WO2024148128A1 - Follicle stimulating hormone dosage forms and methods - Google Patents

Abstract

The present disclosure relates generally to ingestible devices containing follicle stimulating hormone (FSH), wherein the devices are structured and formulated to deliver therapeutically effective amounts of FSH into a gastrointestinal (GI) lumen wall or surrounding tissue thereof (e.g., peritoneum or peritoneal cavity) after ingestion of the device, and achieve desired pharmacokinetic and therapeutic effects.

Description

FOLLICLE STIMULATING HORMONE DOSAGE FORMS AND METHODS

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. provisional application 63/437,265, filed January 5, 2023, the entire contents of which are incorporated herein by reference.

FIELD OF INVENTION

[0002] The present disclosure relates generally to compositions, dosage forms, devices, and methods for delivery of follicle stimulating hormone (FSH) by ingestion. More specifically, the present disclosure relates to ingestible dosage forms (e.g., ingestible devices) that contain a composition comprising FSH that are structured and formulated to deliver therapeutically effective amounts of FSH into a gastrointestinal (GI) lumen wall (e.g., stomach wall, intestinal wall, colon, etc.) of the subject or surrounding tissue thereof (e.g., peritoneum or peritoneal cavity) to achieve desired pharmacokinetic and therapeutic results. The compositions, devices, and methods may be useful, for example, for treating infertility (e.g., stimulating follicle development or stimulating ovulation induction in a female patient or treating hypogonadotropic hypogonadism or idiopathic infertility in a male patient (e.g., for stimulation of spermatogenesis)) and other conditions in which treatment with FSH may be indicated.

BACKGROUND

[0003] The following discussion is merely provided to aid the reader in understanding the disclosure and is not admitted to describe or constitute prior art thereto.

[0004] There are a number of approved FSH pharmaceutical products that are administered by subcutaneous or intramuscular injection. Several approved FSH products contain FSH extracted from the urine of post-menopausal women (e.g., REPRONEX®, MENOPUR®, and BRAVELLE®). Other approved FSH products contain recombinant FSH, e.g., recombinant human FSH expressed in mammalian cells, such as Chinese Hamster Ovary (CHO) cells (e.g., GONAL-F® and FOLLISTIM®) or expressed in a human cell line such as the Per.C6 cell line (REKOVELLE®). Urinary-derived and CHO-cell derived FSH products are dosed in terms of international units, with typical doses ranging from 50 IU to 450 IU depending on the patient and condition being treated. For example, for induction of ovulation, GONAL-F® (follitropin alfa) may be administered subcutaneously at a starting dose of 75 IU per day for 14 days, with subsequent dosing individualized (increased or decreased) based on the patient’s response. For development of multiple follicles for assisted reproductive technology (ART), GONAL-F® (follitropin alfa) may be administered subcutaneously at a starting dose of 150 IU per day for 3 to 5 days, with subsequent dosing individualized (increased or decreased) based on the patient’s response. REKOVELLE® (follitropin delta) is dosed in pg. For example, for controlled ovarian stimulation for the development of multiple follicles in women undergoing assisted reproductive technologies (ART) such as in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) cycle, REKOVELLE® (follitropin delta) may be administered subcutaneously at a dose of 12 pg per day, or more or less, depending on the patient’s serum anti -Mullerian hormone (AMH) concentration and body weight. Reported clinical trial data suggest that a daily dose of 10.0 pg REKOVELLE® (follitropin delta) provides, for the majority of patients, an ovarian response close to that obtained with 150 lU/day GONAL-F® (follitropin delta).

[0005] Shaped masses and ingestible comprising biologically active proteins or polypeptides have been described, for example, in U.S. Patent No. 10,098,931, U.S. Patent No. 10,227,403, U.S. Patent No. 11,304,993, U.S. Patent No. 9,283,179, U.S. Patent No. 9,808,510, U.S. Patent No. 10,322,167, and U.S. Patent No. 10,864,254.

[0006] There remains a need for compositions, dosage forms, devices, and methods for delivery of FSH by ingestion.

SUMMARY

[0007] In accordance with one aspect, there are provided ingestible devices containing a payload formed from, or containing, a composition comprising FSH, wherein the device is structured to deliver the composition into a gastrointestinal (GI) lumen wall of the subject or surrounding tissue thereof. The FSH may be urinary-derived human FSH. The FSH may be recombinant human FSH. The device may contain a dose of FSH of from about 75 IU to about 450 IU, optionally wherein the FSH is follitropin alfa. The device may contain a dose of FSH selected from 75 IU, 100 IU, 125 IU, 150 IU, 175 IU, 200 IU, 225 IU, 250 IU, 275 IU, 300 IU, 325 IU, 350 IU, 375 IU, 400 IU, 425 IU, and 450 IU, optionally wherein the FSH is follitropin alfa. The device may contain a dose of FSH of about 12 pg, optionally wherein the FSH is follitropin delta. The composition may comprise the FSH, a lubricant, a bulking agent, an antioxidant, and, optionally, a buffering agent. The composition may comprise the FSH, a phosphate salt, PEG-3350, D-mannitol, and L-methionine. The composition may comprise about 1 % w/w of FSH, about 2 % w/w of phosphate salts, about 5 % PEG-3350, about 52 % D mannitol, and about 40% w/w L-methionine. The composition may comprise about 3.5 % w/w of FSH, about 6.5 % w/w of phosphate salts, about 5 % PEG- 3350, about 45 % D mannitol, and about 40% w/w L-methionine. [0008] The payload may be in the form of a solid tissue penetrating member structured to be inserted into a GI lumen wall of the subject or surrounding tissue thereof. The composition may be fdled in a hollow, biodegradable microneedle constituting the solid tissue penetrating member. The composition may be a shaped mass constituting the solid tissue penetrating member. The device may comprise one or multiple payloads of the FSH. The device may be structured to deliver one or more payloads into the GI lumen wall or surrounding tissue thereof at different times.

[0009] The ingestible device may be comprised within a swallowable capsule.

[0010] The device may be structured to deliver the composition into a stomach wall of the subject. The device may be structured to deliver the composition into an intestinal wall of the subject. The device may be structured to deliver the composition into a wall of the small intestine. The device may be structured to deliver the composition into the peritoneum, or peritoneal cavity of the subject.

[0011] The bioavailability of FSH administered by the device may be substantially the same as a bioavailability of subcutaneously administered FSH.

[0012] In accordance with another aspect, there are provided uses of a device as described herein in methods of administering FSH to a subject in need thereof. The uses and methods include administering to the subject by ingestion an ingestible device as described herein containing a payload formed from, or containing, a composition comprising FSH in accordance with any embodiments described herein, wherein the device is structured to deliver the composition into a gastrointestinal (GI) lumen wall of the subject surrounding tissue thereof (e.g., peritoneum or peritoneal cavity). The uses and methods may be for treatment of infertility. The uses and methods may be for stimulating follicle development in a female patient. The uses and methods may be for stimulating ovulation induction in a female patient. The uses and methods may be for one or more of treating hypogonadotropic hypogonadism in a male patient, treating idiopathic infertility in a male patient, and stimulation of spermatogenesis in a male patient. The uses and methods may comprise once daily administration of the ingestible device. The uses and methods may comprise twice daily administration of the ingestible device.

[0013] In accordance with another aspect, there are provided uses of FSH in the preparation of a medicament for treating infertility, wherein the medicament is an ingestible device containing a payload formed from, or containing, a composition comprising FSH as described herein, wherein the device is structured to deliver the composition into a gastrointestinal (GI) lumen wall of the subject or surrounding tissue thereof, as described herein. BRIEF DESCRIPTION OF THE DRAWINGS

[0014] Figure 1A (FIG. 1A) shows an example of an embodiment of an expandable component of a selfsizing device as disclosed herein prior to being folded and/or rolled, and an example of an embodiment of a capsule as disclosed herein.

[0015] Figure IB (FIG. IB) shows the expandable component of FIG. 1A in an embodiment of a folded and/or rolled arrangement prior to disposing the expandable component in the capsule.

[0016] Figure 1C (FIG. 1C) shows the expandable component of FIG. 1A in the folded and/or rolled arrangement of FIG. IB and disposed within the capsule.

[0017] Figure 2A (FIG. 2A), Figure 2B (FIG. 2B), and Figure 2C (FIG. 2C) show an example of an embodiment of a capsule as disclosed herein including a self-sizing device as disclosed herein, including an expandable component within a degradable capsule, as the device traverses a lumen.

[0018] Figure 2D (FIG. 2D), Figure 2E (FIG. 2E), and Figure 2F (FIG. 2F) show a progression of the expandable component of FIG. 2C in a rotated view as the expandable component expands within the lumen.

[0019] Figure 3 (FIG. 3) shows an example of an embodiment of a self-sizing device as disclosed herein including an expandable component in a fully-extended state within a lumen.

[0020] Figure 4A (FIG. 4A) shows an example of an embodiment of a self-sizing device as disclosed herein including an expandable component with one non-compliant section and no hinge.

[0021] Figure 4B (FIG. 4B) shows an example of an embodiment of a self-sizing device including an expandable component with two non-compliant sections and one hinge.

[0022] Figure 5 (FIG. 5) shows an embodiment of a capsule as disclosed herein encompassing an ingestible device. Inset A shows a fully assembled enteric-coated capsule. Schematic B shows various parts and components of the capsule.

[0023] Figure 6 (FIG. 6) shows the plasma concentration vs. time curve obtained after administration of a single dose of GONAL-F® (follitropin alfa) FSH in a canine study (150 IU by subcutaneous injection — bottom line, 150 IU by oral ingestion of an ingestible device as described herein — middle line, or 450 IU by oral ingestion of an ingestible device as described herein — top line). [0024] Figure 7 (FIG. 7) shows results of a computer-based pharmacokinetic model simulation of FSH dosing, plotting simulated plasma concentration vs. time curves from a pharmacokinetic model simulation of FSH dosing at 75 IU twice daily (BID) vs. 150 IU once daily.

[0025] Figure 8 (FIG. 8) shows results of a computer-based pharmacokinetic model simulation of FSH dosing, plotting simulated plasma concentration vs. time curves from a pharmacokinetic model simulation of FSH dosing at 75 IU twice daily with one missed dose on Day 3 vs. 75 IU twice daily without missed dose vs. 150 IU once daily.

[0026] Figure 9 (FIG. 9) shows results of a computer-based pharmacokinetic model simulation of FSH dosing, plotting simulated plasma concentration vs. time curves from a pharmacokinetic model simulation of FSH dosing at 100 IU twice daily with one missed dose on Day 3 vs. 100 IU twice daily without missed dose vs. 150 IU once daily vs. 225 IU once daily.

DETAILED DESCRIPTION

[0027] The present disclosure provides compositions, dosage forms, devices, and methods for delivery of follicle stimulating hormone (FSH) using an ingestible dosage form (an ingestible device) containing a payload formed from, or containing, a composition including the FSH, where the device is structured to deliver the FSH into a GI lumen wall (e.g., stomach wall, intestinal wall, colon, etc.) of the subject or surrounding tissue thereof (e.g., a peritoneum or peritoneal cavity), and thereafter into the bloodstream. The payload may be in the form of a solid tissue penetrating member structured to penetrate a GI lumen wall of the subject and/or be inserted into a peritoneum or peritoneal cavity of the subject after ingestion of the device. The ingestible device may be disposed within a capsule, such as a swallowable capsule.

I. Definitions

[0028] It is to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting.

[0029] Technical and scientific terms used herein have the meanings commonly understood by one of ordinary skill in the art, unless otherwise defined. Unless otherwise specified, materials and/or methodologies known to those of ordinary skill in the art can be utilized in carrying out the methods described herein, based on the guidance provided herein. [0030] As used herein, the singular terms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Reference to an object in the singular is not intended to mean “one and only one” unless explicitly so stated, but rather “one or more”.

[0031] As used herein, the terms “e.g.,” “such as”, “for example”, “for an example”, “for another example”, “examples of’, “by way of example”, and “etc.” indicate that a list of one or more non-limiting example(s) precedes or follows; it is to be understood that other examples not listed are also within the scope of the present disclosure.

[0032] As used herein, the terms “substantially” and “about” when used with a numerical value mean the numerical value stated as well as up to and including plus or minus 10% of the numerical value. For example, “about 10” should be understood as both “10” and “in a range between and including 9 and 11”.

[0033] As used herein, a phrase in the form “A/B” or in the form “A and/or B” means (A), (B), or (A and

B); a phrase in the form “at least one of A, B, and C” means (A), (B), (C), (A and B), (A and C), (B and

C), or (A, B, and C).

[0034] As used herein, the terms “comprising”, “comprise”, “comprises”, “includes”, and “including” are intended to mean that the compositions and methods include the recited elements, but do not exclude others.

[0035] As used herein, the phrase “therapeutically effective amount” with reference to FSH means a dose that provides the specific pharmacological effect for which the drug is administered in a subject in need of such treatment. It is emphasized that a therapeutically effective amount of FSH will not always be effective in treating the condition for which it is administered in every individual subject, even though such dose is deemed to be a therapeutically effective amount by those of skill in the art. Those skilled in the art can adjust what is deemed to be a therapeutically effective amount in accordance with standard practices as needed to treat a specific subject. A therapeutically effective amount may vary based on, for example, the age and weight of the subject, and/or the subject’s overall health, the condition being treated, and/or the severity of the condition of the subject being treated.

[0036] A “therapeutic level” of circulating FSH in a human subject means a plasma level associated with the specific pharmacological effect for which the drug is administered in a subject in need of such treatment. A “therapeutic level” of circulating FSH in a human female patient being treated for infertility may be a plasma level sufficient to stimulate follicle development or to stimulate ovulation induction, such as a plasma level of about 10-12 IU/L (10-12 mIU/mL). A single subcutaneous dose of 300 TU of GONAL-F® (follitropin alfa) achieved a Cmax of 9.83 IU/L in a clinical study in healthy pre-menopausal female volunteers who had previously received a GnRH agonist for pituitary down-regulation.

[0037] The term “ingest” or a grammatical variation thereof (e.g., “ingesting”, “ingestion,” “ingested” or “ingestible”) refers herein to taking into the stomach, whether by swallowing or by other means of depositing into the stomach (e g., by depositing into the stomach by endoscope or depositing into the stomach via a port).

[0038] The term “lumen” refers herein to the inside space of a tubular structure. Examples of lumens in a body include arteries, veins, and tubular cavities within organs. The term “gastrointestinal lumen” or “GI lumen” refers generally to any lumen of the GI tract (e.g., a lumen of the esophagus, stomach, small intestine, large intestine, or colon); the term “GI lumen wall” refers to a lumen wall of a GI lumen.

[0039] The term “lumen wall” refers to a wall of a lumen, where the wall includes all layers from an inner perimeter to an outer perimeter of the lumen, such as, with respect to lumens in a body, the mucosa, submucosa, muscularis, serosa, and an outer wall of the lumen, with the constituent blood vessels and tissues.

[0040] The term “gastrointestinal tract” or “GI tract” as used herein refers herein to the intake/expulsion system of a body including, for example, the mouth, pharynx, esophagus, stomach, pylorus, small intestine, cecum, large intestine, colon, rectum, anus, and valves or sphincters therebetween.

[0041] The terms “individual,” “subject,” and “patient” are used interchangeably herein, and include any individual mammalian subject (e.g., bovine, canine, feline, equine, or human). In specific embodiments, the subject, individual, or patient is a human.

[0042] The term “component” refers herein to one item of a set of one or more items that together make up a device, a composition, or a system under discussion. A component may be in a solid, powder, gel, plasma, fluid, gas, or other constitution. For example, a device may include multiple solid components which are assembled together to structure the device and may further include a fluid component that is disposed in the device. For another example, a composition may include a single component, or two or more components which are mixed together to make the composition. A composition may be in the form of a fluid, a slurry, a powder, or a solid (e.g., in a condensed or a consolidated form such as a tablet or microtablet). A device or system can include one or more compositions and/or one or more other components.

[0043] The term “design” or a grammatical variation thereof (e.g., “designing” or “designed”) refers herein to characteristics intentionally incorporated based on, for example, estimates of tolerances (e.g., component tolerances and/or manufacturing tolerances) and estimates of environmental conditions expected to be encountered (e.g., temperature, humidity, external or internal ambient pressure, external or internal mechanical pressure, stress from external or internal mechanical pressure, age of product, or shelf life, or, if introduced into a body, physiology, body chemistry, biological composition of fluids or tissue, chemical composition of fluids or tissue, pH, species, diet, health, gender, age, ancestry, disease, or tissue damage); it is to be understood that actual tolerances and environmental conditions before and/or after delivery can affect characteristics so that different components, devices, compositions, or systems with a same design can have different actual values with respect to those characteristics. Design encompasses also variations or modifications before or after manufacture.

[0044] The term “manufacture” or a grammatical variation thereof (e.g., “manufacturing” or “manufactured”) as related to a component, device, composition, or system refers herein to making or assembling the component, device, composition, or system. Manufacture may be wholly or in part by hand and/or wholly or in part in an automated fashion.

[0045] The term “structured” or a grammatical variation thereof (e.g., “structure” or “structuring”) refers herein to a component, device, composition, or system that is manufactured according to a concept or design or variations thereof or modifications thereto (whether such variations or modifications occur before, during, or after manufacture) whether or not such concept or design is captured in a writing.

[0046] The term “degrade” or a grammatical variation thereof (e.g., “degrading”, “degraded”, “degradable”, and “degradation”) refers herein to weakening, partially degrading, or fully degrading, such as by dissolution, chemical degradation (including biodegradation), decomposition, chemical modification, mechanical degradation, or disintegration, which encompasses also, without limitation, dissolving, crumbling, deforming, shriveling, or shrinking.

[0047] The term “non-degradable” refers to an expectation that degradation will be minimal, or within a certain acceptable design percentage, for at least an expected duration in an expected environment. [0048] The terms “follicle stimulating hormone composition”, “FSH composition”, “composition of follicle stimulating hormone” and “composition of FSH” may be used interchangeably herein and refer to a composition including one or more components where at least one of the components is follicle stimulating hormone (FSH). The FSH composition can include FSH either as the sole active agent or along with one or more additional active agents.

[0049] The term “follicle stimulating hormone” (or “FSH”) as used herein refers to human FSH, which is a glycoprotein heterodimer consisting of two polypeptide units, the alpha subunit consisting of 92 amino acids, and the beta subunit consisting of 111 amino acids. The oligosaccharide structures and glycosylation pattern of human FSH may vary depending on its source (e.g., urinary derived vs. recombinant CHO-cell expressed vs. recombinant Per.C6-cell expressed), and all glycosylation variants are included in “FSH” as used herein. Unless otherwise specified, “FSH” as used herein includes FSH isolated from human urine (human urinary-derived FSH) (e.g., REPRONEX®, MENOPUR®, and BRAVELLE®), and recombinant FSH, including recombinant human FSH expressed in mammalian cells, such as CHO cells (e.g., GONAL-F® (follitropin alfa) and FOLLISTIM® (follitropin beta)) or expressed in a human cell line such as the Per.C6 cell line (REKOVELLE® (follitropin delta)).

[0050] Various abbreviations may be used herein for standard units, such as deciliter (dl), milliliter (ml), microliter (pl), international unit (IU), centimeter (cm), millimeter (mm), nanometer (nm), inch (in), kilogram (kg), gram (gm), milligram (mg), microgram (pg), nanogram (ng), millimole (mM), degrees Celsius (°C), degrees Fahrenheit (°F), millitorr (mTorr), hour (hr), minute (min), second (s or sec), millisecond (ms), microsecond (ps), or nanosecond (ns).

[0051] Disclosed herein are ingestible dosage forms (ingestible devices) useful for delivering FSH to a subject in need thereof. The devices contain a payload formed from, or containing, a composition comprising FSH, and are structured to deliver the composition into a GI lumen wall of the subject or surrounding tissue thereof, e.g., a peritoneum or peritoneal cavity of the subject, after ingestion. As noted above, the FSH provided in the devices may be any form of human FSH, including one or more of FSH isolated from human urine (human urinary-derived FSH) (e.g., REPRONEX®, MENOPUR®, and BRAVELLE®), and recombinant FSH, including recombinant human FSH expressed in mammalian cells, such as CHO cells (e.g., GONAL-F® (follitropin alfa) and FOLLISTIM® (follitropin beta)) or expressed in a human cell line such as the Per.C6 cell line (REKOVELLE® (follitropin delta). II. Ingestible Dosage Forms (Ingestible Devices)

[0052] As noted above, the ingestible dosage forms described herein are ingestible devices that contain a payload made from or comprising a composition including FSH. The payload may be in the form of a solid tissue penetrating member structured to penetrate a GI lumen wall of the subject and be inserted into the GI lumen wall or surrounding bodily environment (e.g., surrounding tissue such as peritoneum or peritoneal cavity) of the subject after ingestion of the device (e.g., after swallowing the device or after ingestion of the device by another mode, such as via an endoscope or stomach port), thereby delivering the FSH into the blood stream of the subject. The payload may be formed from, or may contain, the composition. Specific embodiments of such devices are described in more detail below. Any devices disclosed or referenced herein optionally may be disposed within a capsule, such as a swallowable capsule. Typically, the materials used to form the components of the devices are classified as food grade, food additive, active or inactive food ingredient or GRAS (Generally Recognized As Safe by the FDA). The devices (including any capsule shell) may be biodegradable.

[0053] FIG. 5 diagrammatically illustrates an ingestible device (e.g., a swallowable device) according to an embodiment of this disclosure. As illustrated, the device is disposed within a capsule, which may be any suitably sized swallowable capsule, such as a 000 sized HPMC (hydroxypropyl methylcellulose) capsule, or such as the capsule illustrated in inset A of FIG. 5. The capsule may be provided with a coating, such as an enteric coating, such as an enteric polymer, (e.g., a polymer that dissolves at a target pH within the digestive tract). For example, the enteric coating can be selected to dissolve at a pH > 6 to avoid dissolution in the acidic environment of the stomach. In embodiments in which the device is incorporated into an enteric coated capsule, after the capsule leaves the stomach and enters the duodenum, the higher intestinal pH of the small intestine dissolves the enteric coating and capsule shell, exposing an interior of the device and the components contained therein to intestinal fluid.

[0054] Thus, in some embodiments, the capsule and/or the coating are designed to degrade in the presence of a particular chemical, or after a certain length of time under the conditions expected at a target site within the GI tract (e.g., under certain values or ranges of pH, temperature, pressure exerted against the capsule, or a combination of the foregoing). In an embodiment, the coating includes a material to improve swallowability and/or ingestibility, such as guar gum or xanthan gum.

[0055] The device may contain a mechanism to effectuate delivery of the payload into a location of the GI tract, such as the intestinal wall or into and through an intestinal wall into, e.g., a peritoneum or peritoneal cavity of the subject. In an embodiment, the mechanism includes an actuator that is triggered when the device is at a target delivery site, such as within the intestine. In other embodiments, the mechanism may effectuate delivery of the pay load at another location in the GI tract, such as the stomach, large intestine, or colon.

[0056] In the embodiment of FIG. 5, the device contains a sealed polyethylene balloon (labeled Sealed Balloon), a delivery construct (labeled Microsyringe), and an actuator in the form of two reactants and a valve, all of which together constitute a mechanism to effectuate delivery of the payload into the intestinal wall or surrounding tissue thereof (e.g., a peritoneum or peritoneal cavity of the subject). In this embodiment, the Microsyringe contains the payload (labeled Microneedle). The two reactants, labeled Reactant A and Reactant B (e g., citric acid and potassium bicarbonate), are separated by a valve (labeled Reaction Valve) in an initial state. When exposed to fluid such as intestinal fluid (e.g., after the capsule degrades), a portion of the valve degrades and allows the two reactants to mix, which results in formation of a gas (e.g., carbon dioxide or other innocuous gas) that expands the balloon. Inflation of the balloon aligns the Microsyringe substantially perpendicular to the long axis of the intestine and builds pressure in the balloon sufficient to provide the force needed to eject the Microneedle from the Microsyringe and inject the Microneedle into the intestinal wall or surrounding tissue thereof. After microneedle deployment, the balloon deflates and the balloon and other components are excreted out through the GI tract with normal bowel movements.

[0057] In general, the mechanism to effectuate delivery of the payload into the intestinal wall may include various mechanical, electrical, electromechanical, and/or chemical components. For example, springs, levers, and/or various movable components may together constitute the mechanism.

[0058] The payload may be disposed within a protective enclosure until just before (e.g., in terms of ms or ps) the payload is delivered into the intestinal wall. For example, in the embodiment of FIG. 5, the Microneedle may be sealed within the Microsyringe in the initial state, and when ejected from the Microsyringe into the intestinal wall, may pierce or break a seal on the Microsyringe to pass out of the Microsyringe.

[0059] After entering the intestinal wall or surrounding bodily environment (e.g., surrounding tissue such as peritoneum or peritoneal cavity), the payload dissolves or degrades in the moist tissue environment to release the FSH composition into the blood stream. [0060] The payload may be a hollow structure in which the FSH composition is disposed, or the payload may itself be formed from the FSH composition (e.g., the FSH composition may be compressed into a desired size and shape). In an embodiment, the FSH composition is compressed into a cylindrically-shaped microtablet or other shaped microtablet. In an embodiment, the FSH composition (in uncompressed or compressed form) is disposed within a degradable shell, and the shell containing the microtablet is the payload. In an embodiment, the shell is approximately needle-shaped. Degradation of the payload may occur within 1, 2, 3, 4, or 5 minutes of injection into the intestinal wall, or may take longer. Properties of the payload (e.g., structure and/or material) may be selected to delay release of the FSH from the payload.

[0061] The device may include a detectable marker, such as a radiolabel, to assist in tracking the device as it proceeds through the subject’s GI tract. Examples of markers include, but are not limited to, barium sulfate (whose dispersion indicates fluid ingress inside the device and imminent delivery of the payload) and bismuth, which optionally may be included on or in a component contained in the device to radiographically track the component’s transit along the GI tract as well as to confirm its excretion.

[0062] In an embodiment, which may be similar to the embodiment illustrated in FIG. 5, a balloon is selfsizing. With respect to embodiments including the self-sizing balloon, the balloon is referred to herein as an “expandable component”. Such embodiments are described in more detail in the following paragraphs.

[0063] In some embodiments, the expandable component includes multiple sections. In the expanded configuration of the expandable component, at least one of the sections is non-compliant and at least one of the sections is compliant. Compliant refers to a state in which the section may be readily deformed, and non-compliant refers to a state in which the section resists deformation. Absent a constraint, each section will expand to a fully-extended state and the expandable component will reach its maximum dimensions, which may depend, for example, on materials used to form the expandable component and/or a capacity of an expansion module that is implemented (e.g., for expansion by inflation, maximum dimensions may be influenced by a limitation on an inflation force available from the expansion module, or by a stretch factor of a material or materials of the expandable component). The expansion module is part of a mechanism to effectuate delivery of the payload into the intestinal wall.

[0064] Each compliant section operates in a similar fashion to a hinge and thus will be referred to for convenience as a hinge. In a fully-extended state of the expandable component (where each section is fully extended), each hinge has at least one design dimension (width, length, and/or circumference) that is substantially smaller than a corresponding design dimension of each non-compliant section. [0065] As the expandable component expands, it will achieve a shape that reflects an equilibrium between a force exerted by the expandable component on an interior of a lumen of the GI tract and a force of the lumen against the expandable component. Said another way, the expandable component may not fully extend and will tend to be bent about the hinge if constrained by the lumen. This bending is due to the smaller dimension(s) of the hinge as compared to the corresponding dimension(s) of the non-compliant section(s), which in the expanded configuration of the expandable component leads to lower rigidity of the hinge as compared to rigidity of the non-compliant section(s).

[0066] In this way, the expandable component expands until the non-compliant sections (which may hereinafter be referred to as NCS) are pressed against the lumen inner wall to maintain the expandable component in a position suitable for delivering a FSH composition to the lumen wall, for a time at least sufficient to accomplish such delivery. The expandable component may then be deflated.

[0067] The expandable component may be removed after deflation, may be left to degrade in situ, or may be allowed to pass out of the lumen. The expandable component can be structured from degradable materials such that the expandable component degrades after a designed period of time after exposure to an environment at a target site.

[0068] A self-sizing device as described above may be used to deliver a therapeutic FSH composition into a GI lumen wall (e.g., stomach wall, intestinal wall, colon) or surrounding tissue thereof (e.g., peritoneum or peritoneal cavity) via ingestion (e.g., swallowing or other mode of ingestion). The self-sizing device may include a capsule. The self-sizing device may include a coating on the capsule and/or on the expandable component (e.g., a coating as described above), designed to degrade at a particular location within the GI tract, such as within the intestine. In an embodiment, all or portions of the capsule and/or the coating are designed to degrade in the presence of a particular chemical, or after a certain length of time under the conditions expected at a target site within the GI tract (e.g., under certain values or ranges of pH, temperature, pressure exerted against the capsule, or a combination of the foregoing). In an embodiment, the coating includes a material to improve swallowability and/or ingestibility, such as guar gum or xanthan gum.

[0069] FIGS. 1A-1C illustrate an example of assembling a self-sizing device 1050, which is an ingestible device as described herein. FIG. 1A illustrates an embodiment of an expandable component 1000 and an embodiment of a capsule shell 1010. Outer dimensions of expandable component 1000 may be several times larger than inner dimensions of capsule 1000. For example, a longest dimension of an embodiment of expandable component 1000 may be two to five times greater than an inner length of capsule shell 1010. Other ratios of outer dimensions of an expandable component to inner dimensions of a capsule are within the scope of the present disclosure. FIG. IB illustrates expandable component 1000 folded and/or rolled into an arrangement 1001 that is smaller than inner dimensions of capsule shell 1010. As illustrated, arrangement 1001 is folded and/or rolled in a complex arrangement in this embodiment, origami style. FIG. 1C illustrates arrangement 1001 disposed into capsule 1010, and capsule shell 1010 assembled together. Device 1050 includes expandable component 1000 (in arrangement 1001) and capsule shell 1010, and may include other components not shown such as an expansion module, a delivery component, one or more coatings, and a deflation valve.

[0070] FIGS. 2A-2F illustrate an example of how device 1050 may be provided to a target delivery site in the GI tract and position expandable component 1000 to deliver a therapeutic FSH composition into a lumen wall 1111 of a GI lumen 1110 (e.g., an intestinal wall, stomach wall, etc.). Referring back to FIGS. 2A-2C, device 1050 is shown from a view approximately perpendicular to a direction of travel of device 1050 (indicated by an arrow), whereas device 1050 in FIGS. 2D-2F is shown as if looking into lumen 1110 (e.g., approximately 90 degrees from the view of FIGS. 2A-2C).

[0071] FIG. 2A illustrates device 1050 within lumen 1110 shown in a relaxed state (e.g., between peristaltic contractions). In this embodiment, an outer diameter of device 1050 is less than an inner diameter of lumen 1110 at this point in the GI tract. Device 1050 traverses lumen 1110, for example through operation of peristalsis, fluid dynamics, and/or gravity.

[0072] FIG. 2B illustrates that, after reaching the designed target site or after encountering conditions (e.g., pH) representative of the designed target site, capsule shell 1010 degrades (or is triggered to break open or degrade) as device 1050 continues to traverse lumen 1110. For example, with respect to delivery within the intestine, a target site may be in a general region (e.g., small intestine), a more specific region (e.g., jejunum), or a specific tissue area (e.g., a tissue area that has been marked).

[0073] FIG. 2C illustrates that, subsequent to (or concurrent with) capsule shell 1010 degrading, expandable component 1000 begins to unfurl from its folded and/or rolled arrangement.

[0074] FIG. 2D illustrates expandable component 1000 mostly unfurled, and FIG. 2E illustrates expandable component 1110 as it is expanded (e.g., by an expansion module). [0075] FIG. 2F illustrates expandable component 1000 after expansion. In this embodiment, expandable component 1000 would have been able to expand if not constrained by lumen 1110 until a reference line 1120 was approximately a straight line. However, lumen 1110 exerts force against expandable component 1000 which causes expandable component 1000 to bend at a hinge 1002. An NCS 1003 and an NCS 1004 of expandable component 1000 then press against the lumen wall of lumen 1110 (e.g., at opposing sides of the lumen) and position expandable component 1000 to deliver a therapeutic FSH composition at or into the lumen wall. Hinge 1002 may also press against the lumen wall. In an embodiment, peristalsis may move expandable component 1000 in its expanded state through lumen 1110. In an embodiment, expandable component 1000 may have sufficient internal pressure (combined with surface tension) to firmly hold expandable component 1000 in approximately a same position even during peristalsis. In an embodiment, expandable component 1000 includes a surface roughness or surface protrusions to assist in maintaining a position of expandable component 1000.

[0076] Expansion of an expandable component may be accomplished by any suitable expansion module. In an embodiment, a spring mechanism is released from a compressed state to deploy, for example, a filler piece of firm or soft material to push outwards and thus expand the expandable component. In an embodiment, two or more reactants are mixed together to form a gas and thus expand the expandable component. In an embodiment, a material is rapidly combusted to generate a gas and thus expand the expandable component. Other expansion modules are within the scope of the present disclosure.

[0077] FIG. 3 illustrates a lumen 1200 in which a self-sizing device 1210 including an expandable component 1250 is positioned. In this embodiment, the force of lumen 1200 against expandable component 1250 is not sufficient to substantially cause a hinge 1251 of expandable component 1250 to bend, so expandable component 1250 is in an approximately fully-extended state. Said another way, a bending of hinge 1251 of expandable component 1250 is negligible at this position in this lumen 1200.

[0078] Expandable component 1250 may be expanded by generation of gas, and may include a valve 1255 to release the gas from within expandable component 1250 into lumen 1200 to deflate expandable component 1250. Valve 1255 may include one or more components. In an embodiment, valve 1255 is a pinch valve that degrades in the presence of fluid (e.g., biological matter) to reveal a port or an opening defined by expandable component 1250. In an embodiment, valve 1255 is a piece of material or a coating over a port or an opening in expandable component 1250, and the piece of material or coating is designed to degrade a period of time after expandable component 1250 delivers a therapeutic FSH composition. In an embodiment, valve 1255 is opened manually.

[0079] The therapeutic composition of FSH (or multiple therapeutic compositions) can be stored within expandable component 1250 in any constitution (e.g., as a solid, fluid, slurry, or powder). The therapeutic composition(s) can be delivered in any constitution (e.g., as a solid, fluid, slurry, or powder). In some embodiments, two or more components of the therapeutic composition are mixed within expandable component 1250 prior to delivery. In an embodiment, expandable component 1250 includes a portal such as portal 1260 defining an opening 1261 through which the therapeutic composition is delivered. In embodiments that include a tissue penetrating member, the tissue penetrating member may be delivered through the portal.

[0080] The therapeutic FSH composition is actively released such that the therapeutic FSH composition is forcibly expelled from expandable component 1250 and into lumen 1200 or beyond the lumen wall into the surrounding bodily environment (e.g., through the mucosa, submucosa, muscularis, serosa, outer wall of lumen 1200, and into the peritoneal cavity); in such an embodiment, the therapeutic FSH composition may be released through one or more portals such as portal 1260.

[0081] The therapeutic composition of FSH may be forcibly expelled from expandable component 1250 by a delivery mechanism. For example, with respect to a solid composition (e.g., tablet, pellet, or pointed form), the therapeutic FSH composition may be expelled by way of a spring mechanism that is released to quickly eject the solid composition out of expandable component 1250, or by way of a piston mechanism in which the piston is moved by a spring mechanism, or a gas expansion to push the solid composition quickly out of expandable component 1250.

[0082] With respect to a fluidic composition (e.g., a liquid), the therapeutic FSH composition may be expelled as a fluid jet by way of a spring mechanism or gas acting on a piston or plunger to eject the preparation from a reservoir through an opening or nozzle of expandable component 1250. The fluid jet of the therapeutic FSH composition can have sufficient force to actively penetrate the GI lumen wall and enter the blood stream.

[0083] Additionally or alternatively, the fluidic composition including FSH may be expelled through a hollow needle coupled to expandable component 1250. The hollow needle can penetrate into and/or through the GI lumen wall by way of a spring mechanism or gas acting on a piston or plunger to eject the composition through the needle and into the GI lumen wall or surrounding tissue thereof. [0084] In some embodiments, a surface of expandable component 1250 through which the therapeutic FSH composition is delivered contacts the wall of lumen 1200 along a stretch of approximately 5 mm to 20 mm.

[0085] In some embodiments, the therapeutic FSH composition is delivered from expandable component 1250 from multiple surfaces. Such embodiments may include more than one tissue penetrating member that is formed from or contains a FSH composition.

[0086] FIG. 4A illustrates an embodiment of a self-sizing device 1300 including an expandable component 1305 which includes one NCS 1310 and no hinge. FIG. 4B illustrates an embodiment of a selfsizing device 1350 including an expandable component 1355 which includes two NCSs, an NCS 1360 and an NCS 1361, and a hinge 1365 between. With respect to these embodiments, a width W1 of expandable component 1305 is similar to a width W2 of expandable component 1355, whereas a height Hl of expandable component 1305 is less than a height H2 of expandable component 1355.

[0087] Multiple devices 1300 (FIG. 4A) structured according to a same design will have approximately a same maximum circumference of NCS 1310 (in a y-z plane) when fully inflated in a lumen due to the non-conformance of NCS 1310, such that expandable component 1305 does not significantly adapt to a variety of different internal lumen circumferences. Different sizes of device 1300 may therefore be appropriate for different animal species and/or different subjects within a species. In contrast, multiple devices 1350 (FIG. 4B) structured according to a same design will likely not have a same maximum circumference (in a y-z plane) when fully inflated in a lumen because each device 1350 will adjust to the size of the lumen in which it is inflated due to the flexibility (non-conformance, bending) of hinge 1365 even when inflated. Maximum circumference with respect to device 1350 within the lumen refers to a maximum circumference of the shape that device 1350 takes within the lumen (e.g., a partially-extended shape or a fully-extended shape).

[0088] Specific materials can be chosen to confer desired structural and material properties to the payload (e.g., column strength for insertion into the lumen wall, or porosity and/or hydrophilicity for controlling disintegration of the payload and thus the release of a therapeutic FSH composition). For example, certain materials may be more suitable when the payload is formed as a tissue penetrating member, whereas other materials may be more suitable when the payload is contained within a tissue penetrating member. In an embodiment, a tip of the payload includes or is coated with a degradable material such as sucrose, maltose, or other sugar, to increase hardness and tissue piercing properties of the tip. Once positioned within a lumen wall, the payload may be degraded by interstitial fluids within tissue so that the therapeutic FSH composition dissolves and is absorbed into the blood stream. Properties of a payload such as size, shape, and chemical composition can be selected to allow for dissolution and absorption of a drug in a matter of seconds, minutes, or hours. Rates of dissolution can be controlled through various excipients such as disintegrants (e.g., starch, sodium starch glycolate, or a cross-linked polymer such as carboxymethyl cellulose). The choice of disintegrants may be specifically adjusted for the environment within a lumen wall (e.g., blood flow and average number of peristaltic contractions).

[0089] A payload can be fabricated entirely from a FSH composition, or can define a cavity that includes a FSH composition. A self-sizing device can include and deliver one or more payloads, each of which can contain the same or a different FSH composition. Each payload can have different properties; for example, two payloads may be designed to deliver respective compositions concurrently (e.g., two instances of one composition, or one instance each of two distinct compositions), or may be designed to deliver respective compositions at different times (e.g., to provide a subsequent dose of a same FSH composition or to provide a different FSH composition subsequently).

III. Microtablets

[0090] Various embodiments of microtablets comprising a FSH composition in the form of solid shaped masses comprising FSH and methods for forming such solid shaped masses are described. A shaped mass may comprise a therapeutic composition that comprises a drug (e.g., FSH) and one or more pharmaceutically acceptable excipients, including degradable material (such as a sugar or sugar alcohol, polyethylene, lactic acid polymer, poly(glutamic acid-co-lactic acid-co-glycolic acid (PGLG), etc.) which degrades within a target delivery site in the body (e.g., the wall of the small intestine or peritoneum or peritoneal cavity) to release drug.

[0091] The shaped mass can be formed from a variety of shaping processes known in the pharmaceutical arts. Typically, the shaped mass will be formed by a compression process such as compression molding. According to one or more embodiments, the biological activity of the FSH in the shaped mass is at least about 70% of that prior to compression, at least 80% of that prior to compression, at least 85% of that prior to compression, about 90% of that prior to compression, or at least 95% of that prior to compression.

[0092] The shaped mass can have a density in a range from about 0.60 mg/mm³ to about 1.15 mg/mm³, from about 0.70 mg/mm³ to about 1.15 mg/mm³, from about 0.80 mg/mm³ to about 1.10 mg/mm³, from about 1.02 to 1.06 mg/mm³, or from about 1.03 to 1.05 mg/mm³. [0093] The shape of the shaped mass may be any shape suitable for use as a component of a device as described herein, e.g., any shape suitable for disposing within a tissue-penetrating member (e.g., a pellet or cylindrical shape) or any shape suitable for use as a tissue-penetrating member (e.g., a needle or dart shape). The shaped mass may comprise a pellet shape, or may have a tablet, conical, pyramidal, hot dog/capsule like, arrow head, cylindrical, cube, sphere, hemisphere or other suitable shape. For embodiments of the shaped mass having a cylindrical or pellet shape, the shaped mass may have a diameter in the range from about 0.5 mm to 1 mm and a length from about 1.75 mm to 3.25 mm.

[0094] As noted above, according to various embodiments, the shaped mass can be formed in part from a degradable material that is configured to dissolve or otherwise degrade, e.g., in the wall of the intestine or in the peritoneum or peritoneal cavity, so as to release the drug for systemic absorption. Suitable degradable materials include various sugars such as trehalose, maltose and sucrose, various sugar alcohols such as mannitol, various lactic acids polymers such as polyglycolic acid (PGA), polylactic acid (PLA); polyglycolic lactic acid (PGLA); poly(glutamic acid-co-lactic acid-co-glycolic acid (PGLG); various polyethylenes such as high density, low density and linear low density PE and PEG (polyethylene oxide), various cellulose polymers such as HPMC (hydroxypropyl methyl cellulose), CMC (carboxy methyl cellulose), MC (methyl cellulose), methacrylic acid-ethyl acrylate copolymer, methacrylic acid-methyl methacrylate copolymer PVOH (polyvinyl alcohol), silicone rubber, and other biodegradable polymers known in the art. The material and other properties of the degradable polymer and shaped mass can be selected to produce selectable rates of degradation in the intestinal wall or other target delivery site (e.g., peritoneum or peritoneal cavity).

[0095] A description will now be provided of a fabrication process used to make various embodiments of a drug-containing shaped mass as described herein. The process includes a process for fabricating a powder containing the drug, and a shaped mass formation process for forming the powder into shaped masses. For convenience, the shaped masses are referred to as microtablets; however it should be appreciated that other forms and/or shapes are equally applicable, as described above.

[0096] A process for formulation of a powder (e.g., dry composition) comprising the drug (e.g., FSH) will now be described. A typical process may include preparing a composition comprising the drug and excipients. The composition may be prepared by combining dry ingredients, or by preparing a solution comprising one or more of the ingredients, and then evaporating the solvent(s) (optionally comprising lyophilisation) to obtain a dry composition, and, optionally, adding one or more dry ingredients to obtain a composition comprising the drug and other excipients.

[0097] The drug (e.g., FSH) may be present in the composition in any amount suitable for providing the target dose in the ingestible device, and in one or more embodiments, may be present in an amount of from about 0.1% to about 99% w/w of the composition, including from about 0.5% to about 5% w/w, including about 0.5% w/w, about 1% w/w, about 1.5% w/w, about 2% w/w, about 2.5% w/w, about 3% , about 3.5% w/w, about 4% w/w, about 4.5 % w/w, and about 5% w/w, or any value therebetween.

[0098] The excipients can include one or more of an antioxidant (e.g., L-methionine or histidine), a lubricant, a bulking agent, and, optionally, a buffering agent (e.g., a buffering salt). In specific embodiments, the excipients include one or more of an antioxidant, a lubricant, a bulking agent, and, optionally, a buffering agent. The antioxidant may comprise L-methionine or histidine, and in one or more embodiments, may be present in an amount of from about 0.5% to about 75% w/w of the composition, including from about 25% to about 50% w/w of the composition, including about 40 % w/w of the composition. The lubricant may be used to facilitate one or both of microtablet formation and ejection from a mold. The lubricant may comprise polyethylene glycol 3350 (PEG-3350) and in one or more embodiments, may be present in an amount of from about 1% to about 20% w/w of the composition, including about 5% w/w. The bulking agent may be a sugar or sugar alcohol, such as mannitol (e.g., D- mannitol), and in one or more embodiments, may be present in an amount of from about 1% to about 99.9% w/w of the composition, including from about 30% to about 66% w/w of the composition, including from about 45% to about 50% w/w of the composition, including about 45% w/w of the composition or about 52% w/w of the composition. The buffering agent may be a phosphate salt buffering agent (e.g., one or more of sodium phosphate and potassium phosphate), and in one or more embodiments, may be present in an amount of from about 1% to about 10% w/w of the composition, from about 2% to about 7% w/w of the composition, including about 2% w/w of the composition or about 6.5% w/w of the composition. Other excipients may be included, such as one or more selected from surfactants, binders, fdlers, disintegrants, stabilizers, buffers and antimicrobials.

[0099] The selection and proportions of the different ingredients may be taken into consideration during the formulation process so as to achieve a desired therapeutic dose of the drug with desired release properties in the resulting microtablet. In one specific embodiment the composition comprises about 1% w/w FSH, about 2% w/w phosphate salts, about 52% D-mannitol, about 5% PEG-3550, and about 40% L-methionine. In further specific embodiments, such a composition is used to provide a dose of! 50 IU FSH (follitropin alfa). In another specific embodiment the composition comprises about 3% w/w FSH, about 7% w/w phosphate salts, about 45% D-mannitol, about 5% PEG-3550, and about 40% L-methionine. In further specific embodiments, such a composition is used to provide a dose of 450 IU FSH (follitropin alfa). These example formulations can be used to provide other doses of FSH as described herein, such as by loading more or less of the composition into a device as described herein, as needed to provide the desired dose. Alternatively, similar compositions can be formulated to provided other doses as described herein in about the same volume/mass, such as by adjusting the FSH concentration (higher or lower), and adjusting the concentrations of the excipients accordingly. Additionally, combination variations of these approaches (e.g., adjustment of amount, adjustment of concentration) can be implemented to provide a desired dose in a desired volume/mass.

[0100] The composition obtained as described above may be milled to produce a fine powder. For example, the composition may be placed in a low-protein-binding tube along with a single high-density milling ball, such as one made of stainless steel or yttrium-stabilized zirconium. The milling may be done using a rotator at max speed containing the tube film-wrapped to avoid moisture absorption or contamination. An ice pack may be placed on top of the tube to keep it cold. The room temperature can be controlled in a range for example from 60 to 64°F. The size of the milling tube, mass of the milling ball and duration of mixing may be selected to produce particular powder grain sizes, grain size homogeneity and powder density. For example, for the production of a 40 mg to 100 mg batch capacity, the use of a bottom-rounded 2 mL tube, a milling ball having a 0.44 g mass and a milling duration of 3 hours have resulted in fine and consistent grain sizes, achieving homogeneous and reliable density values.

[0101] The microtablet formation process is typically done via compression using a compression mold or other fixture to apply a compressive force to the fine powder including the drug (e g., FSH). A semiautomatic or fully automatic compression fixture may be used, as described in U.S. Patent No. 10,098,931, the entire contents of which are incorporated herein by reference. As noted above, in various embodiments, the shaped mass can be formed into the shape of a tissue-penetrating member, i.e. it can be formed to have a tissue-penetrating shape by using molding or other like methods. In these and related embodiments, the shaped mass can have a needle or a dart-like shape (with or without barbs) configured to penetrate and/or be retained in to a tissue, or a membrane such as the intestinal wall. [0102] After the microtablet is fabricated, the length, weight, density and bioactivity of the drug in the pellet may be measured. The bioactivity of the drug in the microtablet may be assayed using an enzyme- linked immunosorbant assay (ELISA) or other immune assay known in the art.

[0103] As described above, the shaped mass can be in the form of a tissue-penetrating member (e.g. in the form of a dart or needle) or contained in a tissue-penetrating member that is configured to be advanced into an intestinal wall or into and through an intestinal wall into a peritoneum or peritoneal cavity and biodegrade to release the FSH in the intestinal wall, peritoneum or or peritoneal cavity and then the bloodstream.

IV. Methods of Treatment and Pharmaceutical Uses

[0104] Also provided herein are treatments (methods of treatment and pharmaceutical uses) comprising administering an ingestible device according to any embodiments described herein by ingestion to a subject in need thereof, e.g., by the subject swallowing the device (orally administering) or by ingesting the device by another mode, such as via an endoscope or stomach port). In some embodiments, the treatments (methods of treatment and pharmaceutical uses) comprise once daily administration of an ingestible device as described herein. In some embodiments, the treatments (methods of treatment and pharmaceutical uses) comprise twice daily administration of an ingestible device as described herein.

[0105] In general, the disclosed methods of treatment and pharmaceutical uses are contemplated for treating any conditions for which FSH is indicated including for treating infertility, such as for stimulating follicle development or stimulating ovulation induction in a female patient or treating hypogonadotropic hypogonadism or idiopathic infertility in a male patient (e.g., for stimulation of spermatogenesis), and other conditions for which treatment with FSH may be indicated.

[0106] The disclosed methods of treatment and pharmaceutical uses may be used for any subject in need of administration of FSH, including female and male subjects in need of treatment for infertility. In some embodiments, the subject is undergoing treatment for infertility. In some embodiments, the subject is a female patient undergoing treatment for infertility. In some embodiments, the subject is a female patient undergoing treatment for stimulating follicle development. In some embodiments, the subject is a female patient undergoing treatment for stimulating ovulation induction. In some embodiments, the subject is a male patient undergoing treatment for infertility. In some embodiments, the subject is a male patient undergoing treatment for hypogonadotropic hypogonadism. In some embodiments, the subject is a male patient undergoing treatment for idiopathic infertility. In some embodiments, the subject is a male patient undergoing treatment for stimulation of spermatogenesis.

[0107] In some embodiments, the payload of the ingestible device contains a dose of FSH effective to achieve a therapeutic plasma level of FSH for the condition being treated. In some embodiments, the payload of the ingestible device contains a dose of FSH effective to achieve a plasma level of FSH of about 10-12 IU/L, or any dose therebetween. In some embodiments, the payload of the ingestible device contains a dose of FSH (including human urinary-derived FSH or recombinant human CHO-cell-derived FSH) of about 75 IU to about 450 IU, or any dose therebetween, including about 75 IU, about 100 IU, about 125 IU, about 150 IU, about 175 IU, about 200 IU, about 225 IU, about 250 IU, about 275 IU, about 300 IU, about 325 IU, about 350 IU, about 375 IU, about 400 IU, about 425 IU, or about 450 IU. In some embodiments, the payload of the ingestible device contains a dose of FSH of about 150 IU or about 450 IU, e.g., a dose of FSH (follitropin alfa) of about 150 IU or about 450 IU or a dose of FSH (follitropin beta) of about 150 IU or about 450 IU, or a dose effective to achieve comparable FSH plasma levels with twice daily administration, or a dose effective to achieve comparable FSH plasma levels with twice daily administration and one missed dose. In some embodiments, the payload of the ingestible device contains a dose of FSH (including recombinant human mammalian-cell-derived FSH) of about 12 pg, e.g., a dose of FSH (follitropin delta) of about 12 pg, or a dose effective to achieve comparable FSH plasma levels with twice daily administration, or a dose effective to achieve comparable FSH plasma levels with twice daily administration and one missed dose. For example, as illustrated in Example 3 below, a dose of 75 IU twice daily (BID) may be effective to achieve comparable FSH plasma levels as once daily administration of 150 IU. Additionally, as also illustrated in Example 3 below, a dose of 100 IU administered twice daily with one missed dose (BID) may be effective to achieve comparable FSH plasma levels as once daily administration of 150 IU.

[0108] In some embodiments, a dose of FSH as described herein is administered once daily. In some embodiments, a dose of FSH as described herein is administered twice daily.

[0109] In some embodiments, the dose comprises about 75 IU of FSH (e.g., follitropin alpha or follitropin beta), and the dose is administered once daily. In some embodiments, the dose comprises about 75 IU of FSH (e.g., follitropin alpha or follitropin beta), and the dose is administered twice daily. In some embodiments, the dose comprises about 100 IU of FSH (e.g., follitropin alpha or follitropin beta), and the dose is administered twice daily. In some embodiments, the dose comprises about 150 IU of FSH (e.g., follitropin alpha or follitropin beta), and the dose is administered once daily. In some embodiments, the dose comprises about 225 IU of FSH (e.g., follitropin alpha or follitropin beta), and the dose is administered once daily. In some embodiments, the dose comprises about 300 IU of FSH (e.g., follitropin alpha or follitropin beta), and the dose is administered once daily. In some embodiments, the dose comprises about 450 IU of FSH (e.g., follitropin alpha or follitropin beta), and the dose is administered once daily.

[0110] In some embodiments the payload of the ingestible device contains an FSH composition as described above, e.g., comprising FSH and one or more other excipients. In specific embodiments, the excipients include one or more of an antioxidant, a lubricant, a bulking agent, and, optionally, a buffering agent, as discussed above. In one specific embodiment the composition comprises about 1% w/w FSH, about 2% w/w phosphate salts, about 52% D-mannitol, about 5% PEG-3550, and about 40% L- methionine. In further specific embodiments, such a composition is used to provide a dose of 150 IU FSH (follitropin alfa). In another specific embodiment the composition comprises about 3% w/w FSH, about 7% w/w phosphate salts, about 45% D-mannitol, about 5% PEG-3550, and about 40% L-methionine. In further specific embodiments, such a composition is used to provide a dose of 450 IU FSH (follitropin alfa). As noted above, to provide other doses of FSH as described herein, more or less of a given composition can be loaded into a device as described herein and/or the concentration of FSH in the composition can be adjusted (higher or lower) with the concentrations of the excipients being adjusted accordingly.

[OHl] As discussed above, currently approved FSH products such as GONAL-F® (follitropin alfa) and REKOVELLE® (follitropin delta) require administration by subcutaneous or intramuscular injection, which can be inconvenient and uncomfortable for patients. The present disclosure addresses this limitation by providing a route of administration that effectively delivers FSH into the bloodstream of a subject being treated without requiring injection, such as oral administration or ingestion by another mode, such as via an endoscope or stomach port. The disclosed treatments are more convenient and less invasive than currently approved FSH products.

[0112] In addition to improved ease of administration, patient comfort, and patient compliance, administration of FSH via an ingestible device as described herein may offer one or more other advantages, such as reduced immunogenicity as compared to another route of administration, such as subcutaneous injection. In some embodiments, FSH administered via an ingestible device as described herein exhibits a bioavailability that is substantially the same as a bioavailability of subcutaneously administered FSH.

[0113] Thus, in accordance with some aspects, the present disclosure provides methods of administering FSH to a subject in need thereof, comprising administering to the subject by ingestion an ingestible device containing a payload formed from, or containing, a composition comprising the FSH, wherein the device is structured to deliver the composition into an intestinal wall of the subject or surrounding tissue thereof (e.g., into a peritoneum or peritoneal cavity of the subject), after ingestion. As noted above, the administration may comprise oral administration (e.g., swallowing the device) or ingestion of the device by another mode, such as via an endoscope or stomach port. The payload may be in the form of a solid tissue penetrating member structured to penetrate an intestinal wall of the subject and be inserted into intestinal wall or into and through the intestinal wall into a peritoneum or peritoneal cavity of the subject after ingestion of the device. The administration of such ingestible devices may be repeated, for example, at a frequency of twice daily, once daily, or less frequently. The payload may be formed from, or may contain, the composition including FSH. The payload is protected from the gastrointestinal (GI) tract environment (e.g., protected against degradation due to ingress of fluid reaching the payload) until the payload is injected into the wall of the small intestine, which is insensitive to sharp stimuli so that the subject does not register pain from the injection.

[0114] The present disclosure also provides methods of treating one or more conditions such as infertility in female and male subjects, such as for stimulating follicle development or stimulating ovulation induction in a female patient or treating hypogonadotropic hypogonadism or idiopathic infertility in a male patient (e.g., for stimulation of spermatogenesis), and other conditions for which treatment with FSH may be indicated. Such methods may comprise administering by ingestion to a subject in need thereof an ingestible device as described herein.

[0115] While specific embodiments have been described and illustrated, it should be understood that components or characteristics of one embodiment can be combined or substituted with one or more components or characteristics from other embodiments. Further, for any positive recitation of a component, characteristic, constituent, feature, step or the like, the present disclosure specifically contemplates the exclusion of that component, value, characteristic, constituent, feature, step or the like. It also should be understood that illustrations may not necessarily be drawn to scale. There can be distinctions between the artistic renditions in the present disclosure and the actual apparatus, due to variables in manufacturing processes and such. There can be other embodiments of the present disclosure which are not specifically illustrated. Thus, the specification and drawings are to be regarded as illustrative rather than restrictive.

[0116] The following examples are given to illustrate the present invention. It should be understood, however, that the invention is not to be limited to the specific conditions or details described in these examples.

EXAMPLES

Example 1 - Preparation of ESH Ingestible Devices

[0117] Microtablets of FSH were manufactured as follows, targeting a dose of 150 IU FSH (follitropin alfa) or 450 IU FSH (follitropin alfa) per microtablet.

[0118] A solution comprising FSH (follitropin alfa), phosphate salts, D-mannitol (as a bulking agent), PEG 3350 (as a lubricant), and L-methionine (as an antioxidant) was prepared, and the solution was lyophilized to form the tableting composition. The tableting composition used to prepare the 150 IU strength microtablets contained 1.1% w/w FSH, 2.2 % w/w phosphate salts, 51.7 % w/w D-mannitol, 5.0 % PEG 3350, and 40.0 % w/w L-methionine. The tableting composition used to prepare the 450 IU strength microtablets contained 3.3 % w/w FSH, 6.6 % w/w phosphate salts, 45.1 % w/w D-mannitol, 5.0% PEG 3350, and 40.0 % w/w L-methionine. The microtablets were prepared using a compression pressure of 20-60 PSI.

[0119] FSH stability in the microtablets was assessed after 1, 2, and 4 weeks storage at 2-8 °C, and met acceptance criteria (FSH content 80-120% of label claim; oxidation level <10%).

Example 2 - Oral Delivery of FSH To Canines

[0120] The ability to deliver FSH in an ingestible device as described herein was assessed in canines. Microtablets prepared as described in Example 1 above were incorporated into an ingestible device as described herein, e.g., within a capsule containing a payload comprising a hollow microneedle containing a single microtablet, with each capsule containing a single payload.

[0121] After an overnight fast, canines having a body weight of 6.8-13.0 kg were administered FSH as follows:

SC: subcutaneous injection of Gonal-F (follitropin alfa) (600 lU/mL) at a dose of 20 lU/kg • Oral: oral administration of one ingestible device (capsule) containing a 150 IU or 450 IU FSH (follitropin alfa) microtablet prepared as described in Example 1.

Radiographic imaging was used to monitor capsule transit and confirm deployment within the small intestine. For the oral administration group, blood levels of FSH were assessed pre-dose, and at 2, 4, 6, 8, 10, 12, 24, 48, 72, 96, and 120 hours post-deployment. For the subcutaneous injection group, blood levels of FSH were assessed pre-dose and at 2, 4, 8, 12, 24, 48, 72, 96, and 120 hours post-deployment. Results are reported in FIG. 6 and in the table below (mean ± SEM).

[0122] The results showed that FSH can be successfully delivered by an ingestible device as described herein, with a success rate of 94%. The calculated relative bioavailability for the orally administered FSH (150 IU dose group) was 99% as compared to the subcutaneous route (see FIG. 6, middle vs. bottom lines). The results showed a dose-dependent increase in FSH levels between the 150 IU and 450 IU oral ingestible microtablet groups (see FIG. 6, middle vs. top lines).

Example 3 - Dose Simulation Studies

[0123] The impact of dosing frequency for an ingestible device as described herein on serum FSH concentration (IU/L) was assessed through simulation studies using a computer-based pharmacokinetic model simulation of FSH dosing. In particular, simulated plasma concentration vs. time curves were prepared from pharmacokinetic model simulation of FSH dosing at 75 IU twice daily (BID) vs. 150 IU once daily (FIG. 7), FSH dosing at 75 IU twice daily with one missed dose on Day 3 vs. 75 IU twice daily without missed dose vs. 150 IU once daily (FIG. 8), and FSH dosing at 100 IU twice daily with one missed dose on Day 3 vs. 100 IU twice daily without missed dose vs. 150 IU once daily vs. 225 IU once daily (FIG. 9).

[0124] The results indicate that FSH dosing of 75 IU twice daily (BID) is comparable to 150 IU once daily (FIG. 7), and that after one missed BID dose FSH plasma levels may fall below once daily levels (FIG. 8). The results also show that FSH dosing of 100 IU twice daily (BID) with one missed dose maintains FSH plasma levels at or above levels provided by 150 IU once daily (FIG. 9). Collectively, the results indicate that a dose for twice daily administration could be determined that would maintain FSH plasma concentration at a target level even with a missed dose (e.g., as shown for 100 IU BID relative to 150 IU once daily). The ingestible devices as described herein are particularly advantageous in that regard, because a device can be loaded with any desired dose.

[0125] Collectively, these data underscore the surprising advantages of the compositions, dosage forms, devices, and methods disclosed herein, especially when compared to the current standard of care that requires injections of FSH.

Claims

What is claimed is:

1. A method of administering follicle stimulating hormone (FSH) to a subject in need thereof, comprising administering to the subject by ingestion an ingestible device containing a payload formed from, or containing, a composition comprising FSH, wherein the device is structured to deliver the composition into a gastrointestinal (GI) lumen wall of the subject or surrounding tissue thereof.

2 The method of claim 1, wherein the method achieves a bioavailability of FSH that is substantially the same as a bioavailability of subcutaneously administered FSH.

3 The method of claim 1 or 2, wherein the FSH is human FSH.

4 The method of claim 1 or 2, wherein the FSH is urinary-derived human FSH.

5 The method of claim 1 or 2, wherein the FSH is recombinant human FSH.

6 The method of any one of claims 1-4, wherein the device contains a dose of FSH of from about 75 IU to about 450 IU, optionally wherein the FSH is follitropin alfa.

7 The method of any one of claims 1-4, wherein the device contains a dose of FSH selected from 75 IU, 100 IU, 125 IU, 150 IU, 175 IU, 200 IU, 225 IU, 250 IU, 275 IU, 300 IU, 325 IU, 350 IU, 375 IU 400 IU, 425 IU, and 450 IU, optionally wherein the FSH is follitropin alfa.

8 The method of claim 5, wherein the device contains a dose of recombinant human FSH of about 12 pg, optionally wherein the FSH is follitropin delta.

9 The method of any one of the preceding claims, comprising once daily administration of the device.

10 The method of any one of claims 1-8, comprising twice daily administration of the device.

11 The method of any one of the preceding claims, wherein the composition comprises the FSH, a lubricant, a bulking agent, an antioxidant, and, optionally, a buffering agent.

12 The method of any one of the preceding claims, wherein the composition comprises the FSH, a phosphate salt, PEG-3350, D-mannitol, and L-methionine.

13. The method of any one of the preceding claims, wherein the composition comprises about 1 % w/w of FSH, about 2 % w/w of phosphate salts, about 5 % PEG-3350, about 52 % D-mannitol, and about 40% w/w L-methionine.

14. The method of any one of claims 1-12, wherein the composition comprises about 3.5 % w/w of FSH, about 6.5 % w/w of phosphate salts, about 5 % PEG-3350, about 45 % D-mannitol, and about 40% w/w L-methionine.

15. The method of any one of the preceding claims, wherein the payload is in the form of a solid tissue penetrating member structured to be inserted into a GI lumen wall of the subject or surrounding tissue thereof.

16. The method of claim 15, wherein the composition is filled in a hollow, biodegradable microneedle constituting the solid tissue penetrating member.

17. The method of claim 15, wherein the composition is a shaped mass constituting the solid tissue penetrating member.

18. The method of any one of the preceding claims, wherein the device comprises multiple payloads of the FSH.

19. The method of claim 18, wherein the device is structured to deliver one or more payloads into the GI lumen wall or surrounding tissue thereof at different times.

20. The method of any one of the preceding claims, wherein the ingestible device is comprised within a swallowable capsule.

21. The method of any one of the preceding claims, wherein the device is structured to deliver the composition into a stomach wall of the subject.

22. The method of any one of claims 1-20, wherein the device is structured to deliver the composition into an intestinal wall of the subject.

23. The method of claim 22, wherein the intestinal wall is a wall of the small intestine.

24. The method of any one of claims 1-20, wherein the device is structured to deliver the composition into the peritoneum, or peritoneal cavity of the subject.

25. The method of any one of the preceding claims, wherein the subject is undergoing treatment for infertility.

26. The method of claim 25, wherein the method is for stimulating follicle development in a female patient.

27. The method of claim 25, wherein the method is for stimulating ovulation induction in a female patient.

28. The method of claim 25, wherein the method is for one or more of treating hypogonadotropic hypogonadism in a male patient, treating idiopathic infertility in a male patient, and stimulation of spermatogenesis in a male patient.

29. An ingestible device for use in delivering FSH to a subject in need thereof, the device containing a payload formed from, or containing, a composition comprising FSH, wherein the device is structured to deliver the composition into a gastrointestinal (GI) lumen wall of the subject or surrounding tissue thereof.

30. An ingestible device for use in treating infertility in subject in need thereof, the device containing a payload formed from, or containing, a composition comprising FSH, wherein the device is structured to deliver the composition into a gastrointestinal (GI) lumen wall of the subject or surrounding tissue thereof.

31. The ingestible device for use according to claim 30, wherein the treatment of infertility is selected from stimulating follicle development in a female patient, stimulating ovulation induction in a female patient, treating hypogonadotropic hypogonadism in a male patient, treating idiopathic infertility in a male patient, and stimulating of spermatogenesis in a male patient.

32. The ingestible device for use of any one of claims 20-31, wherein the FSH is urinary-derived human FSH.

33. The ingestible device for use of any one of claims 29-32, wherein the device contains a dose of FSH of from about 75 IU to about 450 IU, optionally wherein the FSH is follitropin alfa.

34. The ingestible device for use of any one of claims 29-33, wherein the device contains a dose of FSH selected from 75 IU, 100 IU, 125 IU, 150 IU, 175 IU, 200 IU, 225 IU, 250 IU, 275 IU, 300 IU, 325 IU, 350 IU, 375 IU, 400 IU, 425 IU, and 450 IU, optionally wherein the FSH is follitropin alfa.

35. The ingestible device for use of any one of claims 29-31, wherein the FSH is recombinant human FSH.

36. The ingestible device for use of claim 35, wherein the device contains a dose of recombinant human FSH of about 12 pg, optionally wherein the FSH is follitropin delta.

37. The ingestible device for use of any one of claims 29-36, wherein the composition comprises the FSH, a lubricant, a bulking agent, an antioxidant, and, optionally, a buffering agent.

38. The ingestible device for use of any one of claims 29-37, wherein the composition comprises the FSH, a phosphate salt, PEG-3350, D-mannitol, and L-methionine.

39. The ingestible device for use of any one of claims 29-38, wherein the composition comprises about 1 % w/w of FSH, about 2 % w/w of phosphate salts, about 5 % PEG-3350, about 52 % D-mannitol, and about 40% w/w L-methionine.

40. The ingestible device for use of any one of claims 29-38, wherein the composition comprises about 3.5 % w/w of FSH, about 6.5 % w/w of phosphate salts, about 5 % PEG-3350, about 45 % D-mannitol, and about 40% w/w L-methionine.

41. The ingestible device for use of any one of claims 29-40, wherein the payload is in the form of a solid tissue penetrating member structured to be inserted into a GI lumen wall of the subject or surrounding tissue thereof.

42. The ingestible device for use of claim 41, wherein the composition is filled in a hollow, biodegradable microneedle constituting the solid tissue penetrating member.

43. The ingestible device for use of claim 41, wherein the composition is a shaped mass constituting the solid tissue penetrating member.

44. The ingestible device for use of any one of claims 29-43, wherein the device comprises multiple payloads of the FSH.

45. The ingestible device for use of claim 44, wherein the device is structured to deliver one or more payloads into the GI lumen wall or surrounding tissue thereof at different times.

46. The ingestible device for use of any one of claims 29-45, wherein the ingestible device is comprised within a swallowable capsule.

47. The ingestible device for use of any one of claims 29-46, wherein the device is structured to deliver the composition into a stomach wall of the subject.

48. The ingestible device for use of any one of claims 29-46, wherein the device is structured to deliver the composition into an intestinal wall of the subject.

49. The ingestible device for use of claim 48, wherein the intestinal wall is a wall of the small intestine.

50. The ingestible device for use of any one of claims 29-46, wherein the device is structured to deliver the composition into the peritoneum, or peritoneal cavity of the subject.

51. The ingestible device for use of any one of claims 29-50, wherein the bioavailability of FSH is substantially the same as a bioavailability of subcutaneously administered FSH.

52. The ingestible device for use of any one of claims 29-51, wherein the use comprises once daily administration of the device.

53. The ingestible device for use of any one of claims 29-51, wherein the use comprises twice daily administration of the device.

54. Use of FSH in the preparation of a medicament for treating infertility, wherein the medicament is an ingestible device containing a payload formed from, or containing, a composition comprising FSH, herein the device is structured to deliver the composition into a gastrointestinal (GI) lumen wall of the subject or surrounding tissue thereof.

55. The use of claim 54, wherein the FSH is urinary-derived human FSH.

56. The use of claim 54, wherein the FSH is recombinant human FSH.

57. The use of any one of claims 54-55, wherein the device contains a dose of FSH of from about 75 IU to about 450 IU, optionally wherein the FSH is follitropin alfa.

58. The use of any one of claims 54-55 or 57, wherein the device contains a dose of FSH selected from 75 IU, 100 IU, 125 IU, 150 IU, 175 IU, 200 IU, 225 IU, 250 IU, 275 IU, 300 IU, 325 IU, 350 IU, 375 IU, 400 IU, 425 IU, and 450 IU, optionally wherein the FSH is follitropin alfa.

59. The use of claim 56, wherein the device contains a dose of recombinant human FSH of about 12 pg, optionally wherein the FSH is follitropin delta.

60. The use of any one of claims 54-59, wherein the composition comprises the FSH, a lubricant, a bulking agent, an antioxidant, and, optionally, a buffering agent.

61. The use of any one of claims 54-60, wherein the composition comprises the FSH, phosphate salts, PEG-3350, D-mannitol, and L-methionine.

62. The use of any one of claims 54-61, wherein the composition comprises about 1 % w/w of FSH, about 2 % w/w of phosphate salts, about 5 % PEG-3350, about 52 % D-mannitol, and about 40% w/w L-methionine.

63. The use of any one of claims 54-61, wherein the composition comprises about 3.5 % w/w of FSH, about 6.5 % w/w of phosphate salts, about 5 % PEG-3350, about 45 % D-mannitol, and about 40% w/w L-methionine.

64. The use of any one of claims 54-63, wherein the payload is in the form of a solid tissue penetrating member structured to be inserted into a GI lumen wall of the subject or surrounding tissue thereof.

65. The use of claim 64, wherein the composition is filled in a hollow, biodegradable microneedle constituting the solid tissue penetrating member.

66. The use of claim 64, wherein the composition is a shaped mass constituting the solid tissue penetrating member.

67. The use of any one of claims 54-66, wherein the device comprises multiple payloads of the FSH.

68. The use of claim 67, wherein the device is structured to deliver one or more payloads into the GI lumen wall or surrounding tissue thereof at different times.

69. The use of any one of claims 54-68, wherein the ingestible device is comprised within a swallowable capsule.

70. The use of any one of claims 54-69, wherein the device is structured to deliver the composition into a stomach wall of the subject.

71. The use of any one of claims 54-69, wherein the device is structured to deliver the composition into an intestinal wall of the subject.

72. The use of claim 71, wherein the intestinal wall is a wall of the small intestine.

73. The use of any one of claims 54-69, wherein the device is structured to deliver the composition into the peritoneum, or peritoneal cavity of the subject.

74. The use of any one of claims 54-73, wherein the bioavailability of FSH is substantially the same as a bioavailability of subcutaneously administered FSH.