Ustekinumab dosage forms and methods

Abstract

The present disclosure generally relates to ingestible devices containing an anti-interleukin antibody, such as ustekinumab, that binds to one or both of human interleukin-23 and human interleukin-12. The devices are structured and formulated to deliver a therapeutically effective amount of the antibody into or across the gastrointestinal (GI) lumen wall to the peritoneum or peritoneal cavity after ingestion of the device to achieve desired pharmacokinetic and therapeutic effects.

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims the benefit of and priority to U.S. Provisional Application No. 63 / 416,854, filed October 17, 2022, the entire contents of which are incorporated herein by reference.

[0002] (Field of invention) The present disclosure generally relates to compositions, dosage forms, devices, and methods for the ingestive delivery of anti-interleukin antibodies, such as ustekinumab. More specifically, the disclosure relates to ingestible dosage forms (e.g., ingestible devices) comprising compositions containing the anti-interleukin antibody ustekinumab, structured and formulated to deliver a therapeutically effective amount of the anti-interleukin antibody to the gastrointestinal (GI) tract wall (e.g., stomach wall, intestinal wall, colon, etc.) or through the GI tract wall to the peritoneum or peritoneal cavity of a subject (and thereafter to the bloodstream) to achieve a desired pharmacokinetic and therapeutic outcome. The compositions, devices, and methods of the present invention are useful for treating, for example, psoriasis (including moderate to severe plaque psoriasis), psoriatic arthritis, Crohn's disease (including moderate to severe Crohn's disease), ulcerative colitis (including moderate to severe ulcerative colitis), and other conditions for which treatment with an anti-interleukin antibody may be indicated. [Background technology]

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

[0004] The anti-interleukin antibody drug STELARA® (generic name: ustekinumab) is currently approved in the United States for the treatment of moderate to severe plaque psoriasis, psoriatic arthritis, moderate to severe Crohn's disease, and moderate to severe ulcerative colitis. STELARA® is administered subcutaneously or intravenously. For patients weighing up to 100 kg, the dosing regimen is 45 mg subcutaneously at the onset and 4 weeks later, followed by 45 mg subcutaneously every 12 weeks. For patients weighing more than 100 kg, the dose is 90 mg subcutaneously at the onset and 4 weeks later, followed by 90 mg subcutaneously every 12 weeks.

[0005] Formed masses of biologically active proteins or polypeptides, including anti-interleukin antibodies, are described, for example, in U.S. Patent Nos. 10,098,931 and 10,227,403. Other anti-interleukin antibody preparations are described in U.S. 18 Month Publication No. 2018 / 0251537.

[0006] There is a need for compositions, dosage forms, devices, and methods for delivering anti-interleukin antibodies, such as ustekinumab, via ingestion.

[0007] (overview) In one embodiment, a method for administering an anti-interleukin antibody to a subject in need thereof is provided. The method comprises administering to the subject, by ingestion, an ingestible device comprising a payload formed from or including a composition comprising the anti-interleukin antibody. The device is structured to deliver the composition to or through the gastrointestinal (GI) lumen wall of the subject to the peritoneum or peritoneal cavity of the subject. The anti-interleukin antibody binds to one or both of human interleukin-23 and human interleukin-12.

[0008] In another embodiment, an ingestible device for use in delivering an anti-interleukin antibody to a subject in need thereof is provided. The device comprises a payload formed from or including a composition comprising an anti-interleukin antibody. The device is configured to deliver the composition to or through the gastrointestinal (GI) lumen wall of the subject and into the peritoneum or peritoneal cavity of the subject. The anti-interleukin antibody binds to one or both of human interleukin-23 and human interleukin-12.

[0009] In one or more embodiments, the anti-interleukin antibody is an antagonist of one or both of human interleukin-23 and human interleukin-12.

[0010] In one or more embodiments, the anti-interleukin antibody comprises ustekinumab or a biosimilar thereof.

[0011] In one or more embodiments, the anti-interleukin antibody comprises ustekinumab.

[0012] In one or more embodiments, the anti-interleukin antibody exhibits a biological activity that is greater than the biological activity of an anti-interleukin antibody administered subcutaneously.

[0013] In one or more embodiments, the anti-interleukin antibody exhibits substantially the same biological activity as that of an anti-interleukin antibody administered subcutaneously.

[0014] In one or more embodiments, the subject is afflicted with one or more diseases selected from psoriasis, moderate to severe plaque psoriasis, psoriatic arthritis, Crohn's disease, and ulcerative colitis.

[0015] In one or more embodiments, the device comprises an anti-interleukin antibody at a dose of about 0.25 mg to about 0.75 mg. In one or more embodiments, the device comprises an anti-interleukin antibody at a dose selected from about 0.5 mg and about 0.75 mg. In one or more embodiments, the device comprises an anti-interleukin antibody dose of about 3.75 mg to about 15 mg.

[0016] In one or more embodiments, the device is administered once daily.

[0017] In one or more embodiments, the composition is a solid composition comprising an anti-interleukin antibody, a buffer, a surfactant, and an antioxidant. In one or more embodiments, the composition (e.g., a solid composition) comprises an anti-interleukin antibody, L-histidine / L-histidine hydrochloride, polyoxyethylene sorbitan monooleate, and L-methionine. In one or more embodiments, the composition (e.g., a solid composition) further comprises a lubricant and a bulking agent. In one or more embodiments, the composition (e.g., a solid composition) comprises an anti-interleukin antibody, L-histidine / L-histidine hydrochloride, polyoxyethylene sorbitan monooleate, trehalose, PEG3350, and L-methionine. In one or more embodiments, the composition (e.g., solid composition) comprises about 67% w / w ustekinumab, about 10% w / w L-histidine / L-histidine hydrochloride, about 1% w / w polyoxyethylene sorbitan monooleate, about 10% w / w trehalose, about 10% w / w PEG 3350, and about 2% w / w L-methionine. In one or more embodiments, the composition (e.g., solid composition) comprises about 75% w / w ustekinumab, about 12% w / w L-histidine / L-histidine hydrochloride, about 1% w / w polyoxyethylene sorbitan monooleate, about 3% w / w trehalose, about 7% w / w PEG 3350, and about 2% w / w L-methionine.

[0018] In one or more embodiments, the composition is a liquid composition.

[0019] In one or more embodiments, the payload is in the form of a solid tissue-piercing member structured to be inserted into the GI lumen wall of a subject and / or inserted into the peritoneum or peritoneal cavity of a subject after ingestion of the device. In one or more embodiments, the composition is loaded into hollow biodegradable microneedles that make up the solid tissue-piercing member. In one or more embodiments, the composition is a shaped mass that makes up the solid tissue-piercing member. In one or more embodiments, the device includes multiple payloads of anti-interleukin antibodies. In one or more embodiments, the device is structured to deliver one or more payloads at different times to the GI lumen wall, peritoneum, or peritoneal cavity of a subject. In one or more embodiments, the GI lumen wall is the stomach wall. In one or more embodiments, the GI lumen wall is the intestinal wall. In one or more embodiments, the intestinal wall is the small intestine wall.

[0020] In one or more embodiments, the ingestible device is configured within a swallowable capsule.

[0021] In one or more embodiments, the method or use comprises an induction dosing period followed by a maintenance dosing period.

[0022] In one or more embodiments, the subject is an adult patient weighing ≦100 kg or a pediatric patient weighing >60 kg; The induction dosing period consists of an induction dosing regimen selected from the following: 45 mg subcutaneously at weeks 0 and 4 Approximately 1.5 mg will be administered once daily via an ingestible device for four weeks. Approximately 12 mg is administered once daily for 4 weeks. Approximately 9 mg per day, once daily, via an ingestible device, administered for 7 days starting at week 0 and again at week 4; and The maintenance dosing period consists of a maintenance dosing regimen selected from the following: 45 mg administered subcutaneously every 12 weeks Approximately 0.5 mg is administered once daily via an ingestible device. Approximately 3.75 mg is administered once weekly via an ingestible device. A monthly short course of approximately 2.5 mg per day for 6 days, administered daily via an ingestible device; Approximately 15 mg is administered quarterly via an ingestible device. a short course of approximately 12 mg per day administered via an ingestible device once per quarter for 5 days; wherein amount refers to a dose of an anti-interleukin antibody, and optionally the anti-interleukin antibody is ustekinumab or a biosimilar thereof; wherein said method or use comprises administration of at least one dose of an anti-interleukin antibody by said ingestible device.

[0023] In one or more embodiments, the subject is an adult patient weighing >100 kg; The induction dosing period consists of an induction dosing regimen selected from the following: 90 mg administered subcutaneously at weeks 0 and 4 Approximately 3.25 mg will be administered once daily via an ingestible device for four weeks. Approximately 1.5 mg twice daily via an ingestible device for four weeks. Approximately 24 mg will be administered once daily via an ingestible device for four weeks. Approximately 18 mg per day, once daily, via an ingestible device, administered for 7 days starting at week 0 and again at week 4; and The maintenance dosing period consists of a maintenance dosing regimen selected from the following: 90 mg administered subcutaneously every 12 weeks Approximately 1 mg is administered once daily via an ingestible device. Approximately 0.5 mg twice daily administered via an ingestible device Approximately 7.5 mg is administered once a week via an ingestible device. a monthly short course of approximately 2.5 mg twice daily for 6 days administered via an ingestible device; Approximately 30 mg is administered quarterly via an ingestible device. a short course of approximately 12 mg per day administered via an ingestible device once per quarter for 9 days; wherein amount refers to a dose of an anti-interleukin antibody, and optionally the anti-interleukin antibody is ustekinumab or a biosimilar thereof; wherein said method or use comprises administration of at least one dose of an anti-interleukin antibody by said ingestible device. [Brief explanation of the drawings]

[0024] (Brief explanation) FIG. 1A shows an example of an embodiment of an expandable component of a self-sizing device as disclosed herein and an example of an embodiment of a capsule as disclosed herein before folding and / or rolling.

[0025] FIG. 1B shows the expandable component of FIG. 1A in an embodiment in a folded and / or rolled configuration, prior to disposing the expandable component within a capsule.

[0026] FIG. 1C shows the expandable component of FIG. 1A disposed within a capsule in the folded and / or rolled configuration of FIG. 1B.

[0027] Figures 2A (FIG. 2A), 2B (FIG. 2B), and 2C (FIG. 2C) show an example of an embodiment of a capsule including an automatic sizing device as disclosed herein, including an expandable component within a degradable capsule, such that the device traverses a lumen.

[0028] 2D (FIG. 2D), 2E (FIG. 2E), and 2F (FIG. 2F) show in rotational view the progression of the expandable component of FIG. 2C as it expands within the lumen.

[0029] FIG. 3 shows an example embodiment of a self-sizing device disclosed herein, including an expandable component in a fully expanded state within a lumen.

[0030] FIG. 4A shows an example embodiment of a self-sizing device disclosed herein that includes an expandable component with one non-compliant section and no hinges.

[0031] FIG. 4B shows an example embodiment of a self-sizing device that includes an expandable component with two non-compliant sections and a hinge.

[0032] FIG. 5 shows an embodiment of a capsule containing an ingestible device disclosed herein. Inset A shows the fully assembled enteric-coated capsule. Schematic B shows the various parts and components of the capsule.

[0033] Figure 6 (FIG. 6) shows the results of a computer-based pharmacokinetic model simulation of ustekinumab administration based on published human pharmacokinetic data. It plots the simulated plasma concentration versus time curves for ustekinumab administered at 45 mg once every 12 weeks (top curve), 0.75 mg once daily (middle curve), or 0.5 mg once daily (bottom curve). The dashed line indicates the minimum therapeutic plasma concentration of 0.69 μg / mL.

[0034] FIG. 7 shows the plasma concentration versus time curves obtained in the dog study of Example 2 after a single oral dose of an ingestible dosage form of ustekinumab described herein.

[0035] FIG. 8 shows the plasma concentration versus time curves obtained after a single administration of ustekinumab via an ingestible device or a single subcutaneous (SC) injection in the dog study of Example 4. DETAILED DESCRIPTION OF THE INVENTION

[0036] (detail) The present disclosure provides compositions, dosage forms, devices, and methods for delivering an anti-interleukin antibody, such as ustekinumab, using an ingestible dosage form (ingestible device) comprising a payload formed from or comprising a composition comprising the antibody, where the device is configured to deliver the anti-interleukin antibody into or through the GI luminal wall (e.g., stomach wall, intestinal wall, colon, etc.) and deliver it to the peritoneum or peritoneal cavity of a subject (and thereafter into the bloodstream). The payload may be in the form of a solid tissue-piercing member structured to penetrate the GI luminal wall of a subject and / or be inserted into the peritoneum or peritoneal cavity of a subject after ingestion of the device. The ingestible device may be disposed within a capsule, such as a swallowable capsule.

[0037] (1.Definition) 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.

[0038] Unless otherwise defined, technical and scientific terms used herein have the meanings commonly understood by those skilled in the art. Unless otherwise specified, materials and / or methodologies known to those skilled in the art can be utilized in carrying out the methods described herein based on the guidance provided herein.

[0039] As used herein, the singular terms "a," "an," and "the" include plural references unless the context clearly dictates otherwise. Singular references do not mean "one, only one," but rather "one or more," unless expressly stated otherwise.

[0040] As used herein, the terms "e / g.," "such as," "for example," "for an example," "for another example," "an example of," "by way of example," and "etc." indicate that they are preceded or followed by a list of one or more non-limiting examples, and it is to be understood that other examples not listed are also within the scope of the present disclosure.

[0041] As used herein, the terms "substantially" and "about" when used in conjunction with a numerical value refer to the stated numerical value as well as a numerical value that includes up to plus or minus 10% of the numerical value. For example, "about 10" should be understood as both "10" and "a range between and including 9 and 11."

[0042] 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), and 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).

[0043] As used herein, the terms "comprising," "comprise," "comprises," "includes," and "including" are intended to mean that compositions and methods include the recited elements, but do not exclude other elements.

[0044] As used herein, a "therapeutically effective amount" of an anti-interleukin antibody, such as ustekinumab, refers to a dose at which the administered agent produces a specific pharmacological effect in a subject in need of such treatment. It is emphasized that a therapeutically effective amount of an anti-interleukin antibody, although considered a therapeutically effective amount by those skilled in the art, is not necessarily effective in treating the condition for which it is administered to the individual subject. Those skilled in the art can adjust what is considered a therapeutically effective amount according to standard practice, as needed to treat a particular subject. A therapeutically effective amount may vary based on, for example, the subject's age and weight, and / or the subject's overall health, condition at the time of treatment, and / or the severity of the condition of the subject being treated.

[0045] With respect to an anti-interleukin antibody such as ustekinumab, a "therapeutic level" of a circulating anti-interleukin antibody in a human subject refers to the plasma concentration associated with the specific pharmacological effect for which the agent is administered in a subject in need of such treatment. A "therapeutic level" of circulating ustekinumab in a human subject is considered to be a plasma concentration of about 0.69 μg / mL or greater. That is, a plasma concentration of ustekinumab of about 0.69 μg / mL or greater can be therapeutically effective.

[0046] The term "ingestion" or grammatical variations thereof (e.g., "ingesting," "ingestion," "ingested," or "ingestable"), as used herein, refers to uptake into the stomach, whether by swallowing or by other means of stomach deposition (e.g., stomach deposition by endoscopy or stomach deposition via a port).

[0047] As used herein, the term "lumen" refers to the interior space of a tubular structure. Examples of lumens in the body include arteries, veins, and lumens within organs. The term "gastrointestinal lumen" or "GI lumen" generally refers to the lumen of the GI tract (e.g., the lumen of the esophagus, stomach, small intestine, large intestine, or colon), and the term "GI lumen wall" refers to the lumen wall of the GI lumen.

[0048] The term "luminal wall" means the wall of a lumen, and includes all layers from the inner periphery to the outer periphery of the lumen. For example, with respect to a lumen in the body, the luminal wall includes the mucosa, submucosa, muscularis, serosa, the outer wall of the lumen, and the blood vessels and tissues that constitute it.

[0049] As used herein, the term "digestive tract" or "GI tract" refers to the intake / excretion system of the body, including, for example, the mouth, pharynx, esophagus, stomach, pylorus, small intestine, cecum, large intestine, colon, rectum, anus, and the valves or sphincters therebetween.

[0050] The terms "individual," "subject," and "patient" are used interchangeably herein and include any mammalian individual (e.g., bovine, canine, feline, equine, or human). In certain embodiments, a subject, individual, or patient is a human.

[0051] As used herein, the term "component" refers to one item of a set of one or more items that together make up the device, composition, or system under discussion. A component may be a solid, powder, gel, plasma, fluid, gas, or other physical property. For example, a device may include multiple solid components that are assembled together to make the device and may further include a fluid component disposed within the device. As another example, a composition may include a single component or two or more components that are mixed together to make the composition. A composition may be in the form of a fluid, slurry, powder, or solid (e.g., a compacted or consolidated form such as a tablet or microtablet). A device or system may include one or more compositions and / or one or more other components.

[0052] The term "design" or grammatical variations thereof (e.g., "designing" or "designed"), as used herein, refers to intentionally incorporated characteristics 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 due to external or internal mechanical pressure, product life or shelf life, or, if introduced into the body, physiology, body chemistry, biological composition of body fluids or tissues, chemical composition of body fluids or tissues, pH, species, diet, health, sex, age, ancestry, disease, or tissue damage). It is understood that different components, devices, compositions, or systems having the same design may have different actual values ​​for these characteristics because actual tolerances and environmental conditions before and / or after delivery may affect the characteristics. Design also includes changes or modifications before or after manufacturing.

[0053] The term "manufacture" or grammatical variations thereof (e.g., "manufacturing" or "manufactured"), as used herein in connection with a component, device, composition, or system, refers to making or assembling the component, device, composition, or system. Manufacturing can be done wholly or partially by manual and / or wholly or partially automated methods.

[0054] The term "structured" or grammatical variations thereof (e.g., "structure" or "structuring"), as used herein, refers to a component, device, composition, or system that is produced according to a concept or design, or variations or modifications thereof, whether such variations or modifications occur before, during, or after production, whether such concept or design is described in writing or not.

[0055] The term "degrade" or grammatical variations thereof (e.g., "degrading," "degraded," "degradable," and "degradation"), as used herein, refers to weakening, partial degradation, or complete breakdown, such as by dissolution, chemical degradation (including biodegradation), breakdown, chemical modification, mechanical degradation, or disintegration, including, but not limited to, dissolving, crumbling, deformation, withering, or shrinking.

[0056] The term "non-degradable" means that degradation will occur minimally, or within some acceptable design rate, in the expected environment for at least the expected period of time.

[0057] The terms "anti-interleukin antibody composition" and "composition of anti-interleukin antibody" can be used interchangeably herein and refer to a composition comprising one or more components, at least one of which is an anti-interleukin antibody. The anti-interleukin antibody composition can, for example, contain an anti-interleukin antibody as the sole active agent, or can include one or more additional active agents.

[0058] As used herein, the term "anti-interleukin antibody" refers to a full-length antibody or fragment thereof that binds to an interleukin protein, such as human interleukin-23 or human interleukin-12, including monoclonal, human, and humanized antibodies. An antibody may be an immunoglobulin (Ig) molecule consisting of four polypeptide chains: two heavy (H) chains and two light (L) chains. A functional antibody fragment comprises a fragment of an antibody, such as at least one complementarity-determining region (CDR) of the heavy chain, at least one complementarity-determining region (CDR) of the light chain, a heavy chain variable region, a light chain variable region, a heavy chain constant region, a light chain constant region, and a framework region. The anti-interleukin antibodies discussed herein may bind to either or both human interleukin-23 and human interleukin-12. The anti-interleukin antibodies discussed herein may be antagonists of either or both human interleukin-23 and human interleukin-12.

[0059] The anti-interleukin antibody may be ustekinumab, a biosimilar antibody thereof, or may consist of ustekinumab. Ustekinumab (included in the FDA-approved product STELARA®) is a recombinant human IgG1κ monoclonal antibody produced in a mouse cell line (Sp2 / 0) and acts as a human interleukin-12 and human interleukin-23 antagonist. Ustekinumab consists of 1,326 amino acids and has a predicted molecular weight of 148,079 to 149,690 daltons.

[0060] As used herein, a "retardant" refers to an ingredient included in a composition to slow the release rate of one or more other ingredients from the composition. The retardant may be, for example, poly(lactic acid) (PLA), poly(glycolic acid) (PGA), polyethylene glycol (PEG), poly(ethylene oxide) (PEO), poly(L-lactic acid) (PLLA), poly(D-lactic acid) (PDLA), other polymers, or hydrogels.

[0061] Various abbreviations may be used herein for standard units such as deciliter (dl), milliliter (ml), microliter (μl), international units (IU), centimeter (cm), millimeter (mm), nanometer (nm), inch (in), kilogram (kg), gram (gm), milligram (mg), microgram (μg), nanogram (ng), millimole (mM), degrees Celsius (°C), degrees Fahrenheit (°F), millitorr (mTorr), hour (hr), minute (min), second (s or sec), millisecond (ms), microsecond (μs), or nanosecond (ns).

[0062] Disclosed herein is an ingestible dosage form (ingestible device) useful for delivering an anti-interleukin antibody to a subject in need thereof. The device comprises a payload formed from or including a composition comprising an anti-interleukin antibody, and is structured to deliver the composition to or through the wall of the GI tract lumen of a subject after ingestion, for example, to the peritoneum or peritoneal cavity of the subject. As described above, the anti-interleukin antibody provided in the device can bind to one or both of human interleukin-23 and human interleukin-12 and / or can be an antagonist of one or both of human interleukin-23 and human interleukin-12. As described above, the anti-interleukin antibody provided in the device can be ustekinumab or a biosimilar thereof, or can consist of ustekinumab or a biosimilar thereof. While the anti-interleukin antibody provided in the device is not limited to ustekinumab, for convenience, the following discussion will refer to ustekinumab. It should be understood that other anti-interleukin antibodies may be used in addition to or in place of ustekinumab, including antibodies that are biosimilar to ustekinumab, and / or other antibodies that bind to one or both of human interleukin-23 and human interleukin-12, and / or antibodies that may be antagonists of one or both of human interleukin-23 and human interleukin-12.

[0063] 2. Ingestible Dosage Forms (Ingestion Devices) As mentioned above, the ingestible dosage forms described herein are ingestible devices containing a payload made from ustekinumab, consisting of a composition comprising ustekinumab, or containing a composition comprising ustekinumab. The payload may be in the form of a solid tissue-piercing member structured to penetrate the wall of a subject's GI tract lumen and be inserted into the wall of the subject's GI tract or the surrounding bodily environment (e.g., the peritoneum or peritoneal cavity) after ingestion of the device (e.g., after swallowing the device or after ingestion of the device by another modality, such as through an endoscope or gastric port), thereby delivering ustekinumab to the subject's bloodstream. The payload may be formed from or include a composition. Specific embodiments of such devices are described in more detail below. Any of the devices disclosed or referenced herein may optionally be placed within a capsule, such as a swallowable capsule. Typically, materials used to form device components are classified as food-grade materials, food additives, active / inactive food ingredients, or GRAS (Generally Recognized as Safe by the FDA) materials. The device (including the capsule shell) may be biodegradable.

[0064] FIG. 5 diagrammatically illustrates an ingestible device (e.g., a swallowable device) according to one embodiment of the present disclosure. As illustrated, the device is disposed within a capsule, which may be a swallowable capsule of any suitable size, such as a 000-size HPMC (hydroxypropyl methylcellulose) capsule, or may be a capsule such as that illustrated in Insert A of FIG. 5. The capsule may comprise a coating, such as an enteric coating (e.g., a polymer that dissolves at a target pH in the gastrointestinal tract), such as an enteric polymer. For example, the enteric coating may 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 high intestinal pH of the small intestine dissolves the enteric coating and capsule shell, exposing the interior of the device and the components contained therein to intestinal fluids.

[0065] Thus, in some embodiments, the capsule and / or coating is designed to degrade after a certain period of time in the presence of a particular chemical or under conditions expected at a target site in the GI tract (e.g., specific values ​​or ranges of pH, temperature, pressure acting on the capsule, or combinations thereof. In one embodiment, the coating includes a material to improve swallowability and / or ingestion, such as guar gum or xanthan gum.

[0066] The device can include a mechanism for effecting delivery of a payload to a location in the GI tract, such as the intestinal wall, or delivery within and through the intestinal wall, such as to the peritoneum or peritoneal cavity of a subject. In one 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 can effect delivery of a payload elsewhere in the GI tract, such as the stomach, large intestine, or colon.

[0067] In the embodiment of FIG. 5, the device includes 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 form a mechanism for delivering a payload into or through the intestinal wall, e.g., to the peritoneum or peritoneal cavity of a subject. In this embodiment, the microsyringe contains the payload (labeled "μ-needle"). Two reactants (e.g., citric acid and potassium bicarbonate), labeled "reactant A" and "reactant B," are initially separated by a valve (labeled "reactant valve"). Upon exposure to a fluid, such as intestinal fluid (e.g., after the capsule disintegrates), a portion of the valve disintegrates, allowing the two reactants to mix, resulting in the production of a gas (e.g., carbon dioxide or other harmless gas) and inflation of the balloon. Inflation of the balloon creates sufficient pressure within the balloon to provide the force necessary to align the microsyringe substantially perpendicular to the long axis of the intestine, eject the microneedle from the microsyringe, and inject the microneedle into the intestinal wall or surrounding tissue. After microneedle deployment, the balloon deflates, and the balloon and any other components are expelled from the gastrointestinal tract with normal bowel movements.

[0068] In general, the mechanism for effecting delivery of a payload to the intestinal wall may include various mechanical, electrical, electromechanical, and / or chemical components, such as springs, levers, and / or various moving components that may work together to form the mechanism.

[0069] The payload may be disposed within a protective enclosure until just prior to delivery of the payload into the intestinal wall (e.g., within ms or μs). For example, in the embodiment of Figure 5, the microneedle may be initially sealed within the microsyringe and may pierce or break the seal of the microsyringe and be expelled from the microsyringe as it is expelled from the microsyringe into the intestinal wall.

[0070] After entering the intestinal wall or the surrounding body environment (e.g., the peritoneum or abdominal cavity), the payload dissolves or degrades in the moist tissue environment, releasing the ustekinumab composition into the bloodstream.

[0071] The payload may be a hollow structure into which the ustekinumab composition is disposed, or the payload itself may be formed from the ustekinumab composition (e.g., the ustekinumab composition may be compressed to a desired size and shape). In embodiments, the ustekinumab composition is compressed into cylindrical or other shaped microtablets. In embodiments, the ustekinumab composition (uncompressed or compressed) is disposed within a degradable shell, and the shell containing the microtablets is the payload. In one embodiment, the shell is approximately needle-shaped. Degradation of the payload may occur within 1, 2, 3, 4, or 5 minutes after injection into the intestinal wall, or it may take longer. The properties (e.g., structure and / or material) of the payload may be selected to delay the release of ustekinumab from the payload.

[0072] The device may include a detectable marker, such as a radiolabel, to aid in tracking the device as it passes through the subject's gastrointestinal tract. Examples of markers include, but are not limited to, barium sulfate (the dispersion of which indicates fluid infiltration into the device and imminent delivery of the payload) and bismuth, and may optionally be included on or in components contained within the device to radiographically track the passage of components along the GI tract and confirm their excretion.

[0073] In embodiments that may be similar to the embodiment shown in Figure 5, the balloon is self-sizing. For embodiments that include a self-sizing balloon, the balloon is referred to herein as the "expandable component." Such embodiments are described in more detail in the following paragraphs.

[0074] 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 can easily deform, and non-compliant refers to a state in which the section resists deformation. Without constraint, each section expands to a fully expanded state, and the expandable component reaches its maximum dimension, which may depend, for example, on the material used to form the expandable component and / or the capacity of the expansion module implemented (e.g., in the case of expansion by inflation, the maximum dimension may be affected by limitations on the expansion force available from the expansion module or the material or material stretch modulus of the expandable component). The expansion module is part of a mechanism for delivering a payload to the intestinal wall.

[0075] Each compliant section operates in a manner similar to a hinge and is therefore conveniently referred to as a hinge. In the fully expanded state of the expandable component (each section fully expanded), each hinge has at least one design dimension (width, length, and / or circumference) that is substantially smaller than the corresponding design dimension of each non-compliant section.

[0076] As the expandable component expands, it achieves a shape that reflects the balance between the force it exerts on the interior of the lumen of the GI tract and the force the lumen opposes the expandable component. Stated another way, when the expandable component is constrained by the lumen, it does not fully expand but tends to bend about the hinge. This bending results from the smaller dimension(s) of the hinge compared to the corresponding dimension(s) of the non-compliant section(s), resulting in a lower stiffness of the hinge compared to the stiffness of the non-compliant section(s) in the expanded configuration of the expandable component.

[0077] In this manner, the expandable component expands until the non-compliant section (hereinafter sometimes referred to as NCS) presses against the intraluminal wall, maintaining the expandable component in a position suitable for delivering the ustekinumab composition to the luminal wall for at least a period of time sufficient to achieve such delivery, after which the expandable component can be contracted.

[0078] The expandable component can be removed after deflation, left to degrade in situ, or passed extraluminally. The expandable component can be constructed from a degradable material such that it degrades after a designed period of time after being exposed to the environment of the target site.

[0079] Such self-sizing devices can be used to deliver therapeutic ustekinumab compositions to the GI tract lumen wall (e.g., stomach wall, intestinal wall, colon) via ingestion (e.g., swallowing or other modes of ingestion). The self-sizing device can include a capsule. The self-sizing device can include a coating (e.g., a coating as described above) on the capsule and / or expandable component that is designed to degrade at a specific location in the GI tract (e.g., in the intestine). In embodiments, all or a portion of the capsule and / or coating is designed to degrade after a certain period of time in the presence of a specific chemical or under conditions expected at a target site in the GI tract (e.g., specific values ​​or ranges of pH, temperature, pressure exerted on the capsule, or a combination thereof). In one embodiment, the coating includes a material to improve swallowability and / or ingestion, such as guar gum or xanthan gum.

[0080] 1A-1C illustrate an example of assembling an ingestible device, an automatic sizing device 1050, as described herein. FIG. 1A illustrates an embodiment of an expandable component 1000 and an embodiment of a capsule shell 1010. The exterior dimensions of the expandable component 1000 may be several times larger than the interior dimensions of the capsule 1000. For example, the longest dimension of an embodiment of the expandable component 1000 may be two to five times the interior length of the capsule shell 1010. Other ratios of the exterior dimensions of the expandable component to the interior dimensions of the capsule are within the scope of this disclosure. FIG. 1B illustrates the expandable component 1000 folded and / or rolled into an arrangement 1001 that is smaller than the interior dimensions of the capsule shell 1010. As shown, the arrangement 1001 is folded and / or rolled into a complex, origami-like arrangement in this embodiment. FIG. 1C illustrates the arrangement 1001 disposed within the capsule 1010 and the capsule shell 1010 assembled together. Device 1050 includes expandable component 1000 (of 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.

[0081] 2A-2F show one example of how device 1050 may be provided to a target delivery site within the GI lumen and position expandable component 1000 to deliver a therapeutic ustekinumab composition to a luminal wall 1111 (e.g., intestinal wall, stomach wall, etc.) of GI lumen 1110. Referring back to FIGS. 2A-2C, device 1050 is shown from a view that is generally perpendicular to the direction of movement of device 1050 (indicated by the arrow), whereas device 1050 in FIGS. 2D-2F is shown looking into lumen 1110 (e.g., approximately 90 degrees from the view of FIGS. 2A-2C).

[0082] 2A shows device 1050 within lumen 1110 shown in a relaxed state (e.g., during a peristaltic contraction). In this embodiment, the outer diameter of device 1050 is smaller than the inner diameter of lumen 1110 at this point in the GI tract. Device 1050 traverses lumen 1110 by actuation of, for example, peristaltic movement, hydrodynamics, and / or gravity.

[0083] 2B shows that after reaching the designed target site or encountering conditions (e.g., pH) representative of the designed target site, the capsule shell 1010 degrades (or is triggered to rupture or degrade) as the device 1050 continues to traverse the lumen 1110. For example, for intestinal delivery, the target site may be a general region (e.g., small intestine), a more specific region (e.g., jejunum), or a specific tissue region (e.g., a marked tissue region).

[0084] FIG. 2C shows that following (or simultaneously with) the degradation of the capsule shell 1010, the expandable component 1000 begins to unfold from its folded and / or rolled configuration.

[0085] FIG. 2D shows the expandable component 1000 in a substantially unfolded state, and FIG. 2E shows the expandable component 1110 in an expanded state (eg, by an expansion module).

[0086] FIG. 2F shows the expandable component 1000 after expansion. In this embodiment, without the constraint of the lumen 1110, the expandable component 1000 could expand until the reference line 1120 was approximately straight. However, the lumen 1110 exerts a force on the expandable component 1000, causing it to bend at the hinge 1002. The NCS 1003 and NCS 1004 of the expandable component 1000 then press against the luminal wall of the lumen 1110 (e.g., on opposite sides of the lumen), positioning the expandable component 1000 to deliver the therapeutic ustekinumab composition at or within the luminal wall. The hinge 1002 may also press against the luminal wall. In an embodiment, peristalsis can move the expandable component 1000 in its expanded state through the lumen 1110. In embodiments, the expandable component 1000 may have sufficient internal pressure (combined with surface tension) to hold the expandable component 1000 firmly in approximately the same position even during peristaltic movement. In embodiments, the expandable component 1000 includes surface roughness or surface protrusions to assist in maintaining the position of the expandable component 1000.

[0087] Expansion of the expandable component can be achieved by any suitable expansion module. In one embodiment, a spring mechanism is released from a compressed state, deploying, for example, a piece of filler material, either hard or soft, to push outward and expand the expandable component. In an embodiment, two or more reactants are mixed to form a gas, causing the expandable component to expand. In one embodiment, a material is rapidly combusted to generate a gas, causing the expandable component to expand. Other expansion modules are within the scope of this disclosure.

[0088] 3 shows a lumen 1200 in which a self-sizing device 1210 including an expandable component 1250 is positioned. In this embodiment, the force of the lumen 1200 on the expandable component 1250 is not sufficient to substantially bend the hinge 1251 of the expandable component 1250, so the expandable component 1250 is in a nearly fully expanded state. Stated another way, bending of the hinge 1251 of the expandable component 1250 is negligible at this position of the lumen 1200.

[0089] Expandable component 1250 can expand by the generation of gas and can include a valve 1255 for releasing gas from within expandable component 1250 into lumen 1200 to contract expandable component 1250. Valve 1255 can include one or more components. In embodiments, valve 1255 is a pinch valve that degrades in the presence of fluid (e.g., biological material) to expose a port or opening defined by expandable component 1250. In one embodiment, valve 1255 is a piece of material or coating that covers a port or opening in expandable component 1250, the piece of material or coating being designed to degrade over a period of time after expandable component 1250 delivers the therapeutic ustekinumab composition. In one embodiment, valve 1255 is manually opened.

[0090] The ustekinumab therapeutic composition (or compositions) may be stored within expandable component 1250 in any physical property (e.g., as a solid, fluid, slurry, or powder). The therapeutic composition(s) may be delivered in any physical property (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 embodiments, expandable component 1250 includes a portal, such as portal 1260, that defines opening 1261 through which the therapeutic composition is delivered. In embodiments that include a tissue-piercing member, the tissue-piercing member may be delivered through the portal.

[0091] The therapeutic ustekinumab composition is actively released such that the therapeutic ustekinumab composition is forced out of expandable component 1250 into lumen 1200 or across the lumen wall into the surrounding body environment (e.g., the mucosa, submucosa, muscularis, serosa, the outer wall of lumen 1200, and into the peritoneal cavity). In such embodiments, the therapeutic ustekinumab composition may be released through one or more portals, such as portal 1260.

[0092] The therapeutic ustekinumab composition may be forcefully ejected from the expandable component 1250 by a delivery mechanism. For example, for a solid composition (e.g., in the form of a tablet, pellet, or point), the therapeutic ustekinumab composition may be ejected by a spring mechanism that is released to rapidly eject the solid composition from the expandable component 1250, or by a piston mechanism in which a piston is moved by a spring mechanism, or by gas expansion to rapidly push the solid composition out of the expandable component 1250.

[0093] For fluid compositions (e.g., liquids), the therapeutic ustekinumab composition can be ejected as a fluid jet by a spring mechanism or gas acting on a piston or plunger to expel the formulation from the reservoir through an opening or nozzle in the expandable component 1250. The fluid jet of the therapeutic ustekinumab composition can have sufficient force to aggressively penetrate the GI lumen wall and enter the bloodstream.

[0094] Additionally or alternatively, the fluid composition comprising ustekinumab can be expelled through a hollow needle coupled to expandable component 1250. The hollow needle can penetrate and / or pierce the GI lumen wall by a spring mechanism or gas acting on a piston or plunger to expel the composition through the needle and into the GI lumen wall or surrounding tissue.

[0095] In some embodiments, the surface of expandable component 1250 through which the therapeutic ustekinumab composition is delivered contacts the wall of lumen 1200 along a stretch of about 5 mm to 20 mm.

[0096] In some embodiments, the therapeutic ustekinumab composition is delivered from multiple surfaces of the expandable component 1250. Such embodiments may include multiple tissue-penetrating members formed from or including the ustekinumab composition.

[0097] 4A shows an embodiment of a self-sizing device 1300 that includes an expandable component 1305 that includes one NCS 1310 and no hinge. FIG. 4B shows an embodiment of a self-sizing device 1350 that includes an expandable component 1355 that includes two NCSs, NCS 1360 and NCS 1361, and a hinge 1365 therebetween. For these embodiments, the width W1 of the expandable component 1305 is similar to the width W2 of the expandable component 1355, while the height H1 of the expandable component 1305 is less than the height H2 of the expandable component 1355.

[0098] Multiple devices 1300 (FIG. 4A) structured according to the same design will have approximately the same maximum circumference (in the y-z plane) of the NCS 1310 when fully expanded within a lumen due to the incompatibility of the NCS 1310, such that the expandable component 1305 does not significantly accommodate a variety of different intraluminal circumferences. Thus, different sizes of device 1300 may be appropriate for different animal species and / or different subjects within a species. In contrast, multiple devices 1350 (FIG. 4B) structured according to the same design will likely not have the same maximum circumference (in the y-z plane) when fully expanded within a lumen, because each device 1350, even when expanded, adapts to the size of the lumen into which it is expanded due to the flexibility (non-compliant, bending) of the hinge 1365. The maximum circumference for a device 1350 within a lumen refers to the maximum circumference of the shape the device 1350 assumes within the lumen (e.g., a partially expanded or fully expanded shape).

[0099] Certain materials can be selected to impart 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 the disintegration of the payload and thus the release of the therapeutic ustekinumab composition). For example, certain materials may be more suitable when the payload is formed as a tissue-penetrating member, while other materials may be more suitable when the payload is contained within the tissue-penetrating member. In one embodiment, the tip of the payload contains or is coated with a degradable material, such as sucrose, maltose, or other sugars, to increase the tip's hardness and tissue-penetrating properties. Once positioned within the lumen wall, the payload is degraded by interstitial fluid within the tissue, dissolving the therapeutic ustekinumab composition and allowing it to be absorbed into the bloodstream. Payload properties, such as size, shape, and chemical composition, can be selected to allow drug dissolution and absorption within seconds, minutes, or hours. The dissolution rate can be controlled by various excipients, such as disintegrants (e.g., starch, sodium starch glycolate, or cross-linked polymers such as carboxymethylcellulose). The choice of disintegrant can be specifically tailored to the environment within the lumen wall (eg, blood flow and average number of peristaltic contractions).

[0100] The payload can be made entirely of a ustekinumab composition, or can define a cavity containing a ustekinumab composition. The self-sizing device can contain and deliver one or more payloads, each of which can contain the same or a different ustekinumab composition. Each payload can have different properties; for example, two payloads can be designed to deliver their respective compositions simultaneously (e.g., two instances of one composition, or one instance each of two different compositions), or can be designed to deliver their respective compositions at different times (e.g., to provide subsequent doses of the same ustekinumab composition, or to provide subsequent doses of different ustekinumab compositions).

[0101] (3. Micro Tablet) Various embodiments of microtablets containing ustekinumab compositions in the form of a solid shaped mass containing ustekinumab, and methods for forming such solid shaped masses are described. The shaped masses can be comprised of a therapeutic composition containing a drug (e.g., ustekinumab) and one or more pharmaceutically acceptable excipients, including degradable materials (e.g., sugars, polyethylene, lactic acid polymers, poly(glutamic-co-lactic-co-glycolic acid (PGLG)), etc.), that degrade to release the drug within a target delivery site in the body (e.g., the wall of the small intestine or the peritoneum or cavity).

[0102] The shaped mass can be formed by various molding processes known in the pharmaceutical arts. Typically, the shaped mass is formed by a compaction process, such as compression molding. According to one or more embodiments, the biological activity of ustekinumab in the shaped mass is at least about 70% of that before compaction, at least 80% of that before compaction, at least 85% of that before compaction, about 90% of that before compaction, or at least 95% of that before compaction.

[0103] The molded mass is approximately 0.60 mg / mm 3 ~about 1.15mg / mm 3 , about 0.70mg / mm 3 ~about 1.15mg / mm 3 , about 0.80mg / mm 3 ~about 1.10mg / mm 3 , approximately 1.02 to 1.06 mg / mm 3 , or approximately 1.03 to 1.05 mg / mm 3 The density can range from 0.01 to 0.1.

[0104] The shape of the shaped mass can be any shape suitable for use as a component of a device described herein, for example, any shape suitable for placement within a tissue-piercing member (e.g., pellet-shaped or cylindrical), or any shape suitable for use as a tissue-piercing member (e.g., needle-shaped or dart-shaped). The shaped mass can include a pellet shape, or can have a tablet, cone, pyramid, hot dog / capsule-like shape, arrowhead, cylinder, cube, sphere, hemisphere, or other suitable shape. For cylindrical or pellet-shaped shaped mass embodiments, the shaped mass can have a diameter ranging from about 0.5 mm to 1 mm and a length ranging from about 1.75 mm to 3.25 mm.

[0105] As mentioned above, according to various embodiments, the shaped mass can be partially formed from a degradable material configured to dissolve or otherwise degrade, for example, in the intestinal wall or peritoneal membrane or cavity, to release the drug for systemic absorption. Suitable degradable materials include various sugars such as trehalose, maltose, sucrose, etc.; various lactic acid polymers such as polyglycolic acid (PGA), polylactic acid (PLA); polyglycollactic acid (PGLA), poly(glutamic acid-co-lactic acid-co-glycolic acid) (PGLG); various polyethylenes such as high-density, low-density, linear low-density PE, polyethylene oxide (PEO); various cellulose polymers such as hydroxypropylmethylcellulose (HPMC), carboxymethylcellulose (CMC), methylcellulose (MC); methacrylic acid-ethyl acrylate copolymer, methacrylic acid-methyl methacrylate copolymer, polyvinyl alcohol (PVOH), silicone rubber, and other biodegradable polymers known in the art. The materials and other properties of the degradable polymer and shaped mass can be selected to produce a selectable degradation rate in the intestinal wall or other target delivery site (eg, the peritoneum or abdominal cavity).

[0106] The fabrication process used to fabricate various embodiments of the drug-containing shaped masses as described herein will now be described. The process includes a step for fabricating a drug-containing powder and a shaped mass formation step for forming the powder into a shaped mass. For convenience, the shaped masses will be referred to as microtablets, although it should be understood that other forms and / or shapes are equally applicable, as discussed above.

[0107] Next, a process for formulating a powder (e.g., a dry composition) containing a drug (e.g., ustekinumab) will be described. A typical process can include preparing a composition containing a drug and excipients. The composition can be prepared by combining dry ingredients or by preparing a solution containing one or more ingredients, then evaporating the solvent(s) (optionally including lyophilization) to obtain a dry composition, and optionally adding one or more dry ingredients to obtain a composition containing the drug and other excipients.

[0108] The drug (e.g., ustekinumab) may be present in the dry composition in any amount suitable to provide a target dose in the ingestible device, and in one or more embodiments, may be present in an amount of about 1% to about 99% w / w of the composition, including about 25% to about 75% w / w, about 50% to about 60% w / w, or about 50% to about 80% w / w, about 55% w / w, e.g., about 55.6% w / w, about 67% w / w, or about 75% w / w. In some embodiments, the drug (e.g., ustekinumab) is present in an amount of about 67% w / w, e.g., 67% w / w. In some embodiments, the drug (e.g., ustekinumab) is present in an amount of about 75% w / w, e.g., 75% w / w.

[0109] The excipients may include one or more of a buffering agent, an antioxidant, a surfactant, a lubricant, a binder, a stabilizer, and a bulking agent.

[0110] The buffering agent may be a histidine HCl buffer system (e.g., L-histidine and L-histidine monohydrochloride monohydrate (L-histidine / L-histidine hydrochloride)), and in one or more embodiments, may be present in an amount of about 1% to about 15% w / w of the composition, e.g., about 1% to about 5% w / w, or about 2% to about 3% w / w, including about 2.4% w / w, or about 10% to about 15% w / w, including about 10% w / w or about 12% w / w. In some embodiments, the buffering agent (e.g., L-histidine / L-histidine hydrochloride) is present in an amount of about 10% w / w, e.g., 10% w / w. In some embodiments, the buffering agent (eg, L-histidine / L-histidine hydrochloride) is present in an amount of about 12% w / w, such as 12% w / w.

[0111] The antioxidant may include L-methionine, which in one or more embodiments may be present in an amount of about 1% to about 10% w / w of the composition, including about 3% to about 8% w / w, about 5% w / w, e.g., about 4.4% w / w, or about 1% to about 5% w / w, about 1% to about 3% w / w, e.g., about 2% w / w. In some embodiments, the antioxidant (e.g., L-methionine) is present in an amount of about 2% w / w, e.g., 2% w / w.

[0112] The surfactant may be polysorbate 80 (polyoxyethylene sorbitan monooleate, e.g., Tween 80), which in one or more embodiments may be present in an amount of about 0.05% to about 3% w / w of the composition, about 0.05% to about 1% w / w, or about 1% to about 3% w / w, including about 0.1% w / w and about 1% w / w. In some embodiments, the surfactant (e.g., polyoxyethylene sorbitan monooleate) is present in an amount of about 1% w / w, e.g., 1% w / w.

[0113] A lubricant may be used to facilitate both the formation of microtablets and their removal from the mold. The lubricant may include polyethylene glycol 3350 (PEG 3350), which in one or more embodiments may be present in an amount of about 5% to about 50% w / w or about 10% to about 50% w / w of the composition, including about 5% to about 15% w / w and about 20% to about 30% w / w, including about 7% w / w, about 10% w / w, or about 25% w / w. In some embodiments, the lubricant (e.g., PEG 3350) is present in an amount of about 10% w / w, e.g., 10% w / w. In some embodiments, the lubricant (e.g., PEG 3350) is present in an amount of about 7% w / w, e.g., 7% w / w.

[0114] The bulking agent or stabilizer may be trehalose, which in one or more embodiments may be present in an amount of about 1% to about 20% w / w, or about 5% to about 20% w / w, or about 1% to about 5% w / w, or about 10% to about 15% w / w, or about 3% w / w, or about 10% w / w, or about 12.5% ​​w / w. In some embodiments, the bulking agent or stabilizer (e.g., trehalose) is present in an amount of about 10% w / w, e.g., 10% w / w. In some embodiments, the bulking agent or stabilizer (e.g., trehalose) is present in an amount of about 3% w / w, e.g., 3% w / w.

[0115] Alternatively, the bulking agent may be mannitol, which in one or more embodiments may be present in an amount of about 5% to about 20% w / w of the composition, about 10% to about 15% w / w, or about 12.5% ​​w / w. Other excipients may be added, such as one or more other binders, fillers, disintegrants, stabilizers, buffers, and antimicrobial agents. For example, the composition may contain sucrose, which may act as a stabilizer. If included, sucrose may be used in any suitable amount, such as about 0.5% to about 4% w / w of the composition, or about 1.1% w / w of the composition, with the amount of one or more other excipients adjusted accordingly.

[0116] In some embodiments, the ustekinumab composition comprises about 55.6% w / w ustekinumab, about 2.4% w / w L-histidine / L-histidine hydrochloride, about 0.1% w / w polyoxyethylene sorbitan monooleate, about 4.4% w / w L-methionine, about 25% w / w PEG 3350, and about 12.5% ​​w / w trehalose. In some embodiments, the ustekinumab composition comprises about 55.6% w / w ustekinumab, about 2.4% w / w L-histidine / L-histidine hydrochloride, about 0.1% w / w polyoxyethylene sorbitan monooleate, about 4.4% w / w L-methionine, about 25% w / w PEG 3350, and about 12.5% ​​w / w mannitol.

[0117] In some embodiments, ustekinumab compositions described herein comprise about 67% w / w ustekinumab, about 10% w / w L-histidine / L-histidine hydrochloride, about 1% w / w polyoxyethylene sorbitan monooleate, about 10% w / w trehalose, about 10% w / w PEG 3350, and about 2% w / w L-methionine. In some embodiments, ustekinumab compositions described herein comprise about 75% w / w ustekinumab, about 12% w / w L-histidine / L-histidine hydrochloride, about 1% w / w polyoxyethylene sorbitan monooleate, about 3% w / w trehalose, about 7% w / w PEG 3350, and about 2% w / w L-methionine.

[0118] The selection and proportions of the different ingredients can be considered during the formulation process to achieve the desired therapeutic dose of drug with the desired properties, including the desired tablet properties and the desired release properties from the resulting microtablets.

[0119] The resulting composition may be milled to produce a fine powder. For example, the composition can be placed in a low-protein-binding tube with a single high-density grinding ball, such as one made of stainless steel or yttrium-stabilized zirconium. Milling can be performed at maximum speed on a rotator with the tube wrapped in film to avoid moisture absorption and contamination. An ice pack can also be placed over the tube to keep it cool. Room temperature can be controlled, for example, between 60 and 64°F. The size of the milling tube, the mass of the milling balls, and the mixing time can be selected to achieve a specific powder particle size, particle size uniformity, and powder density. For example, when producing a batch volume of 40 to 100 mg, a 2 mL round-bottom tube, a 0.44 g mass of milling balls, and a 3-hour milling time resulted in a fine and stable particle size and consistent, consistent density values.

[0120] The process of forming microtablets is typically carried out via compression, using a compression mold or other fixture to apply a compressive force to a fine powder containing the drug (e.g., ustekinumab). Semi-automated or fully automated compression fixtures can be used, as described in U.S. Pat. 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-piercing member, i.e., formed to have a tissue-piercing shape using molding or other similar methods. In these and related embodiments, the shaped mass can have a needle- or dart-like shape (with or without barbs) configured to penetrate and / or be retained in tissue or a membrane, such as the intestinal wall.

[0121] After the microtablets are made, the length, weight, density, and bioactivity of the drug in the pellets can be measured. The bioactivity of the drug in the microtablets can be measured using an enzyme-linked immunosorbent assay (ELISA) or other immunoassays known in the art.

[0122] As noted above, the shaped mass may be in the form of a tissue-penetrating member (e.g., in the form of a dart or needle) or may be included in a tissue-penetrating member configured to be advanced into or through the intestinal wall into the peritoneum or peritoneal cavity and to biodegrade to release ustekinumab into the intestinal wall, the peritoneum or peritoneal cavity, and then into the bloodstream.

[0123] (4. Treatment methods and pharmaceutical uses) Also provided herein are treatments (methods of treatment and pharmaceutical uses) that include administering an ingestible device according to any embodiment described herein to a subject in need thereof by ingestion, for example, by the subject swallowing the device (oral administration) or by another mode of ingestion, such as via an endoscope or gastric port. In some embodiments, the treatments (methods and pharmaceutical uses) include once-daily administration of an ingestible device as described herein. In some embodiments, the treatments (methods and pharmaceutical uses) consist of alternative administration regimens, as described in more detail below.

[0124] In general, the disclosed therapeutic methods and pharmaceutical uses are intended for treating conditions such as psoriasis (including moderate to severe plaque psoriasis), psoriatic arthritis, Crohn's disease (including moderate to severe Crohn's disease), ulcerative colitis (including moderate to severe ulcerative colitis), and other conditions for which treatment with an anti-interleukin antibody may be indicated. In specific embodiments, the disclosed therapeutic methods and pharmaceutical uses are for treating plaque psoriasis. In specific embodiments, the disclosed therapeutic methods and pharmaceutical uses are for treating psoriatic arthritis. In specific embodiments, the disclosed therapeutic methods and pharmaceutical uses are for treating Crohn's disease. In specific embodiments, the disclosed therapeutic methods and pharmaceutical uses are for treating ulcerative colitis.

[0125] The disclosed therapeutic methods and pharmaceutical uses can be used in any subject, including humans and non-human mammals, who require administration of, for example, ustekinumab. Human subjects are not limited to a particular age or size, and can include children, adults, and elderly subjects, as well as subjects whose weight or height is within, above, or below the normal range.

[0126] In some embodiments, the ingestible device or the payload of the ingestible device comprises ustekinumab in a dose effective to achieve a therapeutic plasma level of ustekinumab for the condition being treated, hi some embodiments, the ingestible device or the payload of the ingestible device comprises ustekinumab in a dose effective to achieve a plasma level of ustekinumab of about 0.69 μg / mL or greater, including a plasma level of ustekinumab of 0.69 μg / mL or greater.

[0127] In some embodiments, the ingestible device or the payload of the ingestible device comprises a dose of ustekinumab of about 0.5 mg or more. In some embodiments, the ingestible device or the payload of the ingestible device comprises a dose of ustekinumab of about 0.5 mg. In some embodiments, the ingestible device or the payload of the ingestible device comprises a dose of ustekinumab of about 0.75 mg. In some embodiments, the ingestible device or the payload of the ingestible device comprises a dose of ustekinumab of about 10 mg. In some embodiments, the ingestible device or the payload of the ingestible device comprises a dose of ustekinumab of about 20 mg.

[0128] As reflected in Figure 6, computer-based pharmacokinetic model simulations of ustekinumab administration based on published human pharmacokinetic data indicate that daily administration of 0.5 mg achieves plasma concentrations of 0.69 μg / mL or greater, e.g., plasma concentrations of 0.69 μg / mL or greater (see Figure 6, bottom curve; dashed line = 0.69 μg / mL). The simulation data also indicate that daily administration maintains steady-state therapeutic serum concentrations more effectively than a once-every-12-week subcutaneous dosing regimen. Thus, in some embodiments, the ingestible device or ingestible device payload comprises a dose of ustekinumab less than 0.5 mg, e.g., 0.45 mg, 0.4 mg, 0.35 mg, 0.3 mg, or 0.25 mg.

[0129] In some embodiments, the payload of the ingestible device comprises a solid therapeutic composition comprising ustekinumab and one or more other excipients, such as the microtablet composition described above. In some embodiments, the payload of the ingestible device comprises a ustekinumab composition comprising ustekinumab, L-histidine / L-histidine hydrochloride, polyoxyethylene sorbitan monooleate, and L-methionine, optionally further comprising PEG3350, and trehalose and / or mannitol, as described above. In some embodiments, the payload of the ingestible device comprises a solid ustekinumab composition comprising about 67% w / w ustekinumab, about 10% w / w L-histidine / L-histidine hydrochloride, about 1% w / w polyoxyethylene sorbitan monooleate, about 10% w / w trehalose, about 10% w / w PEG3350, and about 2% w / w L-methionine. In some embodiments, the payload of the ingestible device comprises a solid ustekinumab composition comprising about 75% w / w ustekinumab, about 12% w / w L-histidine / L-histidine hydrochloride, about 1% w / w polyoxyethylene sorbitan monooleate, about 3% w / w trehalose, about 7% w / w PEG3350, and about 2% w / w L-methionine.

[0130] In other embodiments, the ingestible device or the payload of the ingestible device comprises a liquid therapeutic composition comprising ustekinumab and one or more other excipients.

[0131] For the treatment of psoriasis and psoriatic arthritis in adult patients weighing ≤100 kg or pediatric patients weighing >60 kg, STELARA® can be administered at an induction dose of 45 mg at weeks 0 and 4, followed by a maintenance dose of 45 mg every 12 weeks. For the treatment of psoriasis and psoriatic arthritis in patients weighing more than 100 kg, STELARA® can be administered at an induction dose of 90 mg at weeks 0 and 4, followed by a maintenance dose of 90 mg every 12 weeks. The methods of treatment or pharmaceutical use disclosed herein may consist of an induction dosing period (e.g., an induction dosing period on the order of about 4 weeks, such as 4 weeks or 30 days) followed by a maintenance dosing period. Various exemplary induction and maintenance dosing regimens are disclosed below. It should be understood that any induction dosing regimen can be used in combination with any maintenance dosing regimen, and that different maintenance dosing regimens can be used over time (e.g., switching from one maintenance dosing regimen to another). It should also be understood that any maintenance dosing regimen using a device as described herein can be used after an induction dosing period using a subcutaneous injection formulation, such as STELARA® or a biosimilar thereof. Similarly, any induction dosing regimen using a device as described herein can be used followed by a maintenance dose of a subcutaneous injection formulation, such as STELARA® or a biosimilar thereof. Furthermore, any maintenance dose using a device as described herein can be followed by a maintenance dose of a subcutaneous injection formulation, such as STELARA® or a biosimilar thereof, or vice versa.

[0132] Sample induction dosing regimen for treating adult patients weighing ≤100 kg or pediatric patients weighing >60 kg (amounts represent doses of ustekinumab or its biosimilar) 45 mg subcutaneously at weeks 0 and 4 about 1.5 mg (including 1.5 mg) once daily for 4 weeks (e.g., 4 weeks or 30 days) administered with a device as disclosed herein; about 12 mg (including 12 mg) administered once daily for 4 weeks (e.g., 4 weeks or 30 days) with a device as disclosed herein; Approximately 9 mg per day (including 9 mg per day) is administered once daily with a device as disclosed herein for 7 days starting at week 0, and again at week 4.

[0133] Example of a maintenance dosing regimen for treating adult patients weighing ≤100 kg or pediatric patients weighing >60 kg (amounts indicate doses of ustekinumab or its biosimilar formulation) 45 mg administered subcutaneously every 12 weeks about 0.5 mg (including 0.5 mg) once daily administered with a device as disclosed herein; about 3.75 mg (including 3.75 mg) administered once a week via a device as disclosed herein; about 2.5 mg (and inclusive) per day for 6 days administered daily with a device as disclosed herein; A short course of approximately 12 mg per day (including 12 mg per day) administered once quarterly for 5 days.

[0134] Sample induction dosing regimen for treating adult patients weighing >100 kg (amounts represent doses of ustekinumab or its biosimilar) 90 mg administered subcutaneously at weeks 0 and 4 about 3.25 mg (including 3 mg or 3.25 mg) administered once daily for 4 weeks (e.g., 4 weeks or 30 days) with a device as disclosed herein; about 1.5 mg twice daily for 4 weeks (e.g., 4 weeks or 30 days) administered with a device as disclosed herein; about 24 mg (including 24 mg) once daily for 4 weeks (e.g., 4 weeks or 30 days) administered with a device as disclosed herein; Approximately 18 mg per day (including 18 mg per day) will be administered once daily for 7 days starting from week 0, and again in week 4.

[0135] Example of a maintenance dosing regimen for treating adult patients weighing >100 kg (amounts represent doses of ustekinumab or its biosimilar formulation) 90 mg administered subcutaneously every 12 weeks about 1 mg (including 1 mg) administered once daily with a device as disclosed herein; about 0.5 mg (including 0.5 mg) twice daily administered with a device as disclosed herein; about 7.5 mg (including 7.5 mg) administered once a week with a device as disclosed herein; a monthly short course of about 2.5 mg (inclusive) twice daily for 6 days administered with a device as disclosed herein; about 30 mg (inclusive) administered once quarterly with a device as disclosed herein; A short course of approximately 12 mg per day (12 mg per day) administered via an ingestible device once quarterly for 9 days.

[0136] In some embodiments, ingestible devices described herein containing a solid therapeutic composition of ustekinumab (or a biosimilar thereof) are used to provide a dose of up to about 1 mg per device, e.g., about 0.5 mg or about 0.75 mg per device, depending on the formulation of the composition and its concentration.

[0137] In some embodiments, the ingestible devices described herein containing a liquid therapeutic composition of ustekinumab (or a biosimilar thereof) are used to provide a dose of up to about 10 mg per device, such as for a device having a volume of 100 μl, or up to about 20 mg per device, such as for a device having a volume of 200 μl, depending on the formulation of the composition and its concentration.

[0138] In some embodiments, the dosing regimens described above using an ingestible device as described herein to provide a dose of up to about 3.25 mg (including 3 mg or 3.25 mg) comprise a therapeutic solid composition of ustekinumab (or a biosimilar thereof). In some embodiments, the dosing regimens described above using an ingestible device as described herein to provide a dose of about 3.25 mg or more (including 3 mg or more or 3.25 mg or more) comprise a therapeutic liquid composition of ustekinumab (or a biosimilar thereof).

[0139] According to any embodiment using an ingestible device as described herein, the predetermined dose can be provided, for example, by one ingestible device as described herein containing one or more payloads that collectively contain the recited dose of ustekinumab (or a biosimilar thereof), or by administering two or more ingestible devices as described herein, each containing one, two, three, four, five, six, seven, eight, nine, ten, or more payloads consisting of a ustekinumab composition as described herein.

[0140] Currently approved anti-interleukin antibody formulations, such as STELARA® (ustekinumab), require administration by subcutaneous or intravenous injection, which can be inconvenient and uncomfortable for patients. The present disclosure addresses this limitation by providing routes of administration that effectively deliver anti-interleukin antibodies into the bloodstream of a treated subject without the need for injection, such as oral administration or ingestion by another mode, such as via an endoscope or gastric port. The disclosed treatments are simpler and less invasive than currently approved anti-interleukin antibody formulations.

[0141] In addition to ease of administration, patient comfort, and improved patient compliance, administering ustekinumab via an ingestible device as described herein may provide one or more other advantages, such as one or more of enhanced biological activity and reduced immunogenicity, compared to alternative routes of administration, such as subcutaneous injection. In some embodiments, ustekinumab administered via an ingestible device as described herein exhibits greater biological activity than the biological activity of ustekinumab administered subcutaneously. In some embodiments, ustekinumab administered via an ingestible device as described herein exhibits substantially the same biological activity as the biological activity of ustekinumab administered subcutaneously.

[0142] Thus, according to some embodiments, the present disclosure provides a method of administering an anti-interleukin antibody (such as ustekinumab or a biosimilar thereof, or another anti-interleukin antibody that binds to or is an antagonist of one or both of human interleukin-23 and human interleukin-12) to a subject in need thereof. The method includes administering to the subject, by ingestion, an ingestible device formed from or containing a payload comprising a composition comprising the anti-interleukin antibody, the device being structured to deliver the composition into or through the intestinal wall of the subject and into the peritoneum or peritoneal cavity of the subject after ingestion. As described above, administration may include oral administration (e.g., swallowing the device) or ingestion of the device by another mode, such as through an endoscope or gastric port. The payload may be in the form of a solid tissue-piercing member structured to penetrate and be inserted into the intestinal wall of the subject, or to be inserted through the intestinal wall and into the peritoneum or peritoneal cavity of the subject after ingestion of the device. Administration of such ingestible devices can be repeated, for example, once every 1-3 days or less frequently, according to any of the dosing regimens described above. The payload can be formed from or can include a composition containing an anti-interleukin antibody, such as a solid (dry) composition or a liquid composition as described above. The payload is protected from the gastrointestinal (GI) environment (e.g., protected from degradation by infiltration of fluids reaching the payload) until the payload is injected into the wall of the small intestine.

[0143] The present disclosure also provides methods of treating one or more conditions, such as psoriasis (including moderate to severe plaque psoriasis), psoriatic arthritis, Crohn's disease (including moderate to severe Crohn's disease), ulcerative colitis (including moderate to severe ulcerative colitis), and other conditions for which treatment with an anti-interleukin antibody may be indicated, comprising administering, by ingestion, to a subject in need thereof, an ingestible device described herein, such as according to any of the dosing regimens described above.

[0144] While specific embodiments have been described and illustrated, it should be understood that components or features of one embodiment may be combined or substituted with one or more components or features from other embodiments. Furthermore, for any affirmative description of a part, property, component, feature, step, or the like, the present disclosure specifically contemplates excluding that part, value, property, component, feature, step, or the like. It should also be understood that illustrations may not necessarily be drawn to scale. Differences may exist between artistic depictions in the present disclosure and actual devices due to manufacturing process variables, etc. There may be other embodiments of the present disclosure not specifically illustrated. Accordingly, the specification and drawings are to be regarded as illustrative, and not restrictive.

[0145] The following examples are given to illustrate the present invention, however, it should be understood that the invention is not limited to the particular conditions or details set forth in these examples.

[0146] (Example) Example 1 - Preparation of a Ustekinumab Ingestible Device (Formulation A) Ustekinumab microtablets were manufactured under sterile conditions, targeting a dose of 0.5 mg per microtablet, with a target microtablet mass of approximately 0.9 mg.

[0147] A solution containing ustekinumab, L-histidine / L-histidine hydrochloride (as a buffer), polyoxyethylene sorbitan monooleate (as a surfactant), L-methionine (as an antioxidant), PEG 3350 (as a lubricant), and trehalose (as a bulking agent / stabilizer) was prepared and lyophilized to form a tableting composition. The tableting composition used to prepare microtablets contained 55.6% w / w ustekinumab, 2.4% w / w L-histidine / L-histidine hydrochloride (as a buffer), 0.1% w / w polyoxyethylene sorbitan monooleate (as a surfactant), 4.4% w / w L-methionine (as an antioxidant), 25% w / w PEG 3350 (as a lubricant), and 12.5% ​​w / w trehalose (as a bulking agent / stabilizer). Microtablets were prepared using a tableting cylinder pressure of 10-90 PSI (eg, 14-16 PSI) with an applied pressure on the tableting composition of 800-9000 PSI.

[0148] Ustekinumab activity was evaluated in the ustekinumab solution, lyophilized form, and microtablets, and was confirmed to remain highly biologically active and not substantially degraded. Ustekinumab activity in the microtablets was 80% or greater of the target dose (0.5 mg) and 80% or greater of the amount used to prepare the microtablets.

[0149] The microtablets were incorporated into the device in a capsule as described above with reference to Figure 5, with the payload in the form of a hollow microneedle containing a single microtablet, and the capsule device containing the single payload.

[0150] Example 2 - Oral Administration of Ustekinumab in Dogs (Formulation A) The ability of an ingestible device as described herein to deliver ustekinumab was evaluated in dogs. After an overnight fast, dogs weighing 8.5 to 11.5 kg were orally administered a 0.5 mg dose of the capsule device (n=7) described in Example 1 above. Fluoroscopic imaging was used to monitor capsule transit and confirm deployment within the small intestine. Ustekinumab blood concentrations were assessed pre-dose, 4 hours after administration, and 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, and 14 days after administration. Results are reported in Figure 7 and the table below (mean ± SEM). TIFF2025535727000002.tif21165

[0151] The results showed that ustekinumab can be successfully delivered using an ingestible device as described herein, with a delivery success rate of 70%.

[0152] Example 3 - Preparation of Ustekinumab Ingestible Device - (Formulations B and C) Ustekinumab microtablets were manufactured under sterile conditions, targeting a dose of 0.5 mg or 0.75 mg per microtablet.

[0153] A solution containing ustekinumab, L-histidine / L-histidine hydrochloride (as a buffering agent), Tween 80 (as a surfactant), L-methionine (as an antioxidant), PEG 3350 (as a lubricant), and trehalose (as a stabilizer) was prepared and lyophilized to form a tableting composition as follows: TIFF2025535727000003.tif76165

[0154] The 0.5 mg dose was prepared with 0.75 mg microtablets, and the 0.75 mg dose was prepared with 1 mg microtablets. Both types of microtablets were prepared using a tableting cylinder pressure of 10-90 PSI, with an applied pressure of 800-9000 PSI on the tableting composition. Each microtablet was incorporated into a device within a capsule, as described above with reference to Figure 5, with a payload in the form of a hollow microneedle containing a single microtablet, and a capsule device containing a single payload.

[0155] Example 4 - Oral Administration of Ustekinumab in Dogs (Formulations B and C) The ability to deliver ustekinumab via an ingestible device as described herein was evaluated in dogs. The pharmacokinetic profile of a single dose of ustekinumab administered via an ingestible device as described herein was compared to the pharmacokinetic profile obtained via a single subcutaneous (SC) injection. Dogs weighing 7.0 to 9.0 kg were divided into three groups: Group 1 (SC group; n = 6): ustekinumab 0.5 mg / 0.5 ml subcutaneous injection, Group 2 (ingestible device group; n=8): one capsule device containing a microtablet containing 0.5 mg of ustekinumab as described in Example 3; Group 3 (ingestible device group; n=8): One capsule device containing a microtablet containing 0.75 mg of ustekinumab as described in Example 3.

[0156] After fasting for at least 12 hours, dogs were administered ustekinumab according to the study groups described above. Fluoroscopic imaging was used to monitor capsule transit and confirm placement in the small intestine. Ustekinumab blood concentrations were assessed pre-dose, 4 hours, 12 hours, and on days 1-14, 16, 18, 21, 23, and 27 post-dose. Results are reported in Figure 8 and the table below (mean ± SEM). TIFF2025535727000004.tif59166*Dose standardization **Two dogs suspected of having anti-drug antibodies (ADA) were excluded from the dataset. ***One animal was suspected of having ADA and was removed from the dataset.

[0157] The results showed that ustekinumab was successfully delivered by the ingestible device described herein, with a pK success rate of 100% (for all animals in which the device was successfully deployed). Devices containing microtablets containing 0.75 mg and 0.5 mg of ustekinumab demonstrated relative biological activities of 91% and 94%, respectively.

[0158] These data highlight the compositions, dosage forms, devices, and surprising advantages disclosed herein, especially when compared to the current standard of care, which requires injections of ustekinumab.

[0159] (Example 5 - Phase I Clinical Trial) A Phase 1 clinical trial will be conducted in healthy volunteers to evaluate the safety, tolerability, and pharmacokinetics (PK) of the devices described herein, including microtablets described herein containing 0.5 mg or 0.75 mg ustekinumab (generally described in Example 3). The study will enroll healthy male and female participants, aged 18 to 65 years at the time of consent, and will be screened for inclusion and exclusion criteria. The study will include three groups. Group 1 (STELARA®): Participants will fast for at least 8 hours. PK samples will be collected prior to dosing, and STELARA® 0.5 mg will be administered subcutaneously. Group 2: Participants will fast for at least 8 hours, have a PK sample taken before dosing, and orally ingest a capsule containing a 0.5 mg dose of ustekinumab as described herein and swallow it whole with water. Group 3: Participants will fast for at least 8 hours, have a PK sample taken before dosing, and orally ingest a capsule containing 0.75 mg of ustekinumab as described herein and swallow it whole with water.

[0160] Safety and PK assessments will be performed periodically up to day 60. Primary endpoints include the type, incidence, timing, and severity of reported adverse events, and whether they are capsule- or drug-related. Secondary endpoints include serum PK parameters, including Cmax, Tmax, and area under the serum concentration curve (AUC).

Claims

1. 1. A method of administering an anti-interleukin antibody to a subject in need thereof, the method comprising: administering to the subject an ingestible device comprising a payload consisting of or comprising a composition comprising the anti-interleukin antibody; the device is structured to deliver the composition into or across the wall of a gastrointestinal (GI) lumen of the subject to the peritoneum or peritoneal cavity of the subject; The method, wherein the anti-interleukin antibody binds to one or both of human interleukin-23 and human interleukin-12.

2. The method of claim 1, wherein the anti-interleukin antibody is an antagonist of one or both of human interleukin-23 and human interleukin-12.

3. 3. The method of claim 1 or 2, wherein the anti-interleukin antibody comprises ustekinumab or a biosimilar thereof.

4. The method of any one of claims 1 to 3, wherein the anti-interleukin antibody comprises ustekinumab.

5. The method according to any one of claims 1 to 4, wherein the anti-interleukin antibody exhibits a biological activity greater than that of an anti-interleukin antibody administered subcutaneously.

6. The method of any one of claims 1 to 5, wherein the anti-interleukin antibody exhibits substantially the same biological activity as that of an anti-interleukin antibody administered subcutaneously.

7. The method of any one of claims 1 to 6, wherein the device comprises a dose of the anti-interleukin antibody of about 0.25 mg to about 0.75 mg.

8. The method of any one of claims 1 to 7, wherein the device comprises a dose of the anti-interleukin antibody selected from about 0.5 mg and about 0.75 mg.

9. The method of any one of claims 1 to 6, wherein the device comprises a dose of the anti-interleukin antibody of about 3.75 to about 15 mg.

10. The method of any one of claims 1 to 9, comprising once-daily administration of the device.

11. The method according to any one of claims 1 to 10, wherein the composition is a solid composition comprising the anti-interleukin antibody, a buffer, a surfactant, and an antioxidant.

12. The method of claim 11, wherein the composition comprises the anti-interleukin antibody, L-histidine / L-histidine hydrochloride, polyoxyethylene sorbitan monooleate, and L-methionine.

13. 13. The method of claim 11 or 12, wherein the composition further comprises a lubricant and a filler.

14. The method according to any one of claims 11 to 13, wherein the composition comprises the anti-interleukin antibody, L-histidine / L-histidine hydrochloride, polyoxyethylene sorbitan monooleate, trehalose, PEG 3350, and L-methionine.

15. The method according to any one of claims 1 to 10, wherein the composition is a liquid composition.

16. 16. The method of any one of claims 1-15, wherein the payload is in the form of a solid tissue-piercing member structured for insertion into the GI tract lumen wall of the subject and / or into the peritoneum or peritoneal cavity of the subject after ingestion of the device.

17. 17. The method of claim 16, wherein the composition is loaded into hollow biodegradable microneedles that constitute the solid tissue-piercing member.

18. 17. The method of claim 16, wherein the composition is a shaped mass that comprises the solid tissue-piercing member.

19. The method of any one of claims 1 to 18, wherein the device comprises multiple payloads of the anti-interleukin antibody.

20. 20. The method of claim 19, wherein the device is structured to deliver one or more payloads at different times into the GI tract lumen wall, peritoneum, or peritoneal cavity of the subject.

21. The method of any one of claims 1 to 20, wherein the ingestible device is contained within a swallowable capsule.

22. 22. The method of any one of claims 1 to 21, wherein the subject is suffering from one or more diseases selected from psoriasis, moderate to severe plaque psoriasis, psoriatic arthritis, Crohn's disease, and ulcerative colitis.

23. The method of any one of claims 1 to 22, wherein the GI lumen wall is the wall of the stomach.

24. The method of any one of claims 1 to 22, wherein the GI lumen wall is the wall of the intestine.

25. 25. The method of claim 24, wherein the intestinal wall is the wall of the small intestine.

26. The method of any one of claims 1 to 25, comprising an induction administration period followed by a maintenance administration period.

27. the subject is an adult patient weighing 100 kg or less or a pediatric patient weighing more than 60 kg; The induction administration period is 45 mg administered subcutaneously at weeks 0 and 4; administering about 1.5 mg once daily via said ingestible device for four weeks; administering about 12 mg once daily via said ingestible device for 4 weeks; administering about 9 mg per day, once daily, via the ingestible device for 7 days starting at week 0 and again at week 4; an induction dosing regimen selected from The maintenance administration period is 45 mg administered subcutaneously every 12 weeks; administering about 0.5 mg once daily with the ingestible device; administering about 3.75 mg once weekly via the ingestible device; a monthly short course of about 2.5 mg per day administered daily via the ingestible device for six days; administering about 15 mg with the ingestible device once every quarter; a short course of about 12 mg administered per day via the ingestible device once per quarter for 5 days; and said dose refers to the dose of said anti-interleukin antibody, optionally said anti-interleukin antibody is ustekinumab or a biosimilar thereof; 27. The method of claim 26, wherein the method comprises administering at least one dose of the anti-interleukin antibody via the ingestible device.

28. the subject is an adult patient weighing more than 100 kg; The induction administration period is 90 mg administered subcutaneously at weeks 0 and 4; administering about 3.25 mg once daily via the ingestible device for four weeks (e.g., four weeks or 30 days); administering about 1.5 mg twice daily for four weeks via the ingestible device; administering about 24 mg once daily for four weeks (e.g., four weeks or 30 days) via the ingestible device; administering about 18 mg per day (including 18 mg per day) via said ingestible device once daily for 7 days starting at week 0 and again at week 4; an induction dosing regimen selected from The maintenance dosing regimen comprises: 90 mg administered subcutaneously every 12 weeks; administering about 1 mg once daily with the ingestible device; administering about 0.5 mg twice daily with said ingestible device; administering about 7.5 mg once weekly via the ingestible device; a monthly short course of about 2.5 mg twice daily administered via the ingestible device for 6 days; administering about 30 mg with the ingestible device once per quarter; a short course of about 12 mg administered quarterly per day for 9 days via the ingestible device; and said dose refers to the dose of said anti-interleukin antibody, optionally said anti-interleukin antibody is ustekinumab or a biosimilar thereof; 27. The method of claim 26, wherein the method comprises administering at least one dose of the anti-interleukin antibody via the ingestible device.

29. 1. An ingestible device for use in delivering an anti-interleukin antibody to a subject in need thereof or for treating one or more conditions selected from psoriasis, moderate to severe plaque psoriasis, psoriatic arthritis, Crohn's disease, and ulcerative colitis, comprising: the device comprises a payload consisting of or comprising a composition comprising the anti-interleukin antibody; the device is structured to deliver the composition into or across the wall of a gastrointestinal (GI) lumen of the subject to the peritoneum or peritoneal cavity of the subject; The device, wherein the anti-interleukin antibody binds to one or both of human interleukin-23 and human interleukin-12.

30. 30. The device of claim 29, wherein the anti-interleukin antibody is an antagonist of one or both of human interleukin-23 and human interleukin-12.

31. 31. The device of claim 29 or 30, wherein the anti-interleukin antibody comprises ustekinumab or a biosimilar thereof.

32. The device of any one of claims 29 to 31, wherein the anti-interleukin antibody comprises ustekinumab.

33. The device of any one of claims 29 to 32, wherein the device comprises a dose of anti-interleukin antibody of about 0.25 mg to about 0.75 mg.

34. The device of any one of claims 29 to 33, wherein the device comprises a dose of anti-interleukin antibody selected from about 0.5 mg and about 0.75 mg.

35. The device of any one of claims 29 to 32, wherein the device comprises a dose of anti-interleukin antibody of about 3.75 to about 15 mg.

36. The device according to any one of claims 29 to 35, wherein the composition is a solid composition comprising the anti-interleukin antibody, a buffer, a surfactant, and an antioxidant.

37. The device of claim 36, wherein the composition comprises the anti-interleukin antibody, L-histidine / L-histidine hydrochloride, polyoxyethylene sorbitan monooleate, and L-methionine.

38. 38. The device of claim 36 or 37, wherein the composition further comprises a lubricant and a bulking agent.

39. The device of any one of claims 36 to 38, wherein the composition comprises the anti-interleukin antibody, L-histidine / L-histidine hydrochloride, polyoxyethylene sorbitan monooleate, trehalose, PEG 3350, and L-methionine.

40. 40. The ingestible device of any one of claims 36-39, wherein the composition comprises about 67% w / w ustekinumab, about 10% w / w L-histidine / L-histidine hydrochloride, about 1% w / w polyoxyethylene sorbitan monooleate, about 10% w / w trehalose, about 10% w / w PEG 3350, and about 2% w / w L-methionine.

41. 40. The ingestible device of any one of claims 36-39, wherein the composition comprises about 75% w / w ustekinumab, about 12% w / w L-histidine / L-histidine hydrochloride, about 1% w / w polyoxyethylene sorbitan monooleate, about 3% w / w trehalose, about 7% w / w PEG 3350, and about 2% w / w L-methionine.

42. 42. The ingestible device of any one of claims 29-41, wherein the payload is in the form of a solid tissue-piercing member structured for insertion into the GI tract lumen wall of a subject and / or into the peritoneum or peritoneal cavity of a subject after ingestion of the device.

43. 43. The device of claim 42, wherein the composition is filled into hollow biodegradable microneedles that constitute the solid tissue-piercing member.

44. 44. The device of claim 43, wherein the composition is a shaped mass that constitutes the solid tissue-piercing member.

45. The device of any one of claims 29 to 44, wherein the device comprises multiple payloads of the anti-interleukin antibody.

46. 46. ​​The device of claim 45, wherein the device is configured to deliver one or more payloads at different times into the GI tract lumen wall, peritoneum, or peritoneal cavity of a subject.

47. The device of any one of claims 29 to 46, wherein the ingestible device is contained within a swallowable capsule.

48. 48. The device of any one of claims 29 to 47, wherein the GI lumen wall is the wall of the stomach.

49. The device of any one of claims 29 to 47, wherein the GI lumen wall is the wall of the intestine.

50. 50. The device of claim 49, wherein the intestinal wall is the wall of the small intestine.

51. 51. The device of any one of claims 29 to 50, for use in treating one or more diseases selected from psoriasis, moderate to severe plaque psoriasis, psoriatic arthritis, Crohn's disease, and ulcerative colitis.

52. 52. The device of claim 51, wherein the anti-interleukin antibody exhibits a biological activity greater than that of an anti-interleukin antibody administered subcutaneously.

53. 52. The device of claim 51, wherein the anti-interleukin antibody exhibits substantially the same biological activity as that of an anti-interleukin antibody administered subcutaneously.

54. 54. The ingestible device of any one of claims 51 to 53, wherein said use comprises administering said device once daily.

55. 51. Use of the ingestible device of any one of claims 29 to 50 in a method of delivering an anti-interleukin antibody to a subject in need thereof or in a method of treating one or more diseases selected from psoriasis, moderate to severe plaque psoriasis, psoriatic arthritis, Crohn's disease, and ulcerative colitis in a subject in need thereof.

56. 56. The use of claim 55, wherein the anti-interleukin antibody exhibits a biological activity greater than that of an anti-interleukin antibody administered subcutaneously.

57. 56. The use of claim 55, wherein the anti-interleukin antibody exhibits substantially the same biological activity as that of an anti-interleukin antibody administered subcutaneously.

58. 58. The use according to any one of claims 55 to 57, wherein the use comprises administering the device once a day.

59. 59. The use according to any one of claims 55 to 58, comprising an induction administration period followed by a maintenance administration period.

60. the subject is an adult patient weighing 100 kg or less or a pediatric patient weighing more than 60 kg; The induction administration period is 45 mg administered subcutaneously at weeks 0 and 4; administering about 1.5 mg once daily via said ingestible device for four weeks; administering about 12 mg once daily via said ingestible device for 4 weeks; administering about 9 mg per day, once daily, via the ingestible device for 7 days starting at week 0 and again at week 4; an induction dosing regimen selected from The maintenance administration period is 45 mg administered subcutaneously every 12 weeks; administering about 0.5 mg once daily with the ingestible device; administering about 3.75 mg once weekly via the ingestible device; a monthly short course of about 2.5 mg per day administered daily via the ingestible device for six days; administering about 15 mg with the ingestible device once every quarter; a short course of about 12 mg administered per day via the ingestible device once per quarter for 5 days; and the dose refers to the dose of an anti-interleukin antibody, optionally the anti-interleukin antibody is ustekinumab or a biosimilar thereof; 60. The use of claim 59, wherein the use comprises administration of at least one dose of the anti-interleukin antibody by the ingestible device.

61. the subject is an adult patient weighing more than 100 kg; The induction administration period is 90 mg administered subcutaneously at weeks 0 and 4; administering about 3.25 mg once daily via the ingestible device for four weeks (e.g., four weeks or 30 days); administering about 1.5 mg twice daily for four weeks via the ingestible device; administering about 24 mg once daily for four weeks (e.g., four weeks or 30 days) via the ingestible device; administering about 18 mg per day (including 18 mg per day) via said ingestible device once daily for 7 days starting at week 0 and again at week 4; an induction dosing regimen selected from The maintenance administration period is 90 mg administered subcutaneously every 12 weeks; administering about 1 mg once daily with the ingestible device; administering about 0.5 mg twice daily with said ingestible device; administering about 7.5 mg once weekly via the ingestible device; a monthly short course of about 2.5 mg twice daily administered via the ingestible device for 6 days; administering about 30 mg with the ingestible device once per quarter; a short course of about 12 mg administered quarterly per day for 9 days via the ingestible device; and the dose refers to the dose of an anti-interleukin antibody, optionally the anti-interleukin antibody is ustekinumab or a biosimilar thereof; 60. The use of claim 59, wherein the use comprises administration of at least one dose of the anti-interleukin antibody by the ingestible device.

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