Usterinum monoclonal antibody dosage forms and methods

Abstract

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

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of and priority to U.S. Provisional Application No. 63 / 416,854, filed on October 17, 2022, the entire contents of which are hereby incorporated by reference. Field of the Invention

[0003] The present disclosure generally relates to compositions, dosage forms, devices and methods for delivering anti-interleukin antibodies such as ustekinumab by ingestion. More specifically, the present disclosure relates to an ingestible dosage form (e.g., an ingestible device) comprising a composition comprising an anti-interleukin antibody (such as ustekinumab), which is constructed and formulated to deliver a therapeutically effective amount of the anti-interleukin antibody to the gastrointestinal (GI) luminal wall (e.g., stomach wall, intestinal wall, colon, etc.) of a subject or to deliver into and through the GI luminal wall into the peritoneum or peritoneal cavity of the subject (and thereafter into the bloodstream) to achieve the desired pharmacokinetic and therapeutic results. Compositions, devices and methods can be used, for example, to treat 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 that may indicate treatment with anti-interleukin antibodies.

[0004] background

[0005] The following discussion is provided merely to assist the reader in understanding the present disclosure and is not admitted to describe or constitute prior art thereof.

[0006] Anti-interleukin antibody products (ustekinumab) is currently approved in the U.S. for the treatment of moderate to severe plaque psoriasis, psoriatic arthritis, moderate to severe Crohn's disease, and moderate to severe ulcerative colitis. It is administered by subcutaneous injection or intravenous injection. The dosing regimen for patients weighing up to 100 kg is 45 mg subcutaneously initially, and after 4 weeks, 45 mg subcutaneously every 12 weeks. The dosing regimen for patients weighing more than 100 kg is 90 mg subcutaneously initially, and after 4 weeks, 90 mg subcutaneously every 12 weeks.

[0007] Shaped blocks containing biologically active proteins or polypeptides (including anti-interleukin antibodies) have been described, for example, in U.S. Pat. No. 10,098,931 and U.S. Pat. No. 10,227,403. Other anti-interleukin antibody preparations are described in U.S. Pre-Grant Publication No. 2018 / 0251537.

[0008] There remains a need for compositions, dosage forms, devices and methods for delivering anti-interleukin antibodies such as ustekinumab by ingestion.

[0009] Overview

[0010] In one embodiment, a method of administering an anti-interleukin antibody to a subject in need thereof is provided. The method comprises administering to the subject by ingestion a payload formed by a composition containing an anti-interleukin antibody or an ingestible device containing a payload of the composition. The device is configured to deliver the composition to the gastrointestinal (GI) luminal wall of the subject or to deliver it into and through the GI luminal wall 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.

[0011] In another embodiment, an ingestible device for delivering an anti-interleukin antibody to a subject in need thereof is provided. The device comprises a payload formed by a composition comprising the anti-interleukin antibody or a payload comprising the composition. The device is configured to deliver the composition into the gastrointestinal (GI) luminal wall of the subject or into and through the GI luminal wall 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.

[0012] In one or more embodiments, the anti-interleukin antibody is an antagonist of one or both of human interleukin-23 and human interleukin-12.

[0013] In one or more embodiments, the anti-interleukin antibody comprises ustekinumab or a biosimilar thereof.

[0014] In one or more embodiments, the anti-interleukin antibody comprises ustekinumab.

[0015] In one or more embodiments, the anti-interleukin antibody exhibits a bioavailability that is greater than the bioavailability of the anti-interleukin antibody administered subcutaneously.

[0016] In one or more embodiments, the anti-interleukin antibody exhibits a bioavailability that is substantially the same as the bioavailability of the anti-interleukin antibody administered subcutaneously.

[0017] In one or more embodiments, the subject suffers from one or more conditions selected from psoriasis, moderate to severe plaque psoriasis, psoriatic arthritis, Crohn's disease, and ulcerative colitis.

[0018] In one or more embodiments, the device comprises a dose of an anti-interleukin antibody from about 0.25 mg to about 0.75 mg. In one or more embodiments, the device comprises a dose of an anti-interleukin antibody selected from about 0.5 mg and about 0.75 mg. In one or more embodiments, the device comprises a dose of an anti-interleukin antibody from about 3.75 mg to about 15 mg.

[0019] In one or more embodiments, the device is administered once daily.

[0020] 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) also comprises a lubricant and a filler. 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, PEG 3350 and L-methionine. In one or more embodiments, the composition (e.g., a solid composition) comprises about 67% w / w ustekinumab, about 10% w / w L-histidine / L-histidine HCl, 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., a solid composition) comprises about 75% w / w ustekinumab, about 12% w / w L-histidine / L-histidine HCl, 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.

[0021] In one or more embodiments, the composition is a liquid composition.

[0022] In one or more embodiments, the payload is in the form of a solid tissue penetrating member, which is configured to be inserted into the GI luminal wall of the subject and / or into the peritoneum or peritoneal cavity of the subject after the ingestion device. In one or more embodiments, the composition is filled in a hollow, biodegradable microneedle constituting the solid tissue penetrating member. In one or more embodiments, the composition is a shaped block constituting the solid tissue penetrating member. In one or more embodiments, the device comprises multiple payloads of anti-interleukin antibodies. In one or more embodiments, the device is configured to deliver one or more payloads to the GI luminal wall, peritoneum or peritoneal cavity of the subject at different times. In one or more embodiments, the GI luminal wall is the stomach wall. In one or more embodiments, the GI luminal wall is the intestinal wall. In one or more embodiments, the intestinal wall is the small intestine wall.

[0023] In one or more embodiments, the ingestible device is contained within a swallowable capsule.

[0024] In one or more embodiments, the method or use comprises an induction dosing period followed by a maintenance dosing period.

[0025] In one or more embodiments, the subject is an adult patient weighing ≤100 kg or a pediatric patient weighing >60 kg, and

[0026] The induction dosing phase includes an induction dosing regimen selected from the following:

[0027] 45 mg subcutaneous dose at weeks 0 and 4;

[0028] about 1.5 mg administered once daily via an ingestible device for a period of about 4 weeks;

[0029] about 12 mg administered once daily via an ingestible device for a period of about 4 weeks;

[0030] About 9 mg / day administered via an ingestible device once daily for 7 days starting in Week 0 and again for 7 days starting in Week 4; and

[0031] The maintenance dosing period includes a maintenance dosing regimen selected from the following:

[0032] 45 mg subcutaneous dose every 12 weeks;

[0033] About 0.5 mg once daily via an ingestible device;

[0034] About 3.75 mg administered once weekly via an ingestible device;

[0035] A short monthly course of approximately 2.5 mg / day for 6 days administered via an ingestible device;

[0036] About 15 mg is administered quarterly via an ingestible device;

[0037] A short quarterly course of approximately 12 mg / day for 5 days administered daily via an ingestible device;

[0038] wherein the amount refers to a dose of an anti-interleukin antibody, optionally wherein the anti-interleukin antibody is ustekinumab or a biosimilar thereof,

[0039] Wherein the method or use comprises administering at least one dose of an anti-interleukin antibody via an ingestible device.

[0040] In one or more embodiments, the subject is an adult patient weighing >100 kg, and

[0041] The induction dosing phase includes an induction dosing regimen selected from the following:

[0042] 90 mg subcutaneous dose at weeks 0 and 4;

[0043] about 3.25 mg administered once daily via an ingestible device for a period of about 4 weeks;

[0044] about 1.5 mg administered twice daily via an ingestible device for a period of about 4 weeks;

[0045] about 24 mg administered once daily via an ingestible device for a period of about 4 weeks;

[0046] About 18 mg / day administered via an ingestible device once daily for 7 days starting in Week 0 and again for 7 days starting in Week 4; and

[0047] The maintenance dosing period includes a maintenance dosing regimen selected from the following:

[0048] 90 mg subcutaneous dose every 12 weeks;

[0049] About 1 mg is administered once daily via an ingestible device;

[0050] About 0.5 mg twice daily via an ingestible device;

[0051] About 7.5 mg administered once weekly via an ingestible device;

[0052] A short monthly course of about 2.5 mg twice daily for 6 days via an ingestible device;

[0053] About 30 mg administered quarterly via an ingestible device;

[0054] A short quarterly course of approximately 12 mg / day for 9 days administered daily via an ingestible device;

[0055] wherein the amount refers to a dose of an anti-interleukin antibody, optionally wherein the anti-interleukin antibody is ustekinumab or a biosimilar thereof,

[0056] Wherein the method or use comprises administering at least one dose of an anti-interleukin antibody via an ingestible device. BRIEF DESCRIPTION OF THE DRAWINGS

[0058] Figure 1A (Figure 1A)( Figure 1A (FIG. 1A)) shows an example of an embodiment of an expandable component of a self-sizing device as disclosed herein before folding and / or rolling, and an example of an embodiment of a capsule as disclosed herein.

[0059] Figure 1B (Figure 1B)( Figure 1B (FIG.1B)) shows an embodiment of the expandable component in a folded and / or rolled arrangement before being arranged in the capsule. Figure 1A expandable component.

[0060] Figure 1C (Figure 1C)( Figure 1C (FIG.1C)) shows the Figure 1B The folded and / or rolled arrangement and arranged in the capsule Figure 1A expandable component.

[0061] Figure 2A (Figure 2A)( Figure 2A (FIG.2A))、 Figure 2B (Figure 2B)( Figure 2B (FIG.2B)) and Figure 2C (Figure2C)( Figure 2C (FIG.2C)) shows an example of an embodiment of a capsule as disclosed herein, comprising a self-sizing device as disclosed herein, comprising an expandable component within a degradable capsule as the device passes through a lumen.

[0062] Figure 2D (Figure 2D)( Figure 2D (FIG.2D))、 Figure 2E (Figure 2E)( Figure 2E (FIG.2E)) and Figure 2F (Figure 2F)( Figure 2F (FIG.2F)) shows that when Figure 2CThe progression of the expandable component in a rotational view as the expandable component expands within the lumen.

[0063] Figure 3 (Figure 3)( Figure 3 (FIG.3)) shows an example of an embodiment of a self-sizing device as disclosed herein, which includes an expandable component in a fully expanded state within a lumen.

[0064] Figure 4A (Figure 4A)( Figure 4A (FIG.4A)) shows an example of an embodiment of a self-sizing device as disclosed herein, which includes an expandable component having a non-compliant section and no hinges.

[0065] Figure 4B (Figure 4B)( Figure 4B (FIG.4B)) shows an example of an embodiment of a self-sizing device comprising an expandable component having two non-compliant sections and a hinge.

[0066] Figure 5 (Figure 5)( Figure 5 (FIG.5)) shows an embodiment of a capsule as disclosed herein, comprising an ingestible device. Illustration A shows a fully assembled enteric coated capsule. Schematic B shows the various parts and components of the capsule.

[0067] Figure 6 (Figure 6)( Figure 6 (FIG.6)) shows the results of a computer-based pharmacokinetic model simulation of ustekinumab administration based on published human pharmacokinetic data, plotting simulated plasma concentrations versus time curves from pharmacokinetic model simulations of 45 mg ustekinumab administration (top curve) once every 12 weeks relative to daily administration of 0.75 mg (middle curve) or 0.5 mg (bottom curve). The dotted line reflects the minimum therapeutic plasma level of 0.69 μg / mL.

[0068] Figure 7 (Figure 7)( Figure 7 (FIG.7)) shows the plasma concentration versus time profile obtained following oral administration of a single dose of an ingestible dosage form of ustekinumab as described herein in the canine study of Example 2.

[0069] Figure 8 (Figure 8)( Figure 8(FIG.8)) shows the plasma concentration versus time profiles obtained following administration of a single dose of ustekinumab via an ingestible device or a single subcutaneous (SC) injection in the canine study of Example 4.

[0070] Details

[0071] The present disclosure provides compositions, dosage forms, devices and methods for delivering anti-interleukin antibodies (such as ustekinumab) using an ingestible dosage form (ingestible device) comprising a payload formed by a composition containing an antibody or a payload comprising the composition, wherein the device is configured to deliver the anti-interleukin antibody to the GI luminal wall (e.g., stomach wall, intestinal wall, colon, etc.) of a subject or to deliver into and through the GI luminal wall into the peritoneum or peritoneal cavity of the subject (and thereafter into the bloodstream). The payload can be in the form of a solid tissue penetrating member that is configured to penetrate the GI luminal wall of the subject and / or be inserted into the peritoneum or peritoneal cavity of the subject after the device is ingested. The ingestible device can be disposed in a capsule, such as a swallowable capsule.

[0072] I. Definitions

[0073] 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.

[0074] Unless otherwise defined, technical and scientific terms used herein have the meanings commonly understood by one of ordinary skill in the art. Unless otherwise indicated, materials and / or methods known to one of ordinary skill in the art can be used to implement the methods described herein based on the guidance provided herein.

[0075] As used herein, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Unless explicitly stated, reference to an object in the singular is not intended to mean "one and only one," but rather "one or more."

[0076] As used herein, the terms "eg," "such as," "for example," "for an example," "for another example," "examples of," "by way of example," and "etc." indicate that a list of one or more non-limiting examples precedes or follows; it should be understood that other examples not listed are also within the scope of the present disclosure.

[0077] As used herein, when used with numerical values, the terms "substantially" and "about" mean the stated numerical value and up to and including plus or minus 10% of the numerical value. For example, "about 10" should be understood as both "10" and "within the range of 9 and 11, including 9 and 11".

[0078] As used herein, phrases of the form “A / B” or of the form “A and / or B” mean (A), (B), or (A and B); phrases of the form “at least one of A, B, and C” mean (A), (B), (C), (A and B), (A and C), (B and C), or (A, B, and C).

[0079] As used herein, the terms "comprising," "comprise," "comprises," "includes," and "including" are intended to mean that compositions and methods include the listed elements, but not excluding other elements.

[0080] As used herein, the phrase "therapeutically effective amount" with respect to an anti-interleukin antibody such as ustekinumab means a dose that provides the specific pharmacological effect of the drug administered in a subject in need of such treatment. It should be emphasized that a therapeutically effective amount of an anti-interleukin antibody is not always effective in treating the condition for which it is administered in each individual subject, even if such a dose is considered a therapeutically effective amount by a person skilled in the art. A person skilled in the art can adjust the therapeutically effective amount considered according to standard practice required for the treatment of a particular subject. The therapeutically effective amount can vary based on, for example, the age and weight of the subject, and / or the overall health of the subject, the condition being treated, and / or the severity of the condition of the subject being treated.

[0081] With respect to anti-interleukin antibodies such as ustekinumab, "therapeutic levels" of circulating anti-interleukin antibodies in human subjects means plasma levels associated with a specific pharmacological effect achieved by administration of the drug in a subject in need of such treatment. A "therapeutic level" of circulating ustekinumab in a human subject may be a plasma concentration of about 0.69 μg / mL or higher. That is, a plasma concentration of ustekinumab of about 0.69 μg / mL or higher may be therapeutically effective.

[0082] The term "ingest" or grammatical variations thereof (e.g., "ingesting," "ingestion," "ingested," or "ingestible") refers herein to ingestion into the stomach, whether by swallowing or by other means of deposition into the stomach (e.g., endoscopic deposition into the stomach or deposition into the stomach via a port).

[0083] The term "lumen" herein refers to the interior space of a tubular structure. Examples of lumens in vivo include tubular cavities within arteries, veins, and organs. The term "gastrointestinal lumen" or "GI lumen" generally refers to any lumen of the GI tract (e.g., the lumen of the esophagus, stomach, small intestine, large intestine, or colon); the term "GI lumen wall" refers to the lumen wall of the GI lumen.

[0084] The term "luminal wall" refers to the wall of a lumen, wherein the wall includes all layers from the inner periphery to the outer periphery of the lumen, such as, with respect to a lumen in the body, including the mucosa, submucosa, muscularis, serosa, and outer wall of the lumen, as well as constituent blood vessels and tissues.

[0085] As used herein, the term "gastrointestinal tract" or "GI tract" refers herein to the body's ingestion / excretion system including, for example, the mouth, pharynx, esophagus, stomach, pylorus, small intestine, cecum, large intestine, colon, rectum, anus, and valves or sphincters therebetween.

[0086] The terms "individual," "subject," and "patient" are used interchangeably herein and include any individual mammalian subject (e.g., bovine, canine, feline, equine, or human). In specific embodiments, the subject, individual, or patient is a human.

[0087] The term "component" refers to an item in a group of one or more items that together constitute the device, composition or system being discussed in this article. Component can be in solid, powder, gel, plasma, fluid, gas or other composition forms. For example, the device can include multiple solid components assembled together to construct the device, and can also include a fluid component arranged in the device. For another example, the composition can include a single component, or two or more components mixed together to constitute the composition. The composition can be in the form of fluid, slurry, powder or solid (for example, in concentrated form or solidified form, such as tablets or micro tablets). Device or system can include one or more compositions and / or one or more other components.

[0088] The term "design" or its grammatical variations (e.g., "designing" or "desinged") refers herein to properties that are intentionally incorporated based on estimates of, for example, tolerances (e.g., component tolerances and / or manufacturing tolerances) and environmental conditions expected to be encountered (e.g., temperature, humidity, external or internal environmental pressures, external or internal mechanical pressures, stresses from external or internal mechanical pressures, product age or shelf life, or if introduced into the body, physiology, body chemistry, biological composition of fluids or tissues, chemical composition of fluids or tissues, pH, species, diet, health, sex, age, ancestry, disease, or tissue damage); it is understood that actual tolerances and environmental conditions before and / or after delivery can affect the properties, such that different components, devices, compositions, or systems with the same design can have different actual values ​​for those properties. Design also includes changes or modifications before or after manufacture.

[0089] 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 the making or assembling of the component, device, composition, or system. Manufacturing can be performed in whole or in part by hand and / or in whole or in part in an automated manner.

[0090] The term "structured" or its grammatical variations (e.g., "structure" or "structuring") as used herein refers to a component, device, composition or system manufactured according to a concept or design, or variations or modifications thereof (whether such variations or modifications occur before, during or after manufacture), whether or not such concept or design is recorded in writing.

[0091] The term "degrade" or grammatical variations thereof (e.g., "degrading," "degraded," "degradable," and "degradation") refers herein to weakening, partial degradation, or complete degradation, such as by dissolution, chemical degradation (including biodegradation), decomposition, chemical modification, mechanical degradation, or disintegration, which also includes, but is not limited to, dissolution, fragmentation, deformation, shrinkage, or contraction.

[0092] The term "non-degradable" means that degradation is expected to be minimal or within some acceptable design percentage in the expected environment for at least the expected duration.

[0093] The terms "anti-interleukin antibody composition" and "composition of anti-interleukin antibodies" are used interchangeably herein and refer to a composition comprising one or more components, wherein at least one of the components is an anti-interleukin antibody. The anti-interleukin antibody composition may include, for example, an anti-interleukin antibody as the sole active agent or include one or more additional active agents.

[0094] As used herein, the term "anti-interleukin antibody" refers to full-length antibodies and fragments thereof that bind to interleukin proteins (such as one or both of human interleukin-23 and human interleukin-12), and includes monoclonal antibodies, human antibodies, and humanized antibodies. The antibody can be an immunoglobulin (Ig) molecule comprising four polypeptide chains: two heavy (H) chains and two light (L) chains. Functional antibody fragments can include fragments of antibodies, such as at least one complementary determining region (CDR) of the heavy chain, at least one complementary 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, a framework region, etc. The anti-interleukin antibodies as discussed herein can bind to one or both of human interleukin-23 and human interleukin-12. The anti-interleukin antibodies as discussed herein can be antagonists of one or both of human interleukin-23 and human interleukin-12.

[0095] The anti-interleukin antibody may be or include ustekinumab, or an antibody biosimilar thereto. Ustekinumab (available in FDA-approved products Ustekinumab (Ustekinumab) is a recombinant human IgG1κ monoclonal antibody produced in a murine cell line (Sp2 / 0) that acts as an antagonist of human interleukin-12 and human interleukin-23. Ustekinumab contains 1326 amino acids and has an estimated molecular weight ranging from 148,079 to 149,690 Daltons.

[0096] As used herein, "delay agent" refers to a component included in the composition to slow down the release rate of one or more other components from the composition. The delay agent can 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), another polymer or a hydrogel.

[0097] For standard units, various abbreviations may be used herein, such as deciliter (dl), milliliter (ml), microliter (μl), international unit (IU), centimeter (cm), millimeter (mm), nanometer (nm), inch (in), kilogram (kg), gram (gm), milligram (mg), microgram (μg), nanogram (ng), millimole (mM), Celsius (°C), Fahrenheit (°F), millitorr (mTorr), hour (hr), minute (min), second (s or sec), millisecond (ms), microsecond (μs), or nanosecond (ns).

[0098] Disclosed herein is an ingestible dosage form (ingestible device) that can be used to deliver anti-interleukin antibodies to subjects in need thereof. The device comprises a payload formed by a composition containing an anti-interleukin antibody or a payload containing the composition, and is configured to deliver the composition to the GI luminal wall of the subject after ingestion or to deliver it into and through the GI luminal wall into, for example, the peritoneum or peritoneal cavity of the subject. As described above, the anti-interleukin antibody provided in the device can be bound 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 or include ustekinumab or its biosimilar. Although the anti-interleukin antibody provided in the device is not limited to ustekinumab, for convenience, the following discussion relates to ustekinumab. It should be understood that other anti-interleukin antibodies, 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 other antibodies that can be antagonists of one or both of human interleukin-23 and human interleukin-12, can be used in addition to or in place of ustekinumab.

[0099] II. Ingestible Dosage Forms (Ingestible Devices)

[0100] As described above, the ingestible dosage form described herein is an ingestible device comprising a payload made of a composition containing ustekinumab or a payload comprising or containing the composition. The payload can be in the form of a solid tissue penetrating member, which is configured to penetrate the GI luminal wall of the subject after the ingestion device (e.g., after the swallowing device or after the ingestion device in another way, such as via an endoscope or a stomach port) and insert the GI luminal wall of the subject or the surrounding body environment (e.g., peritoneum or peritoneal cavity), thereby delivering ustekinumab to the bloodstream of the subject. The payload can be formed by a composition or can include a composition. The specific embodiments of such a device are described in more detail below. Any device disclosed or mentioned herein can be optionally arranged in a capsule (such as a swallowable capsule). Generally, the material used to form the components of the device is classified as food grade, food additives, active or inactive food ingredients or GRAS (generally considered safe by the FDA). The device (including any capsule shell) can be biodegradable.

[0101] Figure 5 A schematic diagram illustrates an ingestible device (e.g., a swallowable device) according to an embodiment of the present disclosure. As shown, the device is disposed within a capsule, which can be a swallowable capsule of any suitable size, such as a 000-size HPMC (hydroxypropyl methylcellulose) capsule, or a 1000-size capsule such as a 1000-size capsule. Figure 5 The capsule illustrated in Figure A of FIG. The capsule can be provided with a coating, such as an enteric coating, such as an enteric polymer (e.g., a polymer that dissolves at a target pH within the digestive tract). For example, the enteric coating can be selected to dissolve at pH>6 to avoid dissolution in the acidic environment of the stomach. In embodiments where the device is incorporated into an enteric coated capsule, after the capsule leaves the stomach and enters the duodenum, the higher intestinal pH of the small intestine dissolves the enteric coating and the capsule shell, exposing the interior of the device and the components contained therein to the intestinal fluid.

[0102] Thus, in some embodiments, the capsule and / or coating is designed to degrade after a certain length of time in the presence of a particular chemical, or under conditions expected at a target site within the GI tract (e.g., at certain pH values ​​or ranges, temperature, pressure exerted on the capsule, or a combination of the foregoing). In an embodiment, the coating comprises a material that improves swallowability and / or ingestibility, such as guar gum or xanthan gum.

[0103] The device may include a mechanism to effectuate delivery of a payload into a location in the GI tract, such as the intestinal wall, or into and through the intestinal wall, for example, the peritoneum or peritoneal cavity of a subject. In embodiments, the mechanism includes an actuator that is triggered when the device is at a target delivery site, such as within the intestine. In other embodiments, the mechanism may effectuate delivery of a payload at another location in the GI tract, such as the stomach, large intestine, or colon.

[0104] exist Figure 5 In the embodiment of the present invention, the device includes a sealed polyethylene balloon (labeled as a sealed balloon), a delivery structure (labeled as a micro-injector) and an actuator in the form of two reactants and a valve, all of which together constitute a mechanism for achieving the delivery of a payload to the intestinal wall or delivery into and through the intestinal wall into, for example, the peritoneum or peritoneal cavity of a subject. In this embodiment, the micro-injector contains a payload (labeled as a micro-needle). Two reactants (e.g., citric acid and potassium bicarbonate) labeled as reactant A and reactant B are separated by a valve (labeled as a reaction valve) in an initial state. When exposed to a fluid such as intestinal fluid (e.g., after the capsule degrades), a portion of the valve degrades and allows the two reactants to mix, which results in the formation of a gas (e.g., carbon dioxide or other harmless gases) that expands the balloon. The expansion of the balloon aligns the micro-injector substantially perpendicular to the long axis of the intestine, and establishes a pressure in the balloon that is sufficient to provide a micro-needle ejected from the micro-injector and to inject the micro-needle into the intestinal wall or its surrounding tissues. After the micro-needle is deployed, the balloon is deflated, and the balloon and other components are discharged through the GI tract along with normal defecation.

[0105] Typically, the mechanism for achieving delivery of a payload into the intestinal wall may include various mechanical, electrical, electromechanical and / or chemical components. For example, a spring, a lever and / or various movable components may together form a mechanism.

[0106] The payload may be disposed within the protective housing until just before the payload is delivered into the intestinal wall (e.g., in ms or μs). Figure 5 In an embodiment, the microneedle can be sealed within the microsyringe in an initial state, and when ejected from the microsyringe into the intestinal wall, the seal on the microsyringe can be pierced or broken to be discharged from the microsyringe.

[0107] After entering the intestinal wall or the surrounding body environment (eg, peritoneum or peritoneal cavity), the payload dissolves or degrades in the moist tissue environment to release the ustekinumab composition into the bloodstream.

[0108] The payload can be a hollow structure, wherein the ustekinumab composition is provided, or the payload itself can be formed by the ustekinumab composition (for example, the ustekinumab composition can be compressed into a desired size and shape). In an embodiment, the ustekinumab composition is compressed into a cylindrical microtablet or a microtablet of other shapes. In an embodiment, the ustekinumab composition (in an uncompressed form or a compressed form) is arranged in a degradable shell, and the shell containing the microtablet is the payload. In an embodiment, the shell is approximately needle-shaped. The degradation of the payload can occur within 1 minute, 2 minutes, 3 minutes, 4 minutes or 5 minutes injected into the intestinal wall, or may take longer. The properties of the payload (for example, structure and / or material) can be selected to delay the release of ustekinumab from the payload.

[0109] The device may include a detectable marker, such as a radioactive label, to help track the device as it travels through the GI tract of a subject. Examples of markers include, but are not limited to, barium sulfate (whose dispersion indicates fluid entry into the interior of the device and the imminent delivery of a payload) and bismuth, which may optionally be included on or in components contained in the device to radiographically track the transport of the components along the GI tract and to confirm their discharge.

[0110] In a similar Figure 5 In the embodiment of the illustrated embodiment, the balloon is self-sizing. With respect to embodiments that include a self-sizing balloon, the balloon is referred to herein as an "expandable component." Such embodiments are described in more detail in the following paragraphs.

[0111] 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. Compliance refers to a state in which a section can be easily deformed, and non-compliance refers to a state in which a section resists deformation. In the absence of constraints, each section will expand to a fully stretched state, and the expandable component will reach its maximum size, 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., for expansion by expansion, the maximum size may be affected by the limitation of the expansion force that can be obtained from the expansion module, or by the tensile factor of one or more materials of the expandable component). The expansion module is a part of the mechanism that realizes the delivery of the payload to the intestinal wall.

[0112] Each compliant segment operates in a manner similar to a hinge, and thus will be referred to as a hinge for convenience. In the fully extended state of the expandable component (wherein each segment is fully extended), 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 segment.

[0113] As the expandable component expands, it will achieve a shape that reflects the balance between the force exerted by the expandable component on the interior of the lumen of the GI tract and the force of the lumen against the expandable component. In other words, the expandable component may not fully extend and, if constrained by the lumen, will tend to bend about the hinge. This bending is due to the smaller size of the hinge compared to the corresponding size of the non-compliant segment, which results in a lower stiffness of the hinge compared to the stiffness of the non-compliant segment in the expanded configuration of the expandable component.

[0114] In this manner, the expandable component expands until the non-compliant segment (which may be referred to as NCS hereinafter) is pressed against the inner wall of the lumen to maintain the expandable component in a position suitable for delivering the ustekinumab composition to the lumen wall for at least a time sufficient to complete such delivery. The expandable component may then be deflated.

[0115] The expandable component may be removed after deflation, may be left in place to degrade, or may be allowed to exit the lumen.The expandable component may be constructed of a degradable material such that the expandable component degrades after a designed period of time after exposure to the environment at the target site.

[0116] The self-sizing device as described above can be used to deliver therapeutic ustekinumab compositions to the GI luminal wall (e.g., stomach wall, intestinal wall, colon) via ingestion (e.g., swallowing or other ingestion modes). The self-sizing device may include a capsule. The self-sizing device may include a coating (e.g., a coating as described above) on the capsule and / or on the expandable component, which is designed to degrade at a specific location in the GI tract such as in the intestine. In an embodiment, all or part of the capsule and / or coating is designed to degrade after a certain length of time in the presence of a specific chemical, or under conditions expected at a target site in the GI tract (e.g., at certain pH values ​​or ranges, temperature, pressure applied to the capsule, or a combination of the foregoing). In an embodiment, the coating includes a material that improves swallowability and / or ingestibility, such as guar gum or xanthan gum.

[0117] Figure 1A-Figure 1C The figure shows an example of assembling a self-sizing device 1050, which is an ingestible device as described herein. Figure 1A The figure shows an embodiment of an expandable component 1000 and an embodiment of a capsule shell 1010. The outer dimension of the expandable component 1000 can be several times larger than the inner dimension of the capsule 1000. For example, the longest dimension of an embodiment of the expandable component 1000 can be 2 to 5 times larger than the inner length of the capsule shell 1010. Other ratios of the outer dimension of the expandable component to the inner dimension of the capsule are within the scope of the present disclosure. Figure 1BThe figure shows 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 in a complex arrangement (origami style) in this embodiment. Figure 1C The figure shows arrangement 1001 disposed in a capsule 1010 and the assembled capsule shell 1010. Device 1050 includes expandable component 1000 (in arrangement 1001) and capsule shell 1010, and may include other components not shown, such as an expansion module, a delivery component, one or more coatings, and a deflation valve.

[0118] Figure 2A-2F The figure shows an example of how the device 1050 can be provided to a target delivery site in the GI tract and the expandable component 1000 can be positioned to deliver the therapeutic ustekinumab composition into the luminal wall 1111 (eg, intestinal wall, stomach wall, etc.) of the GI lumen 1110. Return to Reference Figure 2A-2C , the device 1050 is shown from a view generally perpendicular to the direction of travel of the device 1050 (indicated by the arrow), and Figure 2D-2F The device 1050 in FIG. 1 is shown as if looking into the lumen 1110 (e.g., with Figure 2A-2C view at approximately 90 degrees).

[0119] Figure 2A The figure shows the device 1050 shown in a relaxed state (e.g., between peristaltic contractions) within the lumen 1110. In this embodiment, the outer dimensions of the device 1050 are smaller than the inner dimensions of the lumen 1110 at this location in the GI tract. The device 1050 is passed through the lumen 1110, for example, by manipulation of peristalsis, fluid dynamics, and / or gravity.

[0120] Figure 2B The figure shows that after reaching the designed target site or after encountering conditions (e.g., pH) representative of the designed target site, the capsule shell 1010 degrades (or is triggered to break or degrade) as the device 1050 continues to pass through the lumen 1110. For example, with respect to enteral delivery, the target site can be in a general area (e.g., the small intestine), a more specific area (e.g., the jejunum), or a specific tissue region (e.g., a marked tissue region).

[0121] Figure 2C The figure shows that after (or while) the capsule shell 1010 is degraded, the expandable component 1000 begins to unfold from its folded and / or rolled arrangement.

[0122] Figure 2D The expandable component 1000 is shown mostly deployed, and Figure 2E The figure shows the expandable component 1110 when the expandable component 1110 is expanded (eg, by an expansion module).

[0123] Figure 2F The figure shows the expandable component 1000 after expansion. In this embodiment, if not constrained by the lumen 1110, the expandable component 1000 will be able to expand until the reference line 1120 is approximately a straight line. However, the lumen 1110 applies force against the expandable component 1000, which causes the expandable component 1000 to bend at the hinge 1002. Then, the NCS1003 and NCS1004 of the expandable component 1000 are pressed against the lumen wall of the lumen 1110 (for example, at the opposite side of the lumen) and position the expandable component 1000 to deliver the therapeutic ustekinumab composition at the lumen wall or deliver the therapeutic ustekinumab composition to the lumen wall. The hinge 1002 can also be pressed against the lumen wall. In an embodiment, peristalsis can move the expandable component 1000 in its expanded state through the lumen 1110. In an embodiment, the expandable component 1000 can have sufficient internal pressure (combined with surface tension) to firmly hold the expandable component 1000 in approximately the same position even during peristalsis. In an embodiment, the expandable component 1000 includes surface roughness or surface protrusions to help maintain the position of the expandable component 1000.

[0124] The expansion of the expandable component can be achieved by any suitable expansion module. In an embodiment, the spring mechanism is released from a compressed state to deploy a filler such as a hard material or a soft material to push outward and thus expand the expandable component. In an embodiment, two or more reactants are mixed together to form a gas, and thereby expand the expandable component. In an embodiment, the material is quickly burned to produce a gas and thereby expand the expandable component. Other expansion modules are within the scope of the present disclosure.

[0125] Figure 3 The figure 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 against the expandable component 1250 is substantially insufficient to bend the hinge 1251 of the expandable component 1250, so the expandable component 1250 is in a state of approximately full extension. In other words, the bending of the hinge 1251 of the expandable component 1250 is negligible at this location in the lumen 1200.

[0126] The expandable component 1250 can be expanded by generating gas, and can include a valve 1255 to release gas from within the expandable component 1250 into the lumen 1200 to deflate the expandable component 1250. The valve 1255 can include one or more components. In an embodiment, the valve 1255 is a pinch valve that degrades in the presence of a fluid (e.g., a biological substance) to expose a port or opening defined by the expandable component 1250. In an embodiment, the valve 1255 is a material sheet or coating on a port or opening in the expandable component 1250, and the material sheet or coating is designed to degrade after the expandable component 1250 delivers the therapeutic ustekinumab composition for a period of time. In an embodiment, the valve 1255 is opened manually.

[0127] The therapeutic composition (or multiple therapeutic compositions) of ustekinumab can be stored in the expandable component 1250 in any composition form (e.g., as a solid, fluid, slurry, or powder). The therapeutic composition can be delivered in any composition form (e.g., as a solid, fluid, slurry, or powder). In some embodiments, two or more components of the therapeutic composition are mixed in the expandable component 1250 before delivery. In an embodiment, the expandable component 1250 includes a portal, such as portal 1260, which defines an opening 1261 through which the therapeutic composition is delivered. In an embodiment including a tissue penetrating member, the tissue penetrating member can be delivered through the portal.

[0128] The therapeutic ustekinumab composition is actively released such that the therapeutic ustekinumab composition is forced out of the expandable component 1250 and into the lumen 1200 or beyond the lumen wall into the surrounding body environment (e.g., through the mucosa, submucosa, muscularis, serosa, outer wall of the lumen 1200, and into the peritoneal cavity); in such an embodiment, the therapeutic ustekinumab composition can be released through one or more portals such as portal 1260.

[0129] The therapeutic composition of ustekinumab can be forcibly expelled from the expandable component 1250 by a delivery mechanism. For example, with respect to a solid composition (e.g., a tablet, pill, or spike form), the therapeutic ustekinumab composition can be expelled by a spring mechanism that is released to quickly eject the solid composition out of the expandable component 1250, or by a piston mechanism, wherein a piston is moved by a spring mechanism, or a gas expands to quickly push the solid composition out of the expandable component 1250.

[0130] With respect to fluid compositions (e.g., liquids), the therapeutic ustekinumab composition can be expelled as a fluid jet by a spring mechanism or gas acting on a piston or plunger to eject the product from the reservoir through the opening or nozzle of the expandable component 1250. The fluid jet of the therapeutic ustekinumab composition can have sufficient force to actively penetrate the GI lumen wall and enter the bloodstream.

[0131] Additionally or alternatively, the fluid composition comprising ustekinumab can be expelled through a hollow needle coupled to the expandable component 1250. The hollow needle can be penetrated into and / or through the GI lumen wall by a spring mechanism or gas acting on a piston or plunger to eject the composition through the needle and into the GI lumen wall or surrounding tissue.

[0132] In some embodiments, the surface of the expandable component 1250 that delivers the therapeutic ustekinumab composition contacts the wall of the lumen 1200 along an extension of about 5 mm to 20 mm.

[0133] In some embodiments, the therapeutic ustekinumab composition is delivered from multiple surfaces of the expandable component 1250. Such embodiments may include more than one tissue penetrating member formed of or comprising the ustekinumab composition.

[0134] Figure 4A The figure shows an embodiment of a self-sizing device 1300 including an expandable component 1305 that includes one NCS 1310 and no hinge. Figure 4B The figure shows an embodiment of a self-sizing device 1350 including an expandable component 1355, which includes two NCSs, NCS 1360 and NCS 1361, and a hinge 1365 therebetween. With respect to these embodiments, the width W1 of the expandable component 1305 is similar to the width W2 of the expandable component 1355, and the height H1 of the expandable component 1305 is less than the height H2 of the expandable component 1355.

[0135] When fully expanded in the lumen due to the non-compliance of the NCS 1310, multiple devices 1300 ( Figure 4A ) will have substantially the same maximum circumference (in the yz plane) of the NCS 1310, such that the expandable component 1305 does not significantly accommodate a variety of different internal lumen circumferences. Thus, different sizes of the device 1300 can be adapted to different animal species and / or different subjects within a species. In contrast, when fully expanded in a lumen, multiple devices 1350 ( Figure 4B) will likely not have the same maximum circumference (in the yz plane) because, even when expanded, each device 1350 will adjust to the size of the lumen in which it is expanded due to the flexibility (non-compliance, bending) of the hinge 1365. The maximum circumference of a device 1350 within a lumen refers to the maximum circumference of the shape (e.g., partially extended shape or fully extended shape) that the device 1350 assumes within the lumen.

[0136] Specific materials can be selected to give the desired structure and material properties of the payload (for example, for inserting the column strength in the lumen wall, or for controlling the disintegration of the payload and thus controlling the porosity and / or hydrophilicity of the release of the therapeutic ustekinumab composition). For example, when the payload is formed as a tissue penetration member, some materials may be more suitable, and when the payload is contained in the tissue penetration member, other materials may be more suitable. In an embodiment, the tip of the payload includes a degradable material (such as sucrose, maltose or other sugars) or is coated with the degradable material to increase the hardness and tissue penetration properties of the tip. Once positioned in the lumen wall, the payload can be degraded by the interstitial fluid in the tissue so that the therapeutic ustekinumab composition is dissolved and absorbed into the bloodstream. The properties of the payload can be selected, such as size, shape and chemical composition, to allow the drug to dissolve and absorb in seconds, minutes or hours. The dissolution rate can be controlled by various excipients such as disintegrants (for example, starch, sodium starch glycolate or cross-linked polymers such as carboxymethyl cellulose). The choice of disintegrant can be specifically tailored to the environment within the lumen wall (eg, blood flow and average number of peristaltic contractions).

[0137] The payload may be made entirely of the ustekinumab composition, or a cavity including the ustekinumab composition may be defined. The self-sizing device may include and deliver one or more payloads, each of which may contain the same or different ustekinumab compositions. Each payload may have different properties; for example, two payloads may be designed to deliver corresponding compositions simultaneously (e.g., two instances of a composition, or one instance of each of two different compositions), or may be designed to deliver corresponding compositions at different times (e.g., to provide sequential doses of the same ustekinumab composition or to provide different ustekinumab compositions sequentially).

[0138] III. Microtablets

[0139] Various embodiments of microtablets containing ustekinumab compositions in the form of solid shaped blocks containing ustekinumab and methods for forming such solid shaped blocks are described. The shaped block may contain a therapeutic composition comprising a drug (e.g., ustekinumab) and one or more pharmaceutically acceptable excipients, including degradable materials (such as sugars, polyethylene, lactic acid polymers, poly (glutamic acid-co-lactic acid-co-glycolic acid) (PGLG), etc.), which degrades within the target delivery site in vivo (e.g., the small intestine wall or peritoneum or peritoneal cavity) to release the drug.

[0140] The shaped block can be formed by various forming processes known in the pharmaceutical field. Typically, the shaped block will be formed by a compression process such as compression molding. According to one or more embodiments, the biological activity of ustekinumab in the shaped block is at least about 70% of the biological activity before compression, at least 80% of the biological activity before compression, at least 85% of the biological activity before compression, about 90% of the biological activity before compression, or at least 95% of the biological activity before compression.

[0141] The shaped block may have a range from about 0.60 mg / mm 3 To about 1.15mg / mm 3 , from about 0.70mg / mm 3 To about 1.15mg / mm 3 , from about 0.80mg / mm 3 To about 1.10mg / mm 3 , from about 1.02mg / mm 3 Up to 1.06 mg / mm 3 or from about 1.03 mg / mm 3 Up to 1.05 mg / mm 3 density within the range of .

[0142] The shape of the shaped block can be any shape suitable for use as a component of a device as described herein, such as any shape suitable for being disposed within a tissue penetrating member (e.g., a pill or cylinder) or any shape suitable for use as a tissue penetrating member (e.g., a needle or dart). The shaped block can include a pill shape, or can have a tablet, cone, cone, hot dog / capsule shape, arrow, cylinder, cube, sphere, hemisphere, or other suitable shape. For embodiments having a cylindrical or pill-shaped shaped block, the shaped block can have a diameter in the range of from about 0.5 mm to 1 mm and a length from about 1.75 mm to 3.25 mm.

[0143] As described above, according to various embodiments, the shaped block can be partially formed of a degradable material, which is configured to dissolve or otherwise degrade, for example, in the intestinal wall or in the peritoneum or peritoneal cavity, so as to release the drug for systemic absorption. Suitable degradable materials include various sugars such as trehalose, maltose and sucrose; various lactic acid polymers such as polyglycolic acid (PGA), polylactic acid (PLA), polyglycolic acid lactic acid (PGLA), poly (glutamic acid-co-lactic acid-co-glycolic acid) (PGLG); various polyethylenes such as high-density, low-density and linear low-density PE and PEO (polyethylene oxide); various cellulose polymers such as HPMC (hydroxypropyl methylcellulose), CMC (carboxymethyl cellulose), MC (methylcellulose), methacrylic acid-ethyl acrylate copolymer, methacrylic acid-methyl methacrylate copolymer PVOH (polyvinyl alcohol), silicone rubber and other biodegradable polymers known in the art. The materials and other properties of the degradable polymer and the shaped block can be selected to produce a selectable degradation rate in the intestinal wall or other target delivery sites (e.g., peritoneum or peritoneal cavity).

[0144] A description of a manufacturing process for preparing various embodiments of drug-containing shaped blocks as described herein will now be provided. The process includes a process for making a drug-containing powder and a shaped block forming process for forming the powder into a shaped block. For convenience, the shaped block is referred to as a microtablet; however, it should be understood that other forms and / or shapes are equally applicable, as described above.

[0145] A process for preparing a powder (e.g., a dry composition) comprising a drug (e.g., ustekinumab) will now be described. A typical process may include preparing a composition comprising a drug and an excipient. The composition may be prepared by combining dry ingredients, or preparing a solution comprising one or more ingredients, and then evaporating the solvent (optionally including lyophilization) to obtain a dry composition, and optionally adding one or more dry ingredients to obtain a composition comprising the drug and other excipients.

[0146] The drug (e.g., ustekinumab) may be present in the dry composition in any amount suitable for providing a target dose in an ingestible device, and in one or more embodiments, may be present in an amount of from about 1% w / w to about 99% w / w of the composition, including from about 25% w / w to about 75% w / w, including from about 50% w / w to about 60% w / w, or from about 50% w / w to about 80% w / w, including about 55% w / w, such as 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, such as 67% w / w. In some embodiments, the drug (e.g., ustekinumab) is present in an amount of about 75% w / w, such as 75% w / w.

[0147] Excipients may include one or more of buffers, antioxidants, surfactants, lubricants, binders, stabilizers, and fillers.

[0148] The buffer can be a histidine HCl buffer system (e.g., L-histidine and L-histidine monohydrochloride monohydrate (L-histidine / L-histidine HCl)), and in one or more embodiments, can be present in an amount from about 1% w / w to about 15% w / w of the composition, including from about 1% w / w to about 5% w / w or from about 2% w / w to about 3% w / w, including about 2.4% w / w, or from about 10% w / w to about 15% w / w, including about 10% w / w or about 12% w / w, such as these amounts of L-histidine / L-histidine HCl. In some embodiments, the buffer (e.g., L-histidine / L-histidine HCl) is present in an amount of about 10% w / w, such as 10% w / w. In some embodiments, the buffer (e.g., L-histidine / L-histidine HCl) is present in an amount of about 12% w / w, such as 12% w / w.

[0149] The antioxidant may include L-methionine, and in one or more embodiments, may be present in an amount of from about 1% w / w to about 10% w / w of the composition, including from about 3% w / w to about 8% w / w, including about 5% w / w, such as about 4.4% w / w, or from about 1% w / w to about 5% w / w, including from about 1% w / w to about 3% w / w, including about 2% w / w. In some embodiments, the antioxidant (e.g., L-methionine) is present in an amount of about 2% w / w, such as 2% w / w.

[0150] The surfactant can be polysorbate 80 (polyoxyethylene sorbitan monooleate, such as Tween 80), and in one or more embodiments, can be present in an amount of from about 0.05% w / w to about 3% w / w of the composition, including from about 0.05% w / w to about 1% w / w, or from about 1% w / w 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, such as 1% w / w.

[0151] Lubricant can be used to promote the formation of microtablets and discharge from mold. Lubricant can include polyethylene glycol 3350 (PEG 3350), and in one or more embodiments, can be with composition from about 5%w / w to about 50%w / w or from about 10%w / w to about 50%w / w, including from about 5%w / w to about 15%w / w and from about 20%w / w to about 30%w / w, including about 7%w / w, about 10%w / w or about 25%w / w amount exists. In some embodiments, lubricant (for example, PEG3350) exists with about 10%w / w, such as 10%w / w amount. In some embodiments, lubricant (for example, PEG 3350) exists with about 7%w / w, such as 7%w / w amount exists.

[0152] Filler or stabilizer can be trehalose, and in one or more embodiments, can be present in an amount of from about 1% w / w to about 20% w / w or from about 5% w / w to about 20% w / w of the composition, including from about 1% w / w to about 5% w / w or from about 10% w / w to about 15% w / w, including about 3% w / w or about 10% w / w, including about 12.5% ​​w / w. In some embodiments, filler or stabilizer (e.g., trehalose) is present in an amount of about 10% w / w, such as 10% w / w. In some embodiments, filler or stabilizer (e.g., trehalose) is present in an amount of about 3% w / w, such as 3% w / w.

[0153] Alternatively, the filler can be mannitol, and in one or more embodiments, can be present in an amount of from about 5%w / w to about 20%w / w of the composition, including from about 10%w / w to about 15%w / w, including about 12.5%w / w. Other excipients can be added, such as one or more other adhesives, fillers, disintegrants, stabilizers, buffers and antimicrobials. For example, the composition can include sucrose, which can be used as a stabilizer. If included, sucrose can be used in any suitable amount, such as from about 0.5%w / w to about 4%w / w of the composition, including about 1.1%w / w of the composition, and the amount of one or more other excipients is adjusted accordingly.

[0154] In some embodiments, the ustekinumab composition comprises about 55.6% w / w ustekinumab, about 2.4% w / w L-histidine / L-histidine HCl, 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 HCl, 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.

[0155] In some embodiments, the ustekinumab composition as described herein comprises about 67% w / w ustekinumab, about 10% w / w L-histidine / L-histidine HCl, 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, the ustekinumab composition as described herein comprises about 75% w / w ustekinumab, about 12% w / w L-histidine / L-histidine HCl, 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.

[0156] The selection and proportions of the various ingredients may be considered during the formulation process in order to obtain a desired therapeutic dose of the drug with desired properties, including desired compression properties and desired release properties from the resulting minitablets.

[0157] The composition obtained as described above can be ground to produce fine powder.For example, the composition can be placed in a low protein binding tube with a single high-density grinding ball, such as a high-density grinding ball made of zirconium stabilized by stainless steel or yttrium. Grinding can be completed using a rotator at the maximum speed of the tube comprising a film wrap to avoid moisture absorption or contamination. An ice bag can be placed on the top of the tube to keep it cold. Room temperature can be controlled in the range of, for example, from 60 ° F to 64 ° F. The size of the grinding tube, the quality of the grinding ball and the duration of mixing can be selected to produce specific powder particle size, particle size uniformity and powder density. For example, for the production of 40mg to 100mg batch capacity, using a 2mL tube with a round bottom, a grinding ball with a quality of 0.44g and a grinding duration of 3 hours have produced fine and consistent particle size, realizing uniform and reliable density values.

[0158] The micro-tablet forming process is usually completed by applying compression force to a fine powder containing a drug (e.g., ustekinumab) via compression using a compression mold or other fixture. Semi-automatic or fully automatic compression fixtures can be used, as described in U.S. Patent No. 10,098,931, the entire contents of which are incorporated herein by reference. As described above, in various embodiments, the shaped block can be formed into the shape of a tissue penetration member, that is, it can be formed into a tissue penetration shape by using molding or other similar methods. In these and related embodiments, the shaped block can have a needle-like or dart-like shape (with or without barbs), which is configured to penetrate and / or remain in a tissue or membrane such as an intestinal wall.

[0159] 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 determined using an enzyme-linked immunosorbent assay (ELISA) or other immunoassays known in the art.

[0160] As described above, the shaped block can be in the form of a tissue penetrating member (e.g., in the form of a dart or needle) or be contained in a tissue penetrating member that is configured to be advanced into the intestinal wall or into and through the intestinal wall into the peritoneum or peritoneal cavity and to biodegrade to release ustekinumab in the intestinal wall, peritoneum, or peritoneal cavity, and then into the bloodstream.

[0161] IV. Methods of treatment and drug use

[0162] Also provided herein are treatments (methods of treatment and pharmaceutical uses) comprising administering an ingestible device according to any embodiment described herein to a subject in need thereof by ingestion, for example by swallowing the device by the subject (oral administration) or by another means (such as via an endoscope or a gastric port) to ingest the device. In some embodiments, treatments (methods of treatment and pharmaceutical uses) comprise administering an ingestible device as described herein once daily. In some embodiments, treatments (methods of treatment and pharmaceutical uses) comprise alternative dosing regimens as described in more detail below.

[0163] In general, the disclosed methods of treatment 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 where treatment with an anti-interleukin antibody may be indicated. In specific embodiments, the disclosed methods of treatment and pharmaceutical uses are used to treat plaque psoriasis. In specific embodiments, the disclosed methods of treatment and pharmaceutical uses are used to treat psoriatic arthritis. In specific embodiments, the disclosed methods of treatment and pharmaceutical uses are used to treat Crohn's disease. In specific embodiments, the disclosed methods of treatment and pharmaceutical uses are used to treat ulcerative colitis.

[0164] The disclosed methods of treatment and pharmaceutical uses can be used for any subject in need of administration of, for example, ustekinumab, including humans and non-human mammals. In human subjects, the age and size of the human are not limited, and can include pediatric subjects, adult subjects, and elderly subjects, as well as subjects within, above, or below the normal weight or height range.

[0165] In some embodiments, the ingestible device or the payload of the ingestible device comprises a dose of ustekinumab effective to achieve a therapeutic plasma level of ustekinumab for the condition being treated. In some embodiments, the ingestible device or the payload of the ingestible device comprises a dose of ustekinumab effective to achieve a plasma level of ustekinumab of about 0.69 μg / mL or more, including a plasma level of ustekinumab of 0.69 μg / mL or more.

[0166] In some embodiments, the ingestible device or the payload of the ingestible device comprises a dose of about 0.5 mg or more of ustekinumab. In some embodiments, the ingestible device or the payload of the ingestible device comprises a dose of about 0.5 mg of ustekinumab. In some embodiments, the ingestible device or the payload of the ingestible device comprises a dose of about 0.75 mg of ustekinumab. In some embodiments, the ingestible device or the payload of the ingestible device comprises a dose of about 10 mg of ustekinumab. In some embodiments, the ingestible device or the payload of the ingestible device comprises a dose of about 20 mg of ustekinumab.

[0167] like Figure 6 As reflected, computer-based pharmacokinetic model simulations of ustekinumab dosing based on published human pharmacokinetic data indicate that daily dosing of 0.5 mg will achieve plasma concentrations of 0.69 μg / mL or higher, for example, will achieve plasma concentrations greater than 0.69 μg / mL (see Figure 6, bottom curve; dashed line = 0.69 μg / mL). The simulation data also showed that daily dosing would be more effective in maintaining steady-state therapeutic serum concentrations than a subcutaneous regimen once every 12 weeks. Therefore, in some embodiments, the ingestible device or the payload of the ingestible device comprises a dose of ustekinumab of less than 0.5 mg, such as 0.45 mg, 0.4 mg, 0.35 mg, 0.3 mg, or 0.25 mg.

[0168] In some embodiments, the payload of the ingestible device comprises a solid therapeutic composition containing ustekinumab and one or more other excipients, such as a microtablet composition as described above. In some embodiments, the payload of the ingestible device comprises a ustekinumab composition comprising ustekinumab, L-histidine / L-histidine HCl, polyoxyethylene sorbitan monooleate, and L-methionine, as described above, optionally further comprising PEG 3350 and about trehalose and / or mannitol. 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 HCl, 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, 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 HCl, 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.

[0169] 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.

[0170] For the treatment of psoriasis and psoriatic arthritis in adults weighing ≤ 100 kg and children weighing > 60 kg. It 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 thereafter. For the treatment of psoriasis and psoriatic arthritis in patients weighing >100 kg, An induction dose of 90 mg may be administered at week 0 and week 4, followed by a maintenance dose of 90 mg every 12 weeks thereafter. The methods of treatment or pharmaceutical uses as disclosed herein may include an induction dosing period (such as, for example, approximately about 4 weeks, such as a 4-week or 30-day induction dosing period), followed by a maintenance dosing period. Various exemplary induction dosing regimens and maintenance dosing regimens are disclosed below. It should be understood that any induction dosing regimen may be used in combination with any maintenance dosing regimen, and different maintenance dosing regimens may be used over time (e.g., switching from one maintenance regimen to another). It should also be understood that any maintenance dosing regimen using a device as described herein may be used in conjunction with a subcutaneous injection product (such as or its biosimilars). Similarly, any induction dosing regimen using a device as described herein may be followed by a subcutaneous injection of a product such as or its biosimilar). In addition, any maintenance dose using a device as described herein may be followed by a subcutaneous injection of a product such as or its biosimilar), or vice versa.

[0171] Sample induction dosing regimen for treatment of adult patients weighing ≤100 kg or pediatric patients weighing >60 kg (amount refers to the dose of ustekinumab or its biosimilar):

[0172] 45 mg subcutaneous dose at weeks 0 and 4

[0173] About 1.5 mg (including 1.5 mg) is administered once daily via a device as disclosed herein for a period of about 4 weeks (e.g., 4 weeks or 30 days)

[0174] About 12 mg (including 12 mg) is administered once daily via a device as disclosed herein for a period of about 4 weeks (e.g., 4 weeks or 30 days)

[0175] • Once daily administration of approximately 9 mg / day (inclusive) for 7 days starting in Week 0 and again for 7 days starting in Week 4.

[0176] Sample maintenance dosing regimen for treatment of adult patients weighing ≤100 kg or pediatric patients weighing >60 kg (amount refers to the dose of ustekinumab or its biosimilar):

[0177] 45 mg subcutaneous dose every 12 weeks

[0178] About 0.5 mg (inclusive) once daily via a device as disclosed herein

[0179] About 3.75 mg (inclusive) administered once a week via a device as disclosed herein

[0180] A short course of monthly treatment of about 2.5 mg / day (including 2.5 mg / day) for 6 days administered daily via a device as disclosed herein

[0181] About 15 mg (inclusive) administered once a quarter via a device as disclosed herein

[0182] - A short quarterly course of treatment of about 12 mg / day (inclusive) for 5 days administered daily via a device as disclosed herein.

[0183] Sample induction dosing regimen for treatment of adult patients weighing >100 kg (amount refers to the dose of ustekinumab or its biosimilar):

[0184] 90 mg subcutaneous dose at weeks 0 and 4

[0185] About 3.25 mg (including 3 mg or 3.25 mg) is administered once daily via a device as disclosed herein for a period of about 4 weeks (e.g., 4 weeks or 30 days)

[0186] About 1.5 mg is administered twice daily via the disclosed device for a period of about 4 weeks (e.g., 4 weeks or 30 days)

[0187] About 24 mg (including 24 mg) administered once daily via a device as disclosed herein for a period of about 4 weeks (e.g., 4 weeks or 30 days)

[0188] • Once daily administration of approximately 18 mg / day (inclusive) for 7 days starting in Week 0 and again for 7 days starting in Week 4.

[0189] Sample maintenance dosing regimen for treatment of adult patients weighing >100 kg (amount refers to the dose of ustekinumab or its biosimilar):

[0190] 90 mg subcutaneous dose every 12 weeks

[0191] About 1 mg (inclusive) once daily administration via a device as disclosed herein

[0192] About 0.5 mg (inclusive) twice daily via a device as disclosed herein

[0193] About 7.5 mg (inclusive) administered once a week via a device as disclosed herein

[0194] A short course of monthly treatment of about 2.5 mg (including 2.5 mg) twice daily for 6 days via a device as disclosed herein

[0195] About 30 mg (inclusive) administered once a quarter via a device as disclosed herein

[0196] - A short quarterly course of treatment of about 12 mg / day (inclusive) for 9 days administered daily via a device as disclosed herein.

[0197] In some embodiments, an ingestible device containing a solid therapeutic composition of ustekinumab (or a biosimilar thereof) as described herein is used to provide a dose of up to about 1 mg / device, such as about 0.5 mg / device or about 0.75 mg / device, including 0.5 mg / device or 0.75 mg / device, depending on the formulation of the composition and its concentration.

[0198] In some embodiments, an ingestible device of a liquid therapeutic composition comprising ustekinumab (or a biosimilar thereof) as described herein is used to provide a dose of up to about 10 mg / device, such as for a device with a 100 μL capacity, or up to about 20 mg / device, such as for a device with a 200 μL capacity, depending on the formulation of the composition and its concentration.

[0199] In some embodiments, the above-described dosing regimen 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) includes a solid therapeutic composition of ustekinumab (or its biosimilar). In some embodiments, the above-described dosing regimen using an ingestible device as described herein to provide a dose of about 3.25 mg or greater (including 3 mg or greater or 3.25 mg or greater) includes a liquid therapeutic composition of ustekinumab (or its biosimilar).

[0200] According to any embodiment using an ingestible device as described herein, a given dose can be provided by one ingestible device as described herein, said one ingestible device containing one or more payloads that together contain said dose of ustekinumab (or a biosimilar thereof); or provided by administering two or more ingestible devices as described herein, wherein the payload of each device together contains a portion of said dose of ustekinumab (or a biosimilar thereof), for example, by administering one, two, three, 4, 5, 6, 7, 8, 9, 10 or more ingestible devices as described herein, each of which contains one, two, three, four or more payloads containing a composition of ustekinumab as described herein.

[0201] Currently approved anti-interleukin antibody products such as (ustekinumab) needs to be administered by subcutaneous or intravenous injection, which can be inconvenient and uncomfortable for patients. The present disclosure addresses this limitation by providing a route of administration that effectively delivers anti-interleukin antibodies to the bloodstream of the treated subject without the need for injection, such as oral administration or ingestion by another means, such as via an endoscope or gastric port. The disclosed treatment is more convenient and less invasive than currently approved anti-interleukin antibody products.

[0202] In addition to improved ease of administration, patient comfort, and patient compliance, administration of ustekinumab via an ingestible device as described herein can provide one or more other advantages, such as one or more of enhanced bioavailability and reduced immunogenicity compared to another route of administration (such as subcutaneous injection). In some embodiments, ustekinumab administered via an ingestible device as described herein exhibits a bioavailability greater than the bioavailability of subcutaneously administered ustekinumab. In some embodiments, ustekinumab administered via an ingestible device as described herein exhibits a bioavailability substantially the same as the bioavailability of subcutaneously administered ustekinumab.

[0203] Thus, according to some aspects, the present disclosure provides a method of administering an anti-interleukin antibody (such as ustekinumab or a biosimilar thereof, or other anti-interleukin antibodies that bind to one or both of human interleukin-23 and human interleukin-12 or other anti-interleukin antibodies that are antagonists of one or both of human interleukin-23 and human interleukin-12) to a subject in need thereof, the method comprising administering to the subject an ingestible device by ingestion, the ingestible device comprising a payload formed of a composition comprising an anti-interleukin antibody or a payload comprising the composition, wherein the device is configured to deliver the composition into the intestinal wall of the subject or into and through the intestinal wall into the peritoneum or peritoneal cavity of the subject after ingestion. As described above, administration can include oral administration (e.g., swallowing the device) or ingestion of the device by another means (such as via an endoscope or a gastric port). Payload can be in the form of solid tissue penetration member, and this solid tissue penetration member is configured to penetrate the intestinal wall of subject after taking in device and insert in the intestinal wall or insert and pass through the intestinal wall into the peritoneum or peritoneal cavity of subject.The administration of such ingestible device can be repeated, for example, at a frequency of once every 1-3 days or at a lower frequency, such as according to any dosing regimen described above.Payload can be formed by the composition comprising anti-interleukin antibody or can comprise the composition, such as solid (dry) composition or liquid composition as described above.Payload is protected from the influence of gastrointestinal (GI) tract environment (for example, protected to prevent degradation caused by fluid entering due to reaching payload), until payload is injected into the small intestinal wall insensitive to sharp stimulation, so that the subject will not feel pain due to injection.

[0204] 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 in which treatment with an anti-interleukin antibody may be indicated, the method comprising administering to a subject in need thereof by ingestion an ingestible device as described herein, such as according to any of the dosing regimens described above.

[0205] Although specific embodiments have been described and illustrated, it should be understood that the components or characteristics of one embodiment can be combined with one or more components or characteristics from other embodiments, or be replaced by one or more components or characteristics from other embodiments. In addition, for any positive description of components, characteristics, compositions, features, steps, etc., the present disclosure specifically contemplates the exclusion of such components, values, characteristics, compositions, features, steps, etc. It should also be understood that the illustrations may not necessarily be drawn to scale. Due to variables in the manufacturing process, etc., there may be differences between the technical reproduction in the present disclosure and the actual equipment. Other embodiments of the present disclosure that are not specifically described may exist. Therefore, the specification and the accompanying drawings are considered to be illustrative rather than restrictive.

[0206] The following examples are given to illustrate the invention. It should be understood, however, that the invention is not to be limited to the specific conditions or details described in these examples. Example

[0207] Example 1 - Preparation of Ustekinumab Ingestible Device (Formulation A)

[0208] Microtablets of ustekinumab were manufactured under sterile conditions with a target dose of 0.5 mg / microtablet and a target microtablet mass of approximately 0.9 mg.

[0209] A solution containing ustekinumab, L-histidine / L-histidine HCl (as a buffer), polyoxyethylene sorbitan monooleate (as a surfactant), L-methionine (as an antioxidant), PEG 3350 (as a lubricant), and trehalose (as a filler / stabilizer) was prepared and lyophilized to form a tableting composition. The tableting composition for preparing microtablets contained 55.6% w / w ustekinumab, 2.4% w / w L-histidine / L-histidine HCl (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 filler / stabilizer). Microtablets are prepared using a compaction cylinder pressure of 10 PSI-90 PSI (eg, 14 PSI-16 PSI), with a pressure of 800 PSI-9000 PSI applied to the tableting composition.

[0210] Ustekinumab activity was evaluated in Ustekinumab solutions, lyophilisates, and microtablets to ensure that the biological activity remained at a high level and was not significantly degraded. The activity of Ustekinumab in the microtablets was greater than 80% of the target amount (0.5 mg) and greater than 80% of the amount used to prepare the microtablets.

[0211] As mentioned above Figure 5Described herein are devices incorporating microtablets into capsules, wherein the payload is in the form of hollow microneedles containing a single microtablet, and the capsule device contains a single payload.

[0212] Example 2 - Oral delivery of ustekinumab in canines (Formulation A)

[0213] The ability to deliver ustekinumab in an ingestible device as described herein was evaluated in canines. After an overnight fast, a capsule device as described in Example 1 above was orally administered to canines with a body weight of 8.5kg-11.5kg at a dose of 0.5 mg (n=7). Fluoroscopic imaging was used to monitor capsule transport and confirm deployment in the small intestine. Blood levels of ustekinumab were assessed before dosing and at 4 hours and 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, and 14 days after administration. Results Figure 7 and reported in the table below (mean ± SEM).

[0214]

[0215] The results showed that ustekinumab could be successfully delivered via an ingestible device as described herein, with a deployment success rate of 70%.

[0216] Example 3 - Preparation of Ustekinumab Ingestible Devices - (Formulation B and Formulation C)

[0217] Microtablets of ustekinumab were manufactured under sterile conditions with a target dose of 0.5 mg / microtablet or 0.75 mg / microtablet.

[0218] A solution containing ustekinumab, L-histidine / L-histidine HCl (as a buffer), Tween 80 (as a surfactant), L-methionine (as an antioxidant), PEG 3350 (as a lubricant) and trehalose (as a stabilizer) was prepared as follows and lyophilized to form a tableting composition.

[0219]

[0220] The 0.5 mg dose was prepared as a 0.75 mg microtablet, while the 0.75 mg dose was prepared as a 1 mg microtablet. Both types of microtablets were prepared using a compacting cylinder pressure of 10 PSI-90 PSI, and the pressure applied to the tableting composition was 800 PSI-9000 PSI. As described above with reference Figure 5 As described, each microtablet is incorporated into a device within a capsule, wherein the payload is in the form of a hollow microneedle containing a single microtablet, and the capsule device contains a single payload.

[0221] Example 4 - Oral delivery of ustekinumab in canines (Formulation B and Formulation C)

[0222] The ability to deliver ustekinumab in an ingestible device as described herein was evaluated in canines. The pharmacokinetic profile of a single dose of ustekinumab administered via an ingestible device as described herein was compared to the pharmacokinetic profile obtained by a single subcutaneous (SC) injection. Canines with a body weight of 7.0 kg-9.0 kg were divided into the following 3 groups:

[0223] Group 1 (SC group; n=6): 0.5 mg / 0.5 mL subcutaneous injection of ustekinumab;

[0224] Group 2 (ingestible device group; n=8): one capsule device containing a microtablet containing 0.5 mg ustekinumab as described in Example 3; and

[0225] • Group 3 (ingestible device group; n=8): one capsule device containing a microtablet as described in Example 3 containing 0.75 mg ustekinumab.

[0226] After fasting for at least 12 hours, canines were administered ustekinumab according to the study groups described above. Fluoroscopic imaging was used to monitor capsule transit and confirm deployment in the small intestine. Blood levels of ustekinumab were assessed prior to dosing and at 4 hours, 12 hours, and 1-14 days, 16 days, 18 days, 21 days, 23 days, and 27 days after administration. Results Figure 8 and reported in the table below (mean ± SEM).

[0227]

[0228] *Dose-normalized

[0229] **Two animals suspected of having anti-drug antibodies (ADA) were excluded from the dataset

[0230] ***One animal was suspected of having ADA and was excluded from the dataset

[0231] The results show that ustekinumab can be successfully delivered by an ingestible device as described herein, with a pK success rate of 100% (for all animals where the device was successfully deployed). Devices containing microtablets containing 0.75 mg and 0.5 mg ustekinumab showed relative bioavailabilities of 91% and 94%, respectively.

[0232] These data highlight the surprising advantages of the compositions, dosage forms, devices, and methods disclosed herein, particularly when compared to the current standard of care which requires injections of ustekinumab.

[0233] Example 5-Phase I Clinical Trial

[0234] A Phase I clinical study is being conducted in healthy volunteers to evaluate the safety, tolerability and pharmacokinetics (PK) of a device as described herein, comprising a microtablet as described herein containing 0.5 mg or 0.75 mg of ustekinumab (as generally described in Example 3). The study will recruit healthy male and female participants aged 18 to 65 years (inclusive) at the time of consent and screened according to the inclusion and exclusion criteria. The study will include three groups:

[0235] Group 1 Participants will fast for at least 8 hours. Pre-dose PK samples will be collected, and participants will then be administered a 0.5 mg dose of

[0236] • Group 2: Participants will fast for at least 8 hours. Pre-dose PK samples will be collected, and participants will then orally ingest capsules containing a 0.5 mg dose of ustekinumab as described herein, swallowed whole with water.

[0237] • Group 3: Participants will fast for at least 8 hours. Pre-dose PK samples will be collected, and participants will then orally ingest capsules containing a 0.75 mg dose of ustekinumab as described herein, swallowed whole with water.

[0238] Safety and pK assessments will be performed regularly through Day 60. Primary endpoints will include the type, incidence, timing, and severity of adverse events reported, and whether they are capsule or drug related. Secondary endpoints will include serum PK parameters, including Cmax, Tmax, and area under the serum concentration curve (AUC).

Claims

1. A method of administering an anti-interleukin antibody to a subject in need thereof, the method comprising administering to the subject, by ingestion, an ingestible device comprising a payload formed from a composition containing the anti-interleukin antibody or a payload containing the composition, wherein the device is configured to deliver the composition into the gastrointestinal (GI) lumen wall of the subject or into and through the GI lumen wall into the peritoneum or peritoneal cavity of the subject, wherein the anti-interleukin antibody binds to one or both of human interleukin-23 and human interleukin-12.

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

3. The method according to any one of the preceding claims, wherein the anti-interleukin antibody comprises ustekinumab or a biosimilar thereof.

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

5. The method according to any one of the preceding claims, wherein the anti-interleukin antibody exhibits a greater bioavailability than an anti-interleukin antibody administered subcutaneously.

6. The method according to any one of the preceding claims, wherein the anti-interleukin antibody exhibits a bioavailability substantially the same as that of an anti-interleukin antibody administered subcutaneously.

7. The method according to any one of the preceding claims, wherein the device contains a dose of the anti-interleukin antibody from about 0.25 mg to about 0.75 mg.

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

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

10. The method according to any one of the preceding claims, comprising administering the device once daily.

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

12. The method according to claim 11, wherein the composition comprises the anti-interleukin antibody, L-histidine / L-histidine hydrochloride, polysorbate 80, and L-methionine.

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

14. The method according to any one of claims 11-13, wherein the composition comprises the anti-interleukin antibody, L-histidine / L-histidine hydrochloride, polysorbate 80, trehalose, PEG 3350, and L-methionine.

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

16. The method according to any one of the preceding claims, wherein the payload is in the form of a solid tissue penetrating member configured to be inserted into the GI lumen wall of the subject and / or into the peritoneum or peritoneal cavity of the subject after ingestion of the device.

17. The method according to claim 16, wherein the composition is filled in hollow, biodegradable microneedles constituting the solid tissue penetrating member.

18. The method according to claim 16, wherein the composition is a shaped block constituting the solid tissue penetrating member.

19. The method according to any one of the preceding claims, wherein the device comprises a plurality of payloads of the anti - interleukin antibody.

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

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

22. The method according to any one of the preceding claims, wherein the subject has one or more conditions selected from psoriasis, moderate - to - severe plaque psoriasis, psoriatic arthritis, Crohn's disease, and ulcerative colitis.

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

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

25. The method according to claim 24, wherein the intestinal wall is the small intestinal wall.

26. The method according to any one of the preceding claims, wherein the method comprises an induction dosing period followed by a maintenance dosing period.

27. The method according to claim 26, wherein the subject is an adult patient with a body weight ≤ 100 kg or a pediatric patient with a body weight > 60 kg, and the induction dosing period comprises an induction dosing regimen selected from: a 45 mg subcutaneous dose at week 0 and week 4; administering approximately 1.5 mg once daily via the ingestible device for a period of approximately 4 weeks; administering approximately 12 mg once daily via the ingestible device for a period of approximately 4 weeks; administering approximately 9 mg / day once daily via the ingestible device starting at week 0 for 7 days and starting again at week 4 for 7 days; and the maintenance dosing period comprises a maintenance dosing regimen selected from: a 45 mg subcutaneous dose every 12 weeks; administering approximately 0.5 mg once daily via the ingestible device; administering approximately 3.75 mg once weekly via the ingestible device; administering approximately 2.5 mg / day once daily via the ingestible device for a 6 - day once - monthly short course; administering approximately 15 mg once quarterly via the ingestible device; administering approximately 12 mg / day once daily via the ingestible device for a 5 - day once - quarterly short course; wherein the amount refers to the dose of the anti - interleukin antibody, optionally wherein the anti - interleukin antibody is ustekinumab or a biosimilar thereof. Wherein the method comprises administering at least one dose of an anti - interleukin antibody via the ingestible device.

28. The method according to claim 26, wherein the subject is an adult patient with a body weight > 100 kg, and the induction dosing period comprises an induction dosing regimen selected from: a 90 mg subcutaneous dose at week 0 and week 4; administering approximately 3.25 mg once daily via the ingestible device for a period of approximately 4 weeks; administering approximately 1.5 mg twice daily via the ingestible device for a period of approximately 4 weeks; administering approximately 24 mg once daily via the ingestible device for a period of approximately 4 weeks; administering approximately 18 mg / day once daily via the ingestible device starting at week 0 for 7 days and starting again at week 4 for 7 days; and the maintenance dosing period comprises a maintenance dosing regimen selected from: a 90 mg subcutaneous dose every 12 weeks; administering approximately 1 mg once daily via the ingestible device; administering approximately 0.5 mg twice daily via the ingestible device; administering approximately 7.5 mg once weekly via the ingestible device; administering approximately 2.5 mg twice daily for 6 days once monthly, a short - course regimen via the ingestible device; administering approximately 30 mg once quarterly via the ingestible device; administering approximately 12 mg / day daily for 9 days once quarterly, a short - course regimen via the ingestible device; wherein the amount refers to the dose of the anti - interleukin antibody, optionally wherein the anti - interleukin antibody is ustekinumab or a biosimilar thereof, wherein the method comprises administering at least one dose of an anti - interleukin antibody via the ingestible device.

29. An ingestible device for 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, the device comprising a payload formed from a composition containing the anti - interleukin antibody or a payload containing the composition, wherein the device is configured to deliver the composition into the gastrointestinal (GI) lumen wall of the subject or to deliver into and through the GI lumen wall into the peritoneum or peritoneal cavity of the subject, wherein the anti - interleukin antibody binds to one or both of human interleukin - 23 and human interleukin - 12.

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

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

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

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

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

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

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

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

38. The ingestible device according to claim 36 or claim 37, wherein the composition further comprises a lubricant and a filler.

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

40. The ingestible device according to 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. The ingestible device according to 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. The ingestible device according to any one of claims 29 - 41, wherein the payload is in the form of a solid tissue - penetrating member configured to be inserted into the GI lumen wall of the subject and / or into the peritoneum or peritoneal cavity of the subject after ingestion of the device.

43. The ingestible device according to claim 42, wherein the composition is filled in hollow, biodegradable microneedles constituting the solid tissue - penetrating member.

44. The ingestible device according to claim 42, wherein the composition is a shaped block constituting the solid tissue - penetrating member.

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

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

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

48. The ingestible device according to any one of claims 29-47, wherein the GI lumen wall is the gastric wall.

49. The ingestible device according to any one of claims 29-47, wherein the GI lumen wall is the intestinal wall.

50. The ingestible device according to claim 49, wherein the intestinal wall is the small intestinal wall.

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

52. The ingestible device according to claim 51, wherein the bioavailability of the anti-interleukin antibody is greater than the bioavailability of the subcutaneously administered anti-interleukin antibody.

53. The ingestible device according to claim 51, wherein the bioavailability of the anti-interleukin antibody is substantially the same as the bioavailability of the subcutaneously administered anti-interleukin antibody.

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

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

56. The use according to claim 55, wherein the bioavailability of the anti-interleukin antibody is greater than the bioavailability of the subcutaneously administered anti-interleukin antibody.

57. The use according to claim 55, wherein the bioavailability of the anti-interleukin antibody is substantially the same as the bioavailability of the subcutaneously administered anti-interleukin antibody.

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

59. The use according to any one of claims 55-58, wherein the use comprises an induction dosing period, followed by a maintenance dosing period.

60. The use according to claim 59, wherein the subject is an adult patient with a body weight ≤ 100 kg or a pediatric patient with a body weight > 60 kg, and the induction dosing period comprises an induction dosing regimen selected from: a 45 mg subcutaneous dose at week 0 and week 4; administering approximately 1.5 mg once daily via the ingestible device for a period of approximately 4 weeks; administering approximately 12 mg once daily via the ingestible device for a period of approximately 4 weeks; Administer about 9 mg / day once daily via the ingestible device for 7 days starting at week 0 and again for 7 days starting at week 4; and The maintenance dosing period comprises a maintenance dosing regimen selected from: A 45 mg subcutaneous dose every 12 weeks; Administer about 0.5 mg once daily via the ingestible device; Administer about 3.75 mg once weekly via the ingestible device; A monthly short course of about 2.5 mg / day for 6 days administered daily via the ingestible device; Administer about 15 mg once every quarter via the ingestible device; A quarterly short course of about 12 mg / day for 5 days administered daily via the ingestible device; Wherein the amount refers to the dose of the anti - interleukin antibody, optionally wherein the anti - interleukin antibody is ustekinumab or a biosimilar thereof, Wherein the use comprises administering at least one dose of the anti - interleukin antibody via the ingestible device.

61. The use according to claim 59, wherein the subject is an adult patient with a body weight > 100 kg, and The induction dosing period comprises an induction dosing regimen selected from: A 90 mg subcutaneous dose at week 0 and week 4; Administer about 3.25 mg once daily via the ingestible device for a period of about 4 weeks; Administer about 1.5 mg twice daily via the ingestible device for a period of about 4 weeks; Administer about 24 mg once daily via the ingestible device for a period of about 4 weeks; Administer about 18 mg / day once daily via the ingestible device for 7 days starting at week 0 and again for 7 days starting at week 4; and The maintenance dosing period comprises a maintenance dosing regimen selected from: A 90 mg subcutaneous dose every 12 weeks; Administer about 1 mg once daily via the ingestible device; Administer about 0.5 mg twice daily via the ingestible device; Administer about 7.5 mg once weekly via the ingestible device; A monthly short course of about 2.5 mg twice daily for 6 days administered via the ingestible device; Administer about 30 mg once every quarter via the ingestible device; A quarterly short course of about 12 mg / day for 9 days administered daily via the ingestible device; Wherein the amount refers to the dose of the anti - interleukin antibody, optionally wherein the anti - interleukin antibody is ustekinumab or a biosimilar thereof, Wherein the use comprises administering at least one dose of the anti - interleukin antibody via the ingestible device.

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