim 6, wherein the second identifier is configured to indicate that it is intended for administration within a second time frame of the day. The first identifier is configured to indicate that the first capsule is intended for administration at a first time slot in the morning and the second capsule is intended for administration at a second time in the afternoon 8. The multi-drug delivery system of Claim 7, wherein the second identifier is configured to indicate that it is intended for dosing in a frame. of claims 6-8, wherein the first identifier is a first color contained on the first capsule and the second identifier is a second color contained on the second capsule. A multi-drug delivery system according to any of the preceding claims. 10. The multi-drug delivery system of any of claims 1-9, further comprising a package comprising multiple compartments configured to house the first capsule and the second capsule. The package comprises a blister card defining a plurality of compartments, wherein the first capsule and the second capsule contained in the plurality of compartments are accessible by piercing the seal of the blister card. Item 11. The multiple drug delivery system of Item 10. 12. The multi-drug delivery system of claim 10 or 11, wherein the package includes information printed thereon relating to when to administer the first capsule and the second capsule to the patient. A blister card includes a first row of multiple compartments and a second row of multiple compartments, wherein a first capsule is contained in the first row and a second capsule is contained in the second row. 11. The multi-drug delivery system of claim 10, wherein the first row and the second row are visually distinct. A capsule for use in delivering a drug to a patient, comprising:
a capsule body containing an interior,
A first tablet within the interior, wherein at least one first tablet comprises a first drug, and a second tablet within the interior, wherein at least the first drug and comprises a second tablet comprising a different second drug, wherein the first tablet and the second tablet are configured for simultaneous release upon dissolution of the capsule body within the patient's body;
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 dissolved after 60 minutes, and A capsule wherein at least 70% of the drug of 2 dissolves after 30 minutes. 15. The capsule of claim 14, wherein the first tablet contains from about 175 mg to about 325 mg of elagolix and the second tablet contains from about 0.75 mg to about 1.25 mg of estradiol. 16. The capsule of Claim 15, wherein the second tablet further comprises about 0.1 mg to about 1.0 mg of norethindrone acetate. 16. Capsules according to claim 15, wherein the release of estradiol is 70% or more after 16 minutes. the capsule body is oblong defining a longitudinal axis, and at least one first tablet and a second tablet are disposed within the interior along the longitudinal axis in a serial relationship; 15. Capsules according to claim 14. 15. The capsule of claim 14, wherein the at least one first tablet and second tablet are separate tablets formed separately from each other and then secured within the interior. 15. A capsule according to claim 14, wherein the capsule body does not contain the drug in powder form. 15. The capsule of claim 14, wherein the capsule body does not include a barrier extending between the first tablet and the second tablet, and the first tablet and the second tablet are not bound together within the interior. agent. A second tablet containing a second drug and a third drug, both for the first 30 days of administration using USP Apparatus 2 at 50 rpm, pH 6.8 and 37.5±0.5°C. 15. The capsule of claim 14, configured to have a dissolution rate of greater than about 80 percent within minutes. 15. The capsule of Claim 14, wherein the first capsule comprises gelatin. A method of delivering a drug to a patient, comprising:
delivering a first capsule to a patient, wherein the first capsule comprises a first capsule body including 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 tablet being at least a second tablet different from the first drug. a second tablet comprising two drugs, the first tablet and the second tablet being configured to be released simultaneously upon dissolution of the first capsule body in the patient's body;
delivering a second capsule packaged with the first capsule to the patient a predetermined amount of time after administration of the first capsule, the second capsule comprising:
a second capsule body comprising a second interior; and a third tablet within the second interior, the third tablet comprising the first drug. 25. The method of claim 24, wherein the first tablet comprises about 175-325 mg of elagolix and the second tablet comprises about 0.75-1.25 mg of estradiol and about 0.1-1.0 mg of norethindrone. the method of. 25. The method of claim 24, wherein after 20 minutes the estradiol release is 70% or more. 25. The method of claim 24, wherein delivering the second capsule comprises delivering the second capsule at least 5 hours after administration of the first capsule. a first time frame in a day wherein the step of delivering the first capsule is in the morning and the step of delivering the second capsule is in the afternoon 25. The method of claim 24, comprising delivering a second capsule in a second time frame of the day. 25. The method of claim 24, further comprising providing a package comprising multiple compartments configured to house the first capsule and the second capsule therein. containing a plurality of first capsules and a plurality of second capsules in a package, wherein the number of first capsules and the number of second capsules contained in the package are each: 30. The method of claim 29, further comprising the step of being a multiple of the number of days in a week. A multi-drug tablet comprising a first tablet and a second tablet coated on the first tablet. 32. The multi-drug tablet of Claim 31, wherein the second tablet is centrally located in the first tablet. 33. The multi-drug tablet of Claim 32, further comprising crospovidone. A drug container assembly comprising:
a first set of compartments, each compartment configured to support a first capsule;
a second set of compartments, each compartment configured to support a second capsule packaged with the first capsule; a first capsule,
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 tablet being at least a second tablet different from the first drug. a second tablet comprising two drugs, wherein the first tablet and the second tablet are configured to be released simultaneously upon dissolution of the first capsule body within the patient's body;
a second capsule, a second capsule body including a second interior, and a third tablet within the second interior, the second capsule comprising a first drug, a second drug, or a third drug A drug container assembly comprising a third tablet comprising at least one drug selected from the group. A multi-drug capsule,
a first tablet comprising a first drug; a second tablet comprising at least a second drug different from the first drug and the first and second drugs; comprises a second tablet comprising a different third drug, wherein the first tablet and the second tablet are configured for simultaneous release upon dissolution of the capsule within the patient's body;
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 dissolved after 60 minutes, and A multi-drug capsule wherein at least 70% of the second and third drugs are dissolved after 30 minutes. 36. The multi-drug capsule of claim 35, wherein the first tablet comprises elagolix. 37. The multi-drug capsule of claim 35 or 36, wherein the first tablet contains from about 175 mg to about 325 mg of elagolix and the second tablet contains from about 0.75 mg to about 1.25 mg of estradiol. An oral multi-drug capsule composition comprising:
(a) 300 mg free acid equivalent of elagolix,
(b) 1 mg estradiol and (c) 0.5 mg norethindrone acetate after administration to a healthy adult subject in a single dose of a composition comprising:
an average peak concentration (Cmax) for Elagolix from about 1218.4 ng/mL to about 2185 ng/mL;
an average peak concentration (Cmax) for estradiol from about 0.0424 ng/mL to about 0.0775 ng/mL;
a mean peak concentration (Cmax) for norethindrone acetate from about 4.56 ng/mL to about 8.0 ng/mL;
about 3293.6 ng. hr/mL to about 5892.5 ng. mean area under the curve (AUC _(t) ) for Elagolix in hr/mL,
about 0.688 ng. hr/mL to about 1.1375 ng. hr/mL mean area under the curve (AUC _(t) ) for estradiol, and about 17.6 ng. hr/mL to about 33.125 ng. Mean area under the curve (AUC _(t) ) for norethindrone acetate in hr/mL
An oral multi-drug capsule composition that results in An oral multi-drug capsule composition comprising:
(a) 300 mg free acid equivalent of elagolix,
(b) 1 mg of estradiol administered once daily, and (c) 0.5 mg of norethindrone acetate, administered to a healthy adult subject in a single dose,
an average peak concentration, Cmax, for ellagorix of about 1218.4 ng/ml to about 2185 ng/mL;
Mean peak concentration, Cmax, for estradiol, from about 0.0424 ng/ml to about 0.0775 ng/ml, and Mean peak concentration, Cmax, for norethindrone acetate, from about 4.56 ng/ml to about 8.0 ng/ml.
An oral multi-drug capsule composition that results in about 3296.6 ng. hr/mL to about 5892.5 ng. Mean Area Under the Curve, AUC _(t) , for Elagolix, hr/mL
about 0.688 ng. hr/mL to about 1.1375 ng. hr/mL mean area under the curve for estradiol, AUC _(t) , and about 17.6 ng. hr/mL to about 33.125 ng. Mean area under the curve for norethindrone acetate in hr/mL, AUC _(t)
40. The oral multi-drug capsule composition of claim 39. An oral multi-drug capsule composition comprising:
(a) 300 mg free acid equivalent of elagolix,
(b) 1 mg of estradiol, and (c) 0.5 mg of norethindrone acetate, further administered to a healthy adult subject in a single dose,
about 3293.6 ng. hr/mL to about 5892.5 ng. Mean Area Under the Curve, AUC _(t) , for Elagolix, hr/mL
about 0.0.688 ng. hr/mL to about 1.1375 ng. hr/mL mean area under the curve for estradiol, AUC _(t) , and about 17.6 ng. hr/mL to about 33.125 ng. Mean area under the curve for norethindrone acetate in hr/mL, AUC _(t)
An oral multi-drug capsule composition that results in By administering the composition to a healthy adult subject,
about 1218.4 ng/mL to about 2185 ng. Mean Peak Concentration, Cmax, for Elagolix in hr/mL
about 0.0424 ng. hr/mL to about 0.0775 ng/mL ng/mL mean peak concentration for estradiol, Cmax, and about 4.56 ng. Average peak concentration for norethindrone acetate, Cmax, from hr/mL to about 8.0 ng/mL
42. The oral multi-drug capsule composition of claim 41, resulting in An oral multi-drug capsule composition comprising:
(a) 300 mg free acid equivalent of elagolix,
(b) 1 mg estradiol, and (c) 0.5 mg norethindrone acetate using USP Apparatus 2 at 50 rpm, pH 6.8 and 37.5±0.5° C. at least 75% of the drug in the second tablet dissolves after 60 minutes, and at least 70% of the second and third drugs in the second tablet dissolves after 30 minutes. A method of safely treating heavy menstrual bleeding associated with uterine leiomyoma (fibroids) in a premenopausal female patient comprising:
(a) 300 mg free acid equivalent of elagolix,
(b) 1 mg estradiol and (c) 0.5 mg norethindrone acetate administered orally to the patient once daily, the method comprising:
about 1218.4 ng. hr/mL to about 2185 ng/mL for Elagolix
from about 0.0424 ng/mL to about 0.0775 ng/mL of estradiol
mean Cmax for norethindrone acetate of about 4.56 ng/mL to about 8.0 ng/mL, and about 3293.6 ng. hr/mL to about 5892.5 ng. hr/mL of approximately 0.0.688 ng.hr/mL for Elagolix. hr/mL to about 1.1375 ng. hr/mL of estradiol and about 17.6 ng. hr/mL to about 33.125 ng. Mean AUC _(t) for Norethindrone Acetate in hr/mL
and after a treatment duration of about 6 months, the patient achieves an increase in hemoglobin of about 2 g/dL or more compared to a baseline in which the patient did not receive elagolix, estradiol and norethindrone. A capsule for use in delivering a drug to a patient, comprising:
a capsule body containing an interior,
A first tablet within the interior, wherein at least one first tablet comprises a first drug, and a second tablet within the interior, wherein at least the first drug and comprises a second tablet comprising a different second drug, wherein the first tablet and the second tablet are configured for simultaneous release upon dissolution of the capsule body within the patient's body;
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 A capsule wherein at least 90% of the second and third drugs dissolve after 30 minutes. An oral multi-drug capsule composition that is bioequivalent to any one of the compositions of claims 31-34, 36-45. A method of delivering co-packaged drugs to a patient for oral use, comprising:
delivering a first capsule to a patient, the first capsule comprising:
a first capsule body including a first interior;
A first tablet within a first interior, the first tablet comprising a first drug, and a second tablet within the first interior, at least different from the first drug a second tablet comprising a second drug, wherein the first tablet and the second tablet are configured to be released simultaneously upon dissolution of the first capsule body in the patient's body; ,
delivering a second capsule packaged with the first capsule to the patient a predetermined amount of time after administration of the first capsule, the second capsule comprising:
a second capsule body comprising a second interior; and a third tablet within the second interior, the third tablet comprising the first drug.

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