CN115989023A

CN115989023A - System and method for multiple drug delivery

Info

Publication number: CN115989023A
Application number: CN202080103493.5A
Authority: CN
Inventors: 邱怡虹; D·周; M·舍普利; W-K·J·吴; A·N·默罕默德; J-H·韩; D·梅茨格尔; A·鲁格尔斯; 祖卉; 邵溪; 龚豫川; Y·陈; J·龚; M·李
Original assignee: AbbVie Inc
Current assignee: AbbVie Inc
Priority date: 2020-08-25
Filing date: 2020-08-25
Publication date: 2023-04-18
Also published as: WO2022040896A1

Abstract

A multi-drug delivery system comprising a first capsule body, the first capsule body comprising a first interior and first and second tablets in the first interior. The first tablet includes a first drug and the second tablet includes 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 in a patient. The system also includes a second capsule comprising a second capsule body including a second interior and a third tablet in the second interior. The third tablet comprises the first drug.

Description

System and method for multiple drug delivery

Background

The field of the present disclosure relates generally to pharmaceutical products and, more particularly, to pharmaceutical dosage forms capable of releasing simultaneously, immediately after ingestion by a patient, more than one drug encapsulated within a capsule, and delivery systems for such drug dosages that ensure patient compliance with the ingestion instructions.

Oral administration of pharmaceuticals such as drugs, supplements, and other nutritional or therapeutic agents is commonly accomplished in tablet and capsule dosage forms. Capsules generally comprise a hollow shell having an interior for storing therein a powder or liquid based medicament, and tablets may be made from a compressed powder of a medicinal substance. For at least some known diseases, it may be beneficial to administer more than one type of drug to a patient. Thus, tablets and capsules can be manufactured to enable the administration or ingestion of two or more drugs to a patient in a single dose or dosage form. For example, at least some known capsules contain a pharmaceutical mixture in liquid or powder form inside a hollow shell. In addition, at least some known tablets include a first drug encapsulated in a second drug. However, encapsulating the first drug in the second drug may hinder dissolution of the first drug and may reduce dissolution of the first and second drugs. In addition, drugs administered in powder or liquid form may dissolve at a rate that is not suitable for the desired efficacy.

In addition, many known prescription drugs have complex instructions and dosing schedules. For example, some prescriptions require oral administration of multiple drug dosage forms containing different types of drugs and/or require administration at different times of the day. Other medications should be taken in the morning, afternoon or evening, with or without food, with or without certain types of food, and in specific amounts. Thus, it may be difficult for a patient to remember and comply with the instructions for administration of a drug or a group of drugs. Failure to comply with such administration instructions may result in undesirable therapeutic effects.

Brief description of the drawings

In one aspect, a multi-drug delivery system is provided. The system includes a first capsule including a first capsule body having a first interior, and first and second tablets included within the first interior. The first tablet includes a first drug and the second tablet includes at least a second drug different from the first drug. For example, the second tablet may include a second and third drug, each different from the first drug and each other. The first tablet and the second tablet are configured to be released simultaneously upon dissolution of the first capsule body in a patient. The system also includes a second capsule co-packaged with the first capsule, the second capsule including a second capsule body having a second interior, and a third tablet included within the second interior. The third tablet may include the first drug, the second drug, and/or one or more other drugs. At least 75% ± 10% of the first drug in the first tablet is 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 is dissolved after 30 minutes when using USP apparatus 2 at 50rpm, pH 6.8 and 37.5 ± 0.5 ℃.

In certain embodiments, the first tablet may include a gonadotropin releasing hormone antagonist. For example, the first tablet may include a combination of oxadegrel, regorac, another gonadotropin releasing hormone antagonist and/or a gonadotropin releasing hormone antagonist. In certain embodiments, the first tablet may include loragol.

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

In certain embodiments, the first capsule may be marked with a first identifier and the second capsule may be marked with a second identifier different from the first identifier, such that the first capsule and the second capsule are visually discernable; the first identifier may be configured to indicate that the first capsule is intended for administration within a first time window of a day, and the second identifier may be configured to indicate that the second capsule is intended for administration within a second time window of a day different from the first time window. In certain embodiments, the first identifier may be configured to indicate that the first capsule is intended for administration at a first window of time before noon, and the second identifier may be configured to indicate that the second capsule is intended for administration at a second window of time after noon; the first identifier may be a first color included on the first capsule and the second identifier may be a second color included on the second capsule.

In certain embodiments, the system may include a package having a plurality of compartments configured to contain the first capsule and the second capsule. The package may include a blister card defining the plurality of compartments, wherein a first capsule and a second capsule contained in the plurality of compartments are accessible by puncturing a seal in the blister card; the package may have information printed thereon relating to when to administer the first and second capsules to the patient; the blister card may have a first row of the plurality of compartments and a second row of the plurality of compartments, wherein the first capsule is contained in the first row, wherein the second capsule is contained in the second row, and wherein the first row and the second row are visually distinct.

In another aspect, a capsule for delivering a medicament to a patient is provided. The capsule includes a capsule body having an interior and at least one first and second tablet included in the interior. The at least one first tablet includes a first drug and the second tablet includes at least a second drug different from the first drug. The at least one first tablet and the second tablet are configured to be released simultaneously upon dissolution of the capsule body in a patient.

In certain embodiments, the first tablet may comprise from about 175mg to about 325mg of a gonadotropin releasing hormone antagonist, such as oxarogrel, and the second tablet comprises from about 0.75mg to about 1.25mg estradiol; the second tablet may further comprise about 0.1mg to about 1.0mg norethindrone acetate. In certain embodiments, wherein the release of estradiol after 16 minutes is equal to or greater than 70% ± 10% or 70% ± 20% or 70% ± 30% or 70% ± 40%; the capsule body may be oblong shaped to define a longitudinal axis, wherein the at least one first tablet and the second tablet are arranged in a row relationship along the longitudinal axis in the interior; said at least one first tablet and said second tablet may be different tablets that have been formed separately from each other and then fixed within said interior; the capsule body may be free of medicament in powder form; the capsule body may not include a barrier extending between the first tablet and the second tablet, and wherein the first tablet and the second tablet are not joined together in the interior; the first capsule may comprise gelatin.

In yet another aspect, a method of delivering a drug to a patient is provided. The method includes delivering a first capsule to the patient, wherein the first capsule includes a first capsule body having a first interior, and a first tablet and a second tablet included within the first interior. The first tablet includes a first drug and the second tablet includes 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 in a patient. The method further includes delivering a second capsule to the patient after a predetermined amount of time has elapsed after administering the first capsule, which is co-packaged with the first capsule. The second capsule includes a second capsule body having a second interior, and a third tablet included within the second interior. The third tablet includes the first drug.

In certain embodiments, the first tablet comprises a first tablet comprising about 175 to 325mg of a gonadotropin-releasing hormone antagonist and the second tablet comprises about 0.75mg to 1.25mg estradiol and about 0.1mg to 1.0mg norethindrone; after 20 minutes, the release of estradiol is equal to or greater than 70% ± 10% or 70% ± 20% or 70% ± 30% or 70% ± 40%; delivering a second capsule comprises delivering the second capsule at least 5 hours after administering the first capsule; comprising providing a package comprising a plurality of compartments configured to contain the first capsule and the second capsule therein; and/or further comprising containing a plurality of first capsules and a plurality of second capsules within the package such that the number of first capsules and the number of second capsules contained within the package are each a multiple of a day of the week.

In certain embodiments, a multi-drug tablet comprises a first tablet and a second tablet coated on the first tablet; the second tablet may be located in the center of the first tablet; and/or the multi-tablet comprises crospovidone.

In certain embodiments, the medicament container assembly comprises a first set of a plurality of compartments, each compartment configured to support a first capsule; a second group of a plurality of compartments, each compartment configured to hold a second capsule; wherein the first capsule comprises a first interior; a first tablet in the first interior, the first tablet comprising a first drug; and a second tablet in the first interior portion comprising at least a second drug different from the first drug, wherein the first and second tablets are configured to be released simultaneously upon dissolution of the first capsule body in a patient; and the second capsule comprises a second capsule body comprising a second interior; and a third tablet in the second interior, the third tablet comprising at least one drug selected from the group consisting of: the first drug, the second drug, or a third drug.

In certain embodiments, a multi-drug capsule comprises a first tablet comprising a first drug; a second tablet co-packaged with the first tablet and comprising at least a second drug different from the first drug; and a third drug different from the first and second drugs, wherein the first tablet and the second tablet are configured to be released simultaneously upon dissolution of the capsule in a patient; wherein at least 75% ± 10% of the first drug in said first tablet is 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 said second tablet is dissolved after 30 minutes using USP apparatus 2 at 50rpm, pH 6.8 and 37.5 ± 0.5 ℃.

In certain embodiments, a multi-drug capsule comprises a first tablet comprising a first drug; a second tablet co-packaged with the first tablet and comprising at least a second drug different from the first drug; and a third drug different from the first and second drugs, wherein the first tablet and the second tablet are configured to be released simultaneously upon dissolution of the capsule in a patient; wherein at least 75% ± 10% of the first drug in said first tablet is dissolved after 45 minutes and at least 90% ± 10% or 90% ± 20% or 90% ± 30% or 90% ± 40% of the second and third drugs in said second tablet is dissolved after 30 minutes using USP apparatus 1 at 100rpm, pH 6.8 and 37.5 ± 0.5 ℃.

In certain embodiments, the first tablet comprises oxarogue, the first tablet has about 175mg to about 325mg of oxarogue, and the second tablet has about 0.75mg to about 1.25mg of estradiol.

In another aspect, the oral multi-drug capsule composition comprises 300mg of free acid equivalent of oxagoril; 1mg estradiol; and 0.5mg norethindrone acetate; and produces a mean peak concentration (Cmax) of the oxadiargyl of about 1218.4ng/mL to about 2185ng/mL after administration of a single dose of the composition to a healthy adult subject; a mean peak concentration (Cmax) of said estradiol from about 0.0424ng/mL to about 0.0775ng/mL; a mean peak concentration (Cmax) of the norethindrone acetate from about 4.56ng/mL to about 8.0 ng/mL; an area under the mean curve (AUC) of the oxarogril from about 3293.6ng.hr/mL to about 5892.5ng.hr/mL _(t) ) (ii) a An average area under the curve (AUC) of the estradiol from about 0.688ng.hr/mL to about 1.1375ng.hr/mL _(t) ) (ii) a And an average area under the curve (AUC) of said norethindrone acetate from about 17.6ng.hr/mL to about 33.125ng.hr/mL _(t) )。

In another aspect, the multi-drug capsule composition includes 300mg of free acid equivalent of oxarogril; 1mg estradiol; and 0.5mg norethindrone acetate; and administration of a single dose of the composition to a healthy adult subject produces a mean peak concentration Cmax of the oxagoril of about 1218.4ng/mL to about 2185ng/mL; a mean peak concentration Cmax of said estradiol from about 0.0424ng/ml to about 0.0775ng/ml; a mean peak concentration Cmax of said norethindrone acetate of about 4.56ng/ml to about 8.0ng/ml.

In one embodiment, the multi-drug composition has an area under the mean curve AUC of the oxogolide of about 3296.6ng.hr/mL to about 5892.5ng.hr/mL _(t) (ii) a About 0.688ng.hr/mL to about 1.1375ng.hr/mL of said mean koji for estradiolArea under line AUC _(t) (ii) a And about 17.6ng.hr/mL to about 33.125ng.hr/mL of said mean area under the curve AUC of norethindrone acetate _(t) 。

In one aspect, the multi-drug capsule composition comprises 300mg of free acid equivalent of oxadegril; 1mg of estradiol; and 0.5mg norethindrone acetate; and administration of a single dose of the composition to a healthy adult subject results in an area under the mean curve AUC of said oxogolide of about 3293.6ng.hr/mL to about 5892.5ng.hr/mL _(t) (ii) a (ii) an area under the mean curve AUC of said estradiol from about 0.688ng.hr/mL to about 1.1375ng.hr/mL _(t) (ii) a And about 17.6ng.hr/mL to about 33.125ng.hr/mL of said mean area under the curve AUC of norethindrone acetate _(t) 。

In one embodiment, administration of the multi-drug capsule to a healthy adult subject produces a mean peak concentration Cmax of the oxogolide of about 1218.4ng/mL to about 2185ng.hr/mL; a mean peak concentration Cmax of said estradiol from about 0.0424ng.hr/mL to about 0.0775ng/mL; and a mean peak concentration Cmax of said norethindrone acetate from about 4.56ng.hr/mL to about 8.0ng/mL.

In another aspect, the oral multi-drug capsule composition comprises 300mg of free acid equivalent of oxagoril; 1mg estradiol; and 0.5mg norethindrone acetate; and at least 75% of the first drug in the first tablet is dissolved after 60 minutes and at least 70% of the second and third drugs in the second tablet are dissolved after 30 minutes using USP apparatus 2 at 50rpm, pH 6.8 and 37.5 ± 0.5 ℃. In another aspect, a method of safely treating menorrhagia (Heavy mental menstruation) associated with uterine fibroids (fibroids) in a pre-menopausal female patient is provided. The method comprises orally administering to the patient once daily: (a) 300mg free acid equivalent of oxa-rogle; (b) 1mg estradiol; and (c) 0.5mg norethindrone acetate, wherein the method produces a mean Cmax of the oxolinic acid of about 1218.4ng.hr/mL to about 2185ng/mL; a mean Cmax of said estradiol from about 0.0424ng/mL to about 0.0775ng/mL; a mean Cmax of said norethindrone acetate of about 4.56ng/mL to about 8.0 ng/mL; and a mean AUC of said oxarogue from about 3293.6ng.hr/mL to about 5892.5ng.hr/mL _(t) (ii) a About 0.0.688ng.An average AUC of said estradiol from hr/mL to about 1.1375ng.hr/mL _(t) (ii) a And an average AUC of said norethindrone acetate from about 17.6ng.hr/mL to about 33.125ng.hr/mL _(t) And wherein after a treatment period of about 6 months, the patient achieves an increase in hemoglobin equal to or greater than about 2g/dL as compared to baseline when the patient did not receive oxargoline, estradiol, and norethindrone.

In another aspect, an oral capsule for delivering a drug to a patient comprises: a capsule body comprising an interior; a first tablet within said interior, said at least one first tablet comprising a first drug; and a second tablet in the interior comprising at least a second drug different from the first drug, wherein the first tablet and the second tablet are configured to release simultaneously upon dissolution of the capsule body in a patient, wherein at least 75% of the first drug in the first tablet dissolves after 45 minutes and at least 90% of the second and third drugs in the second tablet dissolves after 30 minutes using USP apparatus 1 at 100rpm, pH 6.8 and 37.5 ± 0.5 ℃.

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. The method includes delivering a first capsule to the patient, wherein the first capsule comprises: a first capsule body comprising a first interior; a first tablet in the first interior, the first tablet comprising a first drug; and a second tablet in the first interior, the second tablet including at least a second drug different from the first drug, wherein the first and second tablets are configured to be released simultaneously upon dissolution of the first capsule in the patient; and delivering a second capsule co-packaged with the first capsule to the patient after a predetermined amount of time has elapsed after administration of the first capsule, wherein the second capsule comprises: a second capsule body comprising a second interior; and a third tablet in the second interior, the third tablet comprising the first drug.

Brief Description of Drawings

FIG. 1 is an illustration of one embodiment multi-drug delivery system including first and second capsules of a drug.

Fig. 2 is an internal view of an embodiment capsule containing two tablets.

Fig. 3 is an internal view of an embodiment capsule containing a single tablet.

Fig. 4A is an interior view of a first embodiment multiple drug tablet having a first tablet enclosing a second tablet.

Fig. 4B is an interior view of a second embodiment multi-drug tablet having a first tablet encapsulating a second tablet.

Fig. 5 is an internal view of a third embodiment multi-drug tablet having a bilayer with a first layer of a first drug and a second layer of a second and third drug.

Fig. 6 is an internal view of a fourth embodiment multiple drug tablet having a first tablet coated with a mixture of a third and fourth drug.

Fig. 7 is an interior view of a fifth embodiment multiple drug tablet having a bilayer with a first layer of a first drug and a second layer of an embedded tablet.

Fig. 8 is an interior view of a capsule according to the embodiment of fig. 1 with a first tablet and four miniature tablets.

Fig. 9 is an interior view of a capsule according to the embodiment of fig. 1 containing fused granules and tablets.

Fig. 10 is a flow chart showing the process of example 1 for coating the E2/NETA tablet (E2/NETA tablet-in-elagolix tablet) with the loragol tablet and example 2 for embedding the E2/NETA tablet on the surface of the loragol tablet.

The flow chart of FIG. 11A shows the process of example 3-1: bilayer tablet E2/NETA layer: fluid bed granulation, spraying the API solution onto lactose.

The flow chart of FIG. 11B shows the process of example 3-2: bilayer tablet E2/NETA layer: fluid bed granulation, the binder is sprayed onto the API mixture.

The flow chart of FIG. 11C shows the process of example 3-3: a bilayer tablet, directly blended with an E2/NETA layer, has a disintegrant.

The flow chart of FIG. 11D shows the process of examples 3-4: bilayer tablets, blended directly with the E2/NETA layer, without disintegrant.

The flow chart of fig. 12 shows the process of example 4: the loragol core tablets were coated with a solution of E2/NETA.

The flow chart of fig. 13 shows the process of example 5: bilayer tablet, E2/NETA embedded in placebo layer.

The flow chart of fig. 14 shows the process of example 6: oxagolide tablets and E2/NETA tablets in capsules.

The flow chart of fig. 15 shows the process of example 7: oxagobril mini-tablets and one E2/NETA tablet in capsules.

The flow chart of fig. 16 shows the process of example 8: granules of oxadegril filled in capsules and one E2/NETA tablet.

Fig. 17 is a perspective view of an embodiment package that may be used to contain and transport the multiple drug delivery system shown in fig. 1.

Figure 18 is a graph illustrating dissolution rates of drugs administered according to various embodiments of the present disclosure and according to the multi-drug tablet shown in figure 4A and example 1.

Figure 19 is a graph illustrating dissolution rates of drugs administered according to various embodiments of the present disclosure and according to the multi-drug tablet shown in figure 4B and example 2.

Figure 20A is a graph illustrating dissolution rates of drugs administered according to various embodiments of the present disclosure and according to the multi-drug tablet shown in figure 5 and example 3-1.

Figure 20B is a graph illustrating dissolution of a drug administered according to various embodiments of the present disclosure and according to the multi-drug tablet shown in figure 5 and example 3-2.

Figure 20C is a graph illustrating dissolution rates of drugs administered according to various embodiments of the present disclosure and according to the multi-drug tablet shown in figure 5 and examples 3-3.

Figure 20D is a graph illustrating dissolution rates of drugs administered according to various embodiments of the present disclosure and according to the multi-drug tablet shown in figure 5 and examples 3-4.

Figure 21 is a graph illustrating dissolution of a drug administered according to various embodiments of the present disclosure and according to the multi-drug tablet shown in figure 6 and example 4.

Figure 22 is a graph illustrating dissolution rates of drugs administered according to various embodiments of the present disclosure and according to the multi-drug tablet shown in figure 7 and example 5.

Figure 23 is a graph illustrating dissolution of a drug administered according to various embodiments of the present disclosure and according to the capsule shown in figure 2 and example 6.

Figure 24 is a graph illustrating dissolution of a drug administered according to various embodiments of the present disclosure and according to the capsule shown in figure 8 and example 7.

Figure 25 is a graph illustrating dissolution of a drug administered according to various embodiments of the present disclosure and according to the capsule shown in figure 9 and example 8.

FIG. 26 is a graphical representation of the percent change from baseline in lumbar vertebral mineral density (BMD) in women with uterine fibroids who received the system described in example 10 for 12 months and had follow-up BMD at 12 months of treatment discontinuation in the UF-1, UF-2, UF-3 studies.

FIG. 27 is a graphical representation of monthly changes in MBL volume from baseline in women with uterine fibroids in the UF-1 study.

FIG. 28 is a graphical representation of the monthly change in MBL volume from baseline in women with uterine fibroids in a UF-2 study.

Figure 29A is a graph illustrating dissolution of oxalagril administered using USP apparatus 1 according to various embodiments of the present disclosure and according to the multi-drug tablet shown in figure 6.

Figure 29B is a graph illustrating the dissolution rate of E2 administered using USP apparatus 1 according to various embodiments of the present disclosure and according to the multi-drug tablet shown in figure 6.

Fig. 29C is a graph illustrating the dissolution rate of NETA administered using USP apparatus 1 according to various embodiments of the present disclosure and according to the multi-drug tablet shown in fig. 6.

Detailed Description

The following detailed description illustrates the disclosure by way of example and not by way of limitation. The description enables one of ordinary skill in the art to make and use the disclosure, describes several embodiments, adaptations, variations, alternatives, and uses of the disclosure.

Embodiments of the present disclosure relate to a pharmaceutical dosage form capable of releasing more than one drug encapsulated within a capsule substantially simultaneously and immediately after administration by a patient, and a delivery system that helps the patient comply with the dosage specified for administration. The drug delivery system comprises a first capsule and may further comprise a second capsule intended to be administered within different and non-overlapping time windows of the day. For example, in one embodiment, a first capsule is intended to be administered at morning hours (e.g., before noon) and a second capsule is intended to be administered at least 5 hours after the first capsule is administered (e.g., during afternoon or evening hours). The first and second capsules may contain different drugs or combinations of drugs and may be labeled, for example, with an identifier that aids in complying with prescribed instructions for administration. The surfaces of the first and second capsules may have different identifying colors and/or surface characteristics. The first and second capsules may further comprise symbols and/or textual markings indicating in which time window the respective capsule should be administered. Furthermore, the plurality of first capsules and the plurality of second capsules may be contained in a package comprising symbols and/or textual markings, which again indicate within which time window the respective capsule should be administered. Thus, the first and second capsules are marked prominently and prominently or are marked and arranged to enable the patient to easily distinguish the capsules.

In certain embodiments, the system co-packages multiple capsules and may include a single capsule containing two or more different drugs, e.g., a first tablet containing a first drug and a second tablet containing a second and third drug. In certain embodiments, the first agent can be oxadegril or other gonadotropin releasing hormone (GnRH) releasing antagonist. Oral dose size is an important component of patient compliance. Larger oral dose sizes may make patients reluctant to comply with dose recommendations. In one embodiment, the first capsule contains at least two different tablets, wherein the first tablet includes a first drug and the second tablet includes a second drug and a third drug that are different from the first drug. The first, second and third medicaments have different efficacies, and in example embodiments, the second and third medicaments are included in the capsule to at least partially counteract the undesirable adverse effects of the first medicament on the patient. Thus, the first and second tablets are formed separately from one another and then secured within the first capsule to facilitate simultaneous, immediate release of the drug from the first and second tablets after dissolution of the capsule shell within the patient. That is, the fixation of different tablets within the capsule enables the simultaneous dissolution of the tablets to produce the bioavailability desired by the patient. Thus, the dosage form provided by the first capsule facilitates desirable dissolution and bioavailability of the drug in the patient.

A bioequivalent composition or formulation as used herein is a bioequivalent composition or formulation as defined by the U.S. Food and Drug Administration (FDA).

In addition, co-administration of tablets in a capsule may provide a presentation form that is easy for a patient to swallow and easier to manufacture. Furthermore, the expression allows for co-administration of the first, second and third drugs. Such co-administration allows for a desired balance between the therapeutic efficacy and safety of the first drug in the first tablet and at least the second drug or the third drug in the second tablet. Thus, co-administration of a first drug in a first tablet with second and third drugs in a second tablet facilitates a potential reduction in the undesirable effects of the first drug. In one embodiment, the first drug in the first tablet can be oxarogril or another GnRH antagonist,and the second and third drugs in the second tablet may be a combination of estradiol (E2) and Norethindrone (NETA) (e.g., NETA)

Tablets). Thus, E2/NETA is advantageous for a counter-additive therapy that counters certain adverse effects of hormonal regulation caused by exogenous introduction of GnRH antagonists (such as oxagrad, regorac, etc.).

In any of the various aspects of the disclosure, the first drug may suitably be a GnRH antagonist, such as oxargoli and/or regorac, the second drug may suitably be estradiol, and the third drug may suitably be norethindrone acetate. Oxalagogrel is commonly available as sodium oxalagogrel. For these particular drugs, it is important to use a delivery mechanism that: which facilitates improved and desirable drug dissolution and desirable bioavailability in a patient. For example, it has been found that the dissolution of a drug may increase when the drug is administered in powder form, or may decrease when the drug is in the form of an embedded multi-drug tablet (a first tablet embedded in a second tablet). When in powder form, the dissolution rate and hence bioavailability of the drug in the patient may be undesirably high and thus may not be suitable for administration under certain conditions. When in the form of an embedded multi-drug tablet, it has been found that the drug in the first and second tablets do not dissolve together because the second tablet slows the release of the drug from the first tablet.

The total amount of the oxadiargyl contained in the first capsule or the second capsule may be suitably the free acid equivalent of the oxadiargyl administered as a sodium salt. The free acid equivalent of oxalagril may be provided as 100 milligrams (mg), 150mg, 200mg, 250mg, 300mg, 400mg, 450mg, or 500mg, and ranges constructed therefrom, such as from about 100mg to about 500mg, from about 150mg to about 400mg, and from about 175mg to about 325mg. The total amount of estradiol contained in the first capsule may suitably be 0.5mg, 0.75mg, 1.0mg, 1.25mg or 1.5mg, and ranges so constructed, such as from about 0.5mg to about 1.5mg, from about 0.5mg to about 1.25mg, from about 0.75mg to about 1.5mg or from about 0.75mg to about 1.25mg. The total amount of alkali equivalents of norethindrone obtained as norethindrone acetate contained in the first capsule may suitably be 0.05mg, 0.1mg, 0.25mg, 0.4mg, 0.5mg, 0.6mg, 0.75mg, or 1.0mg, and ranges so constructed, such as from about 0.1mg to about 1.0mg, from about 0.25mg to about 0.75mg, or from about 0.4mg to about 0.6mg.

Tablets within the scope of the present disclosure comprise an active drug and one or more excipients including, but not limited to, binders, fillers, disintegrants, surfactants, efficacy/bioavailability enhancers, glidants, and lubricants.

The binder promotes the binding and cohesiveness of the granules and tablets and serves to increase hardness. Some non-limiting examples of binders include: pregelatinized starch, hydroxypropyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, copovidone, povidone, crospovidone, and combinations thereof. Other examples include polyethylene glycol, polyvinylpyrrolidone, and polyvinyl alcohol. In certain aspects, the binder is copovidone, povidone, HMP, pregelatinized starch, and combinations thereof. In certain further aspects, the binder is copovidone.

Fillers that may be used include, by way of non-limiting example, sugars and sugar alcohols, cellulosics (cellulosics), and other fillers. Non-limiting examples of suitable sugars and sugar alcohols include dextrates (dextrates), dextrin, dextrose, lactose, maltodextrin, mannitol, isomalt, sorbitol, sucrose spherical particles, xylitol, fructose, lactitol, erythritol, maltitol, xylose, glucose, mannose, galactose, maltose, cellobiose, trehalose, and raffinose. Non-limiting examples of cellulose articles include microcrystalline cellulose ("MCC") and silicified MCC. Non-limiting examples of other fillers include calcium carbonate, calcium sulfate, calcium silicate, chitin, chitosan, dibasic calcium phosphate dihydrate, glyceryl palmitostearate, hydrogenated vegetable oil, kaolin, magnesium aluminum silicate, magnesium carbonate, magnesium oxide, polymethacrylates, potassium chloride, powdered cellulose, pregelatinized starch, sodium chloride, starch, talc, and calcium hydrogen phosphate and calcium phosphate. Combinations of the fillers listed above are within the scope of the present disclosure.

Disintegrants that may be used include, by way of non-limiting example, modified starches such as sodium carboxymethyl starch (sodium starch glycolate); crosslinked polyvinylpyrrolidones such as crospovidone; modified celluloses such as croscarmellose sodium; cross-linked alginic acid; gums such as gellan gum and xanthan gum; calcium silicate; and combinations thereof.

The surfactant may act to increase the concentration of the drug in the diffusion layer formed at the interface of the drug surface and the aqueous medium after administration and/or to increase the wettability of the drug/formulation. Non-limiting examples of surfactants include vitamin E d-alpha tocopheryl polyethylene glycol succinate, sodium lauryl sulfate, polysorbates, poloxamers, sodium lauryl sulfate, and the like,

Types and combinations thereof.

Lubricants that may be used include, by way of non-limiting example, magnesium stearate, calcium stearate, stearic acid, sodium stearyl fumarate, hydrogenated vegetable oils, polyethylene glycols (4000-6000), sodium lauryl sulfate, and combinations thereof.

Glidants that may be used include, by way of non-limiting example, colloidal silicon dioxide (e.g., highly dispersed silicon dioxide)

) Animal or vegetable fats, waxes, and combinations thereof.

Other excipients that may be present include acidifying or basifying agents. The acidifying agent may be an organic acid such as, for example, but not limited to, fumaric acid, citric acid, and tartaric acid, for adjusting and/or controlling pH after administration.

The excipients and the weight/weight concentration or ratio of active substance to excipient in the tablet may be selected to increase the dissolution of the drug in aqueous media (e.g. stomach and/or intestine) and thereby improve dissolution and bioavailability. Furthermore, in the case of co-administration of a first tablet having a first drug and a second tablet having a second drug, the excipients and the weight/weight concentration or ratio of its active substance to excipients may be selected to increase the drug bioavailability and minimize any interaction between the first and second tablets that may adversely affect the bioavailability of either drug.

The 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, excipients may be blended, the blend may be milled and ground, and the resulting material may be tableted by compression in tableting equipment known in the art. In some such aspects, the crushed and ground material may be referred to as "intragranular" and the material may then be blended with one or more additional excipients as described above prior to tableting. The one or more additional excipients will be present as an "extra-granular" component in the tablet.

Uncoated tablets (e.g., tablet cores) of the present disclosure may optionally be coated with a film coating to provide tablets that are predominantly tasteless and odorless and are easy to swallow. Furthermore, the film coating prevents dust formation during packaging and ensures robustness during transport. Commercially available coating compositions are suitable for the purposes of this disclosure and include, but are not limited to

YS-1-7003、

YS-1-18202 and->

II White 85F18422。

Tablets containing oxa-golide sodium can be used

Are commercially available. The manufacture of different strength oxalagori is described in AbbVie IncPlease US201900540088 and US20190054027, both of which are incorporated herein by reference in their entirety. Other manufacturers also provide various manufactures of active ingredients of oxarogalline and pharmaceutical products containing oxarogalline, as described in applications WO2017/221144, WO2018/189213 and WO 2018/224063. Tablets containing E2/NETA of different intensities can be used as->

Are commercially available.

Referring now to the drawings, FIG. 1 is an illustration of an embodiment multi-drug delivery system 100 including a first capsule 102 and a second capsule 104 of a medicament. 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 capsule body 112 including a second body portion 114 and a second cap portion 116. In this example 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 is different from the first identifier 118 to facilitate making the first capsule 102 and the second capsule 104 visually distinguishable from one another by the patient. First capsule 102 and second capsule 104 may include any suitable identifier that enables multi-drug delivery system 100 to function as described herein. The identifier may include, but is not limited to, a shading, coloring, symbolic marking, and/or textual marking.

For example, in this example embodiment, a first color 122 (shown as a first pattern) is included on the first capsule 102 and a second color 124 (shown as a second pattern) is included on the second capsule 104. More specifically, the first cap portion 110 is a first color 122 and the second cap portion 116 is a second color 124. The first color 122 is different from the second color 124. Thus, the first cap portion 110 may be visually distinct from the first body portion 108, the second body portion 114, and the second cap portion 116 may be visually distinct from the first body portion 108, the first cap portion 110, and the second body portion 114.

The first identifier 118 and the second identifier 120 may also be configured to indicate when the respective capsule is intended to be administered. For example, in this example embodiment, first identifier 118 includes a first text label 126 and second identifier 120 includes a second text label 128. The first textual indicia 126 is configured to indicate that the first capsule 102 is intended for administration within a first time window of the day, and the second textual indicia 128 is configured to indicate that the second capsule 104 is intended for administration within a second time window of the day different from the first time window. More specifically, a first textual indicia 126 ("AM") indicates that the first capsule 102 is intended for administration before noon and a second textual indicia 128 ("PM") indicates that the second capsule 104 is intended for administration after noon. As will be described in more detail below, the first and

second capsules

102, 104 may contain different types of medicaments. Thus, the first textual indicia 126 and the second textual indicia 128 facilitate quickly and easily identifying the capsule and complying with the administration instructions.

Fig. 2 is a cross-sectional view of an embodiment of first capsule 102 that may be used in multi-drug delivery system 100 (shown in fig. 1), and fig. 8 is a cross-sectional view of an additional first capsule 102 that may be used in multi-drug delivery system 100.

Fig. 3 is a cross-sectional view of an embodiment of a second capsule 104 that may be used in multi-drug delivery system 100 (shown in fig. 1). In this example embodiment, the second capsule body 112 includes a second interior 140 sized to receive at least one first tablet 132 therein. Although illustrated as housing a single first tablet 132, it should be understood that any number of first tablets 132 may be contained within second interior 140 such that multi-drug delivery system 100 is capable of functioning as described herein. The second capsule body 112 includes a second body portion 114 and a second cap portion 116. The second body portion 114 includes an open end 142 that is sized to enable the first tablet 132 to be inserted therethrough. After the first tablet 132 is inserted into the second body portion 114, the second cap portion 116 may be joined with the second body portion 114 to enclose the open end 142 and define and seal the second interior 140.

First capsule body 106 (shown in fig. 2 and 3) and second capsule body 112 may be made of any material that enables multi-drug delivery system 100 to function as described herein. Example capsule body materials include, but are not limited to, gelatin (in the form of hard or soft elastic gelatin capsules), starch, carrageenan, and hydroxypropyl methylcellulose. The first capsule 106 and the second capsule 112 may additionally be prepared with coatings that facilitate swallowing, provide taste barriers, or provide other functions.

As described above, the first capsule 102 and the second capsule 104 may each contain a different medicament or different combination of medicaments such that the first capsule 102 and the second capsule 104 are intended for administration at different times of day. Thus, the second capsule 104 contains only the first tablet 132 therein, and no second tablet 134 therein.

Fig. 17 is a perspective view of an embodiment package 144 that may be used to house and transport multiple drug delivery system 100 (shown in fig. 1). In this example embodiment, the package 144 includes a carton 146 and a blister card 148 positioned within the carton 146. The carton 146 includes a first wall 150 having an access opening 152 defined therein. The access opening 152 is sized to provide access to the blister card 148, and more specifically to a plurality of compartments 154 of the blister card 148, each compartment being configured to receive a separate first or

second capsule

102, 104 therein. Thus, the plurality of first capsules 102 and the plurality of second capsules 104 are contained within the package 144. In one embodiment, the number of first capsules 102 and the number of second capsules 104 contained within the package 144 in compartments 154 are each multiples of a day of the week (e.g., 7, 14, or 21), and each compartment 154 or grouping of compartments 154 is labeled according to the respective day of the week. In addition, the first wall 150 includes informational indicia 156 thereon, which may be symbolic indicia or textual indicia to easily distinguish the

capsules

102 and 104 from one another. Informational indicia 156 is printed on the packaging 144 and includes information regarding when the first and

second capsules

102, 104 are to be administered to the patient. Accordingly, inclusion of compartments 154 in the package 144 that are multiples of the days of the week, and including informational indicia 156 on the first wall 150, facilitates patient compliance with the administration instructions.

The present invention further provides a multi-drug capsule composition comprising: (a) 300mg free acid equivalent of oxagolide, administered twice daily; (b) 1mg estradiol, which is administered once daily; and (c) 0.5mg norethindrone acetate, which is administered once daily. Table A7 provides the mean peak concentration Cmax and the area under the mean curve AUC (t) of the formulation when the composition was administered to healthy volunteers. The invention further includes the mean peak concentration Cmax and area under the mean curve AUC τ which are 80% -125% of the Cmax or AUC τ provided in Table A7. Thus, the mean peak concentration Cmax of oxarogril is 1200 ± 45% from about 80% to about 125% or about 528-2175ng/mL. The mean peak concentration of estradiol, cmax, is 0.06 ± 52% of about 80% to about 125% or 0.023-0.114ng/mL. The mean peak concentration of norethindrone acetate Cmax is 6.1 + -35% from about 80% to about 125% of ng/mL or 3.172-10.294ng/mL. Further, the mean area under the curve AUC τ of said Oxarogli is 2826 ± 44% of ng.hr/mL from about 80% to about 125% or 1266.0-5086.8ng.hr/mL. Said estradiol has an average area under the curve AUC τ of 0.86 ± 38% from about 80% to about 125% or 0.4266-1.4835ng.hr/mL. Said mean area under the curve AUC τ of norethindrone acetate is 23.8 ± 48% of about 80% to about 125% or 9.90-44.03ng.hr/mL.

The present invention further provides a multi-drug capsule composition comprising: (a) 300mg free acid equivalent of oxagolide, administered twice daily; (b) 1mg estradiol, which is administered once daily; and (c) 0.5mg norethindrone acetate, which is administered once daily. Table A7 provides the mean peak concentration Cmax and the area under the mean curve AUC (t) of the formulation when the composition was administered to healthy volunteers. The invention further includes mean peak concentrations Cmax and area under the mean curve AUC τ that are 80% -125% of the Cmax AUC τ provided in table A7. Thus, the mean peak concentration Cmax of oxarogril is about 80% to about 125% of 1200ng/mL or about 960-1500ng/mL. The mean peak estradiol concentration Cmax is from about 80% to about 125% of 0.06ng/mL or 0.048-0.075ng/mL. The mean peak concentration Cmax of norethindrone acetate is about 80% to about 125% of 6.1ng/mL or 4.88-7.625ng/mL. Further, the average area under the curve AUC τ of said oxarogril is about 80% to about 125% of 2826ng.hr/mL or 2260.8-3532.5ng.hr/mL. The estradiol has an average area under the curve AUC τ of from about 80% to about 125% of 0.86ng.hr/mL or from 0.688 to 1.075ng.hr/mL. The average area under the curve AUC tau of the norethindrone acetate is about 80 percent to about 125 percent of 23.8ng.hr/mL or 19.04-29.75ng.hr/mL.

The present invention further provides a multi-drug capsule composition comprising: (a) 300mg free acid equivalent of oxadegril, administered twice daily; (b) 1mg estradiol, which is administered once daily; and (c) 0.5mg norethindrone acetate, which is administered once daily. Table A7 provides the mean peak concentration Cmax and the area under the mean curve AUC (t) of the formulation when the composition was administered to healthy volunteers. The invention further includes the mean peak concentration Cmax and area under the mean curve AUC τ being 80% -125% of Cmax, AUC τ provided in table A7. Thus, the mean peak concentration Cmax of oxadegril is about 80% to about 125% of 629-1770ng/mL or about 503-2212.5ng/mL. The mean peak estradiol concentration, cmax, is from about 80% to about 125% of 0.053-0.062ng/mL or 0.0424-0.0775ng/mL. The mean peak concentration Cmax of norethindrone acetate is about 80% to about 125% or 4.56-8.0ng/mL of 5.7-6.4 ng/mL. Further, the area under the mean curve AUC τ of the Oxagoli is from about 80% to about 125% of 1534-4118ng.hr/mL or 1227.2-5147.5ng.hr/mL. The estradiol has an average area under the curve AUC τ of 0.81-0.91ng.hr/mL from about 80% to about 125% or 0.688-1.1375ng.hr/mL. The mean area under the curve AUC τ of norethindrone acetate is from about 80% to about 125% of 22-26.3ng.hr/mL or from 17.6-33.125ng.hr/mL.

In certain embodiments, the present invention provides an oral multi-drug capsule composition comprising: (a) 300mg free acid equivalent of oxa-rogle; (b) 1mg estradiol; and (c) 0.5mg norethindrone acetate.

When the composition is administered to a healthy adult subject as shown in Table 7 (d), it produces a steady-state concentration Cmax of the oxalagogrel of about 503-2212.5ng/mL _s s; a mean peak concentration Cmax of said estradiol of about 0.0424-0.0775 ng/mL; a mean peak concentration Cmax of said norethindrone acetate of about 4.56-8.0 ng/ml; an area under the mean curve (AUC τ) of said oxadegril from about 1227.2-5147.5 ng.hr/mL; about 0.0.688-1.1375ng.hr/mL(ii) the mean area under the curve AUC (t) of said estradiol; and an AUC (t) of said norethindrone acetate of about 17.6-33.125ng.hr/mL. In another embodiment, when the composition is administered to a healthy adult subject as shown in table 7 (d), it produces a mean peak concentration Cmax of the oxalagogrel of about 1218.4-2185 ng/mL; a Cmax of said estradiol from about 0.0424 to 0.0775ng/mL; a Cmax of said norethindrone acetate of about 4.56-8.0 ng/ml; an area under the mean curve (AUC (t)) of said oxadegril from about 3293.6-5892.5 ng.hr/mL; an AUC (t) of said estradiol of about 0.0.688-1.1375 ng.hr/mL; and an AUC (t) of said norethindrone acetate of about 17.6-33.125ng.hr/mL.

In another embodiment, the present invention provides an oral multi-drug capsule composition comprising: (a) 300mg free acid equivalent of oxa-rogle; (b) 1mg estradiol; and (c) 0.5mg norethindrone acetate. When the composition is administered to a healthy adult subject based on table A7 (c) or table A7 (d), it produces a mean steady-state concentration Cmax of the oxarogue of about 503-2212.5ng/mL _ss (ii) a A mean peak concentration Cmax of said estradiol of about 0.0424-0.0775 ng/mL; and a mean peak concentration Cmax of said norethindrone acetate of about 4.56-8.0ng/ml.

In one embodiment, the oral multi-drug capsule composition has an area under the steady-state curve AUC τ of the oxalagril of about 1227.2-5147.5ng.hr/mL; about 0.0.688-1.1375ng.hr/mL of said estradiol AUC τ; and an AUC τ of said norethindrone acetate of about 17.6-33.125ng.hr/mL.

In another embodiment, the present invention provides an oral multi-drug capsule composition comprising: (a) 300mg free acid equivalent of oxa-rogle; (b) 1mg estradiol; and (c) 0.5mg norethindrone acetate. When the composition is administered to a healthy adult subject based on table A7 (c) or table A7 (d), it produces a mean peak concentration Cmax of the oxagolide of about 1218.4-2185 ng/mL; a mean peak concentration Cmax of said estradiol from about 0.0424 to about 0.0775ng/ml; and a mean peak concentration Cmax of said norethindrone acetate of about 4.56-8.0ng/ml.

In one embodiment, the oral multi-drug capsule composition has about 3293.6-5892.5ng.hr/mL of the agoreanArea under the mean curve AUC of profit _(t) (ii) a An AUC (t) of said estradiol of about 0.0.688-1.1375 ng.hr/mL; and an AUC (t) of said norethindrone acetate of about 17.6-33.125ng.hr/mL.

In another embodiment, the present invention provides an oral multi-drug capsule composition comprising: (a) 300mg free acid equivalent of oxarogril; (b) 1mg estradiol; and (c) 0.5mg norethindrone acetate; further when the composition is administered to a healthy adult subject as shown in table A7 (c) and table A7 (d), it produces an area under the mean curve AUC τ of the oxarogrel of about 1227.2-5147.5 ng.hr/mL; about 0.0.688-1.1375ng.hr/mL of said estradiol AUC τ; and AUC τ of said norethindrone acetate of about 17.6-33.125ng.hr/mL.

In another embodiment, the oral multidrug capsule composition produces a steady state peak concentration Cmax of the oxagolide of about 503-2212.5ng/mL _ss (ii) a A mean peak concentration Cmax of said estradiol from about 0.0424 to 0.0775ng/mL _ss (ii) a And a mean peak concentration Cmax of said norethindrone acetate of about 4.56-8.0ng/ml _ss 。

In another embodiment, the present invention provides an oral multi-drug capsule composition comprising: (a) 300mg free acid equivalent of oxarogril; (b) 1mg estradiol; and (c) 0.5mg norethindrone acetate; further when the composition is administered to a healthy adult subject as shown in table A7 (c) and table A7 (d), it produces an area under the mean curve AUC of the loragol of about 3293.6-5892.5ng.hr/mL _(t) (ii) a An AUC (t) of said estradiol from about 0.0.688-1.1375 ng.hr/mL; and an AUC (t) of said norethindrone acetate of about 17.6-33.125ng.hr/mL.

In another embodiment, the oral multi-drug capsule composition produces a mean peak concentration Cmax of the oxadegril of about 1218.4-2185 ng/mL; a mean peak concentration Cmax of said estradiol of about 0.0424-0.0775 ng/mL; and a mean peak concentration Cmax of said norethindrone acetate of about 4.56-8.0ng/ml.

In another aspect, the oral multi-drug capsule composition comprises 300mg of free acid equivalent of oxadegril, which is administered twice daily; 1mg estradiol, to be administered once a day(ii) a And 0.5mg norethindrone acetate, administered once daily; the results of administration of the compositions to healthy subjects are shown in table A7 (a) or table A7 (b). For the administration, a steady state concentration Cmax of the oxalagogrel of about 528-2175ng/mL _ss (ii) a A mean peak concentration Cmax of said estradiol of about 0.023 to 0.114 ng/mL; a mean peak concentration Cmax of said norethindrone acetate of about 3.172-10.294 ng/ml; an area under the mean curve AUC τ of said oxolinic from about 1266.0 to 5086.8ng.hr/ml; (ii) an area under the average curve AUC τ of about 0.4266-1.4835ng.hr/mL of said estradiol; and an average area under the curve AUC τ of said norethindrone acetate of about 9.90-44.03ng.hr/mL.

In another aspect, the oral multi-drug capsule composition includes 300mg of free acid equivalent of oxadegril, which is administered twice daily; 1mg estradiol, which is administered once daily; and 0.5mg norethindrone acetate, administered once daily; further wherein administration of the composition to a healthy subject results in a mean steady state concentration Cmax of the oxalagril of about 960-1500ng/mL _ss (ii) a A mean peak concentration of estradiol, cmax, of about 0.048-0.075ng/mL _ss (ii) a A mean peak concentration Cmax of said norethindrone acetate of about 4.88-7.625ng/ml _ss (ii) a An area under the mean curve AUC τ of said oxarogle from about 2260.8-3532.5 ng.hr/ml; (ii) an area under the mean curve AUC τ of said estradiol from about 0.688 to 1.075ng.hr/mL; and an area under the average curve AUC τ of said norethindrone acetate of about 19.04-29.75ng.hr/mL.

In one embodiment, the oral multidrug capsule can have an area under the mean curve, AUC τ, of the oxogolide of about 1266.0-5086.8ng.hr/mL; (ii) an area under the mean curve AUC τ of about 0.4266-1.4835ng.hr/mL of said estradiol; and an area under the average curve, AUC τ, of said norethindrone acetate of about 9.90-44.031.4835 ng.hr/mL.

In another aspect, the oral multi-drug capsule composition comprises 300mg of free acid equivalent of oxadegril, which is administered twice daily; 1mg estradiol, which is administered once daily; and 0.5mg norethindrone acetate, administered once daily; further wherein administration of said composition to a healthy adult subject results in an area under the mean curve AUC τ of said estradiol of about 0.4266-1.4835 ng.hr/mL; and an average area under the curve AUC τ of said norethindrone acetate of about 9.90-44.03ng.hr/mL.

In one embodiment, administration of the multi-drug capsule composition to a healthy adult subject can further result in a mean steady state concentration Cmax of the oxalagogrel of about 528-2175ng/mL _ss (ii) a A mean peak concentration Cmax of said estradiol of about 0.023 to 0.114ng/mL _ss (ii) a And a mean peak concentration Cmax of said norethindrone acetate of about 3.172-10.294ng/ml _ss 。

In one embodiment, there is provided an oral multi-drug capsule composition comprising: (a) 300mg free acid equivalent of oxadegril, administered twice daily; (b) 1mg estradiol, which is administered once daily; and (c) 0.5mg norethindrone acetate, which is administered once daily; wherein 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 50rpm, pH 6.8 and 37.5 + -0.5 ℃.

In one embodiment, there is provided an oral multi-drug capsule composition comprising: (a) 200mg free acid equivalent of oxadegril, administered twice daily; (b) 1mg estradiol, to be administered once daily; and (c) 0.5mg norethindrone acetate, administered once daily; wherein 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 50rpm, pH 6.8 and 37.5 + -0.5 ℃.

In another aspect, the oral multi-drug capsule composition comprises 300mg of free acid equivalent of oxagoril; 1mg estradiol; and 0.5mg norethindrone acetate; and produces a mean peak concentration (Cmax) of the oxagoril of about 1218.4ng/mL to about 2185ng/mL after administration of a single dose of the composition to a healthy adult subject; a mean peak concentration (Cmax) of said estradiol from about 0.0424ng/mL to about 0.0775ng/mL; a mean peak concentration (Cmax) of said norethindrone acetate from about 4.56ng/mL to about 8.0 ng/mL; an area under the mean curve (AUC) of the oxarogril from about 3293.6ng.hr/mL to about 5892.5ng.hr/mL _(t) ) (ii) a An average area under the curve (AUC) of the estradiol from about 0.688ng.hr/mL to about 1.1375ng.hr/mL _(t) ) (ii) a And an average area under the curve (AUC) of said norethindrone acetate from about 17.6ng.hr/mL to about 33.125ng.hr/mL _(t) )。

In another aspect, the multi-drug capsule composition includes 300mg of free acid equivalent of oxarogril; 1mg estradiol; and 0.5mg norethindrone acetate; and administration of a single dose of the composition to a healthy adult subject produces a mean peak concentration Cmax of the oxadegril of about 1218.4ng/mL to about 2185ng/mL; a mean peak concentration Cmax of said estradiol from about 0.0424ng/ml to about 0.0775ng/ml; and a mean peak concentration Cmax of said norethindrone acetate from about 4.56ng/ml to about 8.0ng/ml.

In one embodiment, the multi-drug composition has an area under the average curve AUC of the oxogolide of about 3296.6ng.hr/mL to about 5892.5ng.hr/mL _(t) (ii) a (iv) an area under the mean curve AUC of said estradiol from about 0.688ng.hr/mL to about 1.1375ng.hr/mL _(t) (ii) a And an average area under the curve AUC of said norethindrone acetate from about 17.6ng.hr/mL to about 33.125ng.hr/mL _(t) 。

In one aspect, the multi-drug capsule composition includes 300mg of free acid equivalent of oxarogril; 1mg estradiol; and 0.5mg norethindrone acetate; and administration of a single dose of the composition to a healthy adult subject results in an area under the mean curve AUC of said oxogolide of about 3293.6ng.hr/mL to about 5892.5ng.hr/mL _(t) (ii) a (iii) an area under the mean curve AUC of said estradiol from about 0.0.688ng.hr/mL to about 1.1375ng.hr/mL _(t) (ii) a And an average area under the curve AUC of said norethindrone acetate from about 17.6ng.hr/mL to about 33.125ng.hr/mL _(t) 。

In one embodiment, administration of the multi-drug capsule to a healthy adult subject results in a mean peak concentration Cmax of the oxalagogrel of about 1218.4ng/mL to about 2185ng.hr/mL; a mean peak concentration Cmax of said estradiol from about 0.0424ng.hr/mL to about 0.0775ng/mL; and a mean peak concentration Cmax of said norethindrone acetate from about 4.56ng.hr/mL to about 8.0ng/mL.

In another aspect, an oral multi-drug capsule composition comprises 300mg of free acid equivalent of oxadegril; 1mg estradiol; and 0.5mg norethindrone acetate; and at least 75% of the first drug in the first tablet is dissolved after 60 minutes and at least 70% of the second and third drugs in the second tablet are dissolved after 30 minutes using USP apparatus 2 at 50rpm, pH 6.8 and 37.5 ± 0.5 ℃.

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, an oral multi-drug capsule composition comprising 300mg free acid equivalent of oxadegril, 1mg free acid equivalent of estradiol, and 0.5mg free acid equivalent of norethindrone acetate may be used to reduce uterine fibroid volume prior to (prior to) surgery to remove uterine fibroids.

In another aspect, certain doses of oxargoline + estradiol and norethindrone acetate therapy may be used to treat pain associated with endometriosis. For example, in one embodiment, 200mg free acid equivalent of oxadegril +1mg free acid equivalent of estradiol and 0.5mg free acid equivalent of norethindrone may be used to treat pain associated with endometriosis.

In another aspect, a method of treating menorrhagia associated with uterine fibroids comprises orally administering to an adult female patient suffering from uterine fibroids once daily a capsule comprising 300mg free acid equivalent of oxalagril, 1mg estradiol, and 0.5mg norethindrone acetate, and the method produces a mean Cmax of oxalagril from about 1218.4ng.hr/mL to about 2185ng/mL, a mean Cmax of estradiol from about 0.0424ng/mL to about 0.0775ng/mL, a mean Cmax of norethindrone acetate from about 4.56ng/mL to about 8.0 ng/mL; and a mean AUC (t) of oxalagrange of about 3293.6ng.hr/mL to about 5892.5ng.hr/mL, a mean AUC (t) of estradiol of about 0.0.688ng.hr/mL to about 1.1375ng.hr/mL, and a mean AUC (t) of norethindrone acetate of about 17.6ng.hr/mL to about 33.125ng.hr/mL.

Examples

Example 1: estradiol (E2) and Norethindrone (NETA) tablets with a compressed coat of oxalagril. As shown in fig. 4A.

As shown in fig. 4A, an oxagrad/E2/NETA tablet 400 is prepared by coating a commercial source E2/NETA tablet 403 with a compression coating using oxagrad particles 401. The composition of tablet 400 is provided in table 1 and the granule composition is provided in table 2, and the process is shown in fig. 10.

Table 1: composition of example 1

^a： (300 mg of the free acid Oxarolide corresponds to about 310.5mg Oxarolide sodium)

Table 2: composition of Oxagolide fusion particles

Components	％w/w
		Oxagolide sodium salt	59.67％
Sodium carbonate monohydrate	29.75％
		Polyethylene glycol 3350	4.80％
Crospovidone	4.80％
		Colloidal silicon dioxide	0.97％
Total of	100％

Table 3: melt granulation temperature setting

	Temperature (. Degree.C.)
		Bucket 1	20
Bucket 2	40
		Bucket 3	55
Bucket 4	60
		Bucket 5	60
Bucket 6	60
		Die set	70

Example 2: oxagolide tablets containing E2/NETA tablets. As shown in fig. 4B.

The loragol/E2/NETA tablets were prepared according to the process shown in fig. 10. By first loading the final blend and then adding

Tablets 403 are placed on the surface of the powder bed and then manually compressed to make tablets 410 of example 2. The composition of tablet 410 is provided in table 4, and tablet 410 is shown in fig. 4B.

Table 4: EXAMPLE 2 composition of tablets

Example 3: oxagolide and E2/NETA bilayer tablet. As shown in fig. 5.

A bilayer tablet 500 consisting of oxadegril 501 and E2/NETA layer 503 as shown in fig. 3 was prepared using the following example:

example 3-1

The loragol/E2/NETA tablet 500 was prepared according to the process shown in fig. 11A.

(the composition of the tablets is provided in table 6.

Table 5: temperature setting for extrusion melt granulation

	Temperature (. Degree.C.)
		Bucket 1	20
Bucket 2	40
		Bucket 3	55
Bucket 4	90
		Bucket 5	110
Bucket 6	70
		Die set	70

Table 6: EXAMPLE 3-1 composition of tablet

^a： (200 mg of free acid Oxarolide corresponds to about 207.0mg of Oxarolide sodium)

Example 3-2

The loragol/E2/NETA tablet 500 was prepared according to the process shown in fig. 11B.

The composition of tablet 500 is provided in table 7.

Table 7: EXAMPLE 3-2 composition of tablets

Examples 3 to 3

The loragol/E2/NETA tablet 500 was prepared according to the process shown in fig. 11C.

The composition of tablet 500 is provided in table 8.

Table 8: EXAMPLES 3-3 composition of tablets

Examples 3 to 4

The oxagolide/E2/NETA tablets were prepared according to the process shown in fig. 11D.

The composition of the tablets is provided in table 9.

Table 9: EXAMPLES 3-4 composition of tablets

Example 4: oxagolide tablets with E2/NETA coating. As shown in fig. 6.

As shown in fig. 4, the oxagradely/E2/NETA tablets were prepared by coating the oxagradely tablet 601 with a layered coating of the E2/NETA formulation. The loragol tablet 601 was first compressed on a tablet press using the final blend described in example 3-1, with a target tablet weight of 352.7mg. The tablet was prepared using the process shown in fig. 12. The composition of tablet 600 is provided in table 9.

Table 9: EXAMPLE 4 composition of tablets

Example 5: oxagolide and E2/NETA bilayer tablets. As shown in fig. 7.

A bilayer tablet consisting of one layer of the oxadegril formulation 701 and the fast decomposing layer 705 (with embedded E2/NETA tablet 703) was prepared for dissolution testing as shown in fig. 7. The composition of each layer is provided in table 10 and prepared according to the process shown in fig. 13.

In addition, the barrel temperature settings are shown in table 11.

The fast disintegrating layer 705 contains a commercially available Prosolv EASYtab (JRS Pharma) excipient complex and a commercially available E2/NETA tablet 703 (Breckenridge Pharmaceutical Inc.). By sequentially filling the cavities of the mold a2310 with: (1) 80mg of EASYtab, (2) one E2/NETA tablet (3) 80mg of EASYtab and (3) 529mg of Oxalagolide granules, which were then compressed into the final tablet, were each prepared as a bilayer tablet 700.

Table 10: EXAMPLE 5 composition of tablets

Table 11: extruder temperature settings for the molten pellets used in example 5

	Temperature (. Degree.C.)
		Bucket 1	20
Bucket 2	80
		Bucket 3	110
Bucket 4	130
		Bucket 5	130
Bucket 6	130
		Concave die	120
Calender roller	25
		Conveying belt	15
Liquid dose-line	80

Example 6: oxagolide and E2/NETA capsules. As shown in fig. 2.

As shown in fig. 2, the capsule of example 6 provides a representation that is easy for the patient to swallow and simpler to manufacture. The capsules were prepared according to the process shown in fig. 14. The formulation allows for the desirable co-administration of oxarogue/E2/NETA, which in turn provides a desirable balance between the therapeutic and safety effects of oxarogue E2 and NETA. Exogenous addition of GnRH antagonists (such as oxalagril) modulates hormones that may produce certain adverse effects. These adverse effects can be effectively counteracted by administration of appropriate doses and formulations of E2/NETA provided with the oxarogue so that the patient is not adversely affected by competitive antagonism of the oxarogue administration. The composition of the capsules is shown in table 12. The use of preformed E2/NETA tablets 134 in the capsules of example 6 avoids further processing of the estradiol (E2) hormone.

Table 12: EXAMPLE 6 composition of capsules

Example 7: an oxalagonide tablet in a capsule. As shown in fig. 8.

The loragol particles were prepared as described previously (see example 1). Further, the capsules were prepared according to the process shown in fig. 15.

Table 13: example 7 composition of Oxagolide tablets

^a： (75 mg of free acid oxa-rogue corresponds to about 77.9mg of sodium oxa-rogue)

Example 8: oxalagolide fused granules and E2/NETA tablets in capsules. As shown in fig. 9.

Capsules 900 containing both the loragol fused granules 901 and the E2/NETA tablets 903 were prepared according to the process shown in fig. 16. Example 6 and an E2/NETA tablet in size 00 capsules 901

903 (as shown in figure 9) was used for dissolution testing. The capsule 900 may include air or any other suitable filler in the interior space 910. In certain embodiments, the loragol melt granules 901 and the E2/NETA tablets 903 may be mixed/placed together in a capsule 900.

Example 9A: dissolution tests of examples 1 to 8

The gelling properties of amorphous loracarbef produce unpredictability in formulations containing both loracarbef and E2/NETA. It is not clear how oxagobine interacts with E2/NETA in the presence of an anti-gelling agent such as sodium carbonate.

The in vitro dissolution of the oxalagril dosage forms of examples 1-8 was tested at 37.5 ± 0.5 ℃ in 900mL of 0.05m pH 6.8 phosphate buffer using USP apparatus 2 at 50rpm, as shown in tables 15-25. The filtrate was analyzed by HPLC. The loragol, E2 and NETA were measured at 310, 220 or 241nm with a multi-wavelength detector, respectively.

Table 15: dissolution data (mean ± SD) for example 1. As shown in fig. 4A.

Description of the invention	15min	30min	45min	60min
					Oxagolide release	58(7.5)	89(8.1)	100(3.5)	103(2.0)
E2 Release	4(6.4)	67(17.2)	85(1.5)	93(0.6)
					NETA release	4(7.5)	77(21.0)	99(1.5)	101(1.5)

Table 16: dissolution data (mean ± SD) for example 2. As shown in fig. 4B.

Description of the invention	15min	30min	45min	60min
					Oxagolide release	47(5.3)	79(8.7)	96(4.0)	100(0.0)
E2 Release	47(18.6)	78(9.1)	89(4.5)	89(0.6)
					NETA release	54(22.6)	90(10.0)	98(4.0)	96(0.6)

Table 17: dissolution data (mean. + -. SD) of example 3-1. As shown in fig. 5.

Description of the invention	15min	30min	45min	60min
					Oxagolide release	61(6.6)	92(5.3)	101(0.5)	102(0.5)
E2 Release	91(4.2)	93(1.7)	94(1.2)	95(1.1)
					NETA release	94(4.7)	96(0.8)	97(1.1)	96(1.0)

Table 18: dissolution data (mean. + -. SD) for example 3-2. As shown in fig. 5.

Description of the invention	15min	30min	45min	60min	90min
						Oxagolide release	54(9.6)	86(8.4)	100(2.8)	102(0.5)	103(0.6)
E2 Release	39(9.7)	79(5.1)	88(2.8)	90(1.0)	90(1.1)
						NETA release	41(9.7)	82(6.2)	91(2.1)	93(1.0)	93(0.7)

Table 19: dissolution data (mean. + -. SD) for examples 3-3. As shown in fig. 5.

Description of the invention	15min	30min	45min	60min	90min
						Oxagolide release	62(2.0)	92(1.9)	99(0.6)	100(0.6)	100(0.5)
E2 Release	72(2.4)	76(1.6)	79(2.1)	80(2.1)	82(1.9)
						NETA release	92(2.3)	93(1.3)	93(1.5)	93(1.4)	93(1.2)

Table 20: dissolution data (mean. + -. SD) for examples 3-4. As shown in fig. 5.

Description of the invention	15min	30min	45min	60min	90min
						Oxagolide release	60(8.9)	90(7.2)	100(1.3)	101(0.4)	101(0.5)
E2 Release	80(5.3)	84(2.4)	86(1.2)	88(1.5)	89(2.6)
						NETA release	93(4.4)	96(1.3)	96(1.0)	96(0.9)	96(0.9)

Table 21: dissolution data for example 4 (mean ± SD). As shown in fig. 6.

Description of the preferred embodiment	15min	30min	45min	60min	90min
						Oxagolide release	57(7.1)	91(6.1)	102(2.2)	104(0.9)	104(0.9)
E2 Release	98(3.5)	98(3.7)	98(3.8)	98(3.6)	98(3.6)
						NETA release	100(3.6)	100(3.5)	100(3.6)	100(3.5)	100(3.6)

Table 22: dissolution results (mean ± SD) of example 5. As shown in fig. 7

Description of the invention	15min	30min	45min	60min	90min
						Oxagolide release	31(4)	55(5)	73(4)	85(5)	97(5)
E2 Release	22(13)	43(18)	60(12)	70(6)	78(2)
						NETA release	16(13)	41(23)	56(11)	60(1)	63(5)

Table 23: dissolution data (mean ± SD) for example 6. As shown in fig. 2

Description of the preferred embodiment	15min	30min	45min	60min	90min
						Oxagolide release	11(3.9)	43(6.9)	73(6.7)	91(4.2)	102(1)
E2 Release	78(17.3)	95(1.4)	96(1.4)	97(1.1)	97(1.2)
						NETA release	79(18.1)	96(1.3)	97(1.7)	98(1.2)	98(1.5)

Table 24: data for the oxalagori dissolution of example 7 (mean ± SD). As shown in fig. 8

Description of the invention	15min	30min	45min	60min
					4 mini-tablets in HG capsules	14(1.4)	68(4.2)	97(7.1)	101(0.7)
4 mini-tablets in HPMC capsules	5(2.8)	26(3.5)	52(2.1)	71(1.4)
					4 mini-tablets	85(0.7)	103(0.7)	103(0.7)	103(0.7)

Table 25: dissolution data (mean ± SD) for example 8. As shown in fig. 9

Description of the preferred embodiment	15min	30min	45min	60min	90min
						Oxagolide release	23(5.6)	76(4.9)	96(4.7)	99(2.7)	99(2.3)
E2 Release	6(14.3)	66(29.9)	93(2.2)	93(2.9)	95(1.0)
						NETA release	6(15.1)	71(31.0)	99(1.6)	100(1.5)	101(1.0)

Example 9B: dissolution test of example 6

The in vitro dissolution of the oxarogrel dosage form of example 6 was tested using USP apparatus 1 at 100rpm using 900mL of 0.05M sodium phosphate buffer (pH 6.8, maintained at 37 ℃). The indicated dissolution release was measured and the release at various time intervals is shown in table 26 and fig. 29A (oxadegril release), 29B (E2 release) and 29C (NETA release). The filtrate was analyzed by HPLC. The loragol, E2 and NETA were measured at 310, 220 or 241nm, respectively, by a multi-wavelength detector.

Table 26: dissolution data (mean ± SD) for example 6. As shown in fig. 29A, 29B, and 29C, n =6.

Example 10: dosage forms and administration

Drug delivery system 100 includes morning capsule 102 labeled "AM" 126. The capsule 102 is white and yellow and includes an additional identifying indicia "EL300". Capsule 102 includes about 300mg of oxarogril, about 1mg estradiol, and about 0.5mg norethindrone acetate. The capsule 104 is labeled "PM" in white and light blue, and is also labeled "EL300". In certain embodiments, capsule 104 may comprise about 300mg loragol. Each

capsule

102, 104 should be administered orally daily at about the same time of day (e.g., 102 in the morning and 104 in the evening). In one embodiment, each capsule may be taken with or without food and the capsules may be administered daily for about 48 months. In another embodiment, each capsule may be taken with or without food and the capsules may be administered daily for about 60 months. In another embodiment, each capsule may be taken with or without food and the capsules may be administered daily for about 72 months. In another embodiment, each capsule may be taken with or without food and the capsules may be administered daily for about 6 months, about 12-24 months, about 24-36 months, about 36-48 months, about 48-60 months, or about 60-72 months. The duration of treatment may be extended based on the assessment of bone mineral density loss or any other adverse effects, for example, if a woman is treated for a duration of 24 months and continues to have positive benefit-risk characteristics, the duration of treatment may be extended to 36 months or more. To continue treatment, bone mineral density loss may be assessed using any suitable method, including radiographic techniques such as DXA scanning. If a patient misses a dose, the patient should be instructed to take the missed dose within 4 hours of the intended dosing time, and they may take the next dose at the usual time. However, if the missing dose has been taken more than 4 hours from the usual time, the patient should not take the missing dose and take the next dose at the usual time. Only one morning capsule and one evening capsule should be taken each day.

Example 11: experience in clinical trials of adverse reactions

The safety of the system of example 10 was evaluated in two randomized, double-blind, placebo-controlled studies [ UF-1 (NCT 02654054) and UF-2 (NCT 02691494) ], in which 790 premenopausal women received either oxarogril, oxarogril 300mg twice daily or placebo for 6 months. The reference group, which is the 300mg of oxagolide, was included twice daily to characterize the effect of estradiol/norethindrone acetate (E2/NETA) on safety and efficacy. Women who completed a6 month treatment period and met eligibility criteria in UF-1 or UF-2 entered an uncontrolled 6 month blind extension study [ UF-EXTEND (NCT 02925494) ] for a total treatment time of up to 12 months and received either Oxagolide or Oxagolide 300mg twice daily.

Common adverse reactions

The most commonly reported adverse events (at least 10% of the incidence) in UF-1 and UF-2 by women treated with the system of example 10 were hot flashes and/or night sweats (see Table A1). Discontinuation of treatment due to any adverse events occurred in 9.6% (n = 38) of the women treated with oxadegril in UF-1 and UF-2, and 6.6% (n = 13) of the women receiving placebo. Adverse reactions reported in ≧ 5% of women receiving the system of example 10 and reported with greater frequency than placebo are shown in Table A1.

Table A1: adverse events occurring in studies UF-1 and UF-2 in at least 5% of women with uterine fibroids receiving the system of example 10 and occurring at a greater incidence than placebo

In both studies UF-1 and UF-2, discontinuation of treatment due to any adverse events occurred in 9.6% (n = 38) of women treated with the system of example 10 and in 6.6% (n = 13) of women receiving placebo.

Less common adverse reactions

In studies UF-1 and UF-2, adverse events reported at > 3% and < 5% in the example 10 system group and with higher incidence than placebo included: decreased libido, joint pain, hypertension, hair loss, mood swings, abdominal distension, menorrhagia, flu, upper respiratory infection, vomiting and weight gain. The adverse reactions most commonly reported in the extended 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 assessed by dual energy X-ray absorptiometry (DXA). In studies UF-1 and UF-2, there was a greater reduction in BMD in women treated with the system of example 10 compared to placebo. Mean changes in lumbar BMD from baseline at month 6 and 12 were-0.6% and-1.5%, respectively, for women receiving the system of example 10 compared to women receiving placebo, as shown in table A2.

Table A2: percent change from baseline in lumbar BMD at month 6 in UF-1 and UF-2

In the extended study UF-EXTEND, continued bone loss was observed for 12 months with the system of example 10. The proportion of women who experienced a greater than 8% BMD reduction in lumbar, hip or femoral neck at month 6 of treatment in studies UF-1 and UF-2 and at month 12 of treatment in study UF-EXTEND is presented in Table A3.

Table A3: percentage of subjects with greater than 8% BMD reduction in women with uterine fibroids in studies UF-1, UF-2 and UF-EXTEND

To assess recovery, women receiving the system of example 10 continued treatment for up to 12 months and then followed up for another 12 months after cessation of treatment were analyzed for changes in lumbar BMD over time (fig. 19). Continued bone loss at the spine, hip and femoral neck was observed in 24%, 32% and 38% of women, respectively, 12 months after the system of example 10 was stopped. Of these women, all but one woman had a reduction in lumbar BMD of < 3% and all women had a reduction of < 5% at either hip site. Complete recovery of bone loss at the spine, hip and femoral neck was observed in 31%, 36% and 24% of women with bone loss after 12 months of treatment with the system of example 10, respectively. The remaining women had partial recovery and the time to maximum recovery in these women was unknown.

Overall, the presence of E2/NETA in the current 300mg twice daily (BID) oxarogue formulation (the system of example 10) reduced BMD loss compared to 300mg twice daily (BID) oxarogue alone without E2/NETA.

Worsening of suicidal ideation, suicidal behavior, and mood disorders

In the placebo-controlled trial (study UF-1 and UF 2), the system of example 10 was associated with adverse mood changes. Depression, depressed mood and/or crying was reported in 3% of women receiving the system of example 10 compared to 1% in the placebo group.

Elevation of hepatic transaminase

In both studies UF-1 and UF-2, an asymptomatic elevation of serum ALT to at least 3 times the range of the upper limit of reference (ULN) occurred in 1.1% (4/379) of women receiving the system of example 10, and 2.2% (4/184) in women receiving 300mg of Oxagolide twice daily, and not in women receiving placebo. ALT elevation was reported to be 8-fold higher than ULN. No concomitant increase in bilirubin was reported.

Changes in lipid parameters

During systemic treatment in example 10 in UF-1 and UF-2, increases in total cholesterol, low density lipoprotein cholesterol (LDL-C), serum triglycerides and apolipoprotein B were noted. Of UF-1 and UF-2, 16.7% and 0% of female subjects with mildly elevated LDL-C (130-159 mg/dL) at baseline had increased LDL-C concentrations of 190mg/dL or greater during treatment with the system of example 10 and placebo, respectively, and none of the women receiving placebo had such increased LDL-C. Of UF-1 and UF-2, 1.5% and 5.6% of subjects with mildly elevated serum triglycerides (150-300 mg/dL) at baseline had serum triglyceride elevations of up to 500mg/dL during treatment with the system of example 10 and placebo, respectively. The highest serum triglyceride concentration measured during treatment with the system of example 10 was 852mg/dL. In women receiving the system of example 10, the lipid changes were reversible and elevated lipid levels returned to near baseline levels within 3 months after treatment cessation. No cases of pancreatitis were reported in the clinical trial.

After 6 months of cessation of treatment with the system of example 10, menstrual recovery was reported within 1, 2 and 6 months for UF-1, 39.0%, 687.8% and 732.9% of women, respectively; and menstrual recovery was reported within 1, 2 and 6 months for UF-2, 39.0%, 84.75% and 91.52% of women, respectively. After 12 months of treatment with the system of example 10 (UF-1 or UF2, then UF-EXTEND), the incidence of amenorrhea with the system of example 10 was 60.0% to 71.6% per month during the second 6 months of treatment in UF-EXTEND, and 40.8X%, 79.3X% and 89.7X% of women reported menstrual recovery within 1, 2 and 6 months, respectively, after cessation of treatment. It is unclear whether subjects who do not recover menstruation transition to peri-menopausal (peri-postmenonopausal) state.

Endometrial effect

Endometrial biopsies were performed at 6 months in UF-1, UF-2 and UF-EXTEND. There were no abnormal biopsy findings in women treated with the system of example 10, including no endometrial hyperplasia or cancer. Treatment with the system of example 10 in UF-1 and UF-2 resulted in a decrease in mean endometrial thickness from baseline to month 6 (-1.65 mm), based on ultrasound.

Example 12: drug interaction

Possibility of affecting other drugs by the System of example 10

Oxalagogrel is a weak to moderate inducer of cytochrome P450 (CYP) 3A). Co-administration with the system of example 10 can reduce plasma concentrations of the drug that is a CYP3A substrate. Oxarogril is a weak inhibitor of CYP2C 19. Co-administration with the system of example 10 can increase plasma concentrations of drugs (e.g., omeprazole and esomeprazole) that are substrates for CYP2C19 ([ see table A5) ].

Oxagolide is an inhibitor of the efflux transporter P-glycoprotein (P-gp). Co-administration with the system of example 10 can increase plasma concentrations of the drug (e.g., digoxin) as a substrate for P-gp ([ see table A5 ]).

Drug interaction-examples and clinical management

The effect of co-administration of the system of example 10 on concomitant drug concentration and the effect of concomitant drugs on the system of example 10 and the clinical recommendation for interaction of these drugs are summarized in table A5.

Table A5: drug interaction: effect of the System of example 10 on other drugs

Example 13: used in a specific population

Exposure to the system of example 10 in the early stages of pregnancy may increase the risk of early pregnancy loss. The system of example 10 is contraindicated in pregnant women. The system of example 10 should be stopped if pregnancy occurred during treatment. When pregnant rats and rabbits were orally administered with loragol during the organogenesis phase, losses after implantation were observed in pregnant rats at a dose 12 times the Maximum Recommended Human Dose (MRHD). Spontaneous abortion and whole-litter loss were observed in rabbits at 4 and 7 times doses of MRHD. For rats and rabbits, the fetus had no structural abnormalities when exposed up to 25-fold and 7-fold of MRHD, respectively.

Human data

In a clinical trial for stage 3 uterine fibroids, one of the 453 women receiving the system of example 10 was pregnant. The pregnancy caused spontaneous abortion and fetal exposure to the system of example 10 was estimated to occur during the first 18 days of pregnancy.

Animal data

Embryonic fetal development studies were performed in rats and rabbits. During organogenesis (6-17 days of gestation in rats and 7-20 days of gestation in rabbits), oxalagogrel was administered to pregnant rats (25 animals/dose) and rabbits (20 animals/dose) at doses of 0, 100, 150 and 200 mg/kg/day by oral gavage. In rats, maternal toxicity was present at all doses and included six deaths as well as a reduction in body weight gain and food consumption. There was an increase in post-implantation loss in the medium dose group, which was 12-fold higher than MRHD based on AUC. In rabbits, three spontaneous abortions and one whole-litter loss were observed at the highest maternal toxic dose (7-fold MRHD based on AUC). At the lower non-maternal toxic dose of 150 mg/kg/day (which is 4 times that of MRHD), a whole-litter loss occurs. Even in the presence of maternal toxicity, fetal abnormalities were not present at any dose level tested in any species.

At the highest dose tested, the exposure margin for rats and rabbits was 25-fold and 7-fold greater than for MRHD, respectively. However, because of poor binding of oxalagogrel to rat gonadotropin releasing hormone (GnRH) receptors (about 1000-fold lower than to human GnRH receptors), it is not possible for rat studies to identify the pharmacologically mediated effects of oxalagogrel on embryonic fetal development. Rat studies are still expected to provide information on the potential non-target related effects of oxarogeli. In prenatal and postnatal development studies in rats, oxalagrine was provided in the diet from day 6 of pregnancy to day 20 of lactation to achieve doses of 0, 100 and 300 mg/kg/day (25 per dose group). There was no evidence of maternal toxicity. At the highest dose, both females had whole-nest loss and one failed to deliver. The survival rate of pups decreases from birth to day 4 postpartum. Pups had lower birth weights and lower weight gains were observed throughout the pre-weaning period of 300 mg/kg/day. At 300 mg/kg/day, smaller body size and effect on startle response were associated with lower pup body weight. Growth, development and behavior end point after weaning are not affected. At 100 and 300 mg/kg/day (47 and 125 ng/mL), the maternal plasma concentrations in the rats on nursing day 21 were 0.04-fold and 0.1-fold, respectively, of the maximum oxalagril concentration (Cmax) in humans at MRHD. Since the exposure achieved in rats is much lower than in human MRHD, this study cannot predict a potentially higher lactation exposure in humans.

Lactation

Risk summary

The system of example 10 is not recommended for use during lactation. Information on the presence of the system of example 10 in human milk, the effect on breastfed children or the effect on milk yield is limited.

Data of

There is no information about the presence of oxalagril or its metabolites in human milk, the effect on breastfed children or the effect on milk production. Administration of estrogen to lactating women has been shown to reduce the amount and quality of breast milk. Detectable amounts of estrogen and progestin have been identified in breast milk of women receiving a combination of estrogen and progestin. There is insufficient animal data regarding the excretion of oxalagrol in milk. The developmental and health benefits of breast feeding as well as the clinical needs of the mother for the system of example 10 and any potential adverse effects of the system of example 10 or potential maternal conditions on breast-fed infants should be considered.

Example 14: clinical pharmacology

Mechanism of action

The system of example 10 combines oxalagogrel, a GnRH receptor antagonist, and estradiol/norethindrone acetate (E2/NETA), an exogenous combination of estrogen and progestin. Oxarogli inhibits endogenous GnRH signaling by competitively binding to GnRH receptors in the pituitary. Estrogens such as E2 act by binding to nuclear receptors in estrogen responsive tissues. Progestogens such as NETA enhance the differentiation of cells and generally antagonize the effects of estrogens as follows: decreasing estrogen receptor levels, increasing local estrogen metabolism to less active metabolites, or inducing gene products that attenuate the cellular response to estrogen. Progestins exert their effects in target cells by binding to specific progesterone receptors that interact with progesterone responsive elements in the target genes.

Pharmacokinetics

Effects on gonadotropins and ovarian hormones. Administration of oxalagogrel results in dose-dependent inhibition of Luteinizing Hormone (LH) and Follicle Stimulating Hormone (FSH), resulting in 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 of administering the system of example 10 for 6 months to women with uterine fibroids, LH and FSH were about 0.40 to 0.70mIU/mL and 1.8 to 2.5mIU/mL, respectively, resulting in a median estradiol concentration of about 42 to 51pg/mL and a median progesterone concentration of about 0.37 to 0.38 nM.

In a multiple ascending dose study of premenopausal healthy female subjects, either oxarogrel 150mg once daily (QD) or 100, 200, 300 or 400mg twice daily (BID) or placebo was administered for 21 days. Dose-dependent inhibition of sex hormones was achieved rapidly within hours after administration of the first dose on day 1 and continued until day 21, where maximum E2 inhibition was achieved with a dose of 200mg of oxalagogrel twice daily or higher. The P concentration was maintained at a non-ovulatory level throughout the 21 day dosing period when the dose of oxarogril was ≧ 100mg twice a day. Dose-dependent inhibition of FSH and LH was also observed, reaching maximum or near maximum inhibition at 300mg twice daily and 200mg twice daily doses of oxalagril, respectively. LH and FSH were inhibited compared to placebo, however, LH inhibition was more pronounced than FSH inhibition in all groups except the 150mg once daily group. When administration of oxarogue was stopped, 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. Dose of oxadegril alone or with hormone counter-addition therapy was evaluated in healthy adult premenopausal women in an open label study

(E2/norethindrone acetate, 1/0.5 mg) effect of different doses and dosing regimens of oxarogrel together on ovulation, ovarian activity and ovarian reserve.

Hormone sampling was performed three times a week during the 3 month treatment period, and gonadotropin and ovarian hormone inhibition was observed in a dose dependent manner. The mean E2 level observed at the 150mg once daily dose was approximately 40 to 50pg/mL, which is consistent with partial E2 inhibition. On the other hand, and consistent with previous studies, near-maximal inhibition was observed using a 200mg twice-daily and 300mg twice-daily regimen, with mean E2 levels of approximately 20 to 40pg/mL. However, when the dose of Activella was administered with the diragolide 300mg twice-a-day regimen, the average E2 level appeared to increase slightly above that observed with the 150mg once-a-day regimen due to exogenous E2 administration.

Effect on ovulation

In a3 month through cycle study of the system of example 10 in healthy women, approximately 10% ovulate.

Cardiac electrophysiology

The effect of oxarogue on QTc interval was evaluated in 48 healthy adult premenopausal women in a randomized, placebo-controlled and positive-controlled, open-label, single dose, crossover, exhaustive QTc study. The concentration of oxarogue in women given a single dose of 1200mg was 9 times the concentration in women given 300mg of oxarogue twice daily. There was no clinically relevant QTc interval prolongation.

Pharmacokinetics

The pharmacokinetic performance of the system of example 10 in healthy subjects is summarized in table A6. The steady state pharmacokinetic parameters under fasting conditions are summarized in table A7.

Table A6: pharmacokinetic Performance of the System of example 10 in healthy subjects

Table A7 (a): average (% CV) pharmacokinetic parameters for the system of example 10

Table A7 (b): mean (. + -. SD) pharmacokinetic parameters of the system of example 10, with 90% confidence intervals around mean Cmax or AUC ratios of 0.8-1.25

Table A7 (c): 95% confidence intervals around the mean of Cmax and AUC for Oxagolide, E2 and NETA, and 80-125% of the geometric mean for the system of example 10

Table A7 (d): the mean Cmax and 80% -125% of the mean AUC τ for the system of example 10 are depicted.

Specific population

Renal damage

The oxalagori exposure (Cmax and AUC) was unchanged by renal damage. Mean plasma exposure of oxarogril is similar in women with moderate to severe or end-stage renal disease (including women receiving dialysis) compared to women with normal renal function. The effect of renal impairment on the pharmacokinetics of E2/NETA has not been studied.

Patients with liver damage

The oxalagoni exposures (Cmax and AUC) were similar between women with normal liver function and women with mild liver damage. The oxarogle exposure in women with moderate and severe liver damage was approximately 3 and 7 times that of women with normal liver function, respectively. The effect of liver damage on the pharmacokinetics of E2/NETA has not been studied.

Race or group of races

No clinically significant differences in the pharmacokinetics of oxalagorin were observed between white and black subjects or between hispanic and others. The pharmacokinetics of loragol are not clinically significant differences between japanese and chinese han subjects. The influence of the race/ethnic group on the pharmacokinetics of E2/NETA has not been studied.

Body weight/body mass index

Body weight or body mass index did not affect the pharmacokinetics of loragol. The effect of body weight/body mass index on the pharmacokinetics of E2/NETA has not been studied.

Study of drug interactions

Drug interaction studies were performed using oxalagogrel and other drugs that may be co-administered, as well as drugs that are commonly used as probes for pharmacokinetic interactions. Tables 8 and 9 summarize the pharmacokinetic effects of loragol when co-administered with these drugs.

Table A8: drug interaction: changes in the pharmacokinetics of oxarogril in the presence of co-administered drugs

No clinically significant changes in the exposure to oxarogue were observed when 300mg of oxarogue was co-administered with rosuvastatin (20 mg once daily), sertraline (25 mg once daily), or fluconazole (200 mg single dose). The effect of co-administered rosuvastatin, sertraline or fluconazole on E2/NETA has not been investigated.

Table A9: drug interaction: pharmacokinetic changes in co-administered drugs in the Presence of Oxagolide

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

Pharmacogenomics

The Disposition Hepatic uptake date (Disposition Hepatic uptake) of oxalagril relates to the OATP 1B1 transporter. Higher plasma concentrations of oxalagril have been observed in the group of patients with two reduced functional alleles of the gene encoding OATP 1B1 (SLCO 1B 1T > C) (these patients may have reduced hepatic uptake of oxalagril; and therefore higher plasma oxalagril concentrations). The frequency of the SLCO1B 1C/C genotype is typically less than 5% in most races/groups. Female patients with this genotype are expected to have about a 2-fold higher mean concentration of oxalagril compared to females with normal transporter function (i.e., SLCO1B1 521T/T genotype). The adverse effects of loragol have not been adequately evaluated in subjects with two reduced functional alleles of the gene encoding OATP 1B1 (SLCO 1B 1T > C). In one embodiment, for clinical management of patients with two reduced functional alleles of the gene encoding OATP 1B1 (SLCO 1B 1T > C), the dose of oxarogue can be reduced to about 50% of the original dose to achieve an average concentration of oxarogue once per day. Thus, for clinical management of patients with two reduced functional alleles of the gene encoding OATP 1B1, the oxarogril dose can be reduced to half the original dose, the dosing interval can be reduced from twice daily to once daily, or the dosing can be reduced from daily to every other day.

Example 15: non clinical toxicology

Loragol and its preparing process

Two-year carcinogenic studies conducted by dietary route administration of oxalagril in mice (50, 150 or 500 mg/kg/day) and rats (150, 300 or 800 mg/kg/day) revealed that tumors in mice did not increase until 11.9-fold MRHD based on AUC. In rats, thyroid (male and female) and liver (male only) tumors increased at high doses (7.7 to 8.1 fold MRHD). Rat tumors may be species specific and have negligible association with humans. In a series of experiments, oxadegril was not genotoxic or mutagenic, including in vitro bacterial back-mutation assays, in vitro mammalian cell forward mutation assays at the thymidine kinase (TK ±) locus in L5178Y mouse lymphoma cells, and in vivo mouse micronucleus assays. In a reproductive study in rats, oxarogine had no effect on reproduction at any dose (50, 150 or 300 mg/kg/day). Based on AUC, the fold exposure of MRHD in females was about 2.9 fold compared to the highest dose of 300 mg/kg/day in female rats. However, these data have low relevance to humans because of the low affinity of oxalagril for the GnRH receptor in rats and because the effects on reproduction are most likely mediated through the GnRH receptor.

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 research

In two randomized, double-blind, placebo-controlled studies [ UF-1 (NCT 02654054) and UF-2 (NCT 02691494)]In which 790 premenopausal women with at least two Menstrual Blood Loss (MBL) greater than 80mL (assessed by the Alkaline Hemin (AH) method, an objective, validated method of quantifying MBL volume on sanitary products) had received the system of example 10 or the premenopausal women receiving a cycle of at least two menses greater than 80ML (MBL) in this study) demonstrated efficacy of the system of example 10 in controlling menorrhagia (HMB) associated with uterine fibroidsPlacebo lasts for 6 months. Each study also included a reference group of oxagoril at 300mg twice a day to characterize the effect of E2/NETA on efficacy and safety. In UF-1 and UF-2, the median age is 43 years (ranging from 25 to 53 years); 68% of women are black or african americans, 29% are white, and 3% are other races; 16% of women had uterine fibroids and concurrent adenomyosis at baseline as assessed by transvaginal and transabdominal ultrasound (TVU/TAU) and/or MRI; MBL in the range of 83.8mL to 1207.1mL at baseline; passing TVU/TAU at 71.6cm ³ To 3347.9cm ³ A uterine volume within the range; and 1cm by TVU/TAU ³ To 1081.5cm ³ Primary uterine fibroid volumes within range.

Menstrual bleeding

The primary endpoint of both studies was the proportion of women who had received successful treatment, defined as achieving the following two points: 1) MBL volume of less than 80mL in the last month, and 2) a 50% or greater reduction in MBL volume from baseline to the last month. MBL at baseline was defined as the mean of the total MBL volume from at least 2 screening menstrual cycles > 80 mL. The last month is defined as and includes the last 28 days before the last treatment visit date or last administration date. A higher proportion of women treated with the system of example 10 were successfully treated compared to placebo (see table a 10).

Table a10: proportion of women successfully treated in studies of UF-1 and UF-2

Change in volume of MBL

The system of example 10 reduced mean MBL volume from baseline by month 1 to month 6 compared to placebo (see figures 20 and 21). In study UF-1, the mean baseline MBL for the system of example 10 was 238.0mL and placebo was 255.3mL. In study UF-2, the mean baseline MBL for the system of example 10 was 2298.5mL and that for placebo was 254.3mL. Compared to women taking placebo, women taking the system of example 10 had a significant mean reduction in MBL volume from baseline to the last month in both UF-1 and UF-2 studies (study UF-1: system of example 10-176.7 mL and placebo 0.81mL; study UF-2: system of example 10-168.89 mL and placebo-4.3 mL).

Suppression of bleeding

In studies UF-1 and UF-2, a greater proportion (57% and 61%, respectively) of women receiving the system of example 10 experienced hemorrhage suppression in the last month, defined as no bleeding (but allowed drip), compared to 4% and 5% of women receiving placebo, respectively.

Hemoglobin (Hgb)

Over 90% of women with baseline Hgb ≦ 10.5g/dL were iron supplemented. In studies UF-1 and UF-2, a greater proportion of anemic women with baseline Hgb ≦ 10.5g/dL treated with the system of example 10 achieved an increase in Hgb ≧ 2g/dL from baseline to month 6, compared to placebo-treated women (see Table A11).

Table a11: proportion of women with baseline Hgb ≦ 10.5g/dL and an Hgb increase of ≥ 2g/dL at month 6

Example B1

PBPK model-based virtual bioequivalence assessment of different loragol formulations

While oxarogril is approved for the treatment of moderate to severe pain associated with endometriosis at a dose of 150mg once daily and 200mg twice daily, rolled tablets (RC 2) are used as commercial formulations. A combination of 200mg of oxasugole and 0.5mg of estradiol (E2) 1 mg/norethindrone acetate (NETA) is being evaluated in a phase 3 trial of endometriosis. The phase 3 study product consisted of a 200MG tablet of oxalagril co-administered with the E2/NETA tablet, while the proposed commercial product consisted of 200MG Melt Granulated (MG) tablet of oxalagril and the E2/NETA tablet as Fixed Dose Combination (FDC) morning capsule and 200MG evening capsule of oxalagril. Dissolution tests performed using a USP I (basket) apparatus show that the in vitro dissolution profiles of the phase 3 and to-BE-marketed (TBM) capsules are different and therefore require evaluation of Bioequivalence (BE) with respect to in vivo exposure. Physiological-based pharmacokinetic (PBPK) modeling was used with in vitro dissolution data for various formulations to perform virtual BE simulations in order to demonstrate simulated bioequivalent exposure without performing clinical BE studies.

Method

The previously developed PBPK model for oxalagoni (Simcyp V17) validated with clinical PK and drug-drug interaction (DDI) data was used as the basic model (see Chiney et al, 2019, clinical pharmacologics). The PBPK Model was updated by integrating the in vitro Dissolution data of the oxarogril formulation using a mechanical ADAM (Advanced Dissolution and Absorption Model) module that captures the Dissolution and Absorption of the drug in different regions of the gastrointestinal tract. Dissolution testing of the relevant formulation was performed using a USP-I apparatus at 100RPM in 900mL of 0.05M sodium phosphate (pH 6.8). The PBPK model containing the in vitro data was externally validated using clinical data from two clinical bioequivalence studies in which 300mg doses of oxalagori capsules were evaluated against reference RC2 tablets for different indications. The model predicted exposure (Cmax and AUC) in the virtual healthy female population was compared to the clinical observations of each formulation from the BE study. The model predicted exposure ratios of Cmax and AUC for the test capsule formulation relative to the reference (RC 2) tablet were also compared to clinical observations. The clinically validated PBPK model was used to simulate a virtual bioequivalence test in a cross-over fashion to compare the loragol 200mg capsules and the 200mg RC2 tablets. The different virtual objects were subjected to 100 virtual BE trials to evaluate the effect of inter-occasion or inter-trial variability on the bioequivalence of the formulation.

As a result, the

In contrast to the clinical observations from the BE study, the PBPK model predicted exposure of 300mg tablet (RC 2) and 300mg capsule formulations with a prediction error of less than 25%. Model predictions of relative BE ratios comparing test and reference formulations also compare favorably with clinical data from BE studies. These BE study results were not used for model calibration or validation and thus were used as external validation for PBPK model prediction. This provides confidence in using their in vitro dissolution data as input to predict exposure of clinically untested formulations using the PBPK model. Based on the results of the virtual BE test simulation, both capsule formulations at a 200mg dose met the bioequivalence criteria of 0.80-1.25 compared to the reference RC2 formulation. The Cmax and AUC ratios for the test formulation to the reference formulation were bioequivalent, with geometric means of the Cmax and AUC ratios predicted to be 0.9 and 0.95, respectively. The 90% prediction interval of the exposure ratio is also within the BE standard. The results of multiple trial simulations using different virtual subjects also demonstrate that the geometric mean and 90% confidence interval of the exposure ratio for all the dummy trials meet the BE criteria.

Conclusion

This new work combines in vitro and clinical data for different formulations, using PBPK modeling for virtual BE simulation instead of clinical trials. Virtual BE simulation results from a clinically validated PBPK model were used to demonstrate that the TBM formulation of oxarogle may lead to similar exposure as the clinical trial formulation and to demonstrate the rationality of the in vivo bioequivalence exemption request. The analysis also showed that permeability, but not solubility, is a determinant of oxalagril absorption, producing bioequivalent in vivo exposure despite different in vitro dissolution profiles. This work demonstrates the value of combining in vitro and in silico data in the development and evaluation of new formulations.

Example B2

Clinical pharmacology challenges in assessing bioequivalence of loragory fixed dose combination products

Oxalagoril is being developed for the treatment of menorrhagia (HMB) associated with Uterine Fibroids (UF). The study drug product being studied in the UF 3 phase trial was a 300mg twice daily roller compacted 2 (RC 2) tablet of oxalagril co-administered with estradiol/norethindrone acetate (E2/NETA) 1mg/0.5mg once daily tablet. For patient compliance and convenience, the proposed formulation to market (TBM) is a Fixed Dose Combination (FDC) capsule consisting of loracarbef/E2/NETA 300/1/0.5mg (for morning doses) and loracarbef 300mg (for evening doses). The two formulations exhibited different in vitro dissolution profiles, indicating a potentially different in vivo release profile. The objective of the study was to evaluate (1) the BE of TBM oxalagril FDC morning capsule formulation compared to oxalagril RC2 tablets co-administered with E2/NETA tablets in postmenopausal healthy women; (2) TBM loragol evening capsule formulation vs loragol RC2 tablet BE in premenopausal healthy women; and (3) the effect of food (high fat meal) on the bioavailability of oxalagril capsules.

Method

Current studies include two separate large phase 1 BE studies. The first was a randomized, single-centered, single-dose, four-sequence, two-cycle/three-cycle, crossover, phase 1 BE study. The study was conducted in healthy premenopausal women (N = 57) to evaluate BE between the loragol 300mg capsule (test product; T) and the loragol 300mg RC2 tablet (reference product; R), as well as the effect of food on bioavailability of the loragol capsule. Serial blood samples for the oxarogeli assay were collected on the study day before and up to 24 hours after dosing.

Separate randomized, multicenter, single dose, four sequence, two/three cycle, crossover, phase 1 BE studies were performed in healthy postmenopausal women (N = 167) to evaluate BE between the oxarogine/E2/NETA 300/1/0.5mg FDC capsules (T) and the oxarogine 300mg RC2 tablets (co-administered with E2/NETA 1/0.5mg tablets (R)). The effect of food on the bioavailability of oxalagoni FDC capsules was also evaluated. Serial blood samples for the oxarogril, total estrone and norethindrone assays were collected on the study day before and up to 72 hours after dosing.

For both BE studies, non-compartmental analysis (NCA) was performed using SAS software (Certara, princeton, NJ, usa). The geometric mean ratio of the T/R of the maximum observed plasma concentration (Cmax) and the area under the plasma concentration-time curve from time zero to infinity (AUC 0-inf) (90% confidence interval [ CI ]) was calculated for BE evaluation. Food impact was assessed by assessing the relative bioavailability (90% confidence interval) of the oxalagril capsules (both oxalagril capsules and FDC capsules) under fasted and fed conditions.

As a result, the

For the oxarogue study alone, the GMR (90 ci) of the T/R of the oxarogue Cmax and AUC0-inf were 0.87 (0.81-0.94) and 0.97 (0.93-1.01), respectively, under fasting conditions, indicating that the oxarogue 300mg capsule was bioequivalent to the oxarogue 300mg RC2 tablet. The Cmax and AUC0-inf of oxa-gol decreased by 40% and 28%, respectively, after administration of 300mg capsules after a high-fat breakfast. Tmax was delayed by approximately 1 hour compared to fasted conditions. The effect of food on the relative bioavailability of oxalagogrel was not clinically relevant based on exposure-response analysis.

For the Oxaroy FDC study, GMRs (90 CI) of T/Rs of Cmax of Oxaroy, baseline-adjusted total estrone and norethindrone were 0.91 (0.87-0.95), 1.02 (0.96-1.08), 1.12 (1.08-1.15), respectively, while GMRs (90 CI) of T/Rs of AUC0-inf of Oxaroy, baseline-adjusted total estrone and norethindrone were 0.97 (0.95-1.00), 0.93 (0.87-1.00), 0.96 (0.94-0.98), respectively, under fasting conditions. Additional hormone analytes also meet the BE criteria. These findings indicate that the oxalaggrin/E2/NETA 300/1/0.5mg FDC capsules are bioequivalent to oxalaggrin 300mg RC2 tablets co-administered with 1/0.5mg of the E2/NETA tablets. Following administration of oxarogril/E2/NETA 300/1/0.5mg FDC capsules after a high fat breakfast, the Cmax and AUC0-inf were reduced by 36% and 25%, respectively, compared to exposure under fasting conditions.

Conclusion

The results of the BE study showed that TBM oxaroglyne FDC (oxaroglyne/E2/NETA 300/1/0.5 mg) morning capsule and oxaroglyne 300mg evening capsule formulations were bioequivalent to the UF 3 phase clinical trial formulation (co-administered oxaroglyne 300mg tablets and E2/NETA I/0.5mg tablets), despite their different in vitro dissolution profiles. The effect of food (high fat meal) on the TBM product composition was comparable to orilisa previously administered with oxaragoli ^TM The results observed for the commercial tablets were similar, and with the pair E2/NETA ((R))

USPI) as expected. Thus, morning FDC 300/I/0.5mg andnight Oxagolide 300mg capsule.

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

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 the chemical structures, substituents, derivatives, intermediates, syntheses, compositions, formulations or methods of use of the invention, may be made without departing from the spirit and scope thereof.

Claims

1. A multi-drug delivery system comprising

A first capsule, comprising:

a first capsule body comprising a first interior;

a first tablet in the first interior, the first tablet comprising a first drug; and

a second tablet in the first interior, the second tablet comprising at least a second drug different from the first drug and a third drug different from the first and second drugs, wherein the first tablet and the second tablet are configured to be released simultaneously upon dissolution of the first capsule in a patient; and

a second capsule co-packaged with the first capsule comprising:

a second capsule body comprising a second interior; and

a third tablet in the second interior, the third tablet comprising the first drug,

wherein 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 50rpm, pH 6.8 and 37.5 + -0.5 ℃.

2. The multi-drug delivery system of claim 1, wherein the first tablet comprises oxa-golide.

3. The multi-drug delivery system of claim 1 or 2, wherein the first tablet comprises about 175 to about 325mg of oxarogrel and the second tablet comprises about 0.75 to about 1.25mg of estradiol.

4. The multi-drug delivery system of claim 3, wherein the second tablet further comprises from about 0.1mg to about 1mg norethindrone acetate.

5. The multi-drug delivery system of claim 3, wherein the release of estradiol is equal to or greater than 70% after about 15 minutes.

6. The multi-drug delivery system of claim 1, wherein the first capsule is labeled with a first identifier and the second capsule is labeled with a second identifier different from the first identifier such that the first capsule and the second capsule are visually distinguishable.

7. The multi-drug delivery system of claim 6, wherein the first identifier is configured to indicate that the first capsule is intended for administration within a first time window of day, and the second identifier is configured to indicate that the second capsule is intended for administration within a second time window of day different from the first time window.

8. The multi-drug delivery system of claim 7, wherein the first identifier is configured to indicate that the first capsule is intended for administration at a first time window before noon and the second identifier is configured to indicate that the second capsule is intended for administration at a second time window after noon.

9. The multi-drug delivery system of any one of claims 6-8, wherein the first identifier is a first color included on the first capsule and the second identifier is a second color included on the second capsule.

10. The multi-drug delivery system of any one of claims 1-9, further comprising a package containing a plurality of compartments configured to contain the first capsule and the second capsule.

11. The multi-drug delivery system of claim 10, wherein the package comprises a blister card defining the plurality of compartments, wherein the first and second capsules contained in the plurality of compartments are accessible by puncturing a seal in the blister card.

12. The multi-drug delivery system of claim 10 or 11, wherein the packaging contains information printed thereon relating to when to administer the first and second capsules to a patient.

13. The multi-drug delivery system of claim 10, wherein the blister card comprises a first row of the plurality of compartments and a second row of the plurality of compartments, wherein the first capsule is housed in the first row, wherein the second capsule is housed in the second row, and wherein the first row and the second row are visually distinct.

14. A capsule for delivering a medicament to a patient, the capsule comprising:

a capsule body comprising an interior;

a first tablet within said interior, said at least one first tablet comprising a first drug; and

a second tablet in the interior, the second tablet comprising at least a second drug different from the first drug, wherein the first and second tablets are configured to be released simultaneously upon dissolution of the capsule in a patient,

wherein at least 75% of the first drug in the first tablet dissolves after 60 minutes and at least 70% of the second drug in the second tablet dissolves after 30 minutes using USP apparatus 2 at 50rpm, pH 6.8 and 37.5 + -0.5 ℃.

15. The capsule of claim 14, wherein the first tablet comprises about 175mg to about 325mg of oxadegril and the second tablet comprises about 0.75mg to about 1.25mg of estradiol.

16. The capsule of claim 15, wherein the second tablet further comprises about 0.1mg to about 1.0mg norethindrone acetate.

17. The capsule of claim 15, wherein the release of estradiol is equal to or greater than 70% after 16 minutes.

18. The capsule of claim 14, wherein the capsule body is oblong shaped to define a longitudinal axis, wherein the at least one first tablet and the second tablet are arranged in a row relationship along the longitudinal axis in the interior.

19. The capsule of claim 14, wherein said at least one first tablet and said second tablet are distinct tablets that have been formed separately from one another and then secured within said interior.

20. The capsule of claim 14, wherein the capsule body does not contain a medicament in powder form.

21. The capsule of claim 14, wherein the capsule body does not include a barrier extending between the first tablet and the second tablet, and wherein the first tablet and the second tablet are not bonded together in the interior.

22. The capsule of claim 14, wherein the second tablet comprises the second drug and a third drug, both of which are configured to have a dissolution rate of greater than about 80% within the first 30 minutes of administration using USP apparatus 2 at 50rpm, pH 6.8 and 37.5 ± 0.5 ℃.

23. The capsule of claim 14, wherein the first capsule comprises gelatin.

24. A method of delivering a drug to a patient, the method comprising:

delivering a first capsule to the patient, wherein the first capsule comprises:

a first capsule body comprising a first interior;

a second tablet in the first interior, the second tablet comprising at least a second drug different from the first drug, wherein the first and second tablets are configured to be released simultaneously upon dissolution of the first capsule in the patient; and

delivering to the patient a second capsule co-packaged with the first capsule after a predetermined amount of time has elapsed after administration of the first capsule, wherein the second capsule comprises:

a second capsule body comprising a second interior; and

a third tablet in the second interior, the third tablet comprising the first drug.

25. The method of claim 24, wherein the first tablet comprises about 175 to 325mg of oxarogrel and the second tablet comprises about 0.75 to 1.25mg of estradiol and about 0.1 to 1.0mg of norethindrone.

26. The method of claim 24, wherein the release of estradiol is equal to or greater than 70% after 20 minutes.

27. The method of claim 24, wherein delivering a second capsule comprises delivering the second capsule at least 5 hours after administering the first capsule.

28. The method of claim 24, wherein delivering a first capsule comprises delivering the first capsule at a first time window prior to noon of the day, and wherein delivering a second capsule comprises delivering the second capsule at a second time window after noon of the day.

29. The method of claim 24, further comprising providing a package containing a plurality of compartments configured to receive the first and second capsules therein.

30. The method of claim 29, further comprising containing a plurality of first capsules and a plurality of second capsules within the package, wherein the number of first capsules and the number of second capsules contained within the package are each a multiple of a day of the week.

31. A multi-drug tablet having 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 within the first tablet.

33. The multi-drug tablet of claim 32, further comprising crospovidone.

34. A medicament container assembly, comprising:

a first group of a plurality of compartments, each compartment configured to hold a first capsule;

a second group of a plurality of compartments, each compartment configured to hold a second capsule co-packaged with the first capsule;

wherein the first capsule comprises a first interior;

a second tablet in the first interior, the second tablet comprising at least a second drug different from the first drug, wherein the first and second tablets are configured to be released simultaneously upon dissolution of the first capsule in a patient; and

the second capsule comprises a second capsule body comprising a second interior and a third tablet in the second interior, the third tablet comprising at least one drug selected from the group consisting of: the first drug, the second drug, or a third drug.

35. A multi-drug capsule comprising:

a first tablet comprising a first drug;

a second tablet comprising at least a second drug different from the first drug and a third drug different from the first and second drugs,

wherein the first and second tablets are configured to be released simultaneously upon dissolution of the capsule in a patient;

36. The multi-drug capsule of claim 35, wherein the first tablet comprises oxarogril.

37. The multi-drug capsule of claim 35 or 36, wherein the first tablet comprises about 175mg to about 325mg of oxadegril and the second tablet comprises about 0.75mg to about 1.25mg of estradiol.

38. An oral multi-drug capsule composition comprising:

(a) 300mg free acid equivalent of oxa rogle;

(b) 1mg of estradiol; and

(c) 0.5mg norethindrone acetate;

wherein, upon administration of a single dose of the composition to a healthy adult subject, a mean peak concentration (Cmax) of the oxadiargyl of about 1218.4ng/mL to about 2185ng/mL is produced;

a mean peak concentration (Cmax) of said estradiol from about 0.0424ng/mL to about 0.0775ng/mL;

a mean peak concentration (Cmax) of said norethindrone acetate from about 4.56ng/mL to about 8.0 ng/mL;

an area under the mean curve (AUC) of said oxarogue from about 3293.6ng.hr/mL to about 5892.5ng.hr/mL _(t) )；

An area under the mean curve (AUC) of said estradiol from about 0.688ng.hr/mL to about 1.1375ng.hr/mL _(t) ) (ii) a And

about 17.6ng.hr/mL to about 33.125ng.hr/mL of said area under the average Curve (AUC) of norethindrone acetate _(t) )。

39. An oral multi-drug capsule composition comprising:

(a) 300mg free acid equivalent of oxa rogle;

(b) 1mg estradiol, which is administered once daily; and

(c) 0.5mg norethindrone acetate;

wherein administration of a single dose of the composition to a healthy adult subject results in a mean peak concentration Cmax of said oxadegril of about 1218.4ng/mL to about 2185ng/mL;

a mean peak concentration Cmax of said estradiol from about 0.0424ng/ml to about 0.0775ng/ml; and

a mean peak concentration Cmax of said norethindrone acetate of about 4.56ng/ml to about 8.0ng/ml.

40. The oral multi-drug capsule composition of claim 39, wherein produce

Area under average curve AUC of said oxogolide from about 3296.6ng.hr/mL to about 5892.5ng.hr/mL _(t) ；

(iv) an area under the mean curve AUC of said estradiol from about 0.688ng.hr/mL to about 1.1375ng.hr/mL _(t) (ii) a And

(iii) about 17.6ng.hr/mL to about 33.125ng.hr/mL of the mean area under the curve AUC of said norethindrone acetate _(t) 。

41. An oral multi-drug capsule composition comprising:

(a) 300mg free acid equivalent of oxa rogle;

(b) 1mg of estradiol; and

(c) 0.5mg norethindrone acetate;

further wherein administration of a single dose of the composition to a healthy adult subject results

Area under average curve AUC of said oxogolide from about 3293.6ng.hr/mL to about 5892.5ng.hr/mL _(t) ；

(ii) an area under the mean curve AUC of said estradiol from about 0.0.688ng.hr/mL to about 1.1375ng.hr/mL _(t) (ii) a And

(iii) about 17.6ng.hr/mL to about 33.125ng.hr/mL of the mean area under the curve AUC of said norethindrone acetate _(t )。

42. The oral multidrug capsule composition of claim 41, wherein administration of the composition to a healthy adult subject results in

A mean peak concentration Cmax of the oxadegril from about 1218.4ng/mL to about 2185ng.hr/mL;

a mean peak concentration Cmax for said estradiol of about 0.0424ng.hr/mL to about 0.0775ng/mL; and

(iii) a mean peak concentration Cmax of said norethindrone acetate of about 4.56ng.hr/mL to about 8.0ng/mL.

43. An oral multi-drug capsule composition comprising:

(a) 300mg free acid equivalent of oxagoril;

(b) 1mg of estradiol; and

(c) 0.5mg norethindrone acetate;

44. A method of safely treating menorrhagia associated with uterine fibroids (fibroids) in a pre-menopausal female patient, comprising orally administering to said patient once daily:

(a) 300mg free acid equivalent of oxa rogle;

(b) 1mg of estradiol; and

(c) 0.5mg of norethindrone acetate,

wherein said method produces the following mean Cmax

The oxarogue is about 1218.4ng.hr/mL to about 2185ng/mL;

said estradiol is from about 0.0424ng/mL to about 0.0775ng/mL;

the norethindrone acetate is from about 4.56ng/mL to about 8.0ng/mL, and

following average AUC _(t)

Said oxa rogle is about 3293.6ng.hr/mL to about 5892.5ng.hr/mL;

said estradiol is from about 0.0.688ng.hr/mL to about 1.1375ng.hr/mL; and

the norethindrone acetate is from about 17.6ng.hr/mL to about 33.125ng.hr/mL, and

wherein after a treatment period of about 6 months, the patient achieves an increase in hemoglobin equal to or greater than about 2g/dL as compared to baseline when the patient did not receive oxagoril, estradiol, and norethindrone.

45. A capsule for delivering a medicament to a patient, the capsule comprising:

a capsule body comprising an interior;

wherein at least 75% of the first drug in the first tablet dissolves after 45 minutes and at least 90% of the second and third drugs in the second tablet dissolves after 30 minutes using USP apparatus 1 at 100rpm, pH 6.8 and 37.5 + -0.5 ℃.

46. An oral multi-drug capsule composition bioequivalent to any one of the compositions of claims 31-34, 36-45.

47. A method of delivering a co-packaged drug to a patient for oral use, the method comprising:

delivering a first capsule to the patient, wherein the first capsule comprises:

a first capsule body comprising a first interior;

delivering to the patient, after a predetermined amount of time has elapsed after administering the first capsule, a second capsule co-packaged with the first capsule, wherein the second capsule comprises:

a second capsule body comprising a second interior; and